Polysubstituted pyridine derivative and preparation method thereof
阅读说明：本技术 一种多取代吡啶衍生物及其制备方法 (Polysubstituted pyridine derivative and preparation method thereof ) 是由 张洪彬 魏凯 孙玉翠 李�瑞 赵静峰 陈文� 何严萍 羊晓东 于 2021-07-20 设计创作，主要内容包括：本发明公开了一种多取代吡啶衍生物及其制备方法。具体的,多取代吡啶衍生物的制备方法为如下任一方案：方案一：在卤化试剂和/或磺酸酐存在下,化合物1与进行如下所示的环合反应,得化合物2；方案二：在羧酸酐和/或磺酸酐存在下,在BF-(3)·Et-(2)O、CF-(3)SO-(2)OAg和AgBF-(4)中的一种或多种存在下,化合物1与R～(3)C(OR～(6))-(3)进行如下所示的环合反应,得化合物2；方案三：在羧酸酐和/或磺酸酐存在下,在溶剂存在下,化合物1和R～(3)COCl进行如下所示的环合反应,得化合物2。所述的制备方法条件温和、普适性广且无需使用高毒性试剂。(The invention discloses a polysubstituted pyridine derivative and a preparation method thereof. Specifically, the preparation method of the polysubstituted pyridine derivative is any one of the following schemes: the first scheme is as follows: compound 1 with halogenating agent and/or sulfonic anhydride Carrying out cyclization reaction as shown in the specification to obtain a compound 2; scheme II: in the presence of carboxylic and/or sulfonic anhydrides in BF 3 ·Et 2 O、CF 3 SO 2 OAg and AgBF 4 One or more ofCompounds 1 and R in the Presence of a plurality of 3 C(OR 6 ) 3 Carrying out cyclization reaction as shown in the specification to obtain a compound 2; the third scheme is as follows: compounds 1 and R in the presence of carboxylic and/or sulfonic anhydrides in the presence of a solvent 3 The COCl undergoes a cyclization reaction as shown below to give compound 2. The preparation method has mild conditions and wide universality, and does not need to use a high-toxicity reagent.)
1. a preparation method of a polysubstituted pyridine derivative is any one of the following schemes:
the first scheme is as follows:
compound 1 with halogenating agent and/or sulfonic anhydrideCarrying out cyclization reaction as shown in the specification to obtain a compound 2;
scheme II:
in the presence of carboxylic and/or sulfonic anhydrides in BF3·Et2O、CF3SO2OAg and AgBF4In the presence of one or more of (A) and (B), compound 1 and R3C(OR6)3Carrying out cyclization reaction as shown in the specification to obtain a compound 2;
the third scheme is as follows:
compounds 1 and R in the presence of carboxylic and/or sulfonic anhydrides in the presence of a solvent3Performing cyclization reaction on COCl as shown in the specification to obtain a compound 2;
R1is C1-C6Alkyl radical, R1-1Substituted C1-C6Alkyl radical, C2-C6Alkenyl radical, R1-2Substituted C2-C6Alkenyl radical, C3-C12Cycloalkyl radical, R1 -3Substituted C3-C12Cycloalkyl, 6-10 membered aryl, R1-4Substituted 6-10 membered aryl, 5-10 membered heteroaryl, R1-5Substituted 5-10 membered heteroaryl, C2-C8Heterocycloalkyl, R1-6Substituted C2-C8Heterocycloalkyl or
R1-1、R1-2、R1-3、R1-4、R1-5And R1-6Independently represent nitro, Boc, halogen, C1-C6Alkoxy, 6-to 10-membered aryl substituted C1-C6Alkoxy, 6-10 membered aryl, 5-10 membered heteroaryl or Boc substituted 5-10 membered heteroaryl;
R1-7is C1-C6An alkyl group;
R2is H, C1-C6Alkyl radical, C2-C6Alkenyl, 6-10 membered aryl orR2-1Is H or C1-C6An alkyl group;
R3is H, C1-C6Alkyl or halogen substituted C1-C6An alkyl group;
R4、R5and R6Are each independently C1-C6An alkyl group.
2. The process for producing a polysubstituted pyridine derivative according to claim 1, wherein:
at R1In C1-C6In the alkyl group, said C1-C6Alkyl is C1-C3Alkyl, preferably propyl;
and/or, at R1In R1-1Substituted C1-C6In the alkyl group, said C1-C6Alkyl is C1-C3Alkyl, preferably methyl or ethyl;
and/or, at R1In C2-C6Alkenyl or R1-2Substituted C2-C6In the alkenyl group, the C2-C6Alkenyl is C2-C4Alkenyl, preferably butenyl, e.g.
And/or, at R1In C3-C12Cycloalkyl or R1-3Substituted C3-C12In the cycloalkyl group, said C3-C12Cycloalkyl being monocyclic C3-C12Cycloalkyl, preferably C3-C6Cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and still more preferably cyclobutyl or cyclopentylA group;
and/or, at R1In 6-to 10-membered aryl or R1-4Of the substituted 6-to 10-membered aryl groups, the 6-to 10-membered aryl group being phenyl or naphthyl, e.g.
And/or, at R1In 5-10 membered heteroaryl or R1-5Of the substituted 5-to 10-membered heteroaryl groups, the 5-to 10-membered heteroaryl group is a 5-to 9-membered heteroaryl group, such as a thienyl, furyl, indolyl, benzofuryl or quinolyl group, and further such as
And/or, at R1In C2-C8Heterocycloalkyl or R1-6Substituted C2-C8In the heterocycloalkyl group, said C2-C8Heterocycloalkyl being C3-C6Heterocycloalkyl, preferably tetrahydropyrrolyl, e.g.
And/or, at R1-1In 6-to 10-membered aryl-substituted C1-C6In the alkoxy, the 6-10 membered aryl is phenyl;
and/or, at R1-1In 6-to 10-membered aryl-substituted C1-C6In alkoxy, said C1-C6Alkoxy is C1-C3Alkoxy, preferably methoxy; said 6-to 10-membered aryl-substituted C1-C6Alkoxy is preferred
And/or, at R1-1In the 6-to 10-membered aryl group,the 6-10 membered aryl is phenyl;
and/or, at R1-4Among the halogens, said halogen is fluorine, chlorine or bromine, preferably fluorine or chlorine;
and/or, at R1-4In C1-C6In alkoxy, said C1-C6Alkoxy is C1-C3Alkoxy, preferably methyl;
and/or, at R1-7In (b), the C1-C6Alkyl is C1-C3Alkyl, preferably ethyl;
and/or, R1-1、R1-2、R1-3、R1-4、R1-5And R1-6The number of (a) is one, two or three, preferably one;
and/or, at R2In (b), the C1-C6Alkyl is C1-C3An alkyl group;
and/or, at R2In (b), the C2-C6Alkenyl is C2-C4An alkenyl group;
and/or, at R2Wherein said 6-to 10-membered aryl is phenyl;
and/or, at R3In halogen-substituted C1-C6In the alkyl, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine;
and/or, at R3In halogen-substituted C1-C6In the alkyl group, the number of the halogen is one, two or three;
and/or, at R3In halogen-substituted C1-C6In the alkyl group, said C1-C6Alkyl is C1-C3Alkyl, preferably methyl.
3. The process for producing a polysubstituted pyridine derivative according to claim 1 or 2, wherein:
at R1In R1-5In substituted 5-10 membered heteroaryl, said 5-10 membered heteroaryl comprises the structure NH, at R1-5In the case of Boc, the substitution site of Boc is preferably NH structure, and said 5-to 10-membered heteroaryl is preferably indolyl, more preferably indolyl
And/or, at R1In R1-6Substituted C2-C8In the heterocycloalkyl group, said C2-C8The heterocycloalkyl group contains the structure NH, at R1-6In the case of Boc, the substitution site of Boc is preferably NH structure;
and/or, at R1-1Wherein, in Boc substituted 5-10 membered heteroaryl, said 5-10 membered heteroaryl comprises NH structure, the Boc substitution site is preferably NH structure, said 5-10 membered heteroaryl is preferably indolyl, more preferably
And/or, at R1In when R is1Is R1-1Substituted C1-C6Alkyl radical, R1-1Is 6-10 membered aryl substituted C1-C6At alkoxy, said R1Is composed of
And/or, at R1In when R is1Is R1-1Substituted C1-C6Alkyl radical, R1-1When it is a 6-to 10-membered aryl group, said R1Is composed of
And/or, at R1In when R is1Is R1-1Substituted C1-C6Alkyl radical, R1-1In the case of Boc-substituted 5-to 10-membered heteroaryl, said R1Is composed of
And/or, at R1In when R is1Is R1-4Substituted 6-to 10-membered aryl, R1-4When is nitro, the R is1Is composed of
And/or, at R1In when R is1Is R1-4Substituted 6-to 10-membered aryl, R1-4When it is halogen, R is1Is composed of
And/or, at R1In when R is1Is R1-4Substituted 6-to 10-membered aryl, R1-4Is C1-C6At alkoxy, said R1Is composed of
And/or, at R1In when R is1Is R1-5Substituted 5-10 membered heteroaryl, R1-4When Boc is used, R is1Is composed of
And/or, at R1In when R is1Is R1-6Substituted C2-CaHeterocycloalkyl radical, R1-6When Boc is used, R is1Is composed of
And/or, at R2In C1-C6In the alkyl group, said C1-C6Alkyl is ethyl;
and/or, at R2In C2-C6In the alkenyl group, the C2-C6Alkenyl is
And/or, at R3In (b), said halogen substituted C1-C6The alkyl group is trifluoromethyl.
