Pyrrolidone and preparation method thereof
阅读说明：本技术 吡咯烷酮及其制备方法 (Pyrrolidone and preparation method thereof ) 是由 陈玉忠 于 2018-03-16 设计创作，主要内容包括：本申请涉及式II的化合物。<Image he="587" wi="489" file="DDA0002210951810000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>还公开了用于制备式II的化合物的方法,所述方法包括使用式IV和V的化合物<Image he="350" wi="700" file="DDA0002210951810000012.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>还公开了用于制备式I的化合物的方法,<Image he="468" wi="700" file="DDA0002210951810000013.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>所述方法包括使式II的化合物与式VI的化合物的化合物接触,其中,A<Sup>1</Sup>、A<Sup>2</Sup>、A<Sup>3</Sup>、R<Sup>1</Sup>、R<Sup>2</Sup>、R<Sup>3a</Sup>、R<Sup>3b</Sup>、R<Sup>4</Sup>、B<Sup>1</Sup>、B<Sup>2</Sup>和B<Sup>3</Sup>如本公开中所定义。(The present application relates to compounds of formula II. Also disclosed are methods for preparing compounds of formula II, comprising using compounds of formulae IV and V Also disclosed are processes for preparing compounds of formula I, the method comprises reacting a compound of formula II with a compound of formula VIIn contact with, A 1 、A 2 、A 3 、R 1 、R 2 、R 3a 、R 3b 、R 4 、B 1 、B 2 And B 3 As defined in this disclosure.)
1. A compound of formula II and salts thereof,
wherein the content of the first and second substances,
A1is CCF3，A2Is CH, and A3Is CH; or
A1Is CH, A2Is CCF3And A is3Is CH; or
A1Is N, A2Is CCF3And A is3Is CH; or
A1Is CCH3，A2Is N, and A3Is COCHF2；
R1Is C1-C4An alkyl group; and is
R2Is H or C1-C4An alkyl group.
2. The compound according to claim 1 and salts thereof,
R1is methyl, ethyl or propyl; and is
R2Is H or methyl.
3. A compound according to claim 2, selected from:
(3R, 4S) -1-methyl-2-oxo-4- [3- (trifluoromethyl) phenyl ] -3-pyrrolidinecarboxylic acid methyl ester; and
(3R, 4S) -1-methyl-2-oxo-4- [3- (trifluoromethyl) phenyl ] -3-pyrrolidinecarboxylic acid.
4. A process for preparing a compound of formula II-A,
wherein the content of the first and second substances,
A1is CCF3，A2Is CH, and A3Is CH; or
A1Is CH, A2Is CCF3And A is3Is CH; or
A1Is N, A2Is CCF3And A is3Is CH; or
A1Is CCH3，A2Is N, and A3Is COCHF2；
R1Is C1-C4An alkyl group; and is
R2Is a compound of formula (I) wherein the compound is H,
the process comprises alkylating a compound of formula III with an alkylating agent,
wherein the content of the first and second substances,
A1is CCF3，A2Is CH, and A3Is CH; or
A1Is CH, A2Is CCF3And A is3Is CH; or
A1Is N, A2Is CCF3And A is3Is CH; or
A1Is CCH3，A2Is N, and A3Is COCHF2。
5. The method of claim 4, wherein,
R1is C1-C4An alkyl group;
the method comprises alkylating a compound of formula III, wherein the alkylating agent is a dialkyl sulfate.
6. A compound of formula IV and salts thereof,
wherein the content of the first and second substances,
A1is CCF3，A2Is CH, and A3Is CH; or
A1Is CH, A2Is CCF3And A is3Is CH; or
A1Is N, A2Is CCF3And A is3Is CH; or
A1Is CCH3，A2Is N, and A3Is COCHF2；
R1Is C1-C4An alkyl group;
each R3aAnd R3bIndependently is C1-C4An alkyl group; and is
R4Is a substituted or unsubstituted benzyl group.
7. The compound of claim 6, wherein,
R1is methyl, ethyl or propyl;
each R3aAnd R3bIndependently methyl or ethyl; and is
R4Is an unsubstituted benzyl group.
