Compounds of formula (I) and their use as herbicides
阅读说明：本技术 式(i)化合物及其作为除草剂的用途 (Compounds of formula (I) and their use as herbicides ) 是由 J·D·艾克尔巴杰 J·B·埃普 L·G·费希尔 C·T·洛 J·佩特库斯 J·罗思 N 于 2014-03-12 设计创作，主要内容包括：本申请提供4-氨基-6-(杂环基)吡啶-2-甲酸及其衍生物和6-氨基-2-(杂环基)嘧啶-4-羧酸酯及其衍生物用于控制不期望的植被。不期望的植被例如杂草的产生是农场主在作物、牧场和其他场所中一直遇到的问题。杂草与作物竞争并且不利地影响着作物的收率。使用化学除草剂在防治不期望的植被中是重要的工具。(The present application provides 4-amino-6- (heterocyclyl) pyridine-2-carboxylic acid and derivatives thereof and 6-amino-2- (heterocyclyl) pyrimidine-4-carboxylic acid esters and derivatives thereof for controlling undesirable vegetation. The production of undesirable vegetation, such as weeds, is a constant problem for farmers in crops, pastures and other settings. Weeds compete with crops and adversely affect crop yield. The use of chemical herbicides is an important tool in controlling undesirable vegetation.)
1. A method of controlling undesirable vegetation which comprises contacting the undesirable vegetation or the locus thereof with a herbicidally effective amount of a compound of formula (I):
wherein
X is N, CH, or CF;
R1is OR1′Wherein R is1′Is hydrogen, C1-C8Alkyl, or C7-C10An arylalkyl group;
R2is halogen, C2-C4Alkenyl radical, C2-C4Haloalkenyl, or C2-C4An alkynyl group;
R3and R4Are all hydrogen;
a is one of the groups Ar4 to Ar12 or Ar15 to Ar 18:
R5is hydrogen, halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, or C1-C3Alkoxy, with the proviso that when A is Ar9 or Ar10, R5Is not halogen;
R6is hydrogen, halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, or C1-C3An alkoxy group;
R6′is hydrogen or halogen;
R6″is hydrogen, halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, or C1-C3An alkoxy group;
R7and R7′Independently of one another hydrogen, halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, or C1-C3An alkoxy group;
R8and R8′Independently of one another hydrogen, halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, or C1-C3An alkoxy group;
R9、R9′、R9″and R9″′Independently of one another hydrogen, halogen, C1-C4Alkyl radical, C1-C4Haloalkyl or C1-C3An alkoxy group;
R10is hydrogen, C1-C6Alkyl radical, C1-C6Haloalkyl, formyl, or C1-C3An alkylcarbonyl group;
m, when present, is 0 or 1; and
n, when present, is 0 or 1;
with the proviso that A is not
2. The method of claim 1, wherein a is Ar5, Ar7, Ar9, or Ar 16.
3. The method of claim 1 or 2, wherein R1’Is H or CH3。
4. The method of any one of claims 1-3, wherein R2Is halogen, C2-C4Alkenyl, or C2-C4A haloalkenyl group.
5. The method of any one of claims 1-4, wherein R2Is Cl, vinyl or 1-propenyl.
6. The method of any one of claims 1-5, wherein R2Is Cl.
7. The process of any one of claims 1-6, wherein X is CF.
8. The method of any one of claims 1-7, wherein R5Is hydrogen or halogen, with the proviso that when A is Ar9 or Ar10, R5Is not a halogen.
9. The method of any one of claims 1-8, wherein R5Is hydrogen or F, with the proviso that when A is Ar9 or Ar10, R5Is not F.
10. The method of any one of claims 1-9, wherein R5Is H.
11. The method of any one of claims 1-10, wherein R6Is hydrogen or F.
12. The method of any one of claims 1-11, wherein R6Is hydrogen.
13. The method of any one of claims 1-12, wherein R6′Is hydrogen.
14. The method of any one of claims 1-13, wherein R7、R7′、R8、R8′、R9、R9′、R9″And R9″′Independently hydrogen or fluorine if applicable to the relevant a group.
15. The method of any one of claims 1-14, wherein:
R2is halogen, or C2-C4An alkenyl group;
a is Ar7, Ar9, or Ar 16;
R5is hydrogen or F;
R6is hydrogen or F;
R6′is hydrogen; and
R7、R7′、R8、R8′、R9、R9′、R9″and R9″′Independently hydrogen or fluorine if applicable to the relevant a group.
16. The method of any one of claims 1-15, wherein the compound of formula (I) comprises one of:
17. the method of any one of claims 1-16, wherein the compound of formula (I) is applied at a rate of 1 gram per hectare (g/ha) to 4,000 g/ha.
18. The method of any one of claims 1-17, wherein the compound of formula (I) is applied at a rate of from 35g/ha to 140 g/ha.
19. The method of any one of claims 1-18, wherein the compound of formula (I) is applied post-emergently, pre-emergently, or in water.
20. The method of any one of claims 1-19, wherein the compound of formula (I) is mixed with water prior to contacting the undesirable vegetation or the locus thereof.
21. The method of any one of claims 1-20, further comprising applying at least one additional herbicidal compound.
22. The method of any one of claims 1-21, wherein the compound of formula (I) is mixed with an agriculturally acceptable adjuvant or carrier prior to contacting the undesirable vegetation or the locus thereof.
23. The method of any one of claims 1-22, further comprising administering a safener.
24. The method of any one of claims 1-23, wherein the undesirable vegetation comprises a woody plant, a broadleaf weed, a grassy weed, or a sedge.
25. The method of any one of claims 1-24, wherein the undesirable vegetation comprises a herbicide resistant or tolerant weed.
26. The method of any one of claims 1-25, wherein the undesirable vegetation comprises Chenopodium album (common lambsquarers), CHEAL, sunflower (Helianthus annuus), or a combination thereof.
27. The method of any one of claims 1-26, wherein the undesirable vegetation is controlled in rice, cereals, or pastures and pastures.
28. The method of any one of claims 1-27, wherein the undesirable vegetation is controlled in a cultivated crop.
29. The method of any one of claims 1-28, wherein the undesirable vegetation is controlled in rice, wheat, or corn/maize.
30. The method of any one of claims 1-29, wherein the undesirable vegetation is controlled in rice (Oryza sativa) (rice), ORYSA), wheat (Triticum aestivum) (spring wheat (wheat spring), TRZAS), or corn (Zea mays) (corn/maize), ZEAMX.
Technical Field
The present invention relates to herbicidal compounds and compositions and to methods for controlling undesirable vegetation.
Background
The production of undesirable vegetation, such as weeds, is a constant problem for farmers in crops, pastures and other settings. Weeds compete with crops and adversely affect crop yield. The use of chemical herbicides is an important tool in controlling undesirable vegetation.
There remains a need for new chemical herbicides that have a broader spectrum of weed control, selectivity, minimal damage to crops, storage stability, ease of handling, higher activity against weeds, and/or that address the herbicide resistance developed against currently used herbicides.
Disclosure of Invention
The present application provides compounds of formula (I) or an N-oxide or an agriculturally acceptable salt thereof:
wherein
X is N or CY, wherein Y is hydrogen, halogen, C1-C3Alkyl radical, C1-C3Haloalkyl, C1-C3Alkoxy radical, C1-C3Haloalkoxy, C1-C3Alkoxy radical, C1-C3Alkylthio or C1-C3A haloalkylthio group;
R1is OR1′Or NR1″R1″′Wherein R is1′Is hydrogen, C1-C8Alkyl or C7-C10Arylalkyl radical, and R1″And R1″′Independently of one another is hydrogen, C1-C12Alkyl radical, C3-C12Alkenyl or C3-C12An alkynyl group;
R2is halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C2-C4Alkenyl radical, C2-C4Haloalkenyl, C2-C4Alkynyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy, C1-C4Alkylthio radical, C1-C4Haloalkylthio, amino, C1-C4Alkylamino radical, C2-C4Haloalkyl amino, formyl, C1-C3Alkylcarbonyl group, C1-C3Haloalkyl carbonyl, cyano, or of formula-CR17＝CR18-SiR19R20R21Wherein R is17Is hydrogen, F or Cl; r18Is hydrogen, F, Cl, C1-C4Alkyl or C1-C4A haloalkyl group; and R is19、R20And R21Independently is C1-C10Alkyl radical, C3-C6Cycloalkyl, phenyl, substituted phenyl, C1-C10Alkoxy or OH;
R3and R4Independently of one another is hydrogen, C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Alkenyl radical, C3-C6Haloalkenyl, C3-C6Alkynyl, formyl, C1-C3Alkylcarbonyl group, C1-C3Halogenoalkylcarbonyl group, C1-C6Alkoxycarbonyl group, C1-C6Alkylcarbamoyl, C1-C6Alkylsulfonyl radical, C1-C6Trialkylsilyl group, C1-C6A dialkyl phosphinyl group, or R3And R4Together with N being a 5-or 6-membered saturated or unsaturated ring, or R3And R4Together represent ═ CR3′(R4′) Wherein R is3′And R4′Independently of one another is hydrogen, C1-C6Alkyl radical, C3-C6Alkenyl radical, C3-C6Alkynyl, C1-C6Alkoxy or C1-C6Alkylamino, or R3′And R4′Together with ═ C, represents a 5-or 6-membered saturated ring;
a is one of the groups Ar1 to Ar 28:
R5is hydrogen, halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C3Alkoxy radical, C1-C3Haloalkoxy, C1-C3Alkylthio radical, C1-C3Haloalkylthio, amino, C1-C4Alkylamino or C2-C4A haloalkylamino group.
R6Is hydrogen, halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C3Alkoxy radical, C1-C3Haloalkoxy, C1-C3Alkylthio radical, C1-C3Haloalkylthio, amino, C1-C4Alkylamino or C2-C4A haloalkylamino group;
R6′is hydrogen or halogen;
R6″is hydrogen, halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, cyclopropyl, halocyclopropyl, C2-C4Alkenyl radical, C2-C4Haloalkenyl, C2-C4Alkynyl, C1-C3Alkoxy radical, C1-C3Haloalkoxy, C1-C3Alkylthio radical, C1-C3Haloalkylthio, amino, C1-C4Alkylamino radical, C2-C4Haloalkylamino, CN or NO2；
R7And R7′Independently of one another hydrogen, halogen, C1-C4Alkyl radical, C1-C4Haloalkyl or C1-C3An alkoxy group;
R8and R8′Independently of one another hydrogen, halogen, C1-C4Alkyl radical, C1-C4Haloalkyl or C1-C3An alkoxy group;
R9、R9′、R9″and R9″′Independently of one another hydrogen, halogen, C1-C4Alkyl radical, C1-C4Haloalkyl or C1-C3An alkoxy group;
R10is hydrogen, C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6An alkenyl group,C3-C6Haloalkenyl, C3-C6Alkynyl, formyl, C1-C3Alkylcarbonyl group, C1-C3Halogenoalkylcarbonyl or C1-C6A trialkylsilyl group;
m, when present, is 0,1 or 2; and
n, when present, is 0,1 or 2;
with the proviso that A is not
Also provided are methods of controlling undesirable vegetation comprising applying a compound of formula (I) or an N-oxide or an agriculturally acceptable salt thereof.
The invention comprises the following steps:
1. a compound of formula (I):
wherein
X is N or CY, wherein Y is hydrogen, halogen, C1-C3Alkyl radical, C1-C3Haloalkyl, C1-C3Alkoxy radical, C1-C3Haloalkoxy, C1-C3Alkoxy radical, C1-C3Alkylthio or C1-C3A haloalkylthio group;
R1is OR1′Or NR1″R1″′Wherein R is1′Is hydrogen, C1-C8Alkyl or C7-C10Arylalkyl, and R1″And R1″′Independently of one another is hydrogen, C1-C12Alkyl radical, C3-C12Alkenyl or C3-C12An alkynyl group;
R2is halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C2-C4Alkenyl radical, C2-C4Haloalkenyl, C2-C4Alkynyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy, C1-C4Alkylthio radical, C1-C4Haloalkylthio, amino, C1-C4Alkylamino radical, C2-C4Haloalkyl amino, formyl, C1-C3Alkylcarbonyl group, C1-C3Haloalkyl carbonyl, cyano, or of formula-CR17＝CR18-SiR19R20R21Wherein R is17Is hydrogen, F or Cl; r18Is hydrogen, F, Cl, C1-C4Alkyl or C1-C4A haloalkyl group; and R19、R20And R21Independently is C1-C10Alkyl radical, C3-C6Cycloalkyl, phenyl, substituted phenyl, C1-C10Alkoxy or OH;
R3and R4Independently of one another is hydrogen, C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Alkenyl radical, C3-C6Haloalkenyl, C3-C6Alkynyl, formyl, C1-C3Alkylcarbonyl group, C1-C3Halogenoalkylcarbonyl group, C1-C6Alkoxycarbonyl group, C1-C6Alkylcarbamoyl, C1-C6Alkylsulfonyl radical, C1-C6Trialkylsilyl group, C1-C6Dialkyl phosphinyl or R3And R4Together with N is a 5-or 6-membered saturated or unsaturated ring, or R3And R4Together represent ═ CR3′(R4′) Wherein R is3′And R4′Independently of one another is hydrogen, C1-C6Alkyl radical, C3-C6Alkenyl radical, C3-C6Alkynyl, C1-C6Alkoxy or C1-C6Alkylamino, or R3′And R4′Together with ═ C, represents a 5-or 6-membered saturated ring;
a is one of the groups Ar1 to Ar 28:
R5is hydrogen, halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C3Alkoxy radical, C1-C3Haloalkoxy, C1-C3Alkylthio radical, C1-C3Haloalkylthio, amino, C1-C4Alkylamino or C2-C4A haloalkylamino group;
R6is hydrogen, halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C3Alkoxy radical, C1-C3Haloalkoxy, C1-C3Alkylthio radical, C1-C3Haloalkylthio, amino, C1-C4Alkylamino or C2-C4A haloalkylamino group;
R6′is hydrogen or halogen;
R6″is hydrogen, halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, cyclopropyl, halocyclopropyl, C2-C4Alkenyl radical, C2-C4Haloalkenyl, C2-C4Alkynyl, C1-C3Alkoxy radical, C1-C3Haloalkoxy, C1-C3Alkylthio radical, C1-C3Haloalkylthio, amino, C1-C4Alkylamino radical, C2-C4Haloalkylamino, CN or NO2；
R7And R7′Independently of one another hydrogen, halogen, C1-C4Alkyl radical, C1-C4Haloalkyl or C1-C3An alkoxy group;
R8and R8′Independently of one another hydrogen, halogen, C1-C4Alkyl radical, C1-C4Haloalkyl or C1-C3An alkoxy group;
R9、R9′、R9″and R9″′Independently of one another hydrogen, halogen, C1-C4Alkyl radical, C1-C4Haloalkyl or C1-C3An alkoxy group;
R10is hydrogen, C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Alkenyl radical, C3-C6Haloalkenyl, C3-C6Alkynyl, formyl, C1-C3Alkylcarbonyl group, C1-C3Halogenoalkylcarbonyl or C1-C6A trialkylsilyl group;
m, when present, is 0,1 or 2; and
n, when present, is 0,1 or 2;
or an N-oxide or an agriculturally acceptable salt thereof;
with the proviso that A is not
2. The compound of item 1, wherein
X is N or CY, wherein Y is hydrogen, halogen, C1-C3Alkyl radical, C1-C3Haloalkyl, C1-C3Alkoxy radical, C1-C3Haloalkoxy, C1-C3Alkoxy radical, C1-C3Alkylthio or C1-C3A haloalkylthio group;
R1is OR1′Or NR1″R1″′Wherein R is1′Is hydrogen, C1-C8Alkyl or C7-C10Arylalkyl radical, and R1″And R1″′Independently of one another is hydrogen, C1-C12Alkyl radical, C3-C12Alkenyl or C3-C12An alkynyl group;
R2is halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C2-C4Alkenyl radical, C2-C4Haloalkenyl, C2-C4Alkynyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy, C1-C4Alkylthio radical, C1-C4Haloalkylthio, amino, C1-C4Alkylamino radical, C2-C4Haloalkyl amino, formyl, C1-C3Alkylcarbonyl group, C1-C3Haloalkyl carbonyl, cyano, or of formula-CR17＝CR18-SiR19R20R21Wherein R is17Is hydrogen, F or Cl; r18Is hydrogen, F, Cl, C1-C4Alkyl or C1-C4A haloalkyl group; and R is19、R20And R21Independently is C1-C10Alkyl radical, C3-C6Cycloalkyl, phenyl, substituted phenyl, C1-C10Alkoxy or OH;
R3and R4Independently of one another is hydrogen, C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Alkenyl radical, C3-C6Haloalkenyl, C3-C6Alkynyl, formyl, C1-C3Alkylcarbonyl group, C1-C3Halogenoalkylcarbonyl group, C1-C6Alkoxycarbonyl group, C1-C6Alkylcarbamoyl, C1-C6Alkylsulfonyl radical, C1-C6Trialkylsilyl group, C1-C6A dialkyl phosphinyl group, or R3And R4Together with N, is a 5-or 6-membered saturated ring, or R3And R4Together represent ═ CR3′(R4′) Wherein R is3′And R4′Independently of one another is hydrogen, C1-C6Alkyl radical, C3-C6Alkenyl radical, C3-C6Alkynyl radical、C1-C6Alkoxy or C1-C6Alkylamino, or R3′And R4′Together with ═ C, represents a 5-or 6-membered saturated ring;
a is one of the groups Ar1, Ar2, Ar3, Ar4, Ar5, Ar6, Ar7, Ar8, Ar9, Ar10, Ar11, Ar12, Ar13, Ar14, Ar15, Ar16, Ar17, Ar18, Ar19, Ar20, Ar21, Ar22, Ar23 or Ar 24;
R5is hydrogen, halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C3Alkoxy radical, C1-C3Haloalkoxy, C1-C3Alkylthio, C1-C3Haloalkylthio, amino, C1-C4Alkylamino or C2-C4A haloalkylamino group.
R6Is hydrogen, halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C3Alkoxy radical, C1-C3Haloalkoxy, C1-C3Alkylthio radical, C1-C3Haloalkylthio, amino, C1-C4Alkylamino or C2-C4A haloalkylamino group;
R6′is hydrogen or halogen;
R6″is hydrogen, halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, cyclopropyl, halocyclopropyl, C2-C4Alkenyl radical, C2-C4Haloalkenyl, C2-C4Alkynyl, C1-C3Alkoxy radical, C1-C3Haloalkoxy, C1-C3Alkylthio radical, C1-C3Haloalkylthio, amino, C1-C4Alkylamino radical, C2-C4Haloalkylamino, CN or NO2；
R7And R7′Independently of one another hydrogen, halogen, C1-C4Alkyl radical, C1-C4Haloalkyl or C1-C3Alkoxy radical；
R8And R8′Independently of one another hydrogen, halogen, C1-C4Alkyl radical, C1-C4Haloalkyl or C1-C3An alkoxy group;
R9、R9′、R9″and R9″′Independently of one another hydrogen, halogen, C1-C4Alkyl radical, C1-C4Haloalkyl or C1-C3An alkoxy group;
R10is hydrogen, C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Alkenyl radical, C3-C6Haloalkenyl, C3-C6Alkynyl, formyl, C1-C3Alkylcarbonyl group, C1-C3Halogenoalkylcarbonyl or C1-C6A trialkylsilyl group;
m, when present, is 0,1 or 2; and
n, when present, is 0,1 or 2;
or an N-oxide or an agriculturally acceptable salt thereof;
with the proviso that A is not
3. A compound of item 2, wherein Ar is Ar1, Ar2, Ar3, Ar4, Ar5, Ar6, Ar7, Ar8, Ar15, Ar16, Ar17, or Ar 18.
4. The compound of any one of items 1-2, wherein m, when present, is 0 or 1, wherein n, when present, is 0 or 1.
5. The compound of any one of items 1 to 4, wherein R1Is OR1′。
6. The compound of any one of items 1 to 5, wherein R2Is halogen, C2-C4-alkenyl, C2-C4Haloalkenyl or C1-C4-alkoxy groups.
7. The compound of any one of items 1 to 6, wherein R2Is Cl, methoxy, vinyl or 1-And (3) a propenyl group.
8. The compound of any one of items 1 to 7, wherein R3And R4Are all hydrogen.
9. The compound of any one of items 1 to 8, wherein X is N, CH or CF.
10. The compound of any one of items 1 to 9, wherein R5Is hydrogen or halogen.
11. The compound of item 10, wherein R5Is hydrogen or F.
12. The compound of any one of items 1 to 11, wherein R6Is hydrogen or F.
13. The compound of any one of items 1 to 12, wherein R6′Is hydrogen.
14. The compound of any one of items 1-13, wherein:
R2is halogen, C2-C4-alkenyl or C1-C4-an alkoxy group;
R3and R4Is hydrogen; and
x is N, CH or CF;
ar is Ar1, Ar3, Ar7, Ar9, Ar10, Ar13, Ar15, Ar16, Ar19, Ar21 or Ar 22;
R5is hydrogen or F;
R6is hydrogen or F;
R6′is hydrogen;
R7、R7′、R8、R8′、R9、R9′、R9″and R9″′Independently hydrogen or fluorine if applicable to the relevant Ar group;
15. the compound of any one of items 1-14, wherein:
R2is chlorine;
R3and R4Is hydrogen; and
x is N, CH or CF.