4. The process for producing a polysubstituted pyridine derivative according to claim 1, wherein:
said R1Is phenyl, Propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
And/or, said R2Is H, formyl, ethyl, phenyl or
And/or, said R3Is H or trifluoromethyl.
5. The process for producing a polysubstituted pyridine derivative according to claim 1, wherein:
said R1Is C1-C6Alkyl radical, R1-1Substituted C1-C6Alkyl radical, C2-C6Alkenyl radical, C3-C12Cycloalkyl, 6-10 membered aryl, R1-4Substituted 6-10 membered aryl, 5-10 memberedHeteroaryl, R1-5Substituted 5-10 membered heteroaryl, R1-6Substituted C2-C8Heterocycloalkyl orPreferably, R is1Is C1-C6Alkyl radical, R1-1Substituted C1-C6Alkyl radical, C2-C6Alkenyl radical, C3-C12Cycloalkyl, 6-10 membered aryl, R1-4Substituted 6-10 membered aryl, 5-9 membered heteroaryl or R1-5Substituted 5-9 membered heteroaryl; more preferably, R is1Is C2-C6Alkenyl, cyclobutyl, cyclopentyl, 6-10 membered aryl, R1-4Substituted 6-10 membered aryl or 5-9 membered heteroaryl;
and/or, said R1-1Is 6-10 membered aryl substituted C1-C6Alkoxy, 6-to 10-membered aryl or Boc-substituted 5-to 10-membered heteroaryl, preferably 6-to 10-membered aryl-substituted C1-C6Alkoxy or Boc substituted 5-10 membered heteroaryl;
and/or, said R1-4Is nitro, halogen or C1-C6Alkoxy, preferably halogen or C1-C6Alkoxy, more preferably fluoro or chloro;
and/or, said R1-5Is Boc;
and/or, said R1-6Is Boc;
and/or, said R2Is H, C1-C6Alkyl radical, C2-C6Alkenyl, 6-10 membered aryl orR2-1Is H; preferably, R2Is H, C1-C6Alkyl radical, C2-C6Alkenyl or 6-10 membered aryl; more preferably, R2Is H or C2-C6An alkenyl group;
and/or, R3Is H or halogen-substituted C1-C6Alkyl, preferably H;
and/or, at R4、R5Or R6In (b), the C1-C6Alkyl is C1-C3Alkyl, preferably methyl.
6. The process for producing a polysubstituted pyridine derivative according to claim 1, wherein:
the group definition in the preparation method of the polysubstituted pyridine derivative is any scheme as follows:
scheme A:
R1is C1-C6Alkyl radical, R1-1Substituted C1-C6Alkyl radical, C2-C6Alkenyl radical, C3-C12Cycloalkyl, 6-10 membered aryl, R1-4Substituted 6-10 membered aryl, 5-10 membered heteroaryl, R1-5Substituted 5-10 membered heteroaryl, R1-6Substituted C2-C8Heterocycloalkyl or
R1-1Is 6-10 membered aryl substituted C1-C6Alkoxy, 6-10 membered aryl or Boc substituted 5-10 membered heteroaryl;
R1-4is nitro, halogen or C1-C6An alkoxy group;
R1-5is Boc;
R1-6is Boc;
R2is H, C1-C6Alkyl radical, C2-C6Alkenyl, 6-10 membered aryl orR2-1Is H;
R3is H or halogen-substituted C1-C6An alkyl group;
scheme B:
R1is C1-C6Alkyl radical, R1-1Substituted C1-C6Alkyl radical, C2-C6Alkenyl radical, C3-C12Cycloalkyl, 6-10 membered aryl, R1-4Substituted 6-10 membered aryl, 5-9 membered heteroaryl or R1-5Substituted 5-9 membered heteroaryl;
R1-1is 6-10 membered aryl substituted C1-C6Alkoxy or Boc substituted 5-10 membered heteroaryl;
R1-4is halogen or C1-C6An alkoxy group;
R1-5is Boc;
R2is H, C1-C6Alkyl radical, C2-C6Alkenyl or 6-10 membered aryl;
R3is H or halogen-substituted C1-C6An alkyl group;
scheme C:
R1is C2-C6Alkenyl, cyclobutyl, cyclopentyl, 6-10 membered aryl, R1-4Substituted 6-10 membered aryl or 5-9 membered heteroaryl;
R1-4is fluorine or chlorine;
R1-5is Boc;
R2is H or C2-C6An alkenyl group.
7. The process for producing a polysubstituted pyridine derivative according to claim 1, wherein:
in the first embodiment, the halogenating agent is POCl3、(COCl)2、POBr3、SOCl2、COCl2、PCl5Or PCl3Preferably POCl3、(COCl)2Or POBr3More preferably POCl3；
And/or, in the first scheme, the sulfonic anhydride is (C)1-C6Alkyl SO2)2O or (halogen-substituted C)1-C6Alkyl SO2)2O; said C1-C6Alkyl is preferably C1-C3Alkyl, more preferably methyl, said halogen being preferablySelected from fluorine, chlorine, bromine or iodine, said halogen substituted C1-C6Alkyl is preferably trifluoromethyl;
and/or, in the first scheme, the cyclization reaction further comprises a solvent orAs a solvent;
and/or, in the first mentioned embodiment, the reaction temperature is-10 ℃ to 70 ℃, preferably-10 ℃ to 10 ℃,20 ℃ to 30 ℃ or 40 ℃ to 60 ℃, for example 0 ℃ or 50 ℃;
and/or, in the first scheme, the reaction time is 0.5 to 10 hours, preferably lh to 5 hours;
and/or, in the first scheme, the reaction steps of the cyclization reaction are as follows: in the solvent, the halogenating agent and/or the sulfonic anhydride and theAfter a Vilsmeier reagent is formed, adding the compound 1 to obtain a compound 2; preferably, the reaction steps of the ring closure reaction are preferably as follows: in the solvent, at-10 deg.C under the action of said halogenating agent and/or sulfonic anhydrideAfter Vilsmeier reagent is formed, adding the compound 1 at the temperature of 20-60 ℃ to obtain a compound 2;
and/or, in the cyclization reaction, the post-treatment is included after the cyclization reaction is finished, and the post-treatment preferably includes the following steps: after the cyclization reaction is finished, adding an alkali aqueous solution until the pH value is 8-11, extracting, layering, and concentrating an organic phase to obtain a compound 2; the alkali is preferably sodium bicarbonate;
and/or, in the second scheme, the carboxylic anhydride is trifluoroacetic anhydride;
and/or, in the second scheme, the sulfonic anhydride is trifluoromethanesulfonic anhydride;
and/or, in the second embodiment, the BF3·Et2O、CF3SO2OAg and AgBF4One or more of them is BF3·Et2O；
And/or, in the second scheme, the R6Is methyl or ethyl, preferably methyl;
and/or, in the second scheme, the R3C(OR6)3Is methyl orthoformate, ethyl orthoformate orPreferably methyl orthoformate or
And/or, in the second scheme, the cyclization reaction further comprises a solvent or R3C(OR6)3As a solvent;
and/or, in the second embodiment, the reaction temperature is-10 ℃ to 70 ℃, preferably-10 ℃ to 10 ℃,10 ℃ to 30 ℃ or 40 ℃ to 60 ℃, for example, 0 ℃ or 50 ℃;
and/or, in the second scheme, the reaction time is 0.5 to 15 hours, preferably 0.6 to 9 hours;
and/or, in the second scheme, the reaction steps of the cyclization reaction are as follows: in the solvent, after the carboxylic anhydride and/or the sulfonic anhydride and the compound 1 are subjected to a Pummerer rearrangement reaction, the R is added3C(OR6)3And BF3·Et2O、CF3SO2OAg and AgBF4One or more of them to obtain a compound 2; preferably, in the second scheme, the reaction steps of the cyclization reaction are preferably as follows: in the solvent, the carboxylic anhydride and/or the sulfonic anhydride and the compound 1 are jected to a Pumerer rearrangement reaction at the temperature of minus 10 ℃ to 10 ℃, and then the R is added at the temperature of 10 ℃ to 60 DEG C3C(OR6)3And BF3·Et2O、CF3SO2OAg and AgBF4One or more of them to obtain a compound 2;
and/or, in the third scheme, the carboxylic anhydride is trifluoroacetic anhydride;
and/or, in the third scheme, the sulfonic anhydride is trifluoromethanesulfonic anhydride;
and/or, in the third embodiment, the cyclization reaction further comprises BF3·Et2O、CF3SO2OAg and AgBF4Preferably comprising AgBF4(ii) a When the cyclization reaction in scheme III further comprises BF3·Et2O、CF3SO2OAg and AgBF4In one or more of (a), said compound 1 and said BF3·Et2O、CF3SO2OAg and AgBF4The molar ratio of one or more of (a) may be 1:0.1 to 1:10, preferably 1:0.1 to 1:1, for example 1:0.1 to 1: 0.2;
and/or, in the third embodiment, the R3Is H, methyl, ethyl, trifluoromethyl, tribromomethyl or trichloromethyl, preferably H or trifluoromethyl;
and/or, in the third embodiment, the solvent is a halogenated alkane solvent, such as dichloromethane, trichloromethane or 1, 2-dichloroethane;
and/or, in said scheme III, said Compound 1 with said R3The mol ratio of COCl is 1: 3-1: 10, preferably 1: 6-1: 10;
and/or, in the third embodiment, the molar ratio of the compound 1 to the carboxylic anhydride and/or the sulfonic anhydride is 1: 1-1: 3, preferably 1: 1.5;
and/or, in the third embodiment, the reaction temperature is-10 ℃ to 70 ℃, preferably-10 ℃ to 10 ℃,10 ℃ to 30 ℃ or 40 ℃ to 60 ℃, for example, 0 ℃ or 50 ℃;
and/or, in the third scheme, the reaction time is 0.5 to 15 hours, preferably 0.6 to 9 hours;
and/or, in the third scheme, the reaction steps of the cyclization reaction are as followsShown in the figure: in the solvent, after the carboxylic anhydride and/or the sulfonic anhydride and the compound 1 are subjected to a Pummerer rearrangement reaction, the R is added3COCl to obtain a compound 2; preferably, in the third scheme, the reaction steps of the cyclization reaction are as follows: in the solvent, the carboxylic anhydride and/or the sulfonic anhydride and the compound 1 are jected to a Pumerer rearrangement reaction at the temperature of minus 10 ℃ to 10 ℃, and then the R is added at the temperature of 10 ℃ to 60 DEG C3COCl to obtain a compound 2.