8. The compound of claim 6, which is
1, 3-dimethyl 2- [ (1S) -2- [ methyl (phenylmethyl) amino ] -1- [3- (trifluoromethyl) phenyl ] ethyl ] malonate.
9. A process for preparing a compound of formula II-B,
wherein the content of the first and second substances,
A1is CCF3，A2Is a group of atoms selected from the group consisting of CH,and A is3Is CH; or
A1Is CH, A2Is CCF3And A is3Is CH; or
A1Is N, A2Is CCF3And A is3Is CH; or
A1Is CCH3，A2Is N, and A3Is COCHF2；
R1Is C1-C4An alkyl group; and is
R2Is C1-C4An alkyl group, a carboxyl group,
the method comprises reducing a compound of formula IV with a reducing agent,
wherein the content of the first and second substances,
A1is CCF3，A2Is CH, and A3Is CH; or
A1Is CH, A2Is CCF3And A is3Is CH; or
A1Is N, A2Is CCF3And A is3Is CH; or
A1Is CCH3，A2Is N, and A3Is COCHF2；
R1Is C1-C4An alkyl group;
each R3aAnd R3bIndependently is C1-C4An alkyl group; and is
R4Is a substituted or unsubstituted benzyl group.
10. The method of claim 9, wherein,
R1is methyl, ethyl or propyl; and is
R2Is methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl,
the process comprises reducing a compound of formula IV, wherein,
R1is methyl, ethyl or propyl;
each R3aAnd R3bIndependently methyl or ethyl; and is
R4Is an unsubstituted benzyl group, which is substituted,
wherein the reducing agent comprises a catalyst.
11. A process for the preparation of a compound of formula IV,
wherein the content of the first and second substances,
A1is CCF3，A2Is CH, and A3Is CH; or
A1Is CH, A2Is CCF3And A is3Is CH; or
A1Is N, A2Is CCF3And A is3Is CH; or
A1Is CCH3，A2Is N, and A3Is COCHF2；
R1Is C1-C4An alkyl group;
each R3aAnd R3bIndependently is C1-C4An alkyl group; and is
R4Is a substituted or unsubstituted benzyl group, wherein the alkyl group is substituted or unsubstituted,
the method comprises reacting a compound of formula V or a salt thereof with a di- (C)1-C4Alkyl) malonic ester to react with the alkyl group,
wherein the content of the first and second substances,
A1is CCF3，A2Is CH, and A3Is CH; or
A1Is CH, A2Is CCF3And A is3Is CH; or
A1Is N, A2Is CCF3And A is3Is CH; or
A1Is CCH3，A2Is N, and A3Is COCHF2；
R1Is C1-C4An alkyl group; and is
R4Is a substituted or unsubstituted benzyl group.
12. The method of claim 11, wherein,
R1is methyl, ethyl or propyl;
each R3aAnd R3bIndependently methyl, ethyl or propyl; and is
R4Is an unsubstituted benzyl group, which is substituted,
the method comprises reacting a compound of formula V or a salt thereof with a di- (C)1-C4Alkyl) malonate or salt thereof, wherein,
R1is methyl, ethyl or propyl; and is
R4Is an unsubstituted benzyl group, which is substituted,
the di- (C)1-C4Alkyl) malonate or salt thereof is selected from: dimethyl malonate, diethyl malonate, diisopropyl malonate or di-n-propyl malonate, or sodium salt, lithium salt or potassium salt thereof.
13. A process for the preparation of a compound of formula I,
wherein the content of the first and second substances,
A1is CCF3，A2Is CH, and A3Is CH; or
A1Is CH, A2Is CCF3And A is3Is CH; or
A1Is N, A2Is CCF3And A is3Is CH; or
A1Is CCH3，A2Is N, and A3Is COCHF2；
R1Is C1-C4An alkyl group;
B1is CF, B2Is CH, and B3Is CH; or
B1Is CF, B2Is CF, and B3Is CH; or
B1Is CF, B2Is N, and B3Is a reaction product of CF,
the method comprises contacting a compound of formula II-A with a compound of formula VI,
the compound of formula II-A is prepared by the process for preparing the compound of formula II-A as described in the summary of the invention,
wherein the content of the first and second substances,
A1is CCF3，A2Is CH, and A3Is CH; or
A1Is CH, A2Is CCF3And A is3Is CH; or
A1Is N, A2Is CCF3And A is3Is CH; or
A1Is CCH3，A2Is N, and A3Is COCHF2；
R1Is C1-C4An alkyl group; and is
R2Is a compound of formula (I) wherein the compound is H,
wherein the content of the first and second substances,
B1is CF, B2Is CH, and B3Is CH; or
B1Is CF, B2Is CF, and B3Is CH; or
B1Is CF, B2Is N, and B3Is CF.