16. The compound of any one of items 1-14, wherein:
R2is methoxy;
R3and R4Is hydrogen; and
x is N, CH or CF.
17. The compound of any one of items 1-14, wherein:
R2is vinyl or 1-propenyl;
R3and R4Is hydrogen; and
x is N, CH or CF.
18. A herbicidal composition comprising a compound of any one of claims 1 to 17 and an agricultural adjuvant or carrier.
19. The composition of item 18, further comprising at least one additional herbicidal compound.
20. The composition of item 18 or 19, further comprising a herbicidal safener.
21. A method of controlling undesirable vegetation which comprises applying a herbicidally effective amount of a compound of any of claims 1 to 17 or a herbicidal composition of any of claims 18 to 20.
Detailed Description
Definition of
Herbicides and herbicidally active ingredients, as used herein, refer to compounds that control undesirable vegetation when applied in appropriate amounts.
Controlling undesirable vegetation as used herein refers to killing or preventing the vegetation, or causing other adverse alteration effects on the vegetation, such as deviation from natural growth or development, regulation, desiccation, retardation, and the like.
As used herein, an herbicidally effective or vegetation controlling amount is the amount of the herbicidally active ingredient that is applied to control the associated undesirable vegetation. .
Application of an herbicide or herbicidal composition as used herein refers to its delivery directly to the target vegetation or to the locus of the target vegetation or to the area where control of undesirable vegetation is desired. Methods of application include, but are not limited to, pre-emergence contact with soil or water, post-emergence contact with undesirable vegetation, or contact with an area adjacent to the undesirable vegetation.
Plants and vegetation as used herein include, but are not limited to, dormant seeds, germinating seedlings (germinating seeds), plants germinating from vegetative propagules (plants), immature vegetation and established vegetation (vegetation).
Agriculturally acceptable salts and esters as used herein refer to salts and esters which exhibit herbicidal activity, or are or can be converted to the herbicide in plants, water or soil. Exemplary agriculturally acceptable esters are those which are or can be converted by hydrolysis, oxidation, metabolism, or other means (e.g., in plants, water, or soil) to the corresponding carboxylic acid, which may or may not be in dissociated form depending on the pH.
Suitable salts include those derived from alkali or alkaline earth metals and those derived from ammonia and amines. Preferred cations include sodium, potassium, magnesium and ammonium of the formula:
R13R14R15R16N+
wherein R is13、R14、R15And R16Each independently represents hydrogen or C1-C12Alkyl radical, C3-C12Alkenyl or C3-C12Alkynyl, each of which is optionally substituted by one or more hydroxy, C1-C4Alkoxy radical, C1-C4Alkylthio or phenyl, with the proviso that R13、R14、R15And R16Are sterically compatible. Furthermore, R13、R14、R15And R16Any two of which may represent aliphatic difunctional moieties containing from 1 to 12 carbon atoms and up to 2 oxygen or sulfur atoms. Salts of the compounds of formula I may be prepared by treating a compound of formula I with: metal hydroxides such as sodium hydroxide; amines such as ammonia, triethylamine, diethanolamine, 2-methylthiopropylamine, diallylamine, 2-tert-butoxyethylamine, morpholine, cyclododecylamine or benzylamine, or; tetraalkylammonium hydroxide or choline hydroxide. Amine salts are often the preferred form of the compounds of formula I because they are water soluble and are themselves readily prepared into the desired aqueous-based herbicidal compositions.
Compounds of formula (I) include N-oxides. Pyridine N-oxides can be obtained by oxidation of the corresponding pyridine. Suitable oxidation processes are described, for example, in Houben-Weyl, Methoden der organischen chemistry [ Methods in organic chemistry ] (this is a fourth edition of roll-up and roll-over), volume E7 b, p.565f.
As used herein, unless otherwise indicated, acyl means formyl, C1-C3Alkylcarbonyl and C1-C3A haloalkylcarbonyl group. C1-C6Acyl is formyl, C1-C5Alkylcarbonyl and C1-C5Haloalkyl carbonyl (said groups containing 1 to 6 carbon atoms in total).
Alkyl, as used herein, refers to a saturated, straight or branched chain saturated hydrocarbon moiety. Unless otherwise indicated, it is intended to mean C1-C10An alkyl group. Examples include methyl, ethyl, propyl, 1-methyl-ethyl, butyl, 1-methyl-propyl, 2-methyl-propyl, 1-dimethyl-ethyl, pentyl, 1-methyl-butyl, 2-methyl-butyl, 3-methyl-butyl, 2-dimethyl-propyl, 1-ethyl-propyl, hexyl, 1-dimethyl-propyl, 1, 2-dimethyl-propyl, 1-methyl-pentyl, 2-methyl-pentyl, 3-methyl-pentyl, 4-methyl-pentyl, 1-dimethyl-butyl, 1, 2-dimethyl-butyl, 1, 3-dimethyl-butyl, 1-methyl-butyl, 2-methyl-pentyl, 2,2, 2-dimethyl-butyl, 2, 3-dimethyl-butyl, 3-dimethyl-butyl, 1-ethyl-butyl, 2-ethyl-butyl, 1, 2-trimethyl-propyl, 1,2, 2-trimethyl-propyl, 1-ethyl-1-methyl-propyl and 1-ethyl-2-methyl-propyl.
"haloalkyl" as used herein refers to a straight or branched alkyl group in which hydrogen atoms may be partially or fully substituted with halogen atoms. Unless otherwise indicated, is intended to mean C1-C8A group. Examples include chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2, 2-difluoroethyl, 2,2, 2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2-difluoroethyl, 2, 2-dichloro-2-fluoroethyl, 2,2, 2-trichloroethyl, pentafluoroethyl and 1,1, 1-trifluoropropan-2-yl.
Alkenyl as used herein means containing a bisUnsaturated, straight or branched hydrocarbon moieties of the bond. Unless otherwise indicated, is intended to mean C2-C8An alkenyl group. The alkenyl group may contain more than one unsaturated bond. Examples include ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-2-butenyl, 2-methyl-2, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1-dimethyl-2-propenyl, 1, 2-dimethyl-1-propenyl, 1, 2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-3-pentenyl, 1-methyl-2-pentenyl, 3-methyl-1-pentenyl, 3-methyl-pentenyl, 2-methyl-pentenyl, 3-methyl-2-pentenyl, 3, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1-dimethyl-2-butenyl, 1-dimethyl-3-butenyl, 1, 2-dimethyl-1-butenyl, 1, 2-dimethyl-2-butenyl, methyl-2-pentenyl, methyl-3-pentenyl, methyl-2-butenyl, 1,1, 2-dimethyl-3-butenyl, 1, 3-dimethyl-1-butenyl, 1, 3-dimethyl-2-butenyl, 1, 3-dimethyl-3-butenyl, 2-dimethyl-3-butenyl, 2, 3-dimethyl-1-butenyl, 2, 3-dimethyl-2-butenyl, 2, 3-dimethyl-3-butenyl, 3-dimethyl-1-butenyl, 3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-dimethyl-3-butenyl, 2-dimethyl-2-butenyl, 2-ethyl-1-butenyl, 2-dimethyl-3-butenyl, 2-dimethyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1, 2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl and 1-ethyl-2-methyl-2-propenyl. Vinyl means having the structure-CH ═ CH2A group of (a); 1-propenyl means a compound having the structure-CH ═ CH-CH3A group of (a); and 2-propenyl means having a-CH2-CH＝CH2Groups of the structure.
Alkynyl, as used herein, refers to a straight or branched hydrocarbon moiety containing a triple bond. Unless otherwise indicated, is intended to mean C2-C8Alkynyl. The alkynyl group may contain more than one unsaturated bond. Examples include C2-C6Alkynyl groups, such as ethynyl, 1-propynyl, 2-propynyl (or propargyl), 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3-methyl-1-butynyl, 1-methyl-2-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 3-methyl-1-pentynyl, 4-methyl-1-pentynyl, 1-methyl-2-pentynyl, 4-methyl-2-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 1-dimethyl-2-butynyl, 1-dimethyl-3-butynyl, 1, 2-dimethyl-3-butynyl, 2-dimethyl-3-butynyl, 3-dimethyl-1-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 2-methyl-4-pentynyl, 1-dimethyl-2-butynyl, 1-, 2-ethyl-3-butynyl and 1-ethyl-1-methyl-2-propynyl.
Alkoxy as used herein refers to a group of formula R-O-, wherein R is alkyl as defined above. Unless otherwise indicated, it is intended to indicate where R is C1-C8Alkoxy groups of alkyl groups. Examples include methoxy, ethoxy, propoxy, 1-methyl-ethoxy, butoxy, 1-methyl-propoxy, 2-methyl-propoxy, 1-dimethyl-ethoxy, pentyloxy, 1-methyl-butoxy, 2-methyl-butoxy, 3-methyl-butoxy, 2-di-methyl-propoxy, 1-ethyl-propoxy, hexyloxy, 1-dimethyl-propoxy, 1, 2-dimethyl-propoxy, 1-methyl-pentyloxy, 2-methyl-pentyloxy, 3-methyl-pentyloxy, 4-methyl-pentyloxy, 1-dimethyl-butoxy, 1, 2-dimethyl-butoxy, 1-methyl-butoxy, n-butyl-oxy, n-butyl, 1, 3-dimethyl-butoxy, 2, 2-dimethyl-butoxy, 2, 3-dimethyl-butoxy, 3-dimethyl-butoxy, 1-ethyl-butoxy, 2-ethylbutoxy, 1, 2-trimethyl-propoxy, 1,2, 2-trimethyl-propoxy, 1-ethyl-1-methyl-propoxy and 1-ethyl-butoxyThe radical-2-methyl-propoxy.
Haloalkoxy, as used herein, refers to a group of the formula R-O-wherein R is haloalkyl as defined above. Unless otherwise indicated, it is intended to indicate where R is C1-C8Haloalkoxy of alkyl. Examples include chloromethoxy, bromomethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 1-chloroethoxy, 1-bromoethoxy, 1-fluoroethoxy, 2, 2-difluoroethoxy, 2,2, 2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro, 2-difluoroethoxy, 2, 2-dichloro-2-fluoroethoxy, 2,2, 2-trichloroethoxy, pentafluoroethoxy and 1,1, 1-trifluoroprop-2-oxy.
Alkylthio as used herein refers to a group of the formula R-S-wherein R is alkyl as defined above. Unless otherwise indicated, it is intended to indicate where R is C1-C8Alkylthio of alkyl groups. Examples include methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methyl-propylthio, 2-methylpropylthio, 1-dimethylethylthio, pentylthio, 1-methylbutylthio, 2-methylbutylthio, 3-methylbutylthio, 2-di-o-methylpropylthio, 1-ethylpropylthio, hexylthio, 1-dimethylpropylthio, 1, 2-dimethylpropylthio, 1-methylpentylthio, 2-methylpentylthio, 3-methyl-pentylthio, 4-methyl-pentylthio, 1-dimethylbutylthio, 1, 2-dimethyl-butylthio, 1, 3-dimethyl-butylthio, 2, 2-dimethylbutylthio, 2, 3-dimethylbutylthio, 3-dimethylbutylthio, 1-ethylbutylthio, 2-ethylbutylthio, 1, 2-trimethylpropylthio, 1,2, 2-trimethylpropylthio, 1-ethyl-1-methylpropylthio and 1-ethyl-2-methylpropylthio.
Haloalkylthio, as used herein, refers to an alkylthio group as defined above wherein the carbon atoms are partially or fully substituted with halogen atoms. Unless otherwise indicated, it is intended to indicate where R is C1-C8Haloalkylthio of alkyl. Examples include chloromethylthio, bromomethylthio, dichloromethylAlkylthio, trichloromethylthio, fluoromethylthio, difluoromethylthio, trifluoromethylthio, chlorofluoromethylthio, dichlorofluoro-methylthio, chlorodifluoromethylthio, 1-chloroethylthio, 1-bromoethylthio, 1-fluoroethylthio, 2, 2-difluoroethylthio, 2,2, 2-trifluoroethylthio, 2-chloro-2-fluoroethylthio, 2-chloro-2-difluoroethylthio, 2, 2-dichloro-2-fluoroethylthio, 2,2, 2-trichloroethylthio, pentafluoroethylthio and 1,1, 1-trifluoroprop-2-ylthio.
Aryl as used herein, and derivative terms such as aryloxy, refer to phenyl, indanyl or naphthyl, preferably phenyl. The term "heteroaryl" and derivative terms such as "heteroaryloxy" refer to a 5-or 6-membered aromatic ring containing one or more heteroatoms, i.e., N, O or S; these heteroaromatic rings may be fused with other aromatic systems. The aryl or heteroaryl substituents may be unsubstituted or substituted with one or more substituents selected from: halogen, hydroxy, nitro, cyano, formyl, C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, C1-C6Alkoxy radical, C1-C6Haloalkyl, C1-C6Haloalkoxy, C1-C6Acyl radical, C1-C6Alkylthio radical, C1-C6Alkylsulfinyl radical, C1-C6Alkylsulfonyl radical, C1-C6Alkoxycarbonyl group, C1-C6Carbamoyl, hydroxycarbonyl, C1-C6Alkylcarbonyl, aminocarbonyl, C1-C6Alkylaminocarbonyl radical, C1-C6A dialkylaminocarbonyl group, provided that the substituents are sterically compatible and satisfy chemical bonding and strain energies. Preferred substituents include halogen, C1-C2Alkyl and C1-C2A haloalkyl group.
Alkylcarbonyl, as used herein, refers to an alkyl group bonded to a carbonyl group. C1-C3Alkylcarbonyl and C1-C3Haloalkyl carbonyl means wherein C1-C3Bond of alkyl to carbonyl(iii) a combined group (which group contains a total of 2 to 4 carbon atoms).
Alkoxycarbonyl, as used herein, refers to the formulaA group wherein R is alkyl.
Arylalkyl, as used herein, refers to an alkyl group substituted with an aryl group. C7-C10Arylalkyl means a group having a total of 7 to 10 carbon atoms in the group.
Alkylamino as used herein refers to an amino group substituted with one or two alkyl groups which may be the same or different.
Haloalkyl amino as used herein refers to alkylamino wherein the alkyl carbon atoms are partially or fully substituted with halogen atoms.
As used herein, C1-C6Alkylaminocarbonyl means where R is C1-C6Alkyl group of the formula RNHC (O) -and C1-C6Dialkylaminocarbonyl means a radical in which each R is independently C1-C6Alkyl of the formula R2NC (O) -group.
Alkylcarbamoyl, as used herein, refers to carbamoyl substituted on the nitrogen with an alkyl group.
Alkylsulfonyl as used herein refers to the formulaA group wherein R is alkyl.
Carbamoyl (also referred to as carbamoyl and aminocarbonyl) as used herein refers to a compound of formula (la)A group.
The term dialkylphosphinyl as used herein refers to a compound of formulaA group wherein R is independently at each occurrence an alkyl group.
As used herein C1-C6Trialkylsilyl is intended to mean a radical of the formula-SiR3Wherein each R is independently C1-C6Alkyl groups (the groups contain a total of 3 to 18 carbon atoms).
Me as used herein refers to methyl; OMe is methoxy; i-Pr is isopropyl.
The term "halogen" as used herein includes derivative terms such as "halogen" and refers to fluorine, chlorine, bromine and iodine.
Plants and vegetation as used herein include, but are not limited to, germinated seeds, germinated seedlings, plants emerging from vegetative propagules, immature vegetation, and established vegetation.
A compound of formula (I)
The present invention provides compounds of formula (I) as defined above and the N-oxides and agriculturally suitable salts thereof.
In some embodiments, the compound is a carboxylic acid or an agriculturally acceptable ester or salt. In some embodiments, the compound is a carboxylic acid or a methyl ester thereof.
In some embodiments, the compound is a compound of formula (I) or an N-oxide or an agriculturally acceptable salt thereof:
wherein
X is N or CY, wherein Y is hydrogen, halogen, C1-C3Alkyl radical, C1-C3Haloalkyl, C1-C3Alkoxy radical, C1-C3Haloalkoxy, C1-C3Alkoxy radical, C1-C3Alkylthio or C1-C3A haloalkylthio group;
R1is OR1′Or NR1″R1″′Wherein R is1′Is hydrogen, C1-C8Alkyl or C7-C10Arylalkyl radical, and R1″And R1″′Independently of one another is hydrogen, C1-C12Alkyl radical, C3-C12Alkenyl or C3-C12Alkynyl radical；
R2Is halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C2-C4Alkenyl radical, C2-C4Haloalkenyl group, C2-C4Alkynyl, C1-C4Alkoxy radical, C1-C4Haloalkoxy, C1-C4Alkylthio radical, C1-C4Haloalkylthio, amino, C1-C4Alkylamino radical, C2-C4Haloalkyl amino, formyl, C1-C3Alkylcarbonyl group, C1-C3Haloalkyl carbonyl, cyano, or of formula-CR17＝CR18-SiR19R20R21Wherein R is17Is hydrogen, F or Cl; r18Is hydrogen, F, Cl, C1-C4Alkyl or C1-C4A haloalkyl group; and R is19、R20And R21Independently is C1-C10Alkyl radical, C3-C6Cycloalkyl, phenyl, substituted phenyl, C1-C10Alkoxy or OH;
R3and R4Independently of one another is hydrogen, C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Alkenyl radical, C3-C6Haloalkenyl, C3-C6Alkynyl, formyl, C1-C3Alkylcarbonyl group, C1-C3Halogenoalkylcarbonyl group, C1-C6Alkoxycarbonyl group, C1-C6Alkylcarbamoyl, C1-C6Alkylsulfonyl radical, C1-C6Trialkylsilyl group, C1-C6A dialkyl phosphinyl group, or R3And R4Together with N, is a 5-or 6-membered saturated ring, or R3And R4Together represent ═ CR3′(R4′) Wherein R is3′And R4′Independently of one another is hydrogen, C1-C6Alkyl radical, C3-C6Alkenyl radical, C3-C6Alkynyl, C1-C6Alkoxy or C1-C6Alkylamino, or R3′And R4′Together with ═ C, represents a 5-or 6-membered saturated ring;
a is one of the groups Ar1 to Ar 24:
R5is hydrogen, halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C3Alkoxy radical, C1-C3Haloalkoxy, C1-C3Alkylthio radical, C1-C3Haloalkylthio, amino, C1-C4Alkylamino or C2-C4A haloalkylamino group.
R6Is hydrogen, halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C3Alkoxy radical, C1-C3Haloalkoxy, C1-C3Alkylthio radical, C1-C3Haloalkylthio, amino, C1-C4Alkylamino or C2-C4A haloalkylamino group;
R6′is hydrogen or halogen;
R6″is hydrogen, halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, cyclopropyl, halocyclopropyl, C2-C4Alkenyl radical, C2-C4Haloalkenyl, C2-C4Alkynyl, C1-C3Alkoxy radical, C1-C3Haloalkoxy, C1-C3Alkylthio radical, C1-C3Haloalkylthio, amino, C1-C4Alkylamino radical, C2-C4Haloalkylamino, CN or NO2；
R7And R7′Independently of one another hydrogen, halogen, C1-C4Alkyl radical, C1-C4Haloalkyl or C1-C3An alkoxy group;
R8and R8′Independently of one another hydrogen, halogen, C1-C4Alkyl radical, C1-C4Haloalkyl or C1-C3An alkoxy group;
R9、R9′、R9″and R9″′Independently of one another hydrogen, halogen, C1-C4Alkyl radical, C1-C4Haloalkyl or C1-C3An alkoxy group;
R10is hydrogen, C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Alkenyl radical, C3-C6Haloalkenyl, C3-C6Alkynyl, formyl, C1-C3Alkylcarbonyl group, C1-C3Halogenoalkylcarbonyl or C1-C6A trialkylsilyl group;
m, when present, is 0,1 or 2; and
n, when present, is 0,1 or 2;
with the proviso that A is not
In some embodiments, m, when present, is 0 or 1; and n, when present, is 0 or 1. In some embodiments, m, when present, is 0; and n, when present, is 0. In some embodiments, m, when present, is 1; and n, when present, is 1.
In some embodiments, R1Is OR1′Wherein R is1′Is hydrogen, C1-C8Alkyl or C7-C10An arylalkyl group.
In some embodiments, R2Is halogen, C2-C4-alkenyl, C2-C4-haloalkenyl or C1-C4-alkoxy groups. In some embodiments, R2Is halogen, C2-C4-alkenyl or C1-C4-alkoxy groups. In some embodiments, R2Cl, OMe, vinyl or 1-propenyl. In some embodiments, R2Is Cl. In some embodiments, R2Is OMe. In one embodiment, R2Is vinyl or 1-propenyl.