8. The process for producing a polysubstituted pyridine derivative according to claim 7, wherein:
in the first embodiment, when the ring closure reaction further comprises a solvent:
the solvent is halogenated alkane solvent, such as dichloromethane, trichloromethane or 1, 2-dichloroethane;
and/or the molar ratio of the compound 1 to the halogenating agent and/or the sulfonic anhydride is 1: 2-1: 10, preferably 1: 4-1: 6;
and/or said halogenating agent and/or sulfonic anhydride with saidThe molar ratio of (A) to (B) is 1:1 to 1:100, preferably 1:1 to 1:10, for example 1:1.7 or 1: 2.5;
and/or the concentration of said halogenating agent and/or sulfonic anhydride in said solvent is from 0.01mol/L to 10mol/L, preferably from 0.1mol/L to 1.0mol/L, for example 0.2mol/L or 0.3 mol/L;
in the first scheme, the cyclization reaction is carried outWhen used as a solvent:
the molar ratio of the compound 1 to the halogenating agent and/or the sulfonic anhydride is 1: 2-1: 10, preferably 1: 5-1: 10;
and/or said halogenating agent and/or sulfonic anhydride is present in saidIs/are as followsThe concentration of (B) is 0.1 to 10mol/L, preferably 0.1 to 1.0mol/L, and most preferably 0.25 to 1.0 mol/L;
in the second embodiment, when the ring closure reaction further comprises a solvent:
and/or the solvent is a halogenated alkane solvent, such as dichloromethane, trichloromethane or 1, 2-dichloroethane;
and/or said compound 1 and said BF3·Et2O、CF3SO2OAg and AgBF4In a molar ratio of 1:0.1 to 1:10, more preferably 1:0.1 to 1:1, for example 1:0.1 to 1: 0.2;
and/or the molar ratio of the compound 1 to the carboxylic anhydride and/or the sulfonic anhydride is 1: 1-1: 3, preferably 1: 1.5;
and/or, said BF3·Et2O、CF3SO2OAg and AgBF4With said R3C(OR6)3The molar ratio of (A) to (B) is 0.01:1 to 1:100, preferably 0.03:1 to 1:10, for example 0.03:1 to 0.3: 1;
and/or, said BF3·Et2O、CF3SO2OAg and AgBF4In the solvent at a concentration of 0.001 to 1mol/L, preferably 0.005 to 0.05 mol/L;
in the second scheme, the cyclization is carried out with R3C(OR6)3When used as a solvent;
said compound 1 and said BF3·Et2O、CF3SO2OAg and AgBF4In a molar ratio of 1:0.1 to 1:10, preferably 1:0.1 to 1:1, for example 1:0.1 to 1: 0.2;
and/or the molar ratio of the compound 1 to the carboxylic anhydride and/or the sulfonic anhydride is 1: 1-1: 3, preferably 1: 1.5:
and/or, aThe acid chloride or BF3·Et2O、CF3SO2OAg and AgBF4In said R3C(OR6)3The concentration of (B) is 0.001 to 1mol/L, preferably 0.005 to 0.05 mol/L;
in the third embodiment, when the ring closure reaction further comprises BF3·Et2O、CF3SO2OAg and AgBF4In one or more of the above, the reaction steps of the cyclization reaction are as follows:
in the solvent, after the carboxylic anhydride and/or the sulfonic anhydride and the compound 1 are subjected to a Pummerer rearrangement reaction, the R is added3COCl and BF3·Et2O、CF3SO2OAg and AgBF4One or more of them to obtain a compound 2; preferably, the reaction steps of the cyclization are as follows: in the solvent, the carboxylic anhydride and/or the sulfonic anhydride and the compound 1 are jected to a Pumerer rearrangement reaction at the temperature of minus 10 ℃ to 10 ℃, and then the R is added at the temperature of 10 ℃ to 60 DEG C3COCl and BF3·Et2O、CF3SO2OAg and AgBF4One or more of them to obtain compound 2.
9. A compound 2 which is a derivative of a compound,
wherein R is1、R2And R3Is as defined in any one of claims 1 to 6.
10. Compound 2 according to claim 9, wherein compound 2 is of any one of the following structures:
11. a process for preparing a compound 1 which comprises reacting,
wherein R is1Is C3-C12Cycloalkyl, Boc substituted C2-C8Heterocycloalkyl or C2-C6An alkenyl group;
R2is H or C2-C6An alkenyl group;
when R is1Is C2-C6When an alkenyl radical, R2Is C2-C6An alkenyl group.
12. Compound 1 according to claim 11,
in R of Compound 11In C3-C12In the cycloalkyl group, said C3-C12Cycloalkyl being C3-C6A cycloalkyl group, preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, further preferably a cyclobutyl group or a cyclopentyl group;
and/or, in the compound 1, R1In C2-C8In the heterocycloalkyl group, said C2-C8Heterocycloalkyl being C3-C6Heterocycloalkyl, preferably tetrahydropyrrolyl, e.g.
And/or, in the compound 1, R1In C2-C6In the alkenyl group, the C2-C6Alkenyl is C2-C4Alkenyl, preferably
And/or, in the compound 1, R2In C2-C6In the alkenyl group, the C2-C6Alkenyl is C2-C4Alkenyl, preferably
13. Compound 1 according to claim 11 or 12, wherein compound 1 is of any one of the following structures:
14. a preparation method of a polysubstituted pyridine derivative is any one of the following schemes:
the first scheme is as follows:
compound 3 with halogenating agent and/or sulfonic anhydrideCarrying out cyclization reaction as shown below to obtain a compound 4;
scheme II:
in the presence of carboxylic and/or sulfonic anhydrides in BF3·Et2O、CF3SO2OAg and AgBF4In the presence of one or more of (a) compound 3 and R3C(OR6)3Carrying out cyclization reaction as shown below to obtain a compound 4;
the third scheme is as follows:
compounds 3 and R in the presence of carboxylic and/or sulfonic anhydrides in the presence of a solvent3The COCl undergoes a cyclization reaction as shown below to give compound 4;
R7is a 6-to 10-membered arylene radical, R7-1Substituted 6-10 membered arylene, 5-10 membered heteroarylene, or R7-2A substituted 5-10 membered heteroarylene;
R7-1and R7-2Each independently is nitro, halogen or C1-C6An alkoxy group;
R2、R3、R4、R5and R6Is as defined in any one of claims 1 to 6.
15. The process for producing a polysubstituted pyridine derivative according to claim 14, wherein:
at R7In 6-to 10-membered arylene or middle R7-1In the substituted 6-to 10-membered arylene group, the 6-to 10-membered arylene group is phenylene, preferably
And/or, at R7In 5-10 membered heteroarylene or middle R7-1Among the substituted 5-to 10-membered heteroarylenes, the 5-to 10-membered heteroarylene is a pyridylene group, and it is preferable that
Preferably, the compound 3 isAccordingly, said compound 4 is
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a polysubstituted pyridine derivative and a preparation method thereof.
Background
The polysubstituted pyridine compounds are a very important class of nitrogen heterocyclic compounds, and have great application value as chemical industrial raw materials or organic synthesis building blocks. The polysubstituted pyridine is widely applied to various production and research fields of medicines, pesticides, functional materials, fine chemical catalysis, coordination chemistry and the like, and the compounds are always the key points of attention and the hot points of research of chemists for a long time. To date, chemists have developed many effective methods for synthesizing polysubstituted pyridines, but many methods have limitations such as severe reaction conditions, difficult preparation of reaction raw materials, single type of reaction synthesized products, difficult further conversion of products, and the need for rare and precious metal catalysis. Pyridine is produced industrially in two general ways: one is extracted from coal tar; the other is to obtain the pyridine compound by the processes of condensation, cyclization, dehydration, oxidation aromatization and the like of amine and carbonyl-containing compounds. The former has complex acquisition mode, expensive separation cost, more product impurities and more limited structure. The latter has relatively easily obtained raw materials and cheap reaction reagents, and can obtain more functionalized pyridine compounds to be widely applied.
The prior synthesis technology I is as follows: the Hantzsch pyridine synthesis method is one of the classic methods for preparing pyridine compounds, namely, two molecules of 1, 3-dicarbonyl compounds react with three components of aldehyde and amine to obtain dihydropyridine compounds, and then the dihydropyridine compounds are oxidized and aromatized to obtain the pyridine compounds. The method has the disadvantages of poor economy, large limitation and single product structure because an oxidizing reagent is needed for aromatization after the reaction is finished.
The prior synthesis technology II comprises the following steps: the synthesis of zizipabine (Chichibabin) is a method for synthesizing polysubstituted pyridine by reacting three molecule enolized aldehyde with ammonia gas. The controllability of the technology in the process of forming the 1, 5-dicarbonyl compound is poor, an oxidant needs to be added for aromatization, and the multi-substituted pyridine formed subsequently is difficult to obtain a multi-functionalized product.