14. The method of claim 13, wherein,
R1is methyl, ethyl or propyl;
the method comprises contacting a compound of formula II-A with a compound of formula VI,
R1is methyl, ethyl or propyl
The compounds of formula II-A are prepared by the processes described in the summary of the invention for preparing compounds of formula II-A.
15. A process according to claim 14, wherein the compound of formula II-a is prepared using a process as claimed in claim 4, which process comprises alkylating a compound of formula III.
16. The process of claim 14, wherein the compound of formula II-a is prepared by first hydrolyzing the compound of formula II-B.
17. A process for the preparation of a compound of formula I,
wherein the content of the first and second substances,
A1is CCF3，A2Is CH, and A3Is CH; or
A1Is CH, A2Is CCF3And A is3Is CH; or
A1Is N, A2Is CCF3And A is3Is CH; or
A1Is CCH3，A2Is N, and A3Is COCHF2；
R1Is C1-C4An alkyl group;
B1is CF, B2Is CH, and B3Is CH; or
B1Is CF, B2Is CF, and B3Is CH; or
B1Is CF, B2Is N, and B3Is a reaction product of CF,
the method comprises contacting a compound of formula II-B with a compound of formula VI,
the compound of formula II-B is prepared by the process for preparing the compound of formula II-B described in the summary of the invention,
wherein the content of the first and second substances,
A1is CCF3，A2Is CH, and A3Is CH; or
A1Is CH, A2Is CCF3And A is3Is CH; or
A1Is N, A2Is CCF3And A is3Is CH; or
A1Is CCH3，A2Is N, and A3Is COCHF2；
R1Is C1-C4An alkyl group; and is
R2Is C1-C4An alkyl group, a carboxyl group,
wherein the content of the first and second substances,
B1is CF, B2Is CH, and B3Is CH; or
B1Is CF, B2Is CF, and B3Is CH; or
B1Is CF, B2Is N, and B3Is CF.
18. The method of claim 17, wherein,
R1is a methyl group, an ethyl group or a propyl group,
the method comprises contacting a compound of formula II-B with a compound of formula VI,
R1is methyl, ethyl or propyl; and is
R2Is methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl,
the compounds of formula II-B are prepared by the processes described in the summary of the invention for preparing compounds of formula II-B.
19. A process according to claim 17, wherein the compound of formula II-B is prepared using a process as claimed in claim 9, which comprises reducing the compound of formula IV.
20. A process according to claim 17, wherein the compound of formula II-B is prepared using a process as claimed in claim 9, which comprises reducing a compound of formula IV; and preparing the compound of formula IV using the process of claim 11, comprising reacting a compound of formula V or a salt thereof with di- (C)1-C4Alkyl) malonate or salt thereof.
Technical Field
The present invention relates to certain pyrrolidones, intermediates, and processes for their preparation.
Background
WO2015/084796 and WO2016/196593 disclose various substituted cyclic amides, methods of using them as herbicides, and methods of their preparation. WO2016/094117 discloses certain 3-oxo-3- (arylamino) propionates, their salts and compositions, processes for their preparation, and their use in the preparation of certain pyrrolidones useful as herbicides.
The pyrrolidones of the invention and their preparation are not disclosed in these publications.
Disclosure of Invention
The present application relates to compounds of formula II and salts thereof.
Wherein the content of the first and second substances,
A1is CCF3，A2Is CH, and A3Is CH; or
A1Is CH, A2Is CCF3And A is3Is CH; or
A1Is N, A2Is CCF3And A is3Is CH; or
A1Is CCH3，A2Is N, and A3Is COCHF2；
R1Is C1-C4An alkyl group; and is
R2Is H or C1-C4An alkyl group.