In some embodiments, R3And R4Independently of one another is hydrogen, C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Alkenyl radical, C3-C6Haloalkenyl, C3-C6Alkynyl, formyl, C1-C3Alkylcarbonyl group, C1-C3Halogenoalkylcarbonyl group, C1-C6Alkoxycarbonyl group, C1-C6Alkylcarbamoyl, or R3And R4Together represent ═ CR3′(R4′) Wherein R is3′And R4′Independently of one another is hydrogen, C1-C6Alkyl radical, C3-C6Alkenyl radical, C3-C6Alkynyl, C1-C6Alkoxy or C1-C6An alkylamino group. In some embodiments, R3And R4Independently of one another is hydrogen, C1-C6Alkyl radical, C1-C6Haloalkyl, C3-C6Alkenyl radical, C3-C6Haloalkenyl, formyl, C1-C3Alkylcarbonyl group, C1-C3Haloalkylcarbonyl, or R3And R4Together represent ═ CR3′(R4′) Wherein R is3′And R4′Independently of one another is hydrogen, C1-C6Alkyl radical, C1-C6Alkoxy or C1-C6An alkylamino group. In some embodiments, R3And R4At least one of which is hydrogen. In some embodiments, R3And R4Are all hydrogen.
In some embodiments, X is N, CH or CF. In some embodiments, X is N. In some embodiments, X is CH. In some embodiments, X is CF.
In some embodiments: ar is Ar1, Ar3, Ar4, Ar7, Ar9, Ar10, Ar13, Ar15, Ar16, Ar19, Ar21, Ar22, Ar25 or Ar 27.
In some embodiments: ar is Ar1, Ar2, Ar3, Ar4, Ar5, Ar6, Ar7, Ar8, Ar15, Ar16, Ar17, Ar18, Ar25, Ar26, Ar27 or Ar 28.
In some embodiments: ar is Ar1, Ar3, Ar7, Ar9, Ar10, Ar13, Ar15, Ar16, Ar19, Ar21 or Ar 22.
In some embodiments: ar is Ar2, Ar4, Ar5, Ar6, Ar8, Ar11, Ar12, Ar14, Ar17, Ar18, Ar20, Ar23, Ar24, Ar26 or Ar 28.
In some embodiments: ar is Ar2, Ar5, Ar6, Ar8, Ar11, Ar12, Ar14, Ar17, Ar18, Ar20, Ar23 or Ar 24.
In some embodiments: ar is Ar1, Ar2, Ar3, Ar4, Ar6 or Ar 7.
In some embodiments: ar is Ar15, Ar16, Ar17 or Ar 18.
In some embodiments, R5Is hydrogen, halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C3Alkoxy radical, C1-C3Haloalkoxy, C1-C3Alkylthio or C1-C3A haloalkylthio group.
In some embodiments, R5Is hydrogen, halogen, C1-C4Alkyl radical, C1-C4Haloalkyl or C1-C3An alkoxy group. In some embodiments, R5Is hydrogen or F. In some embodiments, R5Is hydrogen. In some embodiments, R5Is F.
In some embodiments, R6Is hydrogen or halogen. In some embodiments, R6Is hydrogen or F. In some embodiments, R6Is hydrogen. In some embodiments, R6Is F.
In some embodiments, R6′Is hydrogen or halogen. In some embodiments, R6′Is hydrogen or F. In some embodiments, R6′Is hydrogen. In some embodiments, R6′Is F.
In some embodiments, R6″Is hydrogen, halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, cyclopropyl, C2-C4Alkynyl, CN or NO2. In some embodiments, R6″Is hydrogen, halogen, C1-C4Haloalkyl or cyclopropyl. In some embodiments, R6″Is hydrogen or halogen. In some embodiments, R6″Is C1-C4A haloalkyl group. In some embodiments, R6″Is CN. In some embodiments, R6″Is NO2。
In some embodiments:
R2is halogen, C2-C4-alkenyl, C2-C4Haloalkenyl or C1-C4-an alkoxy group;
R3and R4Are all hydrogen; and
x is N, CH or CF.
In some embodiments:
R2is halogen, C2-C4-alkenyl or C1-C4-an alkoxy group;
R3and R4Are all hydrogen; and
x is N, CH or CF;
ar is Ar1, Ar3, Ar7, Ar9, Ar10, Ar13, Ar15, Ar16, Ar19, Ar21 or Ar 22;
R5is hydrogen or F;
R6is hydrogen or F;
R6′is hydrogen;
R7、R7′、R8、R8′、R9、R9′、R9″and R9″′Independently hydrogen or fluorine if applicable to the relevant Ar group.
In some embodiments:
R2is halogen, C2-C4-alkenyl or C1-C4-an alkoxy group;
R3and R4Are all hydrogen; and
x is N, CH or CF;
ar is Ar1, Ar2, Ar3, Ar4, Ar5, Ar6, Ar7, Ar8, Ar9, Ar10, Ar11, Ar12, Ar15, Ar16, Ar25, Ar26, Ar27 or Ar 28;
R5is hydrogen or F;
R6is hydrogen or F;
R6′is hydrogen;
R7、R7′、R8、R8′、R9、R9′、R9″and R9″′Independently hydrogen or fluorine if applicable to the relevant Ar group.
In some embodiments:
R2is chlorine, methoxy, vinyl or 1-propenyl;
R3and R4Is hydrogen; and
x is N, CH or CF.
In some embodiments:
R2is chlorine;
R3and R4Is hydrogen; and
x is N, CH or CF.
In some embodiments:
R2is methoxy;
R3and R4Is hydrogen; and
x is N, CH or CF.
In some embodiments:
R2is vinyl or 1-propenyl;
R3and R4Is hydrogen; and
x is N, CH or CF.
In some embodiments:
R2is chlorine, methoxy, vinyl or 1-propenyl;
R3and R4Is hydrogen; and
x is N.
In some embodiments:
R2is chlorine;
R3and R4Is hydrogen; and
x is CH.
In some embodiments:
R2is chlorine, methoxy, vinyl or 1-propenyl;
R3and R4Is hydrogen; and
x is CF.
Exemplary Compounds
Table 1 below describes exemplary compounds of formula (I), wherein
R1Is OR1′；
R3And R4Is hydrogen; and
R1′、R2、X、Ar、m、R5、R6、R6′、R6″、R7and R7′、R8、R8′And R10Is one of the following combinations:
TABLE 1
For compound 107, R8And R8′Are substituted and are each F.
For compound 108, R10Is substituted and is Me.
Process for preparing compounds
Exemplary procedures for synthesizing compounds of formula (I) are provided below.
The 4-amino-6- (heterocyclyl) pyridine-2-carboxylic acids of formula (I) can be prepared in a variety of ways. As shown in scheme I, 4-amino-6-chloro-pyridine-2-carboxylate of formula (II) can be converted to 4-amino-6-substituted-pyridine-2-carboxylate of formula (III) wherein Ar is as defined herein (reaction a) via Suzuki coupling with boronic acid or ester in the presence of a base such as potassium fluoride and a catalyst such as bis (triphenylphosphine) -palladium (II) dichloride in a polar protic solvent mixture such as acetonitrile-water at a temperature of, for example, 110 ℃, e.g., in a microwave reactor1). The 4-amino-6-substituted-pyridine-2-carboxylic acid esters of the formula (III) can be converted into 5-iodo-4-amino-6-substituted-pyridine-2-carboxylic acid esters of the formula (IV) by reaction with iodinating agents such as periodic acid and iodine in polar protic solvents such as methanol (reaction b)1). Stille coupling of 5-iodo-4-amino-6-substituted-pyridine-2-carboxylic acid esters of the formula (IV) with stannanes such as tetramethyltin in the presence of catalysts such as bis (triphenylphosphine) -dichloropalladium (II) in non-reactive solvents such as 1, 2-dichloroethane at temperatures such as 120-1Are alkyl, alkenyl, alkynyl, haloalkenyl and alkylthio (reaction c)1)。
Alternatively, 4-amino-6-chloro-pyridine-2-carboxylic acid esters of formula (II) can be converted into 5-iodo-4-amino-6-chloro-pyridine-2-carboxylic acid esters of formula (V) via reaction with an iodinating agent such as periodic acid or iodine in a polar protic solvent such as methanol (reaction b)2). 5-iodo-4-amino-6-chloro-pyridine-2-carboxylic acid esters of the formula (V) with stannanes such as tetramethyltin in the presence of catalysts such as bis (triphenylphosphine) -palladium (II) dichloride in the absence ofStille coupling in reactive solvents such as 1, 2-dichloroethane at temperatures such as 120-1Are alkyl, alkenyl, alkynyl, haloalkenyl and alkylthio (reaction c)2). The 5-substituted-4-amino-6-chloro-pyridine-2-carboxylic acid esters of formula (VI) can be converted to 5-substituted-4-amino-6-substituted-pyridine-2-carboxylic acid esters of formula (I-a) wherein Ar is as defined herein (reaction a) in the presence of a base such as potassium fluoride and a catalyst such as bis (triphenylphosphine) -palladium (II) dichloride in a polar protic solvent mixture such as acetonitrile-water at a temperature such as 110 ℃, e.g., in a microwave reactor via Suzuki coupling with a boronic acid or ester2)。
Scheme I
As depicted in scheme II, 4,5, 6-trichloro-pyridine-2-carboxylate of formula (VII) can be converted to the corresponding isopropyl ester of formula (VIII) via reaction with isopropyl alcohol and concentrated sulfuric acid, e.g., at reflux temperature under Dean-Stark conditions (reaction d). Isopropyl ester of formula (VIII) can be reacted with a fluoride ion source such as cesium fluoride in a polar aprotic solvent such as dimethyl sulfoxide (DMSO) at a temperature such as 80 ℃ under Dean-Stark conditions to give isopropyl 4,5, 6-trifluoro-pyridine-2-carboxylate of formula (IX) (reaction e). Isopropyl 4,5, 6-trifluoro-pyridine-2-carboxylate of formula (IX) can be aminated in a polar aprotic solvent such as DMSO with a nitrogen source such as ammonia to prepare 4-amino-5, 6-difluoro-pyridine-2-carboxylate of formula (X) (reaction f). The fluoro substituent in the 6-position of the 4-amino-5, 6-difluoro-pyridine-2-carboxylate of formula (X) may be exchanged with the chloro substituent by treatment with a chlorine source such as hydrogen chloride, for example in dioxane at a temperature of, for example, 100 ℃ in a Parr reactor to prepare the 4-amino-5-fluoro-6-chloro-pyridine-2-carboxylate of formula (XI) (reaction g). 4-amino-5-fluoro-6-chloro-pyridine-2-carboxylate of the formula (XI) can be transesterified to the corresponding methyl ester of the formula (XII) by reaction with titanium (IV) isopropoxide in methanol at reflux temperature (reaction h).
Scheme II
As depicted in scheme III, 4-amino-5-fluoro-6-chloro-pyridine-2-carboxylate of formula (XII) can be converted to 3-iodo-4-amino-5-fluoro-6-chloro-pyridine-2-carboxylate of formula (XIII) via reaction with iodinating agents such as periodic acid and iodine in a polar protic solvent such as methanol (reaction b)3). 3-iodo-4-amino-5-fluoro-6-chloro-pyridine-2-carboxylate of formula (XIII) with a stannane such as tributyl (vinyl) stannane in the presence of a catalyst such as bis (triphenylphosphine) -palladium (II) dichloride in a non-reactive solvent such as 1, 2-dichloroethane at a temperature such as 120 ℃ for example, Stille coupling in a microwave reactor gives 3- (substituted) -4-amino-5-fluoro-6-chloro-pyridine-2-carboxylate of formula (XIV), wherein R is2Are alkyl, alkenyl, alkynyl, haloalkenyl and alkylthio (reaction c)3). Alternatively, 3-iodo-4-amino-5-fluoro-6-chloro-pyridine-2-carboxylic acid ester of formula (XIII) may be treated with cesium carbonate and a catalytic amount of both copper (I) iodide and 1, 10-phenanthroline in a polar protic solvent such as methanol at a temperature of, for example, 65 ℃ to give 3- (substituted) -4-amino-5-fluoro-6-chloropyridine-2-carboxylic acid of formula (XIV), wherein R is2Is alkoxy or haloalkoxy (reaction i)1) It can be esterified to the methyl ester, for example, by treatment with hydrogen chloride (gas) and methanol at 50 ℃ (reaction j)1). The 3- (substituted) -4-amino-5-fluoro-6-chloro-pyridine-2-carboxylic acid ester of formula (XIV) can be converted to the 4-amino-6-substituted-pyridine-2-carboxylic acid ester of formula (I-B) via Suzuki coupling with a boronic acid or ester in the presence of a base such as potassium fluoride and a catalyst such as bis (triphenylphosphine) -palladium (II) dichloride in a polar protic solvent mixture such as acetonitrile-water at a temperature such as 110 ℃, e.g. in a microwave reactor(s), wherein Ar is as defined herein (reaction a)3)。
Alternatively, 4-amino-5-fluoro-6-chloro-pyridine-2-carboxylate of formula (XII) may be prepared by reaction with boric acid or boric acid in a microwave reactor, for example, in the presence of a base such as potassium fluoride and a catalyst such as bis (triphenylphosphine) -palladium (II) dichloride in a polar protic solvent mixture such as acetonitrile-water at a temperature such as 110 ℃Suzuki coupling of esters to 4-amino-5-fluoro-6-substituted-pyridine-2-carboxylic acid esters of formula (XV) wherein Ar is as defined herein (reaction a)4). The 4-amino-5-fluoro-6-substituted-pyridine-2-carboxylic acid ester of formula (XV) may be converted to the 3-iodo-4-amino-5-fluoro-6-substituted-pyridine-2-carboxylic acid ester of formula (XVI) via reaction with an iodinating agent such as periodic acid and iodine in a polar protic solvent such as methanol (reaction b)4). Coupling of 3-iodo-4-amino-5-fluoro-6-substituted-pyridine-2-carboxylic acid esters of formula (XVI) with stannanes such as tributyl (vinyl) stannane in the presence of a catalyst such as bis (triphenylphosphine) -palladium (II) dichloride in a non-reactive solvent such as 1, 2-dichloroethane at a temperature of, for example, 120 ℃ e.g., 130 ℃, e.g., in a microwave reactor, affords 3- (substituted) -4-amino-5-fluoro-6-substituted-pyridine-2-carboxylic acid esters of formula (I-B), wherein R is R2Are alkyl, alkenyl, alkynyl, haloalkenyl and alkylthio (reaction c)4). Alternatively, 3-iodo-4-amino-5-fluoro-6-substituted-pyridine-2-carboxylic acid ester of formula (XVI) can be treated with cesium carbonate and a catalytic amount of both copper (I) iodide and 1, 10-phenanthroline in the presence of a polar protic solvent such as methanol at a temperature of, for example, 65 ℃ to give 3- (substituted) -4-amino-5-fluoro-6-substituted pyridine-2-carboxylic acid of formula (I-B), wherein R is2Is alkoxy or haloalkoxy (reaction i)2) It can be esterified to the methyl ester, for example, by treatment with hydrogen chloride (gas) and methanol at a temperature of, for example, 50 ℃ (reaction j)2)。
Scheme III
As depicted in scheme IV, 4-acetamido-6- (trimethylstannanyl) -pyridine-2-carboxylate of formula (XVII), wherein Ar is as defined herein, can be converted to 4-acetamido-6-substituted-pyridine-2-carboxylate of formula (XVIII) via Stille coupling with aryl bromide or aryl iodide in the presence of a catalyst such as bis (triphenylphosphine) -palladium (II) dichloride in a solvent such as 1, 2-dichloroethane, e.g., at reflux temperature (reaction k). 4-amino-6-substituted-pyridine-2-carboxylic acid esters of the formula (I-C), wherein Ar is as defined herein, can be synthesized from 4-acetamido-6-substituted-pyridine-2-carboxylic acid esters of the formula (XVIII) via standard deprotection methods such as hydrochloric acid gas/methanol (reaction l).
Scheme IV
As depicted in scheme V, 2, 4-dichloro-5-methoxypyrimidine (XIX) can be converted to 2, 4-dichloro-5-methoxy-6-vinylpyrimidine (XX) (reaction m) via reaction with vinylmagnesium bromide in a polar aprotic solvent such as tetrahydrofuran. 2, 4-dichloro-5-methoxy-6-vinylpyrimidine (XX) can be converted into 2, 6-dichloro-5-methoxypyrimidine-4-carbaldehyde (XXI) (reaction n) by treatment with ozone, for example in a dichloromethane: methanol solvent mixture. 2, 6-dichloro-5-methoxypyrimidine-4-carbaldehyde (XXI) can be converted to methyl 2, 6-dichloro-5-methoxypyrimidine-4-carboxylate (XXII) (reaction o) by treatment with bromine, for example, in a methanol/water solvent mixture. Methyl 2, 6-dichloro-5-methoxypyrimidine-4-carboxylate (XXII) may be converted to methyl 6-amino-2-chloro-5-methoxypyrimidine-4-carboxylate (XXIII) (reaction p) via treatment with ammonia (e.g., 2 equivalents) in a solvent such as DMSO. Finally, 6-amino-2-substituted 5-methoxypyrimidine-4-carboxylic acid esters of the formula (I-D), wherein Ar is as defined herein, can be prepared via Suzuki coupling of a boronic acid or ester with 6-amino-2-chloro-5-methoxypyrimidine-4-carboxylic acid ester (XXIII) in the presence of a base such as potassium fluoride and a catalyst such as bis (triphenylphosphine) -palladium (II) dichloride in a polar protic solvent mixture such as acetonitrile-water at a temperature such as 110 ℃ (for example, in a microwave reactor (reaction a)5)。
Scheme V
The compounds of formulae I-A, I-B, I-C and I-D obtained by any of these methods can be recovered by conventional means and purified by standard methods such as recrystallization or chromatography. Compounds of formula (I) may be prepared from compounds of formulae I-A, I-B, I-C and I-D using standard procedures well known in the art.
Compositions and methods
In some embodiments, the compounds provided herein are applied in a mixture comprising a herbicidally effective amount of the compound and at least one agriculturally acceptable adjuvant or carrier. Exemplary adjuvants or carriers include those that do not produce phytotoxins or significant toxicity to valuable crops, for example, at the concentrations used to apply the weed control selective composition in the presence of a crop, and/or do not chemically react or do chemically react significantly with the compounds provided herein or other composition ingredients. Such mixtures may be designed for direct application to the weeds or their locus, or may be concentrates or formulations diluted with additional carriers and adjuvants prior to application. They may be solids, such as dusts, granules, water-dispersible granules, or wettable powders, or liquids, such as emulsifiable concentrates, solutions, emulsions, or suspensions. They may also be provided as a premix or tank mixed.
Suitable agriculturally acceptable adjuvants and carriers for preparing the herbicidal mixtures of the present disclosure are well known to those skilled in the art. These adjuvants include, but are not limited to, crop oil concentrate (mineral oil (85%) + emulsifier (15%)); nonylphenol ethoxylate; benzyl coconut alkyl dimethyl quaternary ammonium salt; a blend of petroleum hydrocarbon, alkyl ester, organic acid, and anionic surfactant; c9-C11An alkyl polyglycoside; a phosphorylated alcohol ethoxylate; natural primary alcohol (C)12-C16) An ethoxylate; di-sec-butylphenol EO-PO block copolymers; a polysiloxane-methyl end-cap; nonylphenol ethoxylate + urea ammonium nitrate; an emulsified methylated seed oil; tridecyl alcohol (synthetic) ethoxylate (8 EO); tallow amine ethoxylate (15 EO); PEG (400) dioleate-99.
Liquid carriers that can be employed include water and organic solvents. Commonly used organic solvents include, but are not limited to, petroleum fractions or hydrocarbons such as mineral oil, aromatic solvents, paraffinic oils, and the like; vegetable oils such as soybean oil, grapeseed oil, olive oil, castor oil, sunflower oil, coconut oil, corn oil, cottonseed oil, linseed oil, palm oil, peanut oil, safflower oil, sesame oil, tung oil and the like; and esters of the above vegetable oils; esters of monohydric or dihydric alcohols, trihydric or other lower polyhydric alcohols (containing 4 to 6 hydroxyl groups), such as 2-ethylhexyl stearate, n-butyl oleate, isopropyl myristate, propylene glycol dioleate, dioctyl succinate, dibutyl adipate, dioctyl phthalate, etc.; esters of mono-, di-, and polycarboxylic acids, and the like. Specific organic solvents include toluene, xylene, naphtha, crop oil (crop oil), acetone, methyl ethyl ketone, cyclohexanone, trichloroethylene, perchloroethylene, ethyl acetate, amyl acetate, butyl acetate, propylene glycol monomethyl ether and ethylene glycol monomethyl ether, methanol, ethyl alcohol, isopropyl alcohol, amyl alcohol, ethylene glycol, propylene glycol, glycerol, N-methyl-2-pyrrolidone, N-dimethyl alkylamides, dimethyl sulfoxide, liquid fertilizers and the like. In some embodiments, water is the carrier used to dilute the concentrate.
Suitable solid carriers include talc, pyrophyllite clay, silica, attapulgite clay (attapulgus clay), kaolin, diatomaceous earth, chalk, diatomaceous earth, lime, calcium carbonate, bentonite, fuller's earth, cottonseed hulls, wheat flour, soybean flour, pumice, wood flour, walnut shell flour, lignin and the like.