The prior synthesis technology three: the Bohlmann-Rahtz synthesis method is characterized in that after conjugate addition of enamine ester and alkynone, cyclization and dehydration are carried out to form pyridine compound. In the technology, the alkynone and the enamine ester with higher reaction activity need to be prepared in advance, raw materials are not easy to obtain, and the reaction condition requirement is higher.
The prior synthesis technology is four: the Bonnemann synthesis method is discovered in 1981, acrylonitrile and acetylene are used as raw materials, and the reaction is [2+2+2], and metal such as organic cobalt is used as a catalyst, and the reaction is heated to 150 ℃ in toluene to obtain a vinyl substituted pyridine compound. The method needs higher temperature and pressure, the reaction condition is violent, the operation is dangerous, and the pyridine product synthesized under the condition has a single structure.
The prior art is five: [4+2] cycloaddition synthesis method. The method is an aza-Diels-Alder reaction. The diene is used for carrying out addition reaction on a triple bond of nitrile or alkyne and oxime derivative to generate a dihydropyridine compound, and then aromatization is carried out. Cyclic addition of the cyclic azadiene with an alkene or alkyne can also be used to eliminate the formation of pyridine derivatives. Nitrile or oxime derivatives are too weak to be activated by rare noble metals and cyclic azadienes are not readily available making such syntheses difficult to industrialize.
The prior art is six: cycloaddition synthesis method of 6 pi-electrocyclic reaction. The method is characterized in that propargylamine reacts with alpha, beta-unsaturated aldehyde or ketone to generate imine, and then 6 pi-electrocyclic reaction is carried out to synthesize polysubstituted pyridine. The method is an improved version of aza-Diels-Alder reaction, but propargylamine is not easy to obtain, alpha, beta-unsaturated aldehyde ketone belongs to a high-toxicity compound, the reaction needs higher temperature, and the generated multi-substituted pyridine ring is not easy to further carry out structural modification and transformation.
The following documents (a) to (f) can be referred to as documents for synthesizing polysubstituted pyridines: (a) wei, H.; li, Y.quick Access to Pyridines through 6 π -3-Azatriene Electrolysis: contract Total Synthesis of Suaveoline Alkaloids, Synlett 2019,30, 1615-; grasst, j.m.; rodriguez, j.; constantieux, t.metal-Free Multicomponent Syntheses of pyrimidines, chem.rev.2014,114, 10829-10868, (c) Hill, m.d.recent variants for the Syntheses of Pyridine Derivatives, chem.eur.j.2010,16, 12052-; czarnocki, Z. arylpyridines A Review from Selective Synthesis to Atropiosmerim, Synthesis 2019,51, 587. Anhua 611 (e) Nagata, T.; obora, Y.Transmission-Metal-mediated/catalyzed Synthesis of Pyridines, pyrimidines, and triazines by [2+2+2] cyclic addition reactions, Asian J.Org.Chem.2020,9, 1532. 1547.(f) Stanovnik, B.Enaminone, Enaminoesters, and Related Compounds in the Metal-Free Synthesis of pyrimidines and Fused pyrimidines, Eur.J.Org.Chem.2019, 5120-5132.
Disclosure of Invention
The technical problem to be solved by the invention is that the preparation method of the polysubstituted pyridine in the prior art is single. The application provides a polysubstituted pyridine derivative and a preparation method thereof, and the method is mild in condition, wide in universality and free of using a high-toxicity reagent.
The 2,2, 6-trimethyl-4H-1, 3-dioxycyclohexene-4-ketone and tert-butyl sulfenamide used in the invention are cheap and easily available, have stable properties and are easy to store, and can be subjected to various transformations by chemical means so as to be widely applied to organic synthesis in recent years, in particular to preparation of polyfunctional compounds easy to be derivatized. In addition, the N, N-dimethylformamide, the methyl orthoformate and the derivatives thereof are cheap organic synthesis reagents and solvents, and phosphorus oxychloride, trifluoromethanesulfonic anhydride, trifluoroacetic anhydride and acyl chloride are all readily available organic synthesis reagents and can be used for preparing Vilsmeier reagents or active intermediates with high reactivity. The reagents are used for developing a method with mild conditions and wide universality to synthesize the novel polysubstituted pyridine derivative, and have good application prospects.
The invention provides a preparation method of a polysubstituted pyridine derivative, which is any one of the following schemes:
the first scheme is as follows:
compound 1 with halogenating agent and/or sulfonic anhydrideCarrying out cyclization reaction as shown in the specification to obtain a compound 2;
scheme II:
in the presence of carboxylic and/or sulfonic anhydrides in BF3·Et2O、CF3SO2OAg and AgBF4In the presence of one or more of (A) and (B), compound 1 and R3C(OR6)3Carrying out cyclization reaction as shown in the specification to obtain a compound 2;
the third scheme is as follows:
compounds 1 and R in the presence of carboxylic and/or sulfonic anhydrides in the presence of a solvent3Performing cyclization reaction on COCl as shown in the specification to obtain a compound 2;
R1is C1-C6Alkyl radical, R1-1Substituted C1-C6Alkyl radical, C2-C6Alkenyl radical, R1-2Substituted C2-C6Alkenyl radical, C3-C12Cycloalkyl radical, R1-3Substituted C3-C12Cycloalkyl, 6-10 membered aryl, R1-4Substituted 6-10 membered aryl, 5-10 membered heteroaryl, R1-5Substituted 5-10 membered heteroaryl, C2-C8Heterocycloalkyl, R1-6Substituted C2-C8Heterocycloalkyl or
R1-1、R1-2、R1-3、R1-4、R1-5And R1-6Independently represent nitro, Boc, halogen, C1-C6Alkoxy, 6-to 10-membered aryl substituted C1-C6Alkoxy, 6-10 membered aryl, 5-10 membered heteroaryl or Boc substituted 5-10 membered heteroaryl;
R1-7is C1-C6An alkyl group;
R2is H, C1-C6Alkyl radical, C2-C6Alkenyl, 6-10 membered aryl orR2-1Is H or C1-C6An alkyl group;
R3is H, C1-C6Alkyl or halogen substituted C1-C6An alkyl group;
R4、R5and R6Are each independently C1-C6An alkyl group.
At R1In C1-C6In the alkyl group, said C1-C6Alkyl is preferably C1-C3Alkyl, more preferably propyl.
At R1In R1-1Substituted C1-C6In the alkyl group, said C1-C6Alkyl is preferably C1-C3Alkyl, more preferably methyl or ethyl.
At R1In C2-C6Alkenyl or R1-2Substituted C2-C6In the alkenyl group, the C2-C6Alkenyl is preferably C2-C4Alkenyl, more preferably butenyl, e.g.
At R1In C3-C12Cycloalkyl or R1-3Substituted C3-C12In the cycloalkyl group, said C3-C12Cycloalkyl is preferably monocyclic C3-C12Cycloalkyl, preferably C3-C6Cycloalkyl groups are more preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and still more preferably cyclobutyl or cyclopentyl.
At R1In 6-to 10-membered aryl or R1-4Of the substituted 6-to 10-membered aryl groups, said 6-to 10-membered aryl group is preferably phenyl or naphthyl, for example
At R1In 5-10 membered heteroaryl or R1-5In a substituted 5-to 10-membered heteroaryl group, said 5-to 10-membered heteroarylAryl is preferably 5-to 9-membered heteroaryl, such as thienyl, furyl, indolyl, benzofuryl or quinolyl, and also for example
At R1Among the 5-to 10-membered heteroaryl groups, the 5-to 10-membered aryl group is preferably a thienyl group, a furyl group, a benzofuryl group or a quinolyl group, and more preferably
At R1In R1-5In the substituted 5-10 membered heteroaryl, said 5-10 membered heteroaryl preferably comprises an NH structure at R1-5In the case of Boc, the substitution site of Boc is preferably NH structure, and said 5-to 10-membered heteroaryl is preferably indolyl, more preferably indolyl
At R1In C2-C8Heterocycloalkyl or R1-6Substituted C2-C8In the heterocycloalkyl group, said C2-C8Heterocycloalkyl is preferably C3-C6Heterocycloalkyl, more preferably tetrahydropyrrolyl, e.g.
At R1In R1-6Substituted C2-C8In the heterocycloalkyl group, said C2-C8The heterocycloalkyl group preferably contains an NH structure, at R1-6In the case of Boc, the substitution site with Boc is preferably of NH structure.
At R1-1In 6-to 10-membered aryl-substituted C1-C6In the alkoxy, the 6-to 10-membered aryl is preferably phenyl, the C is1-C6Alkoxy is preferably C1-C3Alkoxy, more preferablySelecting a methoxyl group; said 6-to 10-membered aryl-substituted C1-C6Alkoxy is preferred
At R1-1Among 6-to 10-membered aryl groups, the 6-to 10-membered aryl group is preferably a phenyl group.
At R1-1In the Boc substituted 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group preferably contains an NH structure (e.g., indole), the NH structure is preferably the Boc substitution site, and the 5-10 membered heteroaryl group is preferably the Boc substitution site
At R1-4Among halogens, the halogen is preferably fluorine, chlorine or bromine, more preferably fluorine or chlorine.
At R1-4In C1-C6In alkoxy, said C1-C6Alkoxy is preferably C1-C3Alkoxy, more preferably methyl.
At R1-7In (b), the C1-C6Alkyl is preferably C1-C3Alkyl, more preferably ethyl.