The present application also relates to a process for preparing a compound of formula II-A,
wherein the content of the first and second substances,
A1is CCF3，A2Is CH, and A3Is CH; or
A1Is CH, A2Is CCF3And A is3Is CH; or
A1Is N, A2Is CCF3And A is3Is CH; or
A1Is CCH3，A2Is N, and A3Is COCHF2；
R1Is C1-C4An alkyl group; and is
R2Is H
The process comprises alkylating a compound of formula III with an alkylating agent,
wherein the content of the first and second substances,
A1is CCF3，A2Is CH, and A3Is CH; or
A1Is CH, A2Is CCF3And A is3Is CH; or
A1Is N, A2Is CCF3And A is3Is CH; or
A1Is CCH3，A2Is N, and A3Is COCHF2。
The present application also relates to compounds of formula IV and salts thereof,
wherein the content of the first and second substances,
A1is CCF3，A2Is CH, and A3Is CH; or
A1Is CH, A2Is CCF3And A is3Is CH; or
A1Is N, A2Is CCF3And A is3Is CH; or
A1Is CCH3，A2Is N, and A3Is COCHF2；
R1Is C1-C4An alkyl group;
each R3aAnd R3bIndependently is C1-C4An alkyl group; and is
R4Is a substituted or unsubstituted benzyl group.
The present application also relates to a process for preparing a compound of formula II-B,
wherein the content of the first and second substances,
A1is CCF3，A2Is CH, and A3Is CH; or
A1Is CH, A2Is CCF3And A is3Is CH; or
A1Is N, A2Is CCF3And A is3Is CH; or
A1Is CCH3，A2Is N, and A3Is COCHF2；
R1Is C1-C4An alkyl group; and is
R2Is C1-C4An alkyl group, a carboxyl group,
the process comprises reducing a compound of formula IV with a reducing agent,
wherein the content of the first and second substances,
A1is CCF3，A2Is CH, and A3Is CH; or
A1Is CH, A2Is CCF3And A is3Is CH; or
A1Is N, A2Is CCF3And A is3Is CH; or
A1Is CCH3，A2Is N, and A3Is COCHF2；
R1Is C1-C4An alkyl group;
each R3aAnd R3bIndependently is C1-C4An alkyl group; and is
R4Is a substituted or unsubstituted benzyl group.
The present application also relates to a process for preparing a compound of formula IV,
wherein the content of the first and second substances,
A1is CCF3，A2Is CH, and A3Is CH; or
A1Is CH, A2Is CCF3And A is3Is CH; or
A1Is N, A2Is CCF3And A is3Is CH; or
A1Is CCH3，A2Is N, and A3Is COCHF2；
R1Is C1-C4An alkyl group;
each R3aAnd R3bIndependently is C1-C4An alkyl group; and is
R4Is a substituted or unsubstituted benzyl group, wherein the alkyl group is substituted or unsubstituted,
the process comprises reacting a compound of formula V or a salt thereof with a di- (C)1-C4Alkyl) malonic ester to react with the alkyl group,
wherein the content of the first and second substances,
A1is CCF3，A2Is CH, and A3Is CH; or
A1Is CH, A2Is CCF3And A is3Is CH; or
A1Is N, A2Is CCF3And A is3Is CH; or
A1Is CCH3，A2Is N, and A3Is COCHF2；
R1Is C1-C4An alkyl group; and is
R4Is a substituted or unsubstituted benzyl group.