In some embodiments, one or more surfactants are used in the compositions of the present disclosure. In some embodiments, such surfactants are used in both solid and liquid compositions, e.g., designed to be diluted with a carrier prior to application. Surfactants can be anionic, cationic, or nonionic in nature, and can be used as emulsifying agents, wetting agents, suspending agents, or agents for other purposes. Surfactants which are conventionally used in the formulation field and which can also be used in the formulations of the present application are described, inter alia, in "McCutcheon's Detergents and Emulsifiers annular," MCpublishing Corp., Ridgewood, New Jersey, 1998 and "Encyclopedia of Surfactants," Vol.I-III, Chemical Publishing Co., New York, 1980-81. Typical surfactants include salts of alkyl sulfates, such as diethanolammonium lauryl sulfate; alkyl aryl sulfonates such as calcium dodecylbenzenesulfonate; alkylphenol-alkylene oxide addition products, such as nonylphenol-C18 ethoxylate; alcohol-alkylene oxide addition products, such as tridecyl alcohol-C16 ethoxylate; soaps, such as sodium stearate; alkyl naphthalene-sulfonates, such as sodium dibutylnaphthalene sulfonate; dialkyl esters of sulfosuccinates, such as sodium bis (2-ethylhexyl) sulfosuccinate; sorbitol esters, such as sorbitol oleate; quaternary amines, such as lauryl trimethyl ammonium chloride; polyethylene glycol esters of fatty acids, such as polyethylene glycol stearate; block copolymers of ethylene oxide and propylene oxide; and salts of monoalkyl and dialkyl phosphates; vegetable or seed oils, such as soybean oil, rapeseed/canola oil, olive oil, castor oil, sunflower oil, coconut oil, corn oil, cottonseed oil, linseed oil, palm oil, peanut oil, safflower oil, sesame oil, tung oil, and the like; and esters of the above vegetable oils, such as methyl esters.
Sometimes, some of these materials, such as plant or seed oils and their esters, may be used interchangeably as agricultural adjuvants, as liquid carriers or as surfactants.
Other adjuvants commonly used in agricultural compositions include compatibilizers, defoamers, chelating agents, neutralizing agents and buffers, corrosion inhibitors, dyes, odorants, spreading agents, penetration aids, sticking agents, dispersants, thickeners, antifreeze agents, antimicrobial agents, and the like. The compositions may also contain other compatible components, for example, other herbicides, plant growth regulators (plant growth regulants), fungicides, insecticides, and the like, and may be formulated with liquid fertilizers or solids, particularly fertilizer carriers such as ammonium nitrate, urea, and the like.
The concentration of the active ingredient in the herbicidal compositions of the present disclosure is generally from about 0.001 to about 98 weight percent. Concentrations of about 0.01 to about 90 wt.% are typically used. In compositions designed for use as concentrates, the active ingredient is generally present at a concentration of from about 5 to about 98 weight percent, preferably from about 10 to about 90 weight percent. Such compositions are typically diluted with an inert carrier, such as water, prior to application. Diluted compositions typically applied to weeds or the locus of weeds typically contain from about 0.0001 to about 1% by weight of the active ingredient and preferably contain from about 0.001 to about 0.05% by weight.
The compositions of the present application may be applied to weeds or their locus by the use of conventional ground or aerial dusters, sprayers, and granule applicators, by addition to irrigation or paddy water (flood water), and by other conventional methods known to those skilled in the art.
In some embodiments, the compounds and compositions described herein are applied post-emergence, pre-emergence, in-water to flooded rice paddy rice or bodies of water (e.g., ponds, lakes, or streams), or incinerated.
In some embodiments, the compounds and compositions provided herein are used to control weeds in crops, including but not limited to citrus, apple, rubber, oils, palm, forestry, direct-seeded rice, water-seeded and transplanted rice, cereals, wheat, barley, oats, rye, sorghum, corn/maize, pastures, grasslands, rangelands, fallowland, turf, tree and vine orchards, aquatics, or row-crops, as well as in non-crop locations, such as Industrial Vegetation Management (IVM) or rights-of-way. In some embodiments, the compounds and compositions are used to control woody plants, broadleaf and grass weeds or sedges.
In some embodiments, the compounds and compositions provided herein are used to control undesirable vegetation in rice. In certain embodiments, the undesirable vegetation is Brachiaria platyphylla (Groseb), Nash (broadleaf signalgrass), BRAPP), Digitaria sanguinalis (L.) Scop (red digita crabgrass), DIGSA, Echinochloa cruris-galli (L.) P.beauvv (barnyard), ECHCg, Echinochloa crudus (L.) Line (junglerce), Echinochloa crudus (Echinochloa), Echinochloa crudus (Aritsch) (earylous, HOR), Echinochloa crus (Echinochloa), Echinochloa crus (Arthroides) Fritsch (ear), Faratula japonica (seedling), Lepogora japonica (L.) and Lepogora (Lepogora), Lepogora japonica (Lepogora japonica), Lepogora japonica (L.) Graves (Lepogora japonica), Lepogora japonica (L. japonica), Lepogora japonica (Lepogora japonica, Lepogora japonica (L. japonica), Lepogora japonica (L. japonica, Lepogora japonica (Lepogora japonica, Lepogora, LEFPA), Panicum paniculatum (L.) Michx (fall panicum), PANDI, Paspalum vaginatum (Paspalum vaginatum), Passiflora palustre (Dallas grass), Passiflora heteroclita (Cyperus difformis L.), Cyperus tinctorius (Cyperus floridus. f.) Linne (Cyperus floridus. f.), CyPDI, Cyperus sativus L.) (Cyperus luteus (yellow nuedge), Cypes), Cyperus pulchra (Cyperus L.) (Cyperus bifidus. f.) (Cyperus floridus. f.), Cyperus (Cyperus rugatus. pir), Cyperus rotundus (Cyperus rotundus. f.) (Cyperus roscovezensis (Cyperus granulosa), Cyperus rotundus, Elephus sphaera micranthus (Cyperus), Cyperus rotundus (Cyperus chinensis, Cyperus rotundus. juss (Spirostrie.e.) (Spirostrie.e., Spirostrie.g., Spirostris) Michikura (Spirostris ) Mitsu. crispus, Spirostris eur. purpurea (Spirostris, Spirostri, AESSS), alternanthera philoxeroides (Mart.) harms (greseb.) (alligator weed, ALRPH), Alisma plantago (alima plantago-aquatica L.) (common plantago asiatica (common plantago), ALSPA), Amaranthus species (Amaranthus species) (quinoa (pigweeds) and Amaranthus (amaranths), AMASS), Amaranthus rubra (amanina coricinea Rottb.) (red stem (redstem), AMMCO), Eclipta alba (L.) Hassk.) (American false chrysanthemum flower), pistil lal), rosebush (heterophylla rosea flower) (japanese red flower, rosebush flower (rosebush), rosebush flower (mangrove.) and rosebush (mangrove.) harms (mangrove.) and red stem, rosebush flower (mangrove leaf), rosebush flower (mangrove flower), rosebush flower (mangrove indica flower), mangrove (mangrove indica (mange) and red stem (mange), mange (mange) and red stem (mange indica (mange) and rosebush flower (mange), mange (mange) and red stem, mange (mange indica (mange) and red stem, mange indica (mange indica flower) and red stem, mange indica (mange rosebush flower, mange (mange flower, mange) and red stem, mange (mange flower) and red stem, mange flower (mange flower, mange (mange flower) and rosebush flower (mange flower) and rosee flower (mange flower), mange flower (, MOOKA), Monochoria vaginalis (burm.f.) c.presl exkuth) (Monochoria), morva, mangrove lophatherum nudiflora (L.) Brenan (doveweed), MUDNU), Polygonum palustris (Polygonum pennyroyal L.) (Polygonum pennyroyal (pennyroyal netted), POLPY), Polygonum vernalis (Polygonum persicum L.) (ladysthumb, POLPE), Polygonum perfoliatum (Polygonum hydropiperidum L.) (lady), Polygonum perfoliatum (Polygonum hydropiperidum Michx.) (Polygonum flaccidiforme, polp), Polygonum nodosum (willebrand, polum arvense), Polygonum arvense (rosewood, polp), Polygonum arvense (wilfordii), cannabis sativa (spiceva), cannabis (spiceva ), or spiceva (spiceva).
In some embodiments, the compounds and compositions provided herein are used to control undesirable vegetation in cereals. In certain embodiments, the undesirable vegetation is Alopecurus myosuroides Huds (blackgrass, ALOMY), alexandrium arborescens (apara spicatum-venti.) (windgrass, APESV), Avena sativa (Avena fatua L.) (wild oat, AVEFA), canary broomrape (broomrape L.) (broomrape, brough, broomrape (brown grass), BROTE, Lolium multiflorum (brother), brookite, Lolium multiflorum (Lolium multiflorum), Lolium roseum (milalr grass), Lolium phalaeanum (Lolium roseum), Setaria canary (yellow grass), Setaria viridis (green grass), Setaria viridans (green grass), Setaria viridis (Setaria viridis (green grass), Setaria viridis (Setaria viridis), Setaria viridis (yellow grass, Setaria viridis, Setaria viridis (green grass, Setaria viridis canary), CIRAR, cleavers L. (Galium aparine (cathwed bedstraw), GALAP), Kochia scoparia (L.)) Schrad.) (Kochia), KCHSC), lamiophiun sativum (lamiumpurpurerurum L.) (purple nettle deept), lamu), Matricaria chamomilla (Matricaria recutita L.) (wild chamomile), mat-marianum chamomile (Matricaria chamomile), Matricaria chamomilla (Matricaria), MATMT, melasma (roses), pamonwort), Polygonum hydropiper (Polygonum conum L.) (wild butterbur bedstraw), wild buckwheat (wild butterbur bedstraw (wild grasses), wild buckwheat (wild grassland violet), corn poppy (wild buckwheat (wild grasses potriat), wild buckwheat (wild grasses), wild grasses corn poppy (wild grasses), wild grasses (wild grasses), corn poppy (wild grasses), wild grasses (wild grasses), corn poppy corn eares (wild grasses), wild grasses (wild grasses) L.) (wild grasses, corn eares, wild grasses (wild grasses, corn eares, wild grasses, VIOAR), or pansy (Viola tricolor L.) (wild violet (vild violet), VIOTR).
In some embodiments, the compounds and compositions provided herein are used to control undesirable vegetation in pastures and pastures. In certain embodiments, the undesirable vegetation is ragweed (Ambrosia artemisiifolia L.) (common ragweed), AMBEL), Cassia obtusifolia (Cassia obtusifolia) (simple pod, CASOB), Cesarum maculatum (Centaurea maculosa au.) (non Lam.) (Spotted Knipweered, CEA), Cirsium setosum (Cirsium arvense (L.)) Scop.) (Canada thistle), CIAR), Convolvulus arvensis L.) (wild ConAR.), Eulactaea latifolia (Eupatorium L.) (milk thistle Torri (Euphorbia), HES), Lactuca sativa (Lactuca sativa L.) (Lactuca), Plantago indica (Plantago indica), Plantago indica (Plantago indica), Psyllia indica (L.) (C. indica (L.) (C. indica), Psyllia), Psyllid.) (C. indica), Psyllid.) (C. indica), Psyllia (C. indica), Psyllic) (Makino) L.) (C. indica (C. coli L.) (C. indica), Psyllid, SIDSP), white mustard (Sinapis arvensis L.) (wild mustard), SINAR), endive (Sonchus arvensis L.) (perennial endive (perennial sowthistle, sonor), goldenrod species (solitagospecies) (solanum, soss), medicinal dandelion (Taraxacum of fiscinale g.h. weber ex Wiggers) (dandelion), taro), white clover (Trifolium repens L.) (white clover, tref), or nettle (Urtica dioica L.) (common nettle, urtia).
In some embodiments, the compounds and compositions provided herein are used to control undesirable vegetation found in row crops. In certain embodiments, the undesirable vegetation is Alopecurus major (Alopecurus myosoroides husds.) (black grass, ALOMY), Avena sativa (Avena fatua L.) (wild oat, AVEFA), Brachiaria (brashia platyphylla.) (broadleaf grass, BRAPP), Digitaria sanguinalis (L.) (Scop mark.)) (large Digitaria sanguinalis), DIGSA (algeria graciliata), barnyard grass (ecochloa-galli.) (barnyard grass, ecg), barnyard grass (linochloa-galli (L.) (linum), milfoil (L. Setaria), Setaria japonica (milfoil millet). Seta (Setaria viridis (L.) Beauv.) (green foxtail, SETVI), Jersey grass (Sorghum halepense (L.)) (Johnsongrass, SORHA), millet (Sorghum bicolor (L.)) Moench. Arnidinium) (short, SORVU), Cyperus esculentus (Cyperus esculentus L.) (yellow grass (yellow flower bud), Cyperus rotundus (Cyperus rotundus L.) (purple grass (purple flower bud), CymeMed), Abutilon theophrhrix (Abutilis), Abutili (Amarvilla), Amarvillea (Amarvillosa (Amarvillus), Amaru grass (Amaru), Amarvillea (Amaru), Ambrodensis (Ambrodensis), Ambrodensis (Ambrodensiflora), Ambrodensis (Ambrodensis artemisii), Ambrodensis (Ambrodensis artemia americana) and Ambrodensis (Ambrodensiflora), ASCSY), Chenopodium album L. (common Lambasguariers, CHEAL), Cirsium setosum (L.) Scop. (Canada thistle, CIAR), Commelina americana (Commelina benthamensis L.) (Benghai dayflower, COMBE), stramonium (Daturaria stramonium L.) (stramonium), Dattst), carrot (Daucus carota L.) (wild carrot, DAUCA), petunia (European grass L.) (wild magenta fuschin, EPHHL), Artemisia annua (wild flower), herba Potentillae Anserinae (European flower), Flora japonica (L.) and Carpesium falcatum (L.), Canada (European flower), Carpestalum falcatum L.) (wild cabbage, European flower L.) (Canada), Carpesium falcatum L. (Canada), Carpesium falcata (L.) (European flower L.) (Canada, Carpesium falcata, Carpesium L.) (Canada, Carpesium fallax, Carpesium L.) (Carpesium, Carpesium L.) (Carpesium, Carpesium L.) (Carpesium, Carpesium fallax, Carpesium, IAQTA), pistachio (Ipomoea hederacea (L.) Jacq.) (petunia mouriscus (ivyleaf mourning glory), IPOHE), petunia (Ipomoea lacunosa L.) (white petunia (whitlemoning glory), IPOLA), Lactuca sativa (Lactuca L./Torn.) (pringlet lettuce (lacclevate), LACSE), purslane (Portulaca oleracea L.) (common purslane (common purlan), POROL), midday spica (Sida spinosa L.) (pri sikkenbacea (prinus sikkly Sida), brassica juncea (sinapia arvensis L.) (wild swamp mustard tuber (wild swamp, mustard) and solanum sativum (L.), or (dark green) zandra (L.) (dark yellow flower).
In some embodiments, an application rate of about 1 to about 4,000 grams per hectare (g/ha) is used in the post-emergence procedure. In some embodiments, an application rate of about 1 to about 4,000g/ha is used in the pre-emergence procedure.
In some embodiments, the compounds, compositions, and methods provided herein are used in combination with one or more other herbicides to control a wider range of undesirable vegetation. When used in combination with other herbicides, the compounds of the present application can be formulated with one or more other herbicides, tank mixed with one or more other herbicides, or used sequentially with one or more other herbicides. Some herbicides that can be used in conjunction with the compositions and methods described herein include, but are not limited to: 4-CPA, 4-CPB, 4-CPP, 2,4-D, 2,4-D choline salt, 2,4-D esters and amines, 2,4-DB, 3,4-DA, 3,4-DB, 2,4-DEB, 2,4-DEP, 3,4-DP, 2,3,6-TBA, 2,4,5-T, 2,4,5-TB, acetochlor (acetochlor), acifluorfen (acifluorfen), aclonifen (acifluorfen), acrolein (acrolein), alachlor (alachlor), ethazine (alidochlor), diclofen (alloxydim), allyl alcohol (alloyl alcohol), pentachlorothiazine acid (aloac), tetramethone (triamethyne), ametryn (ametryne), ametryne (butazone), amitrazine (butafenamidosulfuron), pyrazosulfuron (sulfamylon), propyrifos (sulfamylon), pyrine (sulfamylon), pyrimethamidosulfuron (sulfamylon), pyrine (sulfamylon), pyrimethazine (sulfamylon), pyrin (sulfamylon), pyrimethazine (sulfamylon), fenfluramine (amitrale), ammonium sulfamate (ammonium sulfamate), anilofos (anilofos), sulfluron (aniluron), asulam (asulam), atraron (atraton), atrazine (atrazine), azafenidin (azafenidin), azimsulfuron (azimsulfuron), azinprop (azinprop), barban (barban), BCPC (BCC), beflubutamid (flubutamid), benazolin (benalin), benconazole (benfluralin), flumetum (benfluralin), benfuralin (benfuresate), bensulfuron (bensulfuron-methyl), benthos (bensulide), carboxim (bentazocarb), bentazone (bentazone), bentazone (bensul-methyl), bentazone (bentazone), pyrazosulfuron (fenflurazone), pyrithiobac (bensulam), pyrazosulfuron (fenpyrazosulfuron-ethyl), pyrazosulfuron (fenpyrazosulfuron), fenpyrazosulfuron (bensul (fensulfuron), fensulfuron (fenflurazone), fenflurazone (bensul-ethyl), fenflurazone (bensul-bensul), bensul-bensul (bensul), bensul (bensul-ethyl), bensul (bensul-bensul (bensul-bensul), bensul-bensul (bensul-bensul), ben, bromoxynil (bromobionil), bromobutyryl (bromobutride), butachlor (butachlor), butafenacil (butafenacil), butafosinate (butamifofos), butafenacet (butachlor), butralin (butralin), butafenap (butroxydim), meturon (buturon), butralin (buthylate), cacodylate (cacodylate), fenpropiconazole (cafenstrole), calcium chlorate (calchloride), calcium cyanamide (calcoacide), cyromazine (caprate), carbachol (carbachol), fenchloranilate (carbendazim), fenflurazote (carbendazim), chlorambucil (carbendazim), chlorazol (carbendazim (fenchlorazol-methyl), chlorambucil (carbendazim), chlorantranilide (carbendazim), chlorambucil (carbendazim), carbendazim (carbendazim), carbendazim (carbendazim, varroa (chlorotfenac), avenyl ester (chlorefenprox), cimetidine (chlorotflurazone), fluroxypyr (chlorothalonil), chlorambucil (chlorotimuron), cumquat ether (chlorotritron), trichloropropionic acid (chlorotoxin), chlortoluron (chlorotoluron), cumquat (chlorotoluron), chlortoluron (chlorothaloron), chlorfenapyr (chloroxyuron), chlorfenapyr (chloroxynil), dichlorphenazine (chlorofenan), chlorpropham (chlorofenam), chlorsulfuron (chlorothalonil), chlorambucil (chlorothiamide), indolone-ethyl (cinidon-ethyl), cinmethylin (cinhyalin), sultrine (cinolone), fenuron (chlomethyl), clofenate (clofenapyr), clofenapyr (clofenamate), clofenapyr (clofenapyr), clofenapyr (clofenate (clofenapyr), clofenate (clofenate), clofenate (clofenac), clofenac (clofenac, clofenac (clofenac), clofenac (clofenac, clofenac (clofenac), clofenac (clofenac ), clofenac (clofenac, clofenac (clofenac, clo, tribenuron (cymyluron), cyanazine (cycloatryn), cyanazine (cyazozine), chloramate (cyclosulfuron), cyclosulfamuron (cyromuron), cyclosulfuron (cyclosulfuron), cycloxydim (cycloxydim), cyhalouron (cycuron), cyhalofop-butyl (cyhaloquat), cyhalofop-butyl (cyperquat), cyromazine (cyromazine), cyromazine (cyromuron), dalon (dalton), dalton (dazopon), dazomet (dazomet), dichlofen (delachlor), desmodium (desoxyfen), diclofen (desmetryn), dichlofen (diclofen), aven (di-allate), dicamba (dicamba), cyanamide (dimbonitrile (dimbolonil), chlomethyl (chlomethyl), diclofen (chlomethyl (2-ethyl), diclofen (2, diclofen), diclofen (diclofen), diflufenican (diflufenpyrad), diflufenzopyr (diflufenzopyr), dazomet (dimefuron), dimeflufen (dimefuron), dimeflufenate (dimepiperate), butachlor (dimehaclor), dimethenamid (dimethametryn), dimethenamid (dimethenamid-P), dimethenamid (dimethenamid), dimyridazole (dimethenamid), dimethenamid (dimethenamid), dinotape (dinoflagellate), dinofenate (dinofenate), dinotefuran (dinoproprol), dinetop (dinoflagellate), dinotefuran (dinoseb), dinotefuran (dinotefuran), sulfadiazine (ethoxysulfuron (Epstein), sulfadiazinon (Epstein, metosulbensulfuron), sulfadiazinon (Epiflavon (Epstein), sulfadiazinon (Epstein, bensulfuron), bensulfuron (Epstein), bensulfuron (Epstein, bensulfuron), bensulfuron (P), bensulfuron (herbicidal), bensulfuron (P, bencarb (herbicidal), bencarb (fenpyr (bencarb), bencarb (bencarb), bencarb (, nifedipine (ethiofen), pyriftalid (ethiprole), ethaboxam (ethiprole), etofenpyr (etobenzanid), EXD, fenoxycarb (fenasulam), aldicacid (fenoprop), fenoxaprop (fenoxaprop), fenoxaprop-P-ethyl) + isoxadifen-ethyl, fenoxaprop-P-ethyl, fenoxaprop-ethyl, fenoxyethanol (fenteracol), fenoxaprop-P-ethyl, tebuconazole (fentrazamide), fenoxuron (fenuron), ferrous sulfate (ferrosulfate), flurate (flupropp), flufenoxaprop-P (flufenoxaprop-M), flazasulfuron (fluazasulfuron), flufenflurazone (fluflurazone), fluazifop-ethyl, fluazifop (fluazifop), fluazifop-ethyl (fluazifop), fluazifop (fluazin (flurazone), fluazifop-P (fluazifop-P), fluazifop (fluazifop-P (fluazifop), fluazifop (fluazifop-P-butyl), flumetsulam, fluxazine (flumezin), flumetsulam (flumiclorac-pentyl), flumioxazin (flumioxazin), propyzamide (flumetofen), fluometuron (flumetouron), fluroxypyr, flumetofen (flumetofen), fluometuron (fluoxonofen), fluometuron (fluthiuron), flufenuron (fluxoam), fluproparine (fluoxypropane), flupyrronium (fluxonide), flupyruron (fludioxonil), fluridone (fluurone), fluroxypyr (fluxolone), fluroxypyr (fluxofenide), fluroxypyr (fluquinate), flupyr (flupyr), fluroxypyr (flufenuron), flupyr (flupyr), fluroxypyr (flufenim), fluroxypyr (fluroxypyr), fluroxypyr (fluroxypyr), glufosinate (fluroxypyr), glufosinate (fomide (fluroxypyr), glufosinate (fluroxypyr), glufosinate, fluroxypyridine ester (halauxifen-methyl), hexachloroacetone (hexachloroacetone), hexafluoro salt (hexaflurate), hexazinone (hexazinone), imazamox (imazamethabenz z), imazamox (imazamox), imazapic acid (imazapic), imazapyr (imazapyr), imazaquin (imazaquin), imazethapyr (imazapyr), imazosulfuron (imazosulfuron), indoxacin (indoofan), triazinethionam (indofluam), ioxynil (iodobonil), iodomethane (iodomethamine), iodosulfuron (iodosulfuron), iodosulfuron, ionspyrone, ioxynil (ioxynil), oxaziridine (isoproxylon), isoxaflutoluron (isoproxil), isoproxylon (isoproxylon), isoproxylon (isoproxylon, isop, lenacil, linuron (linuron), MAA, MAMA, MCPA esters and amines, metosulam (MCPA-thioethol), MCPB, 2-methyl-4-chloropropionic acid (mecoprop), mefenoxam (mecoprop-P), butadinol (medidinoerb), mefenacet (mefenacet), meflufenamide (meflulidide), metribuzin (mezoprazine), mesosulfuron (mesosulfuron), mesotrione (mesotrione), metam (metam), metamitron (metamitron), metazachlor (metazachlor), diether closulfuron (metazosulfuron), flurazon (fluflurazon), thiuron (thiometon), metosulron (metosulron), metosulam (metosulam), metosulam (metosulam), metosulam (metosulam, metosulam, metoxuron, metribuzin, metsuluron, molinate, heptanoylurea, texauron, monochloroacetic acid, chloroformic acid, chlorsulfuron, metoxuron, metosulon, norflurazon, MSMA, napropamide, naproxamide, napropamide-M, naproxamide, nebroderon, nicosulfuron, metoxuron, metosulam, metominosulf, metoclopramide, metosulam, metoclopramide, meto, pyraflufen-ethyl, parafluron (paraquat), paraquat (paraquat), bengal (pebulate), pelargonic acid (pelargonic acid), pendimethalin (pendimethalin), penoxsulam (penoxsulam), pentachlorophenol (pentachlor phenol), mechlorethamine (pentanochlor), pentoxazone (pentoxazone), fluazinam (perfluridone), pethoxamid (pethoxamid), pyranine (phenosalm), phenmedipham (phenmedipham-ethyl), fensulfuron (phenoxazone), phenylmercuric acetate (phenylmercuric acid), picloram (picolinate), flupyrafluazin (picolinafen), pinoxaden (phenoxazone), profenon (propaquin), proflavone (potassium ferrocyanide), propaquizamide (propaquinol), propaquinol (propaquinol), propaquizamide (propiconazole), propaquinol (propidium), propaquinol (potassium (propiconazole), propaquibencarb (potassium (propiconazole), propaquinol), propaquibencarb (propiconazole) (propaquibencarb-ethyl nicotinonitrile), cycloxydim (profoxdim), propazine (proglinazine), prohexadione-calcium (prohexadione), prometon (prometon), prometryn (prometryn), propafen (propchlorlor), propanil (propanil), propaquizafop (propaquizafop), prometryn (propazine), anil (propham), propisochlor (propachlor), prosulfuron (propaferon), azimson (propaferon), propaferon (propaferon), propafenib (propaferon), propaferon (propaferon), pyrazosulfuron (propaferon), benfurazone (propaferin), pyrithion (propaferon), pyriproxyfen (pyrazone-6-propyl-pyrazofos (propaferon), pyrifos (propiram (4-2-pyrazone (propaferon), pyrifos-2-pyrazone (propaferon), pyrifos (propaferon), pyribensulbenazol (propaferon), pyribenazol-2), pyribenazol (propaferon), pyribenazol-pyrazone (propaferon, pyridate (pyridazate), pyriftalid (pyriftalid), pyribenzoxim (pyriminobac), pyriproxyfen (pyrimisulfan), pyrithiobac (pyrithiobac-methyl), rochlorfenuron (pyroxasulfone), pyroxsulam (pyroxsulam), quinclorac (quinclorac), clorac (quinmerac), chloranil (quinophthalone), chlorambucil (quinonamide), quizalofop (quinozalofop), quizalofop (zalofop-P-ethyl), thiocyananilide (rhodinil), rimsulfuron (rimsulfuron), saflufenacil (saflufenacil), S-metolachlor (S-olachlor), tebufenfenthiuron (sodium sulfadiazine), sodium sulfadiazine (sodium sulfadiazine), sulfosate (sulfosate), sulfosulfuron (sulfosulfosulfuron), sulfuric acid (sulfosubcained), azasulfolane (sulfoglycopine), swep (swep), trichloroacetic acid (TCA), sulfluramid (tebutam), tebuthiuron (tebuthiuron), tefuryltrione (tefuryltrione), tembotrione (tembotrione), tepraloxydim (tepraloxydim), terfenadine (terbacil), terfenadine (terbutarb), terbutachlor (terbuchlor), metoxydim (terbuthyluron), terbuthylazine (terbuthyluron), teflubenzuron (teflubenzthiazone), thifenuron (tefluuron), thiflubenzthiazuron (thifenuron), thifensulfuron (thifenuron), thiopyrazone (thifenuron), thiopyrazone (thifluzone), thifenpyrazone (thifensulfuron-ethyl), thifensulfuron (thifensulfuron-methyl), thifensulfuron (thifensulfuron), thiopyrane (thifensulfuron), thifensulfuron (thiopyrane (thifensulfuron), thiopyrazone (thiopyrazone), thiopyrazone (thiocarb-ethyl (thiocarb), thiocarb-benzoxate (thiopyrazone), thiocarb-thiocarb (thiocarb), tribenuron (tribenuon), dichlorvos (tricamba), triclopyr esters and amines, dichloropetals (tridephane), metribuzin (trietazine), trifloxysulfuron (trifloxysulfuron), trifluralin (trifluralin), triflusulfuron (triflusulfuron), trifluorophenoxypropionic acid (trifop), trifusaxim (trifopsimide), trihydroxytriazines (trihydroxytriazine), triton (trimeturon), indanthrone (tripidan), sodar (tritac), triflusulfuron (tritosulfuron), jimson (vernollate) and xylulamide (xylacor).
The compounds and compositions of the present disclosure are generally used in combination with known herbicide safeners such as benoxacor (benoxacor), carbofuran (benthiocarb), brassinolide (brassinolide), cloquintocet (cloquintocet, e.g., mexyl), chloranil (cyclotrinil), vanillyl (daimuron), dichlormid (dichlormid), dicyclonone (dicyclonon), dimepiperate (dimepipe), disulfoton (disulfoton), fenchlorazole (fenchlorazole-ethyl), fenchlorazole (fenclorim), fluquine (flurazone), flumetoxime (fluxofenim), furilazole (furilazole), hypersensitins (propintens), isoxadifen-ethyl, mefenapyr-ethyl, mefenpyr-ethyl-191, mefenpyr-ethyl, mefenoxate (benzoxazole, mefenoxate (mefenoxapyr-ethyl), mefenoxate (benzoxazole), mefonamide (benzoxazole), mefonyl-60), and mefonyl-amide (naphaloxynil).
The compounds, compositions and methods described herein are useful for controlling undesirable vegetation in: glyphosate-tolerance-, glufosinate-tolerance-, dicamba-tolerance-, phenoxy auxin-tolerance-, pyridyloxyauxin-tolerance-, aryloxyphenoxypropionate-tolerance-, acetyl coa carboxylase (ACCase) inhibitor-tolerance-, imidazolinone-tolerance-, acetolactate synthase (ALS) inhibitor-tolerance-, 4-hydroxyphenyl-pyruvate dioxygenase (HPPD) inhibitor-tolerance-, protoporphyrinogen oxidase (PPO) inhibitor-tolerance-, triazine-tolerance-, and bromoxynil-tolerance-crop plants (such as, but not limited to, soybean, cotton, canola, rice, cereals, corn, turf, etc.), for example, in combination with glyphosate, glufosinate, dicamba, phenoxy auxins, pyridyloxy auxins, aryloxyphenoxypropionates, ACCase inhibitors, imidazolinones, ALS inhibitors, HPPD inhibitors, PPO inhibitors, triazines, and bromoxynil. The compositions and methods can be used to control undesirable vegetation in crops having multiple or stacked properties that confer tolerance to inhibitors of multiple chemical properties and/or multiple modes of action.
The compounds and compositions provided herein are also useful for controlling herbicide resistant or tolerant weeds. Exemplary resistant or tolerant weeds include, but are not limited to, types of organisms that are resistant or tolerant to: acetolactate synthase (ALS) inhibitors, photosystem II inhibitors, acetyl-CoA carboxylase (ACCase) inhibitors, synthetic auxins, photosystem I inhibitors, 5-enolpyruvylshikimate-3-phosphate synthase (EPSP) synthase inhibitors, microtubule assembly inhibitors, lipid synthesis inhibitors, protoporphyrinogen oxidase (PPO) inhibitors, carotenoid biosynthesis inhibitors, Very Long Chain Fatty Acid (VLCFA) inhibitors, Phytoene Dehydrogenase (PDS) inhibitors, glutamyl ammonia synthase inhibitors, 4-hydroxyphenyl-pyruvate dioxygenase (HPPD) inhibitors, mitosis inhibitors, cellulose biosynthesis inhibitors, herbicides with multiple modes of action such as snapdragon, and unclassified herbicides such as arylaminopropionic acids, difenzoquat, sodiosol and organic arsenicals. Exemplary resistant or tolerant weeds include, but are not limited to, biotypes resistant or tolerant to multiple herbicides, biotypes resistant or tolerant to multiple compound classes, biotypes resistant or tolerant to multiple herbicide modes of action
The embodiments and examples below are for illustrative purposes and are not intended to limit the scope of the claims. Other modifications, uses, or combinations relating to the compositions described herein will be apparent to those of ordinary skill in the art without departing from the spirit and scope of the claimed subject matter.
Synthesis of precursors
Preparation of 1: 4-amino-3, 6-dichloropyridine-2-carboxylic acid methyl ester (head A)
Prepared as described in Fields et al, WO 2001051468A 1.
Preparation of methyl 2: 4-amino-3, 6-dichloro-5-fluoropyridine-2-carboxylate (head B)
Prepared as described in Fields et al, Tetrahedron Letters2010,51, 79-81.
Preparation of 3:2, 6-dichloro-5-methoxy-4-vinylpyrimidine
To a solution of commercial 2, 6-dichloro-5-methoxypyrimidine (100g, 0.55 mole (mol)) in anhydrous tetrahydrofuran was added dropwise a1 molar equivalent (M) concentration of vinyl magnesium bromide/tetrahydrofuran solvent (124g,0.94mol) over one hour (h) at room temperature. The mixture was then stirred at room temperature for 4 h. The excess grignard reagent was quenched by the addition of acetone (200 milliliters (mL)) while maintaining the temperature of the mixture below 20 ℃. Immediately thereafter, 2, 3-dichloro-5, 6-dicyano-p-benzoquinone (DDQ; 151g,0.67mol) was added and stirred overnight. A yellow solid precipitated. The solid was filtered and washed with ethyl acetate (500 mL). The filtrate was concentrated under reduced pressure and the resulting crude compound was diluted with ethyl acetate (2 liters (L)). The resulting undissolved black semi-solid was isolated by filtration through ethyl acetate. It was further concentrated under reduced pressure to give a crude compound, which was purified by column chromatography. Eluting the compound with a 5% to 10% ethyl acetate/hexane mixture to give the title compound (70g, 60%) mp 60-61 ℃;1H NMR(CDCl3)δ3.99(s,3H),5.85(d,1H),6.75(d,1H),6.95(dd,1H)。
preparation of 4:2, 6-dichloro-5-methoxy-pyrimidine-4-carbaldehyde
A solution of 2, 6-dichloro-5-methoxy-4-vinylpyrimidine (50g,0.24mol) in dichloromethane methanol (4:1,2L) was cooled to-78 ℃. Ozone gas was bubbled through for 5 h. The reaction was quenched with dimethyl sulfide (50 mL). The mixture was slowly warmed to room temperature and concentrated under reduced pressure at 40 ℃ to give the title compound (50.5g, 100%); high performance liquid chromatography (HPLC; 85% acetonitrile, buffered with 0.1% volume/volume (v/v) acetic acid).
Preparation of 5:2, 6-dichloro-5-methoxy-pyrimidine-4-carboxylic acid methyl ester
A solution of 2, 6-dichloro-5-methoxy-pyrimidine-4-carbaldehyde (50g,0.24mol) in methanol (1L) and water (60mL) was prepared. Sodium bicarbonate (400g) was added to the solution. To the pyrimidine solution was added dropwise, with stirring, a solution of 2M bromine (192g,1.2mol) in methanol/water (600mL,9:1) at 0 ℃ over 45 minutes (min). Stirring was continued at the same temperature for 1 h. After that, the mixture was stirred at room temperature for 4 h. The reaction mixture was then poured onto a mixture of crushed ice (2L), sodium bisulfite (50g) and sodium chloride (NaCl; 200g) while stirring. The product was extracted with ethyl acetate (1L x 2), and the combined organic layers were dried over sodium sulfate and filtered. Evaporation of the solvent under reduced pressure yielded a thick mass which solidified upon standing for a long period of time to give the title compound (50.8g, 87%); ESIMS M/z238([ M + H ]]+)。
Preparation of 6: 6-amino-2-chloro-5-methoxy-pyrimidine-4-carboxylic acid methyl ester (head C)
A solution of methyl 2, 6-dichloro-5-methoxy-pyrimidine-4-carboxylate (25g,0.1mol) and dimethyl sulfoxide (DMSO) was prepared. To this solution is added ammonia (2 equivalents) at 0-5 deg.CDMSO solution. The mixture was stirred at the same temperature of 0-5 ℃ for 10 to 15 minutes. After that, the mixture was diluted with ethyl acetate, and the resulting solid was filtered off. The ethyl acetate filtrate was washed with brine solution and dried over sodium sulfate. After concentration, the crude product was obtained. The crude product was stirred in a minimal amount of ethyl acetate and filtered to give the pure compound. More pure compound was obtained from the filtrate, which was purified by flash chromatography after concentration. This gave the title compound (11g, 50%) mp 158 ℃;1H NMR(DMSO-d6)δ3.71(s,3H),3.86(s,3H),7.65(brs,1H),8.01(brs,1H)。
preparation of 7: 4-amino-3, 6-dichloro-5-iodopyridine-2-carboxylic acid methyl ester
Methyl 4-amino-3, 6-dichloropyridine-2-carboxylate (10.0g,45.2mmol), periodic acid (3.93g,17.2 mmol) and iodine (11.44g,45.1mmol) were dissolved in methanol (30mL) and stirred at 60 ℃ under reflux for 27 h. The reaction mixture was concentrated, diluted with ether and washed twice with saturated aqueous sodium bisulfite solution. The aqueous layer was extracted once with ether and the combined organic layers were dried over anhydrous sodium sulfate. The product was concentrated and purified by flash chromatography (silica gel, 0-50% ethyl acetate/hexanes) to give the title compound as a pale yellow solid (12.44g, 79%): mp 130.0-131.5 ℃;1H NMR(400MHz,CDCl3)δ5.56(s,2H),3.97(s,3H)；13C NMR(101MHz,CDCl3)δ163.80,153.00,152.75,145.63,112.12,83.91,53.21；EIMS m/z 346。
preparation of 8: 4-amino-3, 6-dichloro-5-methylpyridine-2-carboxylic acid methyl ester (head D)
A mixture of methyl 4-amino-3, 6-dichloro-5-iodopyridine-2-carboxylate (8.1g,23.4mmol), tetramethylstannane (8.35g,46.7mmol) and bis (triphenylphosphine) palladium (II) dichloride (2.5g,3.5mmol) in 1, 2-dichloroethane (40mL) was dissolved in BiIrradiation was carried out in an otage Initiator microwave oven at 120 ℃ for 30min, monitored externally from the side with an Infrared (IR) -temperature sensor. The reaction mixture was directly loaded onto a silica gel column and purified by flash chromatography (silica gel, 0-50% ethyl acetate/hexanes) to give the title compound as an orange solid (4.53g, 83%): mp 133-;1H NMR(400MHz,CDCl3)δ4.92(s,2H),3.96(s,3H),2.29(s,3H)；13C NMR(101MHz,CDCl3)δ164.34,150.24,148.69,143.94,117.01,114.60,53.02,14.40；ESIMS m/z 236([M+H]+),234([M-H]-).
preparation of 9: 6-amino-2, 5-dichloropyrimidine-4-carboxylic acid methyl ester (head E)
Prepared as described in Epp et al, WO 2007082076a 1.
Preparation of 10: 4-amino-6-chloro-5-fluoro-3-methoxypyridine-2-carboxylic acid methyl ester (head F)
Prepared as described in Epp et al, WO 2013003740a 1.
Preparation of 11: 4-amino-6-chloro-5-fluoro-3-vinylpyridine-2-carboxylic acid methyl ester (head G)
Methyl 4-amino-6-chloro-5-fluoro-3-iodopyridine-2-carboxylate (7.05g,21.33mmol, prepared as described in Epp et al, WO 2013003740A 1) and vinyltri-n-butyltin (7.52mL,
25.6mmol) was suspended in 1, 2-dichloroethane (71.1mL) and the mixture was degassed with argon for 10 min. Bis (triphenylphosphine) palladium (II) dichloride (1.497g,2.133mmol) was then added and the reaction mixture was stirred at 70 ℃ overnight (clear orange solution). The reaction was monitored by gas chromatography-mass spectrometry (GC-MS). After 20h, the reaction mixture was concentrated and adsorbedOn kieselguhr and by column chromatography (SiO)2Hexane/ethyl acetate gradient) to give the title compound as a light brown solid (3.23g, 65.7%) mp 99-100 ℃;1H NMR(400MHz,CDCl3)δ6.87(dd,J＝18.1,11.6Hz,1H),5.72(dd,J＝11.5,1.3Hz,1H),5.52(dd,J＝18.2,1.3Hz,1H),4.79(s,2H),3.91(s,3H)；19F NMR(376MHz,CDCl3)δ-138.79(s)；EIMS m/z230。
preparation of 12: 4-amino-3, 5, 6-trichloropyridine-2-carboxylic acid methyl ester (head H)
Prepared as described in Finkelstein et al, WO 2006062979A 1.
Preparation of 13: 4-amino-6-bromo-3-chloro-5-fluoropyridine-2-carboxylic acid methyl ester (head I)
Prepared as described in Arndt et al, US 20120190857a 1.
Preparation of 14: 4-amino-3-chloro-5-fluoro-6- (trimethylstannyl) pyridine-2-carboxylic acid methyl ester (head J)
4-amino-6-bromo-3-chloro-5-fluoropyridine-2-carboxylic acid methyl ester (500mg,1.8mmol),1,1,1,2,2, 2-hexamethyldisilazane (580mg,1.8mmol) and bis (triphenylphosphine) -palladium (II) chloride (120mg,0.18mmol) were combined in anhydrous dioxane (6mL), sparged with a stream of nitrogen for 10min, then heated to 80 ℃ for 2 h. The cooled mixture was stirred with ethyl acetate (25mL) and saturated NaCl (25mL) for 15 min. The organic phase is separated off, filtered through celite and dried (Na)2SO4) And evaporated. The residue was taken up in ethyl acetate (4mL), stirred and treated with hexane (15mL) portionwise. The milky white solution was decanted from the resulting solid, filtered through glass wool and evaporated to give the title compoundIt was an off-white solid (660mg, 100%):1H NMR(400MHz,CDCl3)δ4.63(d,J＝29.1Hz,1H),3.97(s,2H),0.39(s,4H)；19F NMR(376MHz,CDCl3)δ-130.28；EIMS m/z 366。
preparation of 15: 4-acetamido-3-chloro-6- (trimethylstannyl) -pyridine-2-carboxylic acid methyl ester (head K)
Prepared as described in Balko et al, WO 2003011853 a 1.