At R1In when R is1Is R1-1Substituted C1-C6Alkyl radical, R1-1Is 6-10 membered aryl substituted C1-C6At alkoxy, said R1Is composed of
At R1In when R is1Is R1-1Substituted C1-C6Alkyl radical, R1-1When it is a 6-to 10-membered aryl group, said R1Is composed of
At R1In when R is1Is R1-1Substituted C1-C6Alkyl radical, R1-1In the case of Boc-substituted 5-to 10-membered heteroaryl, said R1Is composed of
At R1In when R is1Is R1-4Substituted 6-to 10-membered aryl, R1-4When is nitro, the R is1Is composed of
At R1In when R is1Is R1-4Substituted 6-to 10-membered aryl, R1-4When it is halogen, R is1Is composed of
At R1In when R is1Is R1-4Substituted 6-to 10-membered aryl, R1-4Is C1-C6At alkoxy, said R1Is composed of
At R1In when R is1Is R1-5Substituted 5-10 membered heteroaryl, R1-5When Boc is used, R is1Is composed of
At R1In when R is1Is R1-6Substituted C2-C8Heterocycloalkyl radical, R1-6When Boc is used, R is1Is composed of
In one embodiment, R1-1、R1-2、R1-3、R1-4、R1-5And R1-6Preferably one, two or three, more preferably one (said R)1-1、R1-2、R1-3、R1-4、R1-5And R1-6The number of (b) means the number thereof when it is used as a substituent).
In one embodiment, said R is1Is phenyl, Propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
At R2In C1-C6In the alkyl group, said C1-C6Alkyl is preferably C1-C3Alkyl, more preferably ethyl.
At R2In C2-C6In the alkenyl group, the C2-C6Alkenyl is preferably C2-C4Alkenyl, more preferably
At R2Among 6-to 10-membered aryl groups, the 6-to 10-membered aryl group is preferably a phenyl group.
At R3In halogen-substituted C1-C6In the alkyl group, the halogen is preferably fluorine, chlorine, bromine or iodine, more preferably fluorine; said C1-C6Alkyl is preferably C1-C3Alkyl, more preferably methyl; the number of halogens may be oneTwo or three; said halogen substituted C1-C6The alkyl group is preferably a trifluoromethyl group.
In one embodiment, said R is2Is H, formyl, ethyl, phenyl or
In one embodiment, said R is3Is H or trifluoromethyl.
In one embodiment, said R is1Is C1-C6Alkyl radical, R1-1Substituted C1-C6Alkyl radical, C2-C6Alkenyl radical, C3-C12Cycloalkyl, 6-10 membered aryl, R1-4Substituted 6-10 membered aryl, 5-10 membered heteroaryl, R1-5Substituted 5-10 membered heteroaryl, R1-6Substituted C2-C8Heterocycloalkyl orPreferably, R is1Is C1-C6Alkyl radical, R1-1Substituted C1-C6Alkyl radical, C2-C6Alkenyl radical, C3-C12Cycloalkyl, 6-10 membered aryl, R1-4Substituted 6-10 membered aryl, 5-9 membered heteroaryl or R1-5Substituted 5-9 membered heteroaryl; more preferably, R is1Is C2-C6Alkenyl, cyclobutyl, cyclopentyl, 6-10 membered aryl, R1-4Substituted 6-10 membered aryl or 5-9 membered heteroaryl.
In one embodiment, at R1-1In (1), the R is1-1Is 6-10 membered aryl substituted C1-C6Alkoxy, 6-to 10-membered aryl or Boc-substituted 5-to 10-membered heteroaryl, preferably 6-to 10-membered aryl-substituted C1-C6Alkoxy or Boc substituted 5-10 membered heteroaryl.
In one embodiment, at R1-4In (1), the R is1-4Is nitro, halogen or C1-C6Alkoxy, preferably halogen or C1-C6Alkoxy, more preferably fluorine or chlorine.
In one embodiment, at R1-5In (1), the R is1-5Is Boc.
In one embodiment, at R1-6In (1), the R is1-6Is Boc.
In one embodiment, at R2In (1), the R is2Is H, C1-C6Alkyl radical, C2-C6Alkenyl, 6-10 membered aryl orR2-1Is H; preferably, R2Is H, C1-C6Alkyl radical, C2-C6Alkenyl or 6-10 membered aryl, more preferably, R2Is H or C2-C6An alkenyl group.
In one embodiment, R3Is H or halogen-substituted C1-C6Alkyl, preferably H.
In one embodiment, at R4、R5Or R6In (b), the C1-C6Alkyl is preferably C1-C3Alkyl, more preferably methyl.
In one embodiment, the group may be defined as any of the following:
scheme A:
R1is C1-C6Alkyl radical, R1-1Substituted C1-C6Alkyl radical, C2-C6Alkenyl radical, C3-C12Cycloalkyl, 6-10 membered aryl, R1-4Substituted 6-10 membered aryl, 5-10 membered heteroaryl, R1-5Substituted 5-10 membered heteroaryl, R1-6Substituted C2-C8Heterocycloalkyl or
R1-1Is 6-10 membered aryl substituted C1-C6Alkoxy, 6-to 10-membered aryl or Boc substitution5-10 membered heteroaryl of (a);
R1-4is nitro, halogen or C1-C6An alkoxy group;
R1-5is Boc;
R1-6is Boc;
R2is H, C1-C6Alkyl radical, C2-C6Alkenyl, 6-10 membered aryl orR2-1Is H;
R3is H or halogen-substituted C1-C6An alkyl group;
scheme B:
R1is C1-C6Alkyl radical, R1-1Substituted C1-C6Alkyl radical, C2-C6Alkenyl radical, C3-C12Cycloalkyl, 6-10 membered aryl, R1-4Substituted 6-10 membered aryl, 5-9 membered heteroaryl or R1-5Substituted 5-9 membered heteroaryl;
R1-1is 6-10 membered aryl substituted C1-C6Alkoxy or Boc substituted 5-10 membered heteroaryl;
R1-4is halogen or C1-C6An alkoxy group;
R1-5is Boc;
R2is H, C1-C6Alkyl radical, C2-C6Alkenyl or 6-10 membered aryl;
R3is H or halogen-substituted C1-C6An alkyl group;
scheme C:
R1is C2-C6Alkenyl, cyclobutyl, cyclopentyl, 6-10 membered aryl, R1-4Substituted 6-10 membered aryl or 5-9 membered heteroaryl;
R1-4is fluorine or chlorine;
R1-5is Boc;
R2is H or C2-C6An alkenyl group.
In the above-mentioned scheme a, scheme B or scheme C, the scheme further comprises:
R3is H.
In the above-mentioned scheme a, scheme B or scheme C, the scheme further comprises:
R4、R5or R6Is C1-C3Alkyl, preferably methyl.
In the first embodiment, the halogenating agent may be a conventional halogenating agent constituting Vilsmeier reagent (see Qian's right, Cao's Ruozhen, Liu Ji.) Vilsmeier reagent used in organic synthesis in recent years [ J]Organic chemistry 2000,20(001):30-43), e.g. POCl3、(COCl)2、POBr3、SOCl2、COCl2、PCl5Or PCl3Preferably POCl3、(COCl)2Or POBr3More preferably POCl3。
In the first embodiment, the sulfonic anhydride may be a conventional sulfonic anhydride constituting Vilsmeier reagent, for example, (C)1-C6Alkyl SO2)2O or (halogen-substituted C)1-C6Alkyl SO2)2O; said C1-C6Alkyl is preferably C1-C3Alkyl, more preferably methyl, said halogen is preferably fluorine, chlorine, bromine or iodine, preferably fluorine, said halogen being substituted with C1-C6The alkyl is preferably trifluoromethyl, and the sulfonic anhydride is preferably trifluoromethanesulfonic anhydride.
In the first embodiment, the ring-closure reaction may further comprise a solvent orAs a solvent.
In the first embodiment, when the ring closure reaction further comprises a solvent:
the solvent may be a solvent conventionally used in the Vilsmeier reaction in the art so as not to affect the reaction, and preferably a halogenated alkane solvent such as dichloromethane, trichloromethane or 1, 2-dichloroethane;
the molar ratio of the compound 1 to the halogenating agent and/or the sulfonic anhydride can be 1: 2-1: 10, preferably 1: 4-1: 6;
said halogenating agent and/or sulfonic anhydride and saidThe molar ratio of (A) to (B) can be a ratio which is conventional in Vilsmeier reaction in the field, preferably 1:1 to 1:100, more preferably 1:1 to 1:10, such as 1:1.7 or 1: 2.5;
the concentration of the halogenating agent and/or the sulfonic anhydride in the solvent may be a concentration conventional in the art for Vilsmeier reactions, preferably from 0.01mol/L to 10mol/L, more preferably from 0.1mol/L to 1.0mol/L, for example 0.2mol/L or 0.3 mol/L.
In the first scheme, the cyclization reaction is carried outWhen used as a solvent;
the molar ratio of the compound 1 to the halogenating agent and/or the sulfonic anhydride may be 1:2 to 1:10 (e.g., 1:2, 1:3, 1:4, 1:5 or 1:6), preferably 1:5 to 1: 10;
the halogenating agent and/or the sulfonic anhydride is in theThe concentration of (b) may be a ratio conventional in the art for Vilsmeier reactions, preferably from 0.1mol/L to 10mol/L, more preferably from 0.1mol/L to 1.0mol/L (e.g., 0.1mol/L, 0.15mol/L, 0.2mol/L, 0.25mol/L or 0.3mol/L), and most preferably from 0.25mol/L to 1.0 mol/L.
In the first scheme, the reaction temperature can be the reaction temperature conventional in the Vilsmeier reaction in the field, and is preferably-10 ℃ to 70 ℃, more preferably-10 ℃ to 10 ℃,20 ℃ to 30 ℃ or 40 ℃ to 60 ℃, such as 0 ℃ or 50 ℃.