The present application also relates to processes for preparing compounds of formula I,
wherein the content of the first and second substances,
A1is CCF3，A2Is CH, and A3Is CH; or
A1Is CH, A2Is CCF3And A is3Is CH; or
A1Is N, A2Is CCF3And A is3Is CH; or
A1Is CCH3，A2Is N, and A3Is COCHF2；
R1Is C1-C4An alkyl group;
B1is CF, B2Is CH, and B3Is CH; or
B1Is CF, B2Is CF, and B3Is CH; or
B1Is CF, B2Is N, and B3Is a reaction product of CF,
the method comprises contacting a compound of formula II-A with a compound of formula VI,
the compounds of formula II-A are prepared by the process described in the summary of the invention for preparing the compounds of formula II-A,
in the formula II-A, the compound is shown in the specification,
A1is CCF3，A2Is CH, and A3Is CH; or
A1Is CH, A2Is CCF3And A is3Is CH; or
A1Is N, A2Is CCF3And A is3Is CH; or
A1Is CCH3，A2Is N, and A3Is COCHF2；
R1Is C1-C4An alkyl group; and is
R2Is a compound of formula (I) wherein the compound is H,
wherein the content of the first and second substances,
B1is CF, B2Is CH, and B3Is CH; or
B1Is CF, B2Is CF, and B3Is CH; or
B1Is CF, B2Is N, and B3Is CF.
The present application also relates to processes for preparing compounds of formula I,
wherein the content of the first and second substances,
A1is CCF3，A2Is CH, and A3Is CH; or
A1Is CH, A2Is CCF3And A is3Is CH; or
A1Is N, A2Is CCF3And A is3Is CH; or
A1Is CCH3，A2Is N, andA3is COCHF2；
R1Is C1-C4An alkyl group;
B1is CF, B2Is CH, and B3Is CH; or
B1Is CF, B2Is CF, and B3Is CH; or
B1Is CF, B2Is N, and B3Is a reaction product of CF,
the method comprises contacting a compound of formula II-B with a compound of formula VI,
the compounds of formula II-B are prepared by the process described in the summary of the invention for preparing the compounds of formula II-B,
wherein the content of the first and second substances,
A1is CCF3，A2Is CH, and A3Is CH; or
A1Is CH, A2Is CCF3And A is3Is CH; or
A1Is N, A2Is CCF3And A is3Is CH; or
A1Is CCH3，A2Is N, and A3Is COCHF2；
R1Is C1-C4An alkyl group; and is
R2Is C1-C4An alkyl group, a carboxyl group,
wherein the content of the first and second substances,
B1is CF, B2Is CH, and B3Is CH; or
B1Is CF, B2Is CF, and B3Is CH; or
B1Is CF, B2Is N, and B3Is CF.
Detailed Description
As used herein, the terms "comprises," "comprising," "includes," "including," "containing," "has," "having," "characterized by," or any other variation thereof, are intended to cover a non-exclusive inclusion, subject to any limitation explicitly indicated. For example, a composition, mixture, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process, method, article, or apparatus.
The conjunctive phrase "consisting of" excludes any elements, steps or components not specified. If in the claims, this is intended to encompass the claims, in addition to impurities normally associated therewith, also including substances other than those listed. When the phrase "consisting of" appears in a clause of the claims, it limits only the elements listed in the clause, and not the elements immediately following the preamble; other elements are not excluded from the entire claims.
The conjunctive phrase "consisting essentially of.. other than those literally disclosed, is used to define a composition, method or apparatus comprising substances, steps, features, components or elements, provided that such additional substances, steps, features, components or elements do not materially affect the basic and novel characteristics of the claimed invention. The term "consists essentially of.
If applicants have defined an invention or a portion thereof using open-ended terms such as "comprising," it should be readily understood (unless otherwise noted) that this description should be construed as describing the invention also using the term "consisting essentially of or" consisting of.
Further, "or" refers to an inclusive "or" and not to an exclusive "or" unless expressly stated to the contrary. For example, condition a or B is satisfied by any one of: a is true (or present) and B is false (or not present); a is false (or not present) and B is true (or present); and, both a and B are true (or present).
In addition, the indefinite articles "a" and "an" preceding an element or component of the invention are intended to be nonrestrictive as to the number of instances (i.e., occurrences) of the element or component. Thus, "a" or "an" should be understood to include one or at least one and the singular forms of an element or component also include the plural unless the number is obviously singular.
In the above expressions, the term "alkyl" includes straight-chain or branched alkyl groups, such as methyl, ethyl, n-propyl, isopropyl or the different butyl isomers.