Preparation of 16: 4-acetamido-3, 6-dichloropyridine-2-carboxylic acid methyl ester (head L)
Prepared as described in Fields et al, WO 2001051468A 1.
Preparation of 17: 4-amino-3-chloro-6-iodopyridine-2-carboxylic acid methyl ester (head M)
Prepared as described in Balko et al, WO 2007082098 a 2.
Preparation of 18: 4-acetamido-3-chloro-6-iodopyridine-2-carboxylic acid methyl ester (head N)
Prepared as described in Balko et al, WO 2007082098 a 2.
Preparation of 4-amino-6-bromo-3, 5-difluoropyridine-2-carboxylic acid methyl ester (head O)
Prepared as described in Fields et al, WO 2001051468A 1.
Preparation of 20: 6-amino-2-chloro-5-vinylpyrimidine-4-carboxylic acid methyl ester (head P)
Prepared as described in Epp et al, US 20090088322.
Preparation of 21:2,2, 5-trifluoro-6-iodobenzo [ d ] [1,3] dioxole
2,2, 6-trifluorobenzo [ d ]][1,3]Dioxole-5-amine (8.0g,42mmol) was added to concentrated hydrochloric acid (concentrated HCl; 200mL), cooled to 5 deg.C, stirred vigorously and treated with a solution of sodium nitrite (4.3g,63mmol) in water (10mL) dropwise over 10 min. Stirring was continued at 5-10 ℃ for 30min and the mixture was carefully poured into a solution of sodium iodide (19g,130mmol) in water (200mL) with rapid stirring with dichloromethane (100 mL). After 20min, the mixture was washed with 10% sodium bisulfite solution (NaHSO)3(ii) a 20mL) and stirred for another 20 min. The phases were separated and the aqueous phase was extracted with dichloromethane (75 mL). The combined organic phases were washed with saturated NaCl (30mL) and dried (Na)2SO4) And evaporated. The residue was purified by chromatography on silica gel with hexane to give the title compound as a clear liquid (6g, 51%):1H NMR(400MHz,CDCl3)δ7.41(d,J＝5.0Hz,1H),6.90(d,J＝6.6Hz,1H)；19F NMR(376MHz,CDCl3)δ-49.63(s),-95.24(s)；EIMS m/z 302.
preparation of 22:4,4,5, 5-tetramethyl-2- (2,2, 6-trifluorobenzo [ d ] [1,3] dioxol-5-yl) -1,3, 2-dioxaborolan
2,2, 5-trifluoro-6-iodobenzo [ d][1,3]The dioxole (1.0g,3.3mmol) was dissolved in anhydrous tetrahydrofuran (10mL), cooled to 5 ℃ and treated with a solution of isopropyl magnesium chloride-lithium chloride complex (1.3M; 2.7mL,3.5 mmol). Mixture in 5-Stir at 15 ℃ for 1h, treat with 2-isopropoxy-4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolane (720 μ L,660mg,3.5mmol) and stir for 20 min. The reaction was carried out by adding saturated ammonium chloride (NH)4Cl; 5mL) and mixed with ethyl acetate (20mL) and saturated NaCl (10 mL). The separated organic phase was washed with saturated NaCl (10mL) and dried (Na)2SO4) And evaporated to give the title compound as a white solid (1.0g, 100%):1H NMR(400MHz,CDCl3)δ7.37(d,J＝4.3Hz,1H),6.81(d,J＝7.7Hz,1H),1.35(s,12H)；19F NMR(376MHz,CDCl3)δ-49.96(s),-104.21(s))；EIMS m/z 302.
preparation of 23:2, 2, 5-trifluoro-4-iodobenzo [ d ] [1,3] dioxole
Sec-butyllithium (1.4M in cyclohexane; 6.1mL,8.5mmol) was added to anhydrous tetrahydrofuran (15mL) which had been pre-cooled to-40 ℃. The solution was cooled to-75 ℃ and then treated with 2,2, 5-trifluorobenzo [ d ]][1,3]Dioxole (1.5g,8.5mmol) was treated and stirred at this temperature for 90 min. The solution was quickly transferred via a catheter to a stirred solution of iodine (2.8g,11mmol) in tetrahydrofuran (25mL) and the mixture was cooled to-75 ℃. The mixture was stirred for 1h, during which time the temperature rose to-20 ℃. The reaction was carried out by adding saturated NH4Cl (10mL) quenched and then with 10% NaHSO3(15mL) and ethyl acetate (30 mL). The organic phase was washed with saturated NaCl (10mL) and dried (Na)2SO4) And evaporated. The material was purified by flash chromatography with hexanes to give the title compound as a clear liquid (1.5g, 58%):1H NMR(400MHz,CDCl3)δ6.97(dd,J＝8.8,4.0Hz,1H),6.81(dd,J＝11.7,5.4Hz,1H)；19F NMR(376MHz,CDCl3)δ-49.06,-103.15；EIMS m/z 302.
preparation of 24: 5-bromo-4-chloro-2, 2-difluorobenzo [ d ] [1,3] dioxole
2,2,6, 6-tetramethylpiperidine (2.1mL,1.8g,12mmol) was dissolved in anhydrous tetrahydrofuran (15mL), cooled to-75 deg.C and treated with n-butyllithium (n-BuLi, 2.5M; 4.8mL,12mmol), and the mixture was stirred at-75 deg.C for 30 min. Addition of 5-bromo-2, 2-difluorobenzo [ d ]][1,3]Dioxole (2.0g,8.4mmol) and the mixture stirred at-75 ℃ for 2 h. 1,1, 2-trichloro-1, 2, 2-trifluoroethane (2.4mL,3.8g,20mmol) was added and stirring continued for 1.5 h. Addition of saturated NH4Cl (10mL) and the mixture was shaken with diethyl ether (30mL) and water (20 mL). The ether phase was washed with saturated NaCl (10mL) and dried (Na)2SO4) And evaporated in vacuo. The residue was purified by chromatography on silica gel with hexane and then repurified by reverse phase HPLC using 75% acetonitrile to give the title compound as a clear liquid (640mg, 28%):1H NMR(400MHz,CDCl3)δ7.38(dd,J＝8.5,5.1Hz,1H),6.90(dd,J＝9.0,4.7Hz,1H)；EIMS m/z 332.
preparation of 25:2- (4-chloro-2, 2-difluorobenzo [ d ] [1,3] dioxol-5-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan
5-bromo-4-chloro-2, 2-difluorobenzo [ d][1,3]The dioxole (1.0g,3.7mmol) was dissolved in anhydrous tetrahydrofuran (12mL), cooled to-20-30 ℃ and treated with a solution of isopropyl magnesium chloride-lithium chloride complex (1.3M; 3.1mL,4.1mmol) in portions. After 90min at-20 to 0 deg.C, 2-isopropoxy-4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolane (830 μ L,750mg,4.1mmol) was added and stirring continued at 0-20 deg.C for 90 min. The reaction was carried out by adding saturated NH4Cl (10mL) was quenched, and the mixture was extracted with ethyl acetate (30 mL). The aqueous phase was extracted again with ethyl acetate (15mL) and the combined organic phases were washed with saturated NaCl (15mL) and dried (Na)2SO4) And evaporated to give the title compound as a white solid (1.2g, ca.100%):1H NMR(400MHz,CDCl3)δ7.52(d,J＝8.1Hz,1H),6.99–6.94(m,1H),1.36(s,12H)；19F NMR(376MHz,CDCl3)δ-49.62(s)；EIMS m/z 318.
preparation of 26: 4-fluorobenzo [ d ] [1,3] dioxol-2-thione
3-fluorobenzene-1, 2-diol (5.0g,39mmol) and thiophosgene (3.3mL,5.0g,42mmol) were mixed in chloroform (50mL), cooled to 10 deg.C and treated with sodium hydroxide (10% solution; 36g,90mmol) dropwise over 30min with vigorous stirring. After stirring at ambient temperature for 2h, the chloroform was removed in vacuo and the solid formed was collected by filtration and washed with water. The solid was dissolved in ethyl acetate (100mL), the solution was washed with water (30mL) and saturated NaCl (30mL), and dried (Na)2SO4) And evaporated. The crude solid was purified by chromatography on silica gel with 0-30% ethyl acetate-hexanes to give the title compound (1.5g, 77%): mp 58-59 ℃;1H NMR(400MHz,CDCl3)δ7.28(m,1H),7.12(m,2H)；19F NMR(376MHz,CDCl3)δ-131.32；EIMS m/z 170.
preparation of 27: 5-bromo-2, 2, 4-trifluorobenzo [ d ] [1,3] dioxole
4-Fluorobenzo [ d ]][1,3]Dioxole-2-thione (4.8g,28mmol) was dissolved in dichloromethane (75mL), cooled to-30 deg.C and treated with Hydrogen Fluoride (HF) -pyridine (70 weight percent (wt%) solution; 18mL,20g,140 mmol). 1, 3-dibromo-5, 5-dimethylimidazolidine-2, 4-dione (9.7g,34mmol) was added in portions for 30 min. The mixture was stirred at-20 to-30 ℃ for 2h and then with 5% NaHSO3The solution (20mL) was stirred for 10 min. The organic phase was separated and dried (Na)2SO4) And dichloromethane was carefully removed by distillation at atmospheric pressure through a 200 millimeter (mm) Vigreux column. When most of the methylene chloride had been withdrawn overhead, the pressure was reduced to about 150 millimeters of mercury (mmHg). Distillation was continued and fractions boiling at 45-55 ℃ were collected to give the title compound as a clear liquid (3.2g, 45%):1H NMR(400MHz,CDCl3)δ7.28(dd,J＝8.6,6.2Hz,1H),6.81(dd,J＝8.6,1.3Hz,1H)；19F NMR(376MHz,CDCl3)δ-49.25(s),-126.72(s)；EIMS m/z 254.
preparation of 28:4,4,5, 5-tetramethyl-2- (2,2, 4-trifluorobenzo [ d ] [1,3] dioxol-5-yl) -1,3, 2-dioxaborolan
5-bromo-2, 2, 4-trifluorobenzo [ d][1,3]The dioxole (4.0g,16mmol) was dissolved in 20mL anhydrous tetrahydrofuran, cooled to-20 ℃ and treated with isopropyl magnesium chloride-lithium chloride complex (1.3M in tetrahydrofuran; 13mL,17mmol) in portions over 10 min. After stirring for 30min at-20 to 0 deg.C, 2-isopropoxy-4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolane (3.1g,17mmol) was added and stirring continued at 10-15 deg.C for 1 h. In the presence of saturated NH4After treatment with Cl solution (10mL), the mixture was diluted with ethyl acetate (50 mL). The organic phase was washed with saturated NaCl (15mL) and dried (Na)2SO4) And evaporated to give the title compound as a brown solid (3.5g, 72%):1H NMR(400MHz,CDCl3)δ7.46(d,J＝26.5Hz,1H),6.90(dd,J＝18.5,4.5Hz,1H),1.35(s,12H)；19F NMR(376MHz,CDCl3)δ-49.70(s),-126.00(s)；EIMS m/z 302.
preparation 29- (2, 2-difluoro-4-methylbenzo [ d ] [1,3] dioxol-5-yl) -5, 5-dimethyl-1, 3, 2-dioxaborolan
5-bromo-2, 2-difluoro-4-methylbenzo [ d][1,3]Dioxoles (prepared as described in Nakamura, Yuji; Mitani, Shigeru; Tsukuda, Shintar, WO 2007069777; 1.0g,4.0mmol) were mixed with 1,1 '-bis (diphenylphosphino) ferrocene dichloro-palladium (II) complex and dichloromethane (330mg,0.40mmol), potassium acetate (1.2g,12mmol) and 5,5,5',5 '-tetramethyl-2, 2' -bis (1,3, 2-dioxaborolane) (950mg,4.2mmol) in anhydrous DMSO (10mL), heated to 80 ℃ for 4h and then allowed to stand overnight. The mixture is mixed with ethyl acetateThe ester (50mL) and water (30mL) were shaken together. The organic phase is washed with water, with saturated NaCl and dried (Na)2SO4) And evaporated. The residue was purified by chromatography on silica gel with 5-50% ethyl acetate-hexanes to give the title compound (540mg, 48%):1H NMR(400MHz,CDCl3)δ7.55–7.48(m,1H),6.88–6.79(m,1H),5.51–5.47(m,1H),3.83–3.64(m,5H),1.02(d,J＝4.9Hz,7H)；19F NMR(376MHz,CDCl3)δ-49.91(d,J＝7.1Hz)；EIMS m/z 284.
preparation of 30: 1-bromo-2- (2-bromo-1, 1,2, 2-tetrafluoroethoxy) -3-fluorobenzene
2-bromo-6-fluorophenol (10.2g,53mmol), potassium carbonate (7.3g,53mmol),1, 2-dibromo-tetrafluoroethane (21g,80mmol) and 1-butanethiol (1.1g,12mmol) were mixed in dry N, N-dimethylformamide (75mL) and heated to 50 ℃ in a stirred autoclave reactor. After cooling, the contents were mixed with 1.0M sodium hydroxide (NaOH; 100mL) and extracted three times with diethyl ether (80mL portions). The combined extracts were washed with water (15mL), 2.0M NaOH (45mL), and dried (Na)2SO4) And concentrated by rotary evaporation. This material was purified by silica gel chromatography eluting with hexanes to give the title compound as a clear liquid (15g, 76%):1H NMR(400MHz,CDCl3)δ7.48–7.39(m,1H),7.22–7.14(m,2H)；EIMS m/z 368.
preparation of 31:2,2,3,3, 7-Pentafluoro-2, 3-dihydrobenzofuran
1-bromo-2- (2-bromo-1, 1,2, 2-tetrafluoroethoxy) -3-fluorobenzene (14g,38mmol), copper powder (12.2g,192mmol) and 2,2' -bipyridine (610mg,3.9mmol) were mixed in anhydrous DMSO (55mL) and heated to 150 ℃ for 1.5 h. Vacuum (about 20mm) was applied to the reactor and the distillate was removed overhead until the kettle temperature reached 100 ℃. The distillate containing the product and DMSO was diluted with 1:1 diethylether-pentane (30mL) and washed with water (3X 5mL), dried, and at 1 atmosphere(atm) distillation through a 200mm Vigreux column to remove most of the solvent, application of vacuum (about 20mmHg) and collection of fractions at 60-65 ℃ gave the title compound as a clear liquid (5.1g, 64%):1H NMR(400MHz,CDCl3)δ7.40–7.31(m,2H),7.25–7.17(m,1H)；EIMS m/z 210.
preparation of 32:2,2,3,3, 7-Pentafluoro-6-iodo-2, 3-dihydrobenzofuran
2,2,3,3, 7-Pentafluoro-2, 3-dihydrobenzofuran (500mg,2.4mmol) was added in portions to a-70 ℃ solution of Lithium Diisopropylamide (LDA) prepared from dipropylamine (380mg,3.8mmol) and 2.5M n-BuLi (1.4mL,3.6mmol) in anhydrous tetrahydrofuran (7 mL). After 40min at-70 deg.C, a solution of iodine (1.0g,4.0mmol) in tetrahydrofuran (5mL) was added over 15 min. After 20min at-70 ℃ the mixture was warmed to-20 ℃ and saturated NH was added4And (4) quenching by Cl. The mixture is made up by using 10% NaHSO3(15mL), stirred for 10min and extracted twice with diethyl ether (15mL portions). The combined extracts were dried (Na)2SO4) And evaporated. The residue was purified by reverse phase HPLC eluting with 85% acetonitrile-water to give the title compound (200mg, 25%):1H NMR(400MHz,CDCl3)δ7.25(dd,J＝8.1,4.8Hz,1H),6.63(dd,J＝8.0,1.1Hz,1H),4.13(s,3H)；EIMS m/z 336.
preparation of 33-bromo-2, 2-difluoro-4-methoxybenzo [ d ] [1,3] dioxole
A solution of LDA was prepared from diisopropylamine (4.2g,41mmol) and n-BuLi (2.5M; 15.4mL,38mmol) in dry tetrahydrofuran (100 mL). Cooling the solution to-70 ℃ and reacting with 5-bromo-2, 2-difluorobenzo [ d ]][1,3]The dioxole (7.0g,30mmol) was treated in portions. After 2h at-70 ℃ trimethyl borate (4.3g,41mmol) was added in portions, stirred at-70 ℃ for 1.5h and then warmed to ambient temperature overnight. The mixture was cooled to-30 to-40 ℃ and carefully treated with 28% peracetic acidAnd (6) processing. Stirring the mixture at-30 deg.C for 30min, warming to 5-10 deg.C, and adding 10% NaHSO3The solution was treated (100mL) and stirred for 20 min. The mixture was acidified by addition of 6M HCl and diluted with saturated NaCl solution (75 mL). The mixture was extracted with ethyl acetate (2 × 100mL) and the combined extracts were washed with saturated NaCl (50mL), dried (Na)2SO4) And rotary evaporation. The crude phenol was dissolved in anhydrous DMSO (50mL), treated with 95% NaH (750mg,30mmol) and stirred for 30min to give a clear solution. Methyl iodide (5.0g,35mmol) was added in portions and the mixture was stirred at 20 ℃ for 20 h. An additional 200mg NaH was added and stirring continued for an additional 1 h. The mixture was poured into water (100mL) and extracted with diethyl ether (2 × 75 mL). The combined extracts were washed with water (2 × 20mL), with saturated NaCl (20mL), and dried (Na)2SO4) And evaporated. The crude material was purified by chromatography on silica gel with a 0-20% ethyl acetate-hexanes gradient to give the title compound as a clear liquid (2.5g, 31%):1H NMR(400MHz,CDCl3)δ7.25(d,J＝8.5Hz,1H),6.63(d,J＝8.5Hz,1H),4.13(s,3H)；19F NMR(376MHz,CDCl3)δ-49.66；EIMS m/z 266.
preparation 34- (2, 2-difluoro-4-methoxybenzo [ d ] [1,3] dioxol-5-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan
2- (2, 2-difluoro-4-methoxybenzo [ d ]][1,3]Dioxol-5-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (1.1g,4.1mmol) was dissolved in anhydrous tetrahydrofuran (10mL), cooled to 0-5 ℃ and purified with isopropyl magnesium chloride-lithium chloride solution (1.3M; 3.5mL,4.5mmol) were treated in portions. The mixture was stirred at 0-5 ℃ for 1h, treated with 2-isopropoxy-4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolane (840mg,4.5mmol) and stirred at 20 ℃ for 90 min. The mixture is saturated with NH4Treated with Cl (5mL) and stirred for 10 min. The mixture was extracted with ethyl acetate (30mL) and the extract was washed with saturated NaCl (10mL), dried (Na)2SO4) And rotary evaporation gave the title compound as an oil which solidified on standing (1.2g, 93%):1H NMR(400MHz,CDCl3)δ7.42(d,J＝8.0Hz,1H),6.72(d,J＝8.0Hz,1H),4.06(s,3H),1.34(s,12H)；19F NMR(376MHz,CDCl3)δ-50.09；EIMS m/z 314.