In the first scheme, the cyclization reaction takes disappearance or no longer reacting of the compound 1 as a reaction end point, and the reaction time can be 0.5 to 10 hours, preferably 1 to 5 hours.
In the first scheme, the reaction steps of the cyclization reaction can be as follows:
in the solvent, the halogenating agent and/or the sulfonic anhydride and theAfter Vilsmeier reagent is formed, adding the compound 1 to obtain a compound 2.
In the first scheme, the reaction steps of the cyclization reaction are preferably as follows:
in the solvent, at-10 deg.C under the action of said halogenating agent and/or sulfonic anhydrideAfter Vilsmeier reagent is formed, adding the compound 1 at the temperature of 20-60 ℃ to obtain a compound 2.
In the ring-closure reaction, the ring-closure reaction may comprise a post-treatment after the end of the ring-closure reaction, and the post-treatment preferably comprises the following steps: after the cyclization reaction is finished, adding an alkali aqueous solution until the pH value is 8-11, extracting, layering, and concentrating an organic phase to obtain a compound 2; the alkali can be conventional alkali in the field capable of adjusting the pH to 8-11, and sodium bicarbonate is preferred.
In the second scheme, the carboxylic anhydride can be carboxylic anhydride conventionally used in the field of Pummerer rearrangement reaction, and is preferably trifluoroacetic anhydride.
In the second scheme, the sulfonic anhydride may be one conventionally used in the Pummerer rearrangement reaction in the art, and is preferably trifluoromethanesulfonic anhydride.
In the second embodiment, the BF3·Et2O、CF3SO2OAg and AgBF4Preferably BF3·Et2O。
In the second scheme, R is6Preferably methyl or ethyl, more preferably methyl.
In the second scheme, R is3C(OR6)3Preferably methyl orthoformate, ethyl orthoformate orMore preferably methyl orthoformate or
In the second embodiment, the cyclization reaction may further comprise a solvent or R3C(OR6)3As a solvent.
In the second embodiment, when the ring closure reaction further comprises a solvent:
the solvent may be a solvent conventionally used in the Pummerer rearrangement reaction in the art, preferably a haloalkane solvent such as dichloromethane, trichloromethane or 1, 2-dichloroethane;
said compound 1 and said BF3·Et2O、CF3SO2OAg and AgBF4May be in the range of from 1:0.1 to 1:10, more preferably from 1:0.1 to 1:1, for example from 1:0.1 to 1: 0.2;
the molar ratio of the compound 1 to the carboxylic anhydride and/or the sulfonic anhydride can be a conventional ratio in a Pummerer rearrangement reaction in the field, and is preferably 1: 1-1: 3, and more preferably 1: 1.5.
The BF described3·Et2O、CF3SO2OAg and AgBF4With said R3C(OR6)3The molar ratio of (a) may be 0.01:1 to 1:100, preferably 0.03:1 to 1:10, for example 0.03:1 to 0.3: 1;
the BF described3·Et2O、CF3SO2OAg and AgBF4The concentration of one or more of (a) in the solvent may be 0.001 to 1mol/L, more preferably 0.005 to 0.05 mol/L.
In the second scheme, the cyclization is carried out with R3C(OR6)3When used as a solvent;
said compound 1 and said BF3·Et2O、CF3SO2OAg and AgBF4May be in the range of from 1:0.1 to 1:10, more preferably from 1:0.1 to 1:1, for example from 1:0.1 to 1: 0.2;
the molar ratio of the compound 1 to the carboxylic anhydride and/or the sulfonic anhydride can be a conventional ratio in a Pummerer rearrangement reaction in the field, and is preferably 1: 1-1: 3, and more preferably 1: 1.5.
The acyl chloride and BF3·Et2O、CF3SO2OAg and AgBF4In said R3C(OR6)3The concentration of (B) may be 0.001 to 1mol/L, and more preferably 0.005 to 0.05 mol/L.
In the second scheme, the reaction temperature can be the reaction temperature conventional in the field of the Pummerer rearrangement reaction, and is preferably-10 ℃ to 70 ℃, more preferably-10 ℃ to 10 ℃,10 ℃ to 30 ℃ or 40 ℃ to 60 ℃, for example, 0 ℃ or 50 ℃.
In the second scheme, the cyclization reaction takes disappearance or no longer reacting of the compound 1 as a reaction end point, and the reaction time can be 0.5 to 15 hours, preferably 0.6 to 9 hours.
In the second scheme, the reaction steps of the cyclization reaction can be as follows:
in the solvent, after the carboxylic anhydride and/or the sulfonic anhydride and the compound 1 are subjected to a Pummerer rearrangement reaction, the R is added3C(OR6)3And BF3·Et2O、CF3SO2OAg and AgBF4One or more of them to obtain compound 2.
In the second scheme, the reaction steps of the cyclization reaction are preferably as follows:
in the solvent, after the carboxylic anhydride and/or the sulfonic anhydride and the compound 1 are subjected to a Pummerer rearrangement reaction at-10 to 10 ℃, the time of the Pummerer rearrangement reaction is preferably 5 to 15 minutes (for example, 5 to 10 minutes), and the R is added at 10 to 60 DEG C3C(OR6)3And BF3·Et2O、CF3SO2OAg and AgBF4To obtain a compound 2。
In the third scheme, the carboxylic anhydride can be carboxylic anhydride conventionally used in the field of Pummerer rearrangement reaction, and is preferably trifluoroacetic anhydride.
In the third scheme, the sulfonic anhydride may be one conventionally used in Pummerer rearrangement reaction in the art, and is preferably trifluoromethanesulfonic anhydride.
In the third embodiment, the cyclization reaction may further comprise BF3·Et2O、CF3SO2OAg and AgBF4Preferably comprising AgBF4。
When the cyclization reaction in scheme III further comprises BF3·Et2O、CF3SO2OAg and AgBF4In one or more of (a), said compound 1 and said BF3·Et2O、CF3SO2OAg and AgBF4The molar ratio of one or more of (a) may be 1:0.1 to 1:10, more preferably 1:0.1 to 1:1, for example 1:0.1 to 1: 0.2.
In the third aspect, the R3Preferably H, methyl, ethyl, trifluoromethyl, tribromomethyl or trichloromethyl, more preferably H or trifluoromethyl.
In the third scheme, the solvent can be a solvent conventionally used in the field of Pummerer rearrangement reaction, and is preferably a halogenated alkane solvent, such as dichloromethane, trichloromethane or 1, 2-dichloroethane;
in said scheme III, said Compound 1 and said R3The molar ratio of COCl may be 1:3 to 1:10, preferably 1:6 to 1: 10.
In the third scheme, the molar ratio of the compound 1 to the carboxylic anhydride and/or the sulfonic anhydride can be a ratio which is conventional in a Pummerer rearrangement reaction in the field, and is preferably 1: 1-1: 3, and more preferably 1: 1.5.
In the third scheme, the reaction temperature can be the reaction temperature conventional in the field of the Pummerer rearrangement reaction, and is preferably-10 ℃ to 70 ℃, more preferably-10 ℃ to 10 ℃,10 ℃ to 30 ℃ or 40 ℃ to 60 ℃, for example, 0 ℃ or 50 ℃.
In the third scheme, the cyclization reaction takes disappearance or no longer reacting of the compound 1 as a reaction end point, and the reaction time can be 0.5 to 15 hours, preferably 0.6 to 9 hours.
In the third scheme, the reaction steps of the cyclization reaction can be as follows:
in the solvent, after the carboxylic anhydride and/or the sulfonic anhydride and the compound 1 are subjected to a Pummerer rearrangement reaction, the R is added3COCl to obtain a compound 2.
In the third embodiment, when the ring closure reaction further comprises BF3·Et2O、CF3SO2OAg and AgBF4In one or more of the above, the reaction step of the cyclization reaction may be as follows:
in the solvent, after the carboxylic anhydride and/or the sulfonic anhydride and the compound 1 are subjected to a Pummerer rearrangement reaction, the R is added3COCl and BF3·Et2O、CF3SO2OAg and AgBF4One or more of them to obtain compound 2.
In the third scheme, the reaction steps of the cyclization reaction are preferably as follows:
in the solvent, after the carboxylic anhydride and/or the sulfonic anhydride and the compound 1 are subjected to a Pummerer rearrangement reaction at-10 to 10 ℃, the time of the Pummerer rearrangement reaction is preferably 5 to 15 minutes (for example, 5 to 10 minutes), and the R is added at 10 to 60 DEG C3COCl to obtain a compound 2.
In the third embodiment, when the ring closure reaction further comprises BF3·Et2O、CF3SO2OAg and AgBF4In the case of one or more of (a), the reaction step of the cyclization reaction is preferably as follows:
in the solvent, after the carboxylic anhydride and/or the sulfonic anhydride and the compound 1 are subjected to a Pummerer rearrangement reaction at-10 to 10 ℃, the time of the Pummerer rearrangement reaction is preferably 5 to 15 minutes (for example, 5 to 10 minutes), and the R is added at 10 to 60 DEG C3COCl and BF3·Et2O、CF3SO2OAg and AgBF4One or more of them to obtain compound 2.
The present invention also provides a compound 2,
wherein R is1、R2And R3Is as defined above.
In one embodiment, compound 2 is of any of the following structures:
the present invention also provides a compound 1,
wherein R is1Is C3-C12Cycloalkyl, Boc substituted C2-C8Heterocycloalkyl or C2-C6An alkenyl group;
R2is H or C2-C6An alkenyl group;
when R is1Is C2-C6When an alkenyl radical, R2Is C2-C6An alkenyl group.
In R of Compound 11In C3-C12In the cycloalkyl group, said C3-C12Cycloalkyl is preferably C3-C6Cycloalkyl groups are more preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and still more preferably cyclobutyl or cyclopentyl.
In R of Compound 11In C2-C8In the heterocycloalkyl group, said C2-C8Heterocycloalkyl is preferably C3-C6Heterocycloalkyl, more preferably tetrahydropyrrolyl, e.g.
In R of Compound 11In C2-C6In the alkenyl group, the C2-C6Alkenyl is preferably C2-C4Alkenyl, more preferably
In R of Compound 12In C2-C6In the alkenyl group, the C2-C6Alkenyl is preferably C2-C4Alkenyl, more preferably
In one embodiment, compound 1 is of any of the following structures:
the invention also provides another preparation method of the polysubstituted pyridine derivative, which is any one of the following schemes:
the first scheme is as follows:
compound 3 with halogenating agent and/or sulfonic anhydrideCarrying out cyclization reaction as shown below to obtain a compound 4;
scheme II:
in the presence of carboxylic and/or sulfonic anhydrides in BF3·Et2O、CF3SO2OAg and AgBF4In the presence of one or more of (a) compound 3 and R3C(OR6)3Carrying out cyclization reaction as shown below to obtain a compound 4;
the third scheme is as follows:
compounds 3 and R in the presence of carboxylic and/or sulfonic anhydrides in the presence of a solvent3The COCl undergoes a cyclization reaction as shown below to give compound 4;
R7is a 6-to 10-membered arylene radical, R7-1Substituted 6-10 membered arylene, 5-10 membered heteroarylene, or R7-2A substituted 5-10 membered heteroarylene;
R7-1and R7-2Each independently is nitro, halogen or C1-C6An alkoxy group;
R2、R3、R4、R5and R6Is as defined above.
In the above cyclization reaction, other reaction conditions and steps may be as described in the above cyclization reaction, with the only difference being that the halogenating agent and/or sulfonic anhydride and the compound in scheme oneThe dosage of the composition is doubled; the halogenating agent and/or sulfonic anhydride, the BF of the second embodiment3·Et2O、CF3SO2OAg and AgBF4And said R3C(OR6)3The dosage of the composition is doubled; the carboxylic anhydride and/or sulfonic anhydride and the compound of formula III3The amount of COCl used was doubled.
At R7In 6-to 10-membered arylene or middle R7-1Among the substituted 6-to 10-membered arylene groups, the 6-to 10-membered arylene group is preferably a phenylene group, more preferably
At R7In 5-10 membered heteroarylene or middle R7-1Among the substituted 5-to 10-membered heteroarylenes, the 5-to 10-membered heteroarylene is preferably a pyridylene group, more preferably
In one embodiment, the compound 3 is Accordingly, said compound 4 is
In the present invention, unless otherwise indicated, the following terms appearing in the specification and claims of the invention have the following meanings:
the term "halogen" is preferably fluorine, chlorine, bromine, iodine, more preferably fluorine or chlorine.
The term "alkyl" denotes both branched and straight chain saturated aliphatic hydrocarbon groups comprising the specified number of carbon atoms, which alkyl groups may independently be optionally substituted with one or more substituents as described herein. Thus, "C1-C6Alkyl "refers to an alkyl group having 1-6 carbon atoms, (e.g., C1-C3Alkyl, for example methyl); specific examples thereof include, but are not limited to: methyl (Me, -CH)3) Ethyl (Et-CH)2CH3) N-propyl (n-Pr, -CH)2CH2CH3) Isopropyl (i-Pr, -CH (CH)3)2) N-butyl (n-Bu, -CH)2CH2CH2CH3) 2-methylpropyl or isobutyl (i-Bu, -CH)2CH(CH3)2) 1-methylpropyl or sec-butyl (s-Bu, -CH (CH)3)CH2CH3) T-butyl (t-Bu, -C (CH)3)3) N-pentyl (-CH)2CH2CH2CH2CH3) 2-pentyl (-CH (CH)3)CH2CH2CH3) 3-pentyl (-CH (CH)2CH3)2) 2-methyl-2-butyl (-C (CH)3)2CH2CH3) 3-methyl-2-butyl (-CH (CH)3)CH(CH3)2) 3-methyl-1-butyl (-CH)2CH2CH(CH3)2) 2-methyl-1-butyl (-CH)2CH(CH3)CH2CH3) N-hexyl (-CH)2CH2CH2CH2CH2CH3) 4-methylpentyl (-CH)2CH2CH2CH(CH3)CH3) 3-methylpentyl (-CH)2CH2CH(CH3)CH2CH3) 2-methylpentyl (-CH)2CH(CH3)CH2CH2CH3) 2-hexyl (-CH (CH)3)CH2CH2CH2CH3) 3-hexyl (-CH (CH)2CH3)(CH2CH2CH3) 3, 3-dimethylbutyl (-CH)2CH2CH2(CH3)2CH3) 2, 2-dimethylbutyl (-CH)2C(CH3)2CH2CH3) 2-methyl-2-pentyl (-C (CH)3)2CH2CH2CH3) 3-methyl-2-pentyl (-CH (CH)3)CH(CH3)CH2CH3) 4-methyl-2-pentyl (-CH (CH)3)CH2CH(CH3)2) 3-methyl-3-pentyl (-C (CH)3)(CH2CH3)2) 2-methyl-3-pentyl (-CH (CH)2CH3)CH(CH3)2) 2, 3-dimethyl-2-butyl (-C (CH)3)2CH(CH3)2) Or 3, 3-dimethyl-2-butyl (-CH (CH)3)C(CH3)3)。
As used herein, the term "alkenyl" refers to a straight, branched, or cyclic non-linear, branched, or cyclic group containing the specified number of carbon atoms and at least one carbon-carbon double bondAn aromatic hydrocarbon group. Preferably, there is one carbon-carbon double bond, and up to four non-aromatic carbon-carbon double bonds may be present. Thus, "C2-C6Alkenyl "means an alkenyl group having 2 to 6 carbon atoms (e.g., C)2-C4Alkenyl or C2-C3Alkenyl) including ethenyl, propenyl, butenyl, 2-methylbutenyl and cyclohexenyl. The linear, branched, or cyclic portion of the alkenyl group may contain a double bond, and may be substituted if indicated as a substituted alkenyl group.
The term "C1～C6Alkoxy "denotes C attached via an oxygen bridge1～C6An alkyl group; said C1～C6The alkyl group is as defined above.
The term "C3-C12Cycloalkyl "denotes a cyclic hydrocarbon group containing from 3 to 12 carbon atoms which can form a ring, which may be saturated or partially unsaturated (containing 1 or 2 double bonds, but none of the rings having a completely conjugated pi-electron system), and which does not contain heteroatoms; a monocyclic ring comprising 3 to 12 carbon atoms or a bicyclic or tricyclic ring comprising 7 to 12 carbon atoms (including spiro, bridged and fused ring systems); wherein one or more of the ring hydrogen atoms are independently optionally substituted with one or more substituents described herein, and the carbon atoms may be oxidized. The carbocycle having 7 to 12 atoms may be bicyclo [4,5]]，[5,5]，[5,6]Or [6,6]]The system, the carbocycle having 9 or 10 atoms at the same time, may be bicyclo [5,6]]Or [6,6]]And (4) preparing the system. Suitable cycloalkyl groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl groups, such as: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, adamantyl and the like.
The term "C2-C8Heterocycloalkyl "denotes a 3-12 membered monocyclic or polycyclic group (including spiro, bridged and fused rings, preferably spiro, fused and fused) containing 1,2,3 or 4 heteroatoms (one or more selected from N, S and O)A 5-6 membered monocyclic ring) wherein each ring may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system; the heteroatoms may or may not be substituted and the N atoms may be quaternized. Suitable heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyrrolyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1, 3-dioxolanyl, 1, 4-dioxanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydrothiopyranyl, and the like.
The term "heteroaryl" denotes a 5-10 membered monocyclic or polycyclic aromatic system (preferably a 5-6 membered monocyclic aromatic system) comprising 1,2,3 or 4 heteroatoms (one or more selected from N, S and O). The heteroaryl radical may be attached to the main structure at any heteroatom or carbon atom that results in the formation of a stable compound. Heteroaryl groups include, but are not limited to, monocyclic of 3-7 atoms, or bicyclic of 7-10 atoms. The bicyclic ring having 7 to 10 atoms may be a bicyclo [4,5], [5,5], [5,6] or [6,6] system. Heteroaryl groups include, but are not limited to: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazol-5-yl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrimidin-5-yl, pyridazinyl (e.g. 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g. 5-tetrazolyl), triazolyl (e.g. 2-triazolyl and 5-triazolyl), and the like, 2-thienyl, 3-thienyl, pyrazolyl (e.g. 2-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 3-triazolyl, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, 1,3, 4-thiadiazol-2-yl, pyrazinyl, pyrazin-2-yl, 1,3, 5-triazinyl, benzo [ d ] thiazol-2-yl, imidazo [1,5-a ] pyridin-6-yl, benzimidazolyl, benzoxazolyl, quinoxalinyl, 1, 8-diazanaphthyl, benzofuranyl, benzothienyl, benzothiazolyl, thiodiazolyl, 1,2, 5-thiadiazolyl, 1, 4-thiadiazol-2-yl, 1, 2-thiadiazol-yl, 1, 5-a-thiadiazol-6-yl, and a-thienyl, Indolyl (e.g. 2-indolyl), purinyl, quinolyl (e.g. 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (e.g. 1-isoquinolyl, 3-isoquinolyl or 4-isoquinolyl) or tetrahydronaphthyl.
The term "aryl" denotes a monocyclic or bicyclic carbocyclic ring system in which at least one ring system is aromatic, each ring system containing 3 to 7 carbon atoms, and one or more hydrogen atoms in the ring are independently optionally substituted by one or more substituents as described herein. Such as, but not limited to, phenyl, naphthyl, and anthracene.
The term "arylene" refers to a group in which one hydrogen of an aryl group is replaced, the aryl group being as defined above.
The term "heteroarylene" refers to a group formed by substituting one hydrogen in a heteroaryl group, which is as defined above.
In the present invention, Boc means t-butyloxycarbonyl.
The above preferred conditions can be combined arbitrarily to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows:
(1) a new substituted pyridine compound which is difficult to prepare by other methods can be obtained, and the pyridine is easier to be derived;
(2) for the reaction in the application, the traditional preparation method of the polysubstituted pyridine needs to be realized through two steps, and the preparation of the polysubstituted pyridine is realized through one-step reaction, so that the reaction steps are saved, and the cost is greatly reduced; in addition, the polysubstituted pyridine generated in the application is beneficial to further structural modification due to the introduction of a plurality of functional groups;
(3) the reaction is carried out at room temperature or 50 ℃, the reaction time is short, the reaction efficiency is high, the operation is simple and convenient, and the violent reaction conditions or complex operation of other methods are avoided. And under partial conditions, transition metal salt is not needed to participate in the reaction, so that heavy metal pollution can be avoided.
Drawings
FIG. 1 is a structural diagram of the compound 7,7' - (pyridine-2, 6-yl) -bis- (2, 2-dimethyl-4H- [1,3] -dioxino [5,4-c ] pyridin-4-one) in example 17.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
The specific synthesis method (1): dichloromethane (DCM) (20mL) was charged in a round bottom flask, and N, N-Dimethylformamide (DMF) (10mmol,0.77mL), POCl, was added3(6mmol,0.55mL) was reacted at 0 ℃ for 30 minutes, and then the starting t-butylsulfinamide derivative compound 1(1mmol) was added to the round-bottomed flask and reacted at room temperature or 50 ℃ for another 30 minutes. After the reaction is finished, adding saturated sodium bicarbonate aqueous solution to neutralize the reaction solution to be alkalescent, extracting with dichloromethane, drying the combined extract by using anhydrous sodium sulfate, filtering, removing the solvent by reducing pressure, separating the product by using column chromatography, wherein the eluent is petroleum ether/ethyl acetate which is 10/1-1/1, and obtaining the polysubstituted pyridine product 2, and the purity of the product is more than 98%.
The specific synthesis method (2): the starting material, t-butylsulfinamide derivative Compound 1(1mmol), was charged to a round-bottomed flask, Dichloromethane (DCM) (20mL) was added to the round-bottomed flask, and after dissolution, trifluoroacetic anhydride (CF) was added at 0 deg.C3COOH,1.5mmol, 208.6. mu.L), at 0 ℃ for 5-10 minutes, adding acyl chloride or orthoformate (2 mmol for acyl chloride, 5mmol for orthoformate), then adding boron trifluoride diethyl etherate or silver fluoroborate (0.2mmol), and reacting at room temperature or 50 ℃ for 0.5-9 hours. After the reaction is finished, adding saturated sodium bicarbonate aqueous solution to neutralize the reaction solution to be alkalescent, extracting with dichloromethane, drying the combined extract by using anhydrous sodium sulfate, filtering, removing the solvent by reducing pressure, separating the product by using column chromatography, wherein the eluent is petroleum ether/ethyl acetate which is 10/1-1/1, and obtaining the polysubstituted pyridine product 2, and the purity of the product is more than 98%.
And (3) condition screening: only changing the conditions in the following table 1 with reference to a specific synthesis method (1) to obtain the following reactions 1-9 (the difference between the reactions 1-6 and the reactions 7-9 is that only 20mL of DMF is added as a solvent and a reaction reagent in the reactions 1-6, and no additional solvent is added); the following reactions 10 to 22 were obtained by changing only the conditions in the following Table 1 with reference to the specific synthesis method (2).
TABLE 1
Comparative example 1: the synthesis method is the same as the specific synthesis method (1) above, and only the raw materials are usedIn (1)The structure is replaced byStructure, no product was obtained.
The synthesis method is the same as the specific synthesis method (1), and only the raw materials are changed correspondingly to obtain the following compounds in the following embodiments 1-32, specifically as follows:
example 1: 7-phenyl-2, 2-dimethyl-4H- [1,3] -dioxino [5,4-c ] pyridin-4-one in 75% yield.
1H NMR(400MHz,CDCl3)δ9.13(s,1H),8.02–8.00(m,2H),7.49–7.46(m,3H),7.30(s,1H),1.78(s,6H).13C NMR(100MHz,CDCl3):δ164.36,162.83,159.67,151.74,137.76,130.63,129.02,127.45,108.42,108.13,107.68,26.06.
Example 2: 7-phenyl-2, 2-dimethyl-4-oxo-4H- [1,3] -dioxino [5,4-c ] pyridine-8-carbaldehyde in a yield of 10%.
1H NMR(400MHz,CDCl3)δ9.93(s,1H),9.27(s,1H),7.61–7.57(m,2H),7.57–7.52(m,3H),1.85(s,6H).13C NMR(100MHz,CDCl3)δ188.34,168.50,161.96,158.94,153.90,136.72,130.96,130.55,128.92,119.03,108.73,108.69,26.19.
Example 3: 7- (4-chlorophenyl) -2, 2-dimethyl-4H- [1,3] -dioxino [5,4-c ] pyridin-4-one in 70% yield.
1H NMR(400MHz,CDCl3)δ9.13(s,1H),7.97(d,J＝8.1Hz,2H),7.46(d,J＝8.1Hz,2H),7.28(s,1H),1.79(s,6H).13C NMR(100MHz,CDCl3)δ163.03,163.00,159.55,151.85,137.02,136.17,129.33,128.79,108.64,108.07,107.86,26.13.
Example 4: 7- (4-bromophenyl) -2, 2-dimethyl-4H- [1,3] -dioxino [5,4-c ] pyridin-4-one, yield 72%.
1H NMR(400MHz,CDCl3)δ9.11(s,1H),7.89(d,J＝8.4Hz,2H),7.60(d,J＝8.3Hz,2H),7.27(s,1H),1.78(s,6H).13C NMR(100MHz,CDCl3)δ163.06,162.94,159.53,151.84,136.62,132.23,128.97,125.38,108.63,107.99,107.81,26.08.
Example 5: 7- (4-nitrophenyl) -2, 2-dimethyl-4H- [1,3] -dioxino [5,4-c ] pyridin-4-one in 50% yield.
1H NMR(400MHz,CDCl3)δ9.07(s,1H),8.49–8.23(m,2H),8.08–7.86(m,2H),1.87(s,6H).13C NMR(100MHz,CDCl3)δ160.38,159.15,158.38,148.79,148.45,143.04,130.65,123.39,118.63,109.83,108.98,26.06.
Example 6: 7- (4-fluorophenyl) -2, 2-dimethyl-4H- [1,3] -dioxino [5,4-c ] pyridin-4-one in 76% yield.
1H NMR(400MHz,CDCl3)δ9.10(s,1H),8.04–7.99(m,2H),7.25(s,1H),7.19–7.13(m,2H),1.78(s,6H).13C NMR(100MHz,CDCl3):δ164.49(d,J＝250Hz),163.20,162.90,159.63,151.81,133.98(d,J＝3Hz),129.51(d,J＝8Hz),116.08(d,J＝22Hz),108.37,107.78,107.76,26.08.
Example 7: 7- (2-Nitrophenyl) -2, 2-dimethyl-4H- [1,3] -dioxino [5,4-c ] pyridin-4-one in 45% yield.
1H NMR(400MHz,CDCl3)δ9.06(s,1H),7.94(d,J＝8.1Hz,1H),7.72–7.66(m,1H),7.64–7.56(m,2H),7.07(s,1H),1.80(s,6H).13C NMR(100MHz,CDCl3)δ162.77,162.72,159.21,151.66,149.10,134.23,132.82,131.07,130.38,124.80,111.09,109.02,108.08,26.10.
Example 8: 7- (2-methoxyphenyl) -2, 2-dimethyl-4H- [1,3] -dioxino [5,4-c ] pyridin-4-one in 60% yield.
1H NMR(400MHz,CDCl3)δ9.14(s,1H),7.95(dd,J＝7.7,1.7Hz,1H),7.57(s,1H),7.46–7.39(m,1H),7.14–7.05(m,1H),7.01(d,J＝8.3Hz,1H),3.90(s,3H),1.79(s,6H).13C NMR(100MHz,CDCl3)δ162.63,162.02,159.94,157.50,151.11,131.57,131.45,127.15,121.24,112.96,111.58,107.99,107.59,55.71,26.12.
Example 9: 7- (4-bromophenyl) -8-ethyl-2, 2-dimethyl-4H- [1,3] -dioxino [5,4-c ] pyridin-4-one in 65% yield.
1H NMR(400MHz,CDCl3)δ8.99(s,1H),7.62–7.56(m,2H),7.38–7.33(m,2H),2.62(q，J＝7.5Hz，2H)，1.80(s，6H)，1.11(t，J＝7.5Hz，3H).13C NMR(100MHz，CDCl3)δ164.03,161.18,159.88,148.64,138.41,131.64,130.35,125.72,123.35,108.49,107.49,26.10,19.50,14.12.
Example 10: 7- (