"unsubstituted benzyl" means benzyl (i.e., -CH) without any substitution2Ph). "substituted benzyl" refers to a benzyl group that is substituted on the methylene or phenyl moiety that makes up the benzyl group. Benzyl radical derived from C1-C4Alkyl radical, C1-C4Alkoxy or C2-C4Alkenyl, wherein the term "alkyl" is as defined above; "alkoxy" includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy, and the different butoxy isomers; and "alkenyl" includes straight or branched chain alkenes such as ethenyl, 1-propenyl, 2-propenyl, and the different butenyl isomers. "alkenyl" also includes polyenes such as 1, 2-allenyl.
The total number of carbon atoms in the substituent being represented by "Ci-Cj"prefix indicates where i and j are numbers from 1 to 4. E.g. C1-C4Alkyl represents methyl to butyl; c2Alkoxy represents CH3CH2O-；C3Alkenyl represents, for example, CH2＝CHCH2-。
In the compounds of the formulae I, II-A, II-B, III, IV and V, the variables A are contained1、A2And A3Can be connected withRepresented by the structure shown in figure 1, where the key protruding to the right indicates the point of attachment to the rest of formula I, II-A, II-B, III, IV or V.
Exhibit 1
In the compounds of the formulae I and VI, the variable B is contained1、B2And B3Can be represented by the following structure shown in FIG. 2, wherein the bond protruding to the left indicates the-NH-with the rest of formula I or formula VI2The attachment point of (a).
Exhibit 2
The compounds of the present invention (i.e., the compounds of formulas I and VI) may exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. Stereoisomers are isomers that are identical in composition but differ in the arrangement of their atoms in space, and include enantiomers, diastereomers, cis-trans isomers (also known as geometric isomers) and atropisomers. Atropisomers are caused by a restriction of rotation about a single bond, wherein the rotational energy barrier is high enough to allow separation of the isomer species. The process of the invention can produce compounds containing mixtures of enantiomers, diastereomers, atropisomers and geometric isomers. One skilled in the art would know how to isolate, enrich, and/or selectively prepare the stereoisomers. The compounds of the present invention (or processes for their preparation) may be present (or prepared) as a mixture of stereoisomers, as individual stereoisomers, or as an optically active form.
For example, a C ═ o (nh) moiety (bonded to the carbon at the 3-position of the pyrrolidinone ring) and containing the variable a are typically found in the trans configuration1、A2And A3Ring (with the 4-position of the pyrrolidone ring)Carbon bonding at (c). Each of the two carbon atoms has a chiral center. The two most prevalent enantiomeric pairs are depicted as formula I' and formula I ", wherein a chiral center is identified (i.e., as 3S, 4S, or as 3R, 4R). Although the present invention relates to all stereoisomers, the preferred enantiomeric pair for biological operability is identified as formula I' (i.e., 3S, 4S configuration), and the trans configuration is preferred. For a comprehensive discussion of all aspects of stereoisomerism, see "Stereochemistry of organic Compounds", John Wiley, Ernest L.Eliel and Samuel H.Wilen&Sons, 1994.
The molecular descriptions drawn herein follow standard conventions for delineating stereochemistry. To indicate the steric configuration, bonds that rise from the plane of the figure towards the viewer are indicated by solid wedge-shaped lines, where the wide ends of the wedges are attached to atoms that rise from the plane of the figure towards the viewer. Bonds below the plane of the figure and away from the viewer are indicated by dashed wedge lines, where the narrow end of the wedge is attached to atoms closer to the viewer. Lines of constant width indicate bonds having an opposite or neutral orientation relative to bonds represented by solid or dashed wedge lines; the lines of constant width also depict bonds in the molecule or portion of the molecule that are not intended to designate a particular steric configuration.
The present invention includes racemic mixtures, e.g., equal amounts of the enantiomers of formulas I 'and I' and the corresponding pyrrolidones of formulas II, II-A, II-B, and III. Likewise, the present invention includes racemic mixtures of pyrrolidone compounds of formula IV and V. In addition, the invention includes compounds that are enriched compared to the racemic mixture. Also included are substantially pure enantiomers of the compounds of formulas I, II-A, II-B, III, IV and V.