Preparation of 35:3, 5-difluorobenzene-1, 2-diol
3, 5-difluoro-2-methoxyphenol (1.0g,6.3mmol, e.g., Jones, Lyn H.; Randall, Amy; Barba, Oscar; Selby, Matthew D., Organic&Biomolecular Chemistry 2007,5, 3431-3433) was dissolved in anhydrous dichloromethane (11mL), cooled to-20-30 ℃ and treated with boron tribromide (BBr) in dichloromethane3) Solution (1.0M; 13mL,13mmol) were treated in portions. The cooling bath was removed and the mixture was stirred at 20 ℃ for 20 h. The mixture was cooled to-30 ℃, treated with water (3mL) in portions and then warmed to 20 ℃.6M HCl (10mL) and ethyl acetate (30mL) were added and the mixture was stirred for 20min to give two clear phases. The aqueous phase was extracted with ethyl acetate (20mL) and the combined organic phases were washed with saturated NaCl (10mL), dried (Na)2SO4) And rotary evaporation gave the title compound as an oil which solidified on standing (720mg, 78%):1H NMR(400MHz,CDCl3)δ6.51(ddd,J＝9.5,2.8,2.1Hz,1H),6.45(ddd,J＝10.3,8.7,2.9Hz,1H),5.71(s,1H),5.06(s,1H)；19F NMR(376MHz,CDCl3)δ-119.56,-136.16；EIMS m/z 146.
preparation of 36:4, 6-difluorobenzo [ d ] [1,3] dioxol-2-thione
3, 5-difluorobenzene-1, 2-diol (670mg,4.6mmol) was stirred in anhydrous chloroform (8mL), treated with thiophosgene (580mg,5.0mmol), cooled to 5-10 deg.C, and treated with 10% NaOH solution (4.2g,11mmol) dropwise over 45 min. After 30min, volatiles were removed by rotary evaporation and the remaining solid was collected by filtration and washed with water. The solid was dissolved in ethyl acetate (30)mL), wash with water (2 × 20mL), wash with saturated NaCl (1 × 10mL), dry (Na)2SO4) And evaporated. The residue was purified by chromatography on silica gel with a gradient of 0-20% ethyl acetate-hexane to give the title compound (710mg, 82%):1H NMR(400MHz,CDCl3)δ6.95(ddd,J＝6.8,2.3,1.4Hz,1H),6.89(td,J＝9.5,2.3Hz,1H)；19F NMR(376MHz,CDCl3)δ-109.99(s),-127.93(s)；EIMS m/z 188.
preparation 37: 2,2,4, 6-tetrafluorobenzo [ d ] [1,3] dioxoles
4, 6-difluorobenzo [ d ]][1,3]Dioxole-2-thione (9.0g,48mmol) was dissolved in anhydrous dichloromethane (100mL) in a polyethylene bottle, cooled to-30 to-35 ℃ and treated with 70% pyridine-hydrogen fluoride complex (68g,480 mmol). The mixture was kept at this temperature and treated with N-iodosuccinimide (32g,144mmol) in portions over 1 h. The mixture was stirred for 3h while warming to 5 ℃. After cooling to-30 deg.C, the mixture was diluted with 20% NaHSO3(75mL) was treated in portions with vigorous stirring. The mixture was filtered through celite to remove dark solids. The separated aqueous phase was extracted with dichloromethane (75mL) and the combined extracts were washed with water (2x 50mL) and saturated NaCl (1x 50 mL). The solvent was removed by atmospheric distillation through a 300mm Vigreux column. The residue was distilled at 310mmHg and fractions were collected at 40-45 ℃ containing the title compound as a clear liquid (1.3g, 14%):1H NMR(400MHz,CDCl3)δ6.71(m,1H),6.68(m,1H)；19F NMR(376MHz,CDCl3)δ-49.47,-113.41,-131.95；EIMS m/z 194.
preparation of 38:2,2,4, 6-tetrafluoro-5-iodobenzo [ d ] [1,3] dioxole
2,2,4, 6-tetrafluorobenzo [ d ]][1,3]Dioxole (500mg,2.6mmol) was dissolved in anhydrous tetrahydrofuran (7mL) and cooled toTreated with sec-BuLi (1.3M; 2.1mL,2.7mmol) dropwise at-70 ℃ and stirred for 1 h. The mixture was treated with a solution of iodine (1.1g,4.4mmol) in tetrahydrofuran (5mL) dropwise over 10 min. After 2h at-70 ℃ the mixture was saturated with NH4Cl treatment, extraction with diethyl ether, drying (Na)2SO4) And evaporated. The material was purified by reverse phase HPLC with 85% acetonitrile-water to give the title compound (250 mg; 30%):1H NMR(400MHz,CDCl3)δ6.80–6.77(d,J＝8.7Hz,1H),6.77–6.75(d,J＝8.7Hz,1H)；19F NMR(376MHz,CDCl3)δ-48.72,-99.73,-132.62；EIMS m/z 320.
preparation of 39:4, 6-difluorobenzo [ d ] [1,3] dioxoles
3, 5-difluorobenzene-1, 2-diol (10g,69mmol) was dissolved in anhydrous N, N-dimethylformamide (100mL), treated with cesium carbonate (56g,170mmol) and stirred at 20 ℃ for 30 min. Bromochloromethane (12g,90mmol) was added and the mixture was heated and stirred at 60 ℃ for 19 h. After cooling, the mixture was shaken with water (100mL) and diethyl ether (100 mL). The aqueous phase was extracted again with diethyl ether (50 mL). The combined extracts were washed with water (2 × 20mL), with saturated NaCl (1 × 10mL) and dried (Na)2SO4). Most of the ether was removed by atmospheric distillation through a 300mm Vigreux column. The pressure was reduced to 75mmHg and the product distilled at 70-90 ℃ to give the title compound as a thick oil (3.0g, 28%):1H NMR(400MHz,CDCl3)δ6.45(m,1H),6.42(d,J＝2.4Hz,1H),6.39(d,J＝2.4Hz,1H),6.02(s,2H)；19F NMR(376MHz,CDCl3)δ-117.99,-135.90；EIMS m/z 158.
preparation of 40:4, 6-difluoro-5-iodobenzo [ d ] [1,3] dioxole
4, 6-difluorobenzo [ d ]][1,3]Dioxole (300mg,1.9mmol) and N-iodosuccinimide (640mg,2.9mmol) were mixed in anhydrousAcetonitrile (5mL), treated with trifluoroacetic acid (430mg,3.8mmol) and stirred for 20 h. Mixture with NaHSO3The solution (100mg in 2mL water) was stirred together and then shaken with ethyl acetate (30mL) and saturated NaCl (5 mL). The organic phase was washed with saturated NaCl (5mL) and dried (Na)2SO4) And evaporated. This material was purified by chromatography on silica gel with a gradient of 0-5% ethyl acetate-hexanes to give the title compound as a white solid (410mg, 76%): mp 65-66 ℃.1H NMR(400MHz,CDCl3)δ6.54(dd,J＝6.9,1.6Hz,1H),6.07(s,2H)；19F NMR(376MHz,CDCl3)δ-99.31,-117.98；EIMS m/z 284.
Preparation of 41:4,4,5, 5-tetramethyl-2- (2-methylbenzo [ d ] [1,3] dioxol-5-yl) -1,3, 2-dioxaborolane
5-bromo-2-methylbenzo [ d][1,3]Dioxoles (1.0g,4.7mmol, as prepared as described in Matyus, Peter; Magyar, Kalman; Pihlavista, Marjo; Gyires, Klara; Haider, Norbert; Wang, Yinghua; Woda, Patrick; Dunkel, Petra; Toth-Sarudy, Eva; Turos, Gyoergy, WO 2010029379) were dissolved in anhydrous tetrahydrofuran (10mL), cooled to-70 ℃ and treated with n-BuLi (2.5M; 2.1mL,4.7mmol) over 5 min. After 1h, 2-isopropoxy-4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolane (1.1g,6.0mmol) was added and the mixture was stirred at-70 to-30 ℃ for 90 min. Addition of saturated NH4After Cl (5mL), the mixture was shaken with ethyl acetate (40mL) and saturated NaCl (10mL) and dried (Na)2SO4) And evaporated. The material was purified by chromatography on silica gel with a 0-30% ethyl acetate-hexanes gradient to give the title compound (730mg, 59%):1H NMR(400MHz,CDCl3)δ7.33(dd,J＝7.7,1.1Hz,1H),7.18(d,J＝0.9Hz,1H),6.77(d,J＝7.8Hz,1H),6.25(q,J＝5.0Hz,1H),1.66(d,J＝4.9Hz,3H),1.32(s,12H)；EIMS m/z 262.
preparation of 42:2- (benzo [ d ] [1,3] oxathiolan-5-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolane
5-bromobenzo [ d ]][1,3]Oxathiolanes (1.0g,4.6mmol, such as prepared as described in Cabiddu, Salvator; Cerioni, Giovanni; Cocco, Maria Tersa; Maccioni, Antonio; Plumitallo, Antonio, Journal of Heterocyclic Chemistry 1982,19, 135-139) were dissolved in anhydrous tetrahydrofuran (12mL), cooled to-70 ℃, treated with n-BuLi (2.5M; 1.9mL,4.8mmol) in portions and stirred at-70 ℃ for 30 min. 4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolane (900mg,4.8mmol) was added and stirring continued for 1.5h while the temperature was raised to-30 ℃. The mixture is saturated with NH4Treated with Cl (5mL) and extracted with ethyl acetate (2X 25 mL). The combined extracts were washed with saturated NaCl (10mL) and dried (Na)2SO4) And evaporated to give the title compound, which was used without purification (1.2g, 99%):1H NMR(400MHz,CDCl3)δ7.62(d,J＝1.1Hz,1H),7.48(dd,J＝8.0,1.3Hz,1H),6.82(d,J＝8.1Hz,1H),5.69(s,2H),1.32(s,12H)；EIMS m/z 264.
preparation of 43:2, 2-difluoro-5-methoxy-6-nitrobenzo [ d ] [1,3] dioxole
2,2, 5-trifluoro-6-nitrobenzo [ d][1,3]The dioxole (2.5g,11mmol) was dissolved in anhydrous methanol (20mL), treated with 30% sodium methoxide solution (3.1g,17mmol) and stirred at 20 ℃ for 1 h. After excess methanolate was neutralized by addition of acetic acid, volatiles were removed by rotary evaporation. The residue was taken up in ethyl acetate (50mL) as saturated NaHCO3Washed (10mL), saturated NaCl (10mL), and dried (Na)2SO4) And evaporated. This material was purified by chromatography on silica gel with a gradient of 0-30% ethyl acetate-hexanes to give the title compound as a white solid (1.8g, 70%): mp 84-85 ℃.1H NMR(400MHz,CDCl3)δ7.71(s,1H),6.89(s,1H),3.98(s,3H)；19F NMR(376MHz,CDCl3)δ-49.90(s)；EIMS m/z 233.
Preparation of 44:2, 2-difluoro-6-methoxybenzo [ d ] [1,3] dioxol-5-amine
2, 2-difluoro-5-methoxy-6-nitrobenzo [ d][1,3]The dioxole (1.7g,7.3mmol) was dissolved in ethyl acetate (50mL) and treated with 5% palladium on carbon (200mg) and hydrogen (40-50 pounds per square inch (psi)) on a shaker. After 90min, the catalyst was removed by filtration, the solvent was removed by evaporation and the product was dried in vacuo to give the title compound as a brown solid (1.5g, qt (quantitative)):1H NMR(400MHz,CDCl3)δ6.63(s,1H),6.50(s,1H),3.82(s,3H),3.76(d,J＝23.0Hz,2H)；19F NMR(376MHz,CDCl3)δ-50.32(s)；EIMS m/z 203.
preparation of 45:2, 2-difluoro-5-iodo-6-methoxybenzo [ d ] [1,3] dioxole
2, 2-difluoro-6-methoxybenzo [ d][1,3]Dioxol-5-amine (1.4g,6.9mmol) was dissolved in dichloromethane (5mL) and added in portions to concentrated HCl (75mL) with rapid stirring to form a loose white slurry. The mixture was cooled to 0-5 ℃ and treated with sodium nitrite (710mg,10mmol) in portions in water (10 mL). After 40min, the mixture was poured as a thin stream into a solution of sodium iodide (3.1g,21mmol) in water (75mL) and stirred rapidly with dichloromethane (50 mL). After 45min, the mixture was mixed with 15% NaHSO3The solution (20mL) was stirred together for 10 min. The separated aqueous phase was extracted with dichloromethane (30mL) and the combined extracts were washed with saturated NaCl (15mL), dried (Na)2SO4) And evaporated. This material was purified by chromatography on silica gel with a 0-15% ethyl acetate-hexanes gradient to give the title compound as a white solid (1.8g, 83%): mp 50-51 ℃;1H NMR(400MHz,CDCl3)δ7.45(s,1H),6.69(s,1H),3.86(s,3H)；19F NMR(376MHz,CDCl3)δ-49.81(s)；EIMS m/z 314.
preparation of 46- (2, 2-difluoro-6-methoxybenzo [ d ] [1,3] dioxol-5-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan
2, 2-difluoro-5-iodo-6-methoxybenzo [ d][1,3]The dioxole (1.6g,5.0mmol) was dissolved in anhydrous tetrahydrofuran (15mL), cooled to 0-5 deg.C and treated with isopropyl lithium magnesium chloride (1.3M; 4.1mL,5.3mmol) in portions. After 50min, 2-isopropoxy-4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolane (1.0g,5.4mmol) was added and stirring continued at 15-20 ℃ for 40 min. The mixture is saturated with NH4Treated with Cl (10mL) and then mixed with saturated NaCl (10mL) and ethyl acetate (20 mL). The organic phase was washed with saturated NaCl (10mL) and dried (Na)2SO4) And evaporated to give the title compound as a thick oil, which was used without further purification (1.4g, 89%):1H NMR(400MHz,CDCl3)δ7.35(s,1H),6.65(s,1H),3.81(s,3H),1.34(s,12H)；19F NMR(376MHz,CDCl3)δ-50.17(s)；EIMS m/z 314.
preparation 47- (6-chloro-2, 2-difluorobenzo [ d ] [1,3] dioxol-5-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan
5-bromo-6-chloro-2, 2-difluorobenzo [ d][1,3]The dioxole (1.0g,3.7mmol) was dissolved in anhydrous tetrahydrofuran (7mL), cooled to 0-5 deg.C and treated with isopropyl magnesium chloride lithium chloride (1.3M; 3.0mL,3.9mmol) in portions. After 30min, 2-isopropoxy-4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolane (730mg,4.0mmol) was added and stirring continued at 10-15 ℃ for 45 min. Addition of saturated NH4Cl (10mL), and the mixture was shaken with ethyl acetate (20mL) and saturated NaCl (10 mL). The organic phase was washed with saturated NaCl (10mL) and dried (Na)2SO4) And evaporated to give the title compound as a white solid (1.2g, qt):1H NMR(400MHz,DMSO-d6)δ7.64(s,1H),7.53(s,1H),1.30(s,12H)；19F NMR(376MHz,DMSO-d6)δ-48.97(s)；EIMS m/z 318.
preparation of 48- (7-methoxybenzo [ d ] [1,3] dioxol-5-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolane
6-bromo-4-methoxybenzo [ d][1,3]Dioxoles (1.5g,6.5mmol, prepared as described in Shirasaka, Tadashi; Takuma, Yuki; Imaki, Naoshi. synthetic Communications 1990,20, 1223-1232) were dissolved in anhydrous tetrahydrofuran (25mL), cooled to 5 ℃ and treated with isopropyl magnesium chloride lithium chloride (1.3M; 5.2mL,6.8 mmol). After 50min at 10 ℃ the temperature was raised to 40 ℃ and stirred for 5 h. The mixture was cooled to 20 ℃ and treated with 2-isopropoxy-4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolane (1.3g,7.1mmol) and stirred for 3 h. The mixture is saturated with NH4Treated with Cl (2mL), followed by 1M HCl (8mL) and ethyl acetate (20mL), and then stirred for 10 min. The organic phase was washed with saturated NaCl (10mL) and dried (Na)2SO4) And evaporated. The product was purified by flash chromatography in dichloromethane to give the title compound as a white solid (600 mg; 33%) mp 86-88 ℃;1H NMR(400MHz,CDCl3)δ7.01(d,J＝0.5Hz,1H),6.97(d,J＝0.8Hz,1H),5.98(s,2H),3.93(s,4H),1.33(s,12H)；EIMS m/z 278.
preparation of 49.6-bromo-4-fluorobenzo [ d ] [1,3] dioxol-2-thione
5-bromo-3-fluorobenzene-1, 2-diol (2.0g,9.7mmol, prepared according to Lu, Hejun; Tang, Peng Cho; Chen, Yiqian; Wang, Shenglan; Wang, Hua; Zhang, Lei; Li, Jun, WO2011140936A 1) was dissolved in chloroform (25mL), treated with thiophosgene (1.2g,11mmol) and cooled to 0-5 ℃. Sodium hydroxide (10% aqueous solution, 8.9g,22mmol) was added dropwise with vigorous stirring for 30 min. After 1h, the chlorine is removed in vacuoThe pH was adjusted to 2 by the addition of 6M HCl. The solid thus formed was taken up in ethyl acetate (120mL), washed with saturated NaCl (30mL) and dried (Na)2SO4) And evaporated. This material was purified by flash chromatography using a 0-30% ethyl acetate-hexanes gradient to give the title compound as a brown solid (1.5g, 62%): mp 41-42 ℃;1H NMR(400MHz,CDCl3)δ7.35–7.30(m,1H),7.29(d,J＝1.6Hz,1H)；19F NMR(376MHz,CDCl3)δ-128.93；EIMS m/z 248/250.
preparation of 50: 6-bromo-2, 2, 4-trifluorobenzo [ d ] [1,3] dioxole
6-bromo-4-fluorobenzo [ d][1,3]Dioxol-2-thione (6.9g,28mmol) was dissolved in anhydrous dichloromethane (150mL), cooled to-40 ℃ and treated with pyridinium hydrofluoric acid (70 wt% HF; 39g,273 mmol). N-iodosuccinimide (19g,84mmol) was added in portions while maintaining the temperature below-30 ℃. The mixture was stirred at-35 to-0 ℃ for 30min and then warmed to 20 ℃ and stirred for 30 min. Applying external cooling to maintain the temperature below 35 deg.C, mixing with NaHSO3(8g) The solution in water (50mL) was treated in portions and stirred for 15 min. The mixture was treated with additional water (200mL) to dissolve the solids. The organic phase was washed with saturated NaCl (30mL) and dried (Na)2SO4). Most of the solvent was removed by atmospheric distillation through a 7-tray Oldershaw column and when the kettle volume was about 50mL, distillation through a 200mm Vigreux column was continued until the top temperature reached 75 ℃. After cooling to ambient temperature, the pressure was reduced to 50mmHg and the product was taken off overhead at 75-80 ℃ through a simple distillation head to give the title compound as a light pink liquid (5.3g, 74%):1H NMR(400MHz,CDCl3)δ7.11(dd,J＝9.0,1.7Hz,1H),7.07(m,1H)；19F NMR(376MHz,CDCl3)δ-49.56,-132.65；EIMS m/z254.
preparation of 51:4,4,5, 5-tetramethyl-2- (2,2, 7-trifluorobenzo [ d ] [1,3] dioxol-5-yl) -1,3, 2-dioxaborolan
6-bromo-2, 2, 4-trifluorobenzo [ d ]][1,3]The dioxole (2.0g,7.8mmol) was dissolved in anhydrous tetrahydrofuran (10mL), cooled to-5 to 0 ℃ and treated with isopropyl magnesium chloride lithium chloride complex (1.3M; 6.3mL,8.2mmol) in portions. The cooling bath was removed and the mixture was stirred for 30 min. 2-Isopropoxy-4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolane (1.6g,8.4mmol) was added, the mixture was stirred for 1h and then with saturated NH4Cl (5 mL). The mixture was diluted with ethyl acetate (40mL) and saturated NaCl (10mL) and the pH was adjusted to 2 by the addition of HCl. The organic phase was washed with saturated NaCl (5mL) and dried (Na)2SO4) And evaporated to give the title compound, which was used without further purification (2g, 85%):1H NMR(400MHz,CDCl3)δ7.36(d,J＝9.8Hz,1H),7.29(d,J＝6.5Hz,1H),1.33(s,12H)；19F NMR(376MHz,CDCl3)δ-49.79,-136.26；EIMS m/z302.
preparation of 52: 3-bromo-6-fluorobenzene-1, 2-diol
3-bromo-6-fluoro-2-hydroxybenzaldehyde (9.0g,41mmol, according to Castro, Alfred C.; Depew, Kristopher M.; Grogan, Michael J.; Holson, Edward B.; Hopkins, Brian T.; Johannes, Charles W.; Keaney, Gregg F.; Koney, Nii O.; Liu, Tao; Man, David A.; Nevalaine, Marta; Peluso, Stephane; Perez, Lawrence Blas; Snyder, Daniel A.; Tiitts, Thomas T., WO 2008024337A 2) was stirred in 1.0M NaOH (47mL) and treated with hydrogen peroxide (6%; 49g,86 mmol). External cooling was applied to keep the temperature controlled below 50 ℃. After thorough stirring for 2h, the mixture was mixed with NaHSO3A solution in 50mL of water was stirred together and extracted with ethyl acetate (2 × 75 mL). The combined extracts were washed with saturated NaCl (20mL) and dried (Na)2SO4) And evaporated. Catechol derivative, a dark orange liquid, was used without further purification in the subsequent step (8.9g, qt) EIMS m/z 206.
Preparation of 53: 4-bromo-7-fluorobenzo [ d ] [1,3] dioxol-2-thione
3-bromo-6-fluorobenzene-1, 2-diol (8.9g,43mmol) was dissolved in chloroform (100mL), cooled to 0-5 deg.C and treated with thiophosgene (5.4g,47 mmol). Aqueous sodium hydroxide (10 wt%; 40g,99mmol) was added in portions over 30min with vigorous stirring. Stirring was continued at 5-15 ℃ for 60min, and then most of the chloroform was removed by rotary evaporation. The pH was adjusted to 2 by addition of 1MHCl and the precipitated thione was absorbed in ethyl acetate (150 mL). The organic phase was washed with water (25mL), saturated NaCl (25mL) and dried (Na)2SO4) And evaporated. The crude product was purified by flash chromatography eluting with a 0-20% ethyl acetate-hexanes gradient to give the title compound as a brown solid (6.2g, 58%) mp 72-76 ℃;1H NMR(400MHz,CDCl3)δ7.40(dd,J＝9.2,4.1Hz,1H),7.04(t,J＝9.1Hz,1H)；19F NMR(376MHz,CDCl3)δ-132.68；EIMS m/z 248.
preparation of 54: 4-bromo-2, 2, 7-trifluorobenzo [ d ] [1,3] dioxole
4-bromo-7-fluoro-benzo [ d ]][1,3]Dioxole-2-thione (6.1g,25mmol) was dissolved in anhydrous dichloromethane (100mL), cooled to-30 to-40 ℃ and treated with pyridinium hydrofluoric acid (70 wt%; 35g,245 mmol). N-iodosuccinimide was added in portions at-25 to-35 ℃ and the mixture was allowed to warm to 20 ℃ and stirred for 2 h. The dark mixture was cooled to 0 ℃ and washed with 15% NaHSO3The solution (30mL) was treated with stirring. After 20min, the mixture was diluted with dichloromethane (75mL) and water (200mL) to dissolve the solids. The organic phase was washed with saturated NaCl (25mL) and dried (Na)2SO4). The solvent was removed by atmospheric distillation through a 450mm Vigreux column. The product was withdrawn at 80-90 deg.C under 30-40mmHg to give the title compound as a clear liquid (3.0g, 47%):1H NMR(400MHz,CDCl3)δ7.18(dd,J＝9.3,4.2Hz,1H),6.85(t,J＝9.3Hz,1H)；19F NMR(376MHz,CDCl3)δ-49.08,-136.17；EIMS m/z 254.
Preparation of 55:4,4,5, 5-tetramethyl-2- (2,2, 7-trifluorobenzo [ d ] [1,3] dioxol-4-yl) -1,3, 2-dioxaborolan
4-bromo-2, 2, 7-trifluorobenzo [ d ]][1,3]The dioxole (2.0g,7.8mmol) was dissolved in anhydrous tetrahydrofuran (12mL), cooled to-5 ℃ and treated with isopropyl magnesium chloride lithium chloride complex (1.3M; 6.3mL,8.2 mmol). The mixture was stirred at 5 to 15 ℃ for 2h, treated with 2-isopropoxy-4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (1.6g,8.4mmol) and stirred at 10 to 20 ℃ for 2 h. The mixture is saturated with NH4Treated with Cl (5mL), stirred for 10min and then shaken with 1M HCl (10mL) and ethyl acetate (75 mL). The organic phase was washed with saturated NaCl (10mL) and dried (Na)2SO4) And evaporated to give the title compound as a white solid (2.3g, 98%):1H NMR(400MHz,CDCl3)δ7.41(dd,J＝8.7,5.3Hz,1H),6.88(dd,J＝9.5,8.8Hz,1H),1.36(s,12H)；19F NMR(376MHz,CDCl3)δ-49.07,-131.31；EIMS m/z 302.
preparation 56 (2, 2-difluoro-7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ d ] [1,3] dioxol-4-yl) trimethylsilane
(2, 2-Difluorobenzo [ d ]][1,3]Dioxol-4-yl) trimethylsilane (5.0g,22mmol, as in goreka, Joanna; leroux, Frederic; prepared as described in Schlosser, Manfred, European Journal of organic chemistry 2004,1, 64-68) was added to secondary-BuLi (1.4M; 10mL,14mmol) of a stirred solution in anhydrous tetrahydrofuran (28mL) cooled to-75 ℃. At-75 o C2 h, 2-isopropoxy-4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan was addedPentane (4.2g,23mmol) and the mixture stirred at-75 ℃ for 90 min. The mixture is saturated with NH4Treated with Cl (5mL) and warmed to 20 ℃. The mixture was mixed with water (75mL), acidified with 6M HCl and extracted with diethyl ether (100 mL). The organic phase was washed with saturated NaCl (15mL) and dried (Na)2SO4) And evaporated to give the title compound (estimated purity 60%) which was used without purification:1H NMR(400MHz,CDCl3)δ7.39(d,J＝7.5Hz,1H),7.07(d,J＝7.5Hz,1H),1.36(s,,12H),0.33(s,9H)；19F NMR(376MHz,CDCl3)δ-49.33；EIMS m/z 356.
preparation of 57: 4-bromo-5-fluorobenzene-1, 2-diol
To CH in a 50mL round bottom flask2Cl2(30mL) 4-bromo-5-fluoro-2-methoxyphenol (2g,9.05mmol) was added. The reaction mixture was cooled to 0 ℃ in an ice/water bath. Boron tribromide (1.027mL,10.86mmol) was added slowly via syringe over 5min, and the ice/water bath was removed. The reaction mixture was allowed to warm to room temperature and stirred for 18 h. The reaction mixture was placed in an ice/water bath and methanol (30mL) was added slowly via syringe. After removal of the ice/water bath, the reaction mixture was warmed to room temperature. The reaction mixture was transferred to a separatory funnel, diluted with ethyl acetate (200mL) and washed with water (200 mL). The organic layer was washed with Na2SO4Dried and filtered. The organic solution was concentrated to give 4-bromo-5-fluorobenzene-1, 2-diol as a dark brown oil (1.8g, 96%):1H NMR(400MHz,CDCl3)δ7.03(d,J＝6.5Hz,1H),6.72(dd,J＝8.3,3.5Hz,1H)；19F NMR(376MHz,CDCl3)δ-115.91(s)；ESIMS m/z 207([M+H]+),206([M-H]-).
preparation of 58-bromo-6-fluorobenzo [ d ] [1,3] dioxole
To N, N-dimethylformamide (25mL) in a 50mL flask was added 4-bromo-5-fluorobenzene-1, 2-diol (2g,9.66mmol), caesium carbonate (4.72g,14.49mmol) and bromochloromethane (1.875g,14.49 mmol). The reaction mixture was stirred at room temperature for 1h and then heated to an external temperature of 80 ℃ for 3 h. After cooling, the reaction mixture was taken up in Et2O (75mL) was diluted and washed with water (50mL), followed by a saturated NaCl solution (50 mL). The organic layer was MgSO4Dried and filtered. Concentrating the organic solution to obtain 5-bromo-6-fluorobenzo [ d][1,3]Dioxole as a light orange solid (1.8g, 85%):1H NMR(400MHz,CDCl3)δ6.94(d,J＝5.9Hz,1H),6.67(d,J＝7.9Hz,1H),6.00(s,2H)；19F NMR(376MHz,CDCl3)δ-113.82(s)；ESIMS m/z 220([M+H]+),218([M-H]-).
preparation of 59-bromo-2, 2-dimethylbenzo [ d ] [1,3] dioxole
To benzene (50mL) in a 250mL round bottom flask was added 4-bromobenzene-1, 2-diol (1g,5.29mmol), 2-dimethoxypropane (2.204g,21.16mmol) and p-benzenesulfonic acid monohydrate (0.050g,0.265 mmol). The flask was fitted with a Dean-Stark trap and heated to reflux for 18 h. After cooling, the reaction mixture was transferred to a separatory funnel and washed with 2N NaOH solution (100mL) and saturated NaCl solution (100 mL). The organic layer was MgSO4Drying, filtering, and concentrating to obtain 5-bromo-2, 2-dimethylbenzo [ d][1,3]Dioxole as a dark brown oil (767mg, 63%):1H NMR(400MHz,CDCl3)δ6.91–6.85(m,2H),6.62–6.57(m,1H),1.66(s,6H)；13C NMR(101MHz,CDCl3)δ146.81(s),144.25(s),123.64(s),121.02(s),112.05(s),109.40(s),108.46(s),25.83(s)；ESIMS m/z 230([M+H]+),228([M-H]-).
preparation of 60:2- (2, 2-dimethylbenzo [ d ] [1,3] dioxol-5-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolane
To DMSO (10mL) was added potassium acetate (1.671g,17.03mmol), 4,4,4',4',5,5,5',5' -octamethyl-2, 2' -bis (1,3, 2-dioxaborolane) (1.729g,6.81mmol), 5-bromo-2, 2-dimethylbenzo [ d][1,3]Dioxole (1.3g,5.68mmol) and PdCl2(dppf) (0.415g,0.568 mmol). The reaction was heated to an external temperature of 80 ℃ for 18 h. After cooling, the reaction mixture was poured into ice water (50 mL). The ice-water mixture was transferred to a separatory funnel and extracted twice with ethyl acetate (50 mL). The organic layers were combined and washed with Na2SO4Dried and filtered. The solution was concentrated to 5g using ethyl acetate as solutionThe above. The infiltrated Celite was loaded onto a Teledyne Isco purification system and purified by silica gel chromatography using 0-30% ethyl acetate: hexanes to give 2- (2, 2-dimethylbenzo [ d ]][1,3]Dioxol-5-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan as a red semisolid (767mg, 49%):1H NMR(400MHz,CDCl3)δ7.31(dt,J＝6.6,3.3Hz,1H),7.15(s,1H),6.74(d,J＝7.7Hz,1H),1.66(s,6H),1.32(s,12H)；13C NMR(101MHz,CDCl3)δ129.21(s),113.78(s),108.15(s),83.59(s),25.86(s),24.82(s)；ESIMS m/z277([M+H]+),275([M-H]-).
preparation 61- (6-Fluorobenzo [ d ] [1,3] dioxol-5-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolane
2- (6-Fluorobenzo [ d ]][1,3]Dioxolen-5-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolane from 5-bromo-6-fluorobenzo [ d ] as described in preparation 60][1,3]Dioxole preparation gave a brown oil (74%):1H NMR(400MHz,CDCl3)δ7.08(d,J＝4.6Hz,1H),6.55(t,J＝6.4Hz,1H),5.97(d,J＝2.1Hz,2H),1.24(s,12H)；13C NMR(101MHz,CDCl3)δ131.70,131.37,128.34,113.38,101.93,98.12,97.80,83.51,24.80；ESIMS m/z 267([M+H]+),265([M-H]-).
preparation of 62- (2, 2-difluorobenzo [ d ] [1,3] dioxol-5-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan
To a dried three-necked round-bottomed flask was added 5-bromo-2, 2-difluorobenzo [ d ] under nitrogen][1,3]Dioxole (2.516g,10.6mmol) and anhydrous tetrahydrofuran (26 mL). The solution was cooled to 0 ℃. Isopropyl magnesium chloride-lithium chloride complex (1.3M; 10mL,13.0mmol) was added slowly and stirred for 1 h. 2-Isopropoxy-4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolane (2.2mL,10.62mmol) was added and the reaction mixture was stirred for 1 h. The reaction was quenched with saturated aqueous ammonium chloride and extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. The solution is filtered and concentrated to give 2- (2, 2-difluorobenzo [ d ]][1,3]Dioxol-5-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan as a yellow oil (2.54g, 84%):1H NMR(400MHz,CDCl3)δ7.56(dd,J＝8.0,1.0Hz,1H),7.47(d,J＝0.6Hz,1H),7.06(dd,J＝7.9,0.4Hz,1H),1.34(s,12H)；19F NMR(376MHz,CDCl3)δ-50.18；EIMS m/z 284.
preparation of 63:2- (benzo [ d ] [1,3] dioxol-4-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolane
Benzo [ d ] carbonyl][1,3]The dioxole (3.05g,25mmol) was dissolved in tetrahydrofuran (50mL) and cooled to-108 ℃ using a tetrahydrofuran/liquid nitrogen bath. Sec-butyllithium (1.4M in hexanes; 19.64mL,27.5mmol) was added dropwise, maintaining the temperature below-100 ℃. The reaction mixture was then stirred at a temperature of-100 ℃ to-108 ℃ for 2h to ensure complete deprotonation. 2-Isopropoxy-4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolane (4.65g,25.00mmol) was then added dropwise to the reaction mixture, maintaining the temperature below-100 ℃.The reaction mixture was then warmed to room temperature and partitioned between diethyl ether and water. The organic phase was extracted once more with water and the aqueous phases were combined and acidified to pH 4 with HCl. The product was extracted with diethyl ether and the organic phase was dried and concentrated in vacuo. The product was purified by flash chromatography (silica gel) to give the title compound as a white solid (2.14g, 34.5%):1H NMR(300MHz,CDCl3)δ7.21(dd,J＝7.6,1.4Hz,1H),6.90(dd,J＝7.7,1.5Hz,1H),6.82(t,J＝7.6Hz,1H),6.02(s,2H),1.36(s,12H)；EIMS m/z 248.
preparation of 64:2- (2, 2-difluorobenzo [ d ] [1,3] dioxol-4-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolane
2, 2-difluorobenzo [ d ]][1,3]The dioxole (6g,38.0mmol) was dissolved in tetrahydrofuran (100mL) and cooled to-75 ℃. Sec-butyllithium (1.4M in cyclohexane; 29.8mL,41.7mmol) was added dropwise, maintaining the temperature below-65 ℃. The reaction mixture was then stirred at-75 ℃ for 1h to ensure complete deprotonation. 2-Isopropoxy-4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolane (7.06g,38.0mmol) was then added dropwise to the reaction mixture, maintaining the temperature below-65 ℃. The reaction mixture was then warmed to room temperature and allowed to stand at room temperature for 2h, then partitioned between diethyl ether and water. The aqueous phase was then acidified to pH3 with 12 NHCl. The product was extracted with diethyl ether and the organic phase was dried and concentrated in vacuo to give the title compound as an off-white solid (7.06g, 65.5%):1H NMR(300MHz,CDCl3)δ7.43(dd,J＝7.5,1.5Hz,1H),7.13(dd,J＝7.9,1.5Hz,1H),7.05(t,J＝7.7Hz,1H),1.37(s,12H)；EIMS m/z 284.
preparation of 65: 4-chloro-2, 2-difluorobenzo [ d ] [1,3] dioxole
2, 2-difluorobenzo [ d ]][1,3]The dioxole (6.3g,39.8mmol) was dissolved in tetrahydrofuran (66mL) and cooled to-78 ℃. N-butyllithium (2) was added dropwise.5M solution in hexanes; 16.74mL,41.8mmol), maintaining the temperature below-70 ℃. The reaction mixture was then stirred at-78 ℃ for 1h to ensure complete deprotonation. 1,2, 2-Trifluorotrichloroethane (14.93g,80mmol) was dissolved in tetrahydrofuran (33mL) and cooled to-65 ℃. The lithiate was transferred via a catheter to a solution of 1,2, 2-trifluorotrichloroethane at a rate that allowed the temperature to remain between-60 ℃ and-65 ℃ during the addition. The reaction mixture was then warmed to room temperature and partitioned between diethyl ether and water. The organic phase was concentrated and the product was purified by flash chromatography over 100g of silica gel using hexane as solvent to give the title compound as a clear oil (5.74g, 74.8%):1H NMR(400MHz,CDCl3)δ7.08(dd,J＝8.2,1.4Hz,1H),7.03(t,J＝8.0Hz,1H),6.97(dd,J＝7.9,1.5Hz,1H)；EIMS m/z 192.
preparation 66- (7-chloro-2, 2-difluorobenzo [ d ] [1,3] dioxol-4-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan
4-chloro-2, 2-difluorobenzo [ d ]][1,3]The dioxole (3g,15.58mmol) was dissolved in tetrahydrofuran (50mL) and cooled to-75 ℃. N-butyllithium (2.5M in hexanes; 6.86mL,17.14mmol) was added dropwise, maintaining the temperature below-65 ℃. The reaction mixture was then stirred at-75 ℃ for 1h to ensure complete deprotonation. 2-Isopropoxy-4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolane (3.19g,17.14mmol) was then added dropwise to the reaction mixture, maintaining the temperature below-65 ℃. The reaction mixture was then allowed to warm to room temperature, added to diethyl ether (200mL) and extracted with water (2 × 100 mL). The aqueous phases were combined and acidified to pH 4 with concentrated HCl. The product was extracted with diethyl ether and the organic phase was dried and concentrated in vacuo to give the title compound as an off-white solid (3.82g, 77%):1H NMR(400MHz,CDCl3)δ7.38(d,J＝8.4Hz,1H),7.06(d,J＝8.4Hz,1H),1.36(s,12H)；EIMS m/z 318.
preparation 67:2- (2, 2-difluorobenzo [ d ] [1,3] dioxol-5-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolane
To 5-bromo-2, 2-difluorobenzo [ d ]][1,3]A solution of dioxole (1.5g,6.3mmol) in N, N-dimethylformamide (12.7mL) was added 4,4,4',4',5,5,5',5' -octamethyl-2, 2 '-bis (1,3, 2-dioxaborolane) (1.6g,6.3mmol), potassium acetate (1.9g,19.0mmol) and (1,1' -bis (diphenylphosphino) ferrocene) -dichloropalladium (II) (0.3g,0.32 mmol). The reaction mixture was heated at 80 ℃ for 18h, then the reaction mixture was washed with Et2Diluted O and washed with water. Separating the organic layer over Na2SO4Drying, filtration, concentration in vacuo, and purification by silica gel chromatography eluting with 0-100% acetone/hexanes provided a brown oil (0.9g, 50%):1H NMR(400MHz,DMSO-d6)δ7.55(d,J＝8.0Hz,1H),7.53(s,1H),7.43(d,J＝8.0Hz,1H),1.30(s,12H)；19F NMR(376MHz,DMSO-d6)δ-49.26(s)；EIMS m/z 284.
preparation of 68 acetic acid 2, 3-dihydro-1H-inden-2-yl ester
Acetyl chloride (87.86g,1119.40mmol) was added dropwise to 2, 3-dihydro-1H-inden-2-ol (15g,111.94mmol) at 0 ℃ under nitrogen atmosphere. The reaction mixture was stirred at rt for 16 h. The excess acetyl chloride was removed by distillation under reduced pressure. The residue was diluted with ethyl acetate (450mL) and NaHCO3Saturated solution (3X 50mL), brine (30mL), washed with Na2SO4Drying and concentration under reduced pressure gave the title compound (16.2g, 82%) which was used in the next step without further purification.
Preparation 69 acetic acid 5-bromo-2, 3-dihydro-1H-inden-2-yl ester
To a 0 ℃ solution of 2, 3-dihydro-1H-inden-2-yl acetate (16g,90.09mmol) in anhydrous DMF (160mL) was added N-bromosuccinimide in portions(17.8g,99.09mmol), and the mixture was stirred at room temperature for 48 h. The reaction mixture was then diluted with ethyl acetate (450mL), washed with ice-cold water (4 × 50mL) and brine (100mL), over Na2SO4Dried and concentrated under reduced pressure. The residue was purified by column chromatography using ethyl acetate/hexane (silica gel, 100-200 mesh) to give the title compound (9.8g, 42%).
Preparation of 70: 5-bromo-2, 3-dihydro-1H-inden-2-ol
To a 0 deg.C solution of acetic acid 5-bromo-2, 3-dihydro-1H-inden-2-yl ester (9g,35.43mmol) in THF (100mL) was added dropwise a solution of NaOH (2.12g,53.15mmol) in water (25 mL). The reaction mixture was stirred at rt for 16 h. The reaction mixture was then concentrated, neutralized with 6N HCl solution and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with brine (50mL) and Na2SO4Dried and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/hexane, silica gel 100-200 mesh) to give the title compound (4.5g, 56%).
Preparation 71- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-indene-2-ol
To a solution of 5-bromo-2, 3-dihydro-1H-inden-2-ol (4.5g,21.22mmol) in dioxane (54mL) was added pinacol diboron (6.44g,25.47mmol) and potassium acetate (8.3g,84.90 mmol). The reaction mixture was flushed with argon for 20min and then Pd (dppf) Cl was added2(0.755g,1.061 mmol). The reaction mixture was stirred at 110 ℃ for 4h, then cooled to room temperature, and the mixture was filteredThe pad was filtered and washed with ethyl acetate (100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/hexane, silica gel 100-200 mesh) to give the title compound (3.8g, 69%).
Synthesis of Compounds of formula (I)
Example 1: 4-amino-3-chloro-6- (1, 3-dihydroisobenzofuran-5-yl) -5-fluoropyridine-2-carboxylic acid methyl ester
Tert-butyl nitrite (1.3mL,11mmol,1.5 equiv.) was added to a stirred solution of perbenzoic anhydride (36mg,0.15mmol,0.02 equiv.), pinacol diboron (1.9g,7.4mmol,1.0 equiv.) and 1, 3-dihydroisobenzofuran-5-amine (1.0g,7.4mmol,1.0 equiv.) in acetonitrile (25mL) at 23 ℃. The resulting homogeneous orange/brown solution was stirred at 23 ℃ for 3 h. Activated carbon was added and the black mixture was gravity filtered and concentrated by rotary evaporation to give 1.9g of a dark brown oil which appeared to be consistent with 2- (1, 3-dihydroisobenzofuran-5-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolane (. about.30% pure) by crude product1H NMR analysis.
To crude 2- (1, 3-dihydroisobenzofuran-5-yl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolane (estimated 570mg,2.3mmol,1.1 equiv.) was added methyl 4-amino-3, 6-dichloro-5-fluoropyridine-2-carboxylate (500mg,2.1mmol,1.0 equiv.), dichloro [ bis (triphenylphosphino) at 23 deg.C]Palladium (II) (150mg,0.21mmol,0.10 equiv.) and sodium carbonate (240mg,2.3mmol,1.1 equiv.), followed by the addition of a 1:1 mixture of water acetonitrile (7.0 mL). The resulting dark orange/brown mixture was heated to 85 ℃ and stirred for 4 h. The cooled reaction mixture was diluted with water (150mL) and extracted with dichloromethane (4 × 70 mL). The combined organic layers were dried (magnesium sulfate), gravity filtered, and concentrated by rotary evaporation. The residue was purified by reverse phase chromatography (gradient of 5% acetonitrile to 100% acetonitrile) to give the title compound as an orange powder (150mg, 22%): mp 153-156 ℃; IR (pure film) 3468(m),3334(s),3205(m),2952(m),2856(m),1735(s),1623(s),1579(w) cm-1；1H NMR(400MHz,CDCl3)δ7.81–7.86(m,2H),7.33(d,J＝8Hz,1H),5.16(br d,J＝4Hz,1H),4.89(br s,2H),3.97(s,3H)；ESIMS m/z 323[(M+H)+].
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