When enantiomerically enriched, one enantiomer is present in a greater amount than the other enantiomer, and the degree of enrichment can be defined as the ratio of the counterparts (ER) expressed as% of the relative area of the two enantiomers as determined by chiral high performance liquid chromatography.
Preferably, the compounds prepared by the process of the present invention have a more active isomer with an ER of at least 50%, more preferably an ER of at least 75%, still more preferably an ER of at least 90% and most preferably an ER of at least 94%. Of particular note are the enantiomeric purity embodiments of the more desirable isomers. The enantiomeric excess (e.e.) can be calculated from the enantiomeric ratio.
The compounds of formulae II and IV are generally present in more than one form and, therefore, include all crystalline and non-crystalline forms of the compounds they represent. Non-crystalline forms include embodiments of solids (such as waxes and gums) as well as embodiments of liquids (such as solutions and melts). Crystalline forms include embodiments that represent substantially a single crystalline form as well as embodiments that represent mixtures of polymorphic forms (i.e., different crystalline forms). The term "polymorph" refers to a particular crystalline form of a chemical compound that can crystallize in different crystalline forms having different arrangements and/or conformations of molecules in a crystal lattice. Although polymorphs can have the same chemical composition, they can also differ in composition due to the presence or absence of co-crystallized water or other molecules that can be weakly or strongly bound in the crystal lattice. The chemical and physical properties of polymorphs, such as crystal shape, density, hardness, color, chemical stability, melting point, hygroscopicity, suspensibility and dissolution rate, can vary. One skilled in the art will appreciate that one polymorph or polymorphic mixture of a compound of formula II or IV may exhibit beneficial effects (e.g., suitability for isolation, or for use in subsequent steps to improve yield) relative to another polymorph or polymorphic mixture of the same compound of formula II or IV. The preparation and isolation of particular polymorphs of a compound of formula II or IV can be achieved by methods known to those skilled in the art including, for example, crystallization using selected solvents and temperatures. The process for preparing the compounds of formula I, II-A, II-B, III, IV and V may result in one or more specific polymorphs. For a comprehensive discussion of polymorphisms, see "Polymorphism in the Pharmaceutical Industry" edited by r.hilfiker, Wiley-VCH, Weinheim, 2006.
Those skilled in the art will appreciate that not all nitrogen-containing heterocycles can form N-oxides because available lone pairs are required to oxidize nitrogen to oxide; those skilled in the art will recognize those nitrogen-containing heterocycles that can form N-oxides. Those skilled in the art will also recognize tertiary amines that can form N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and ketone peroxides such as dimethyl ketone peroxide. These methods for preparing N-oxides have been widely described and reviewed in several documents, see, for example: "Comprehensive Organic Synthesis" by T.L.Gilchrist, Vol.7, pages 748 to 750, edited by S.V.Ley, Pagasma publishers; tisler and b.stanovnik, "Comprehensive Heterocyclic Chemistry", volume 3, pages 18 to 20, edited by a.j.boulton and a.mckillop, pa cama press; "advanced in heterocyclic Chemistry" by m.r.grimett and b.r.t.keene, volume 43, pages 149 to 161, editors by a.r.katritzky, american academy; tisler and b.stanovnik, "advanced in Heterocyclic Chemistry", volume 9, pages 285 to 291, edited by a.r.katritzky and a.j.boulton, academic press; and "Advances in Heterocyclic Chemistry" by G.W.H.Cheeseman and E.S.G.Werstuk, Vol.22, pp.390 to 392, edited by A.R.Katritzky and A.J.Boulton, U.S. academic Press.
Salts of the compounds of formulae II and IV include acid addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric. When the compounds of formulae II and IV contain an acidic moiety, such as a carboxylic acid or phenol, their salts also include those formed with organic or inorganic bases such as pyridine, triethylamine or ammonia, or amides, hydrides, hydroxides or carbonates of sodium, potassium, lithium, calcium, magnesium or barium. Accordingly, the present invention includes a compound selected from the group consisting of compounds of formulas II and IV, N-oxides and agriculturally suitable salts thereof.
Embodiments of the invention as described in the summary of the invention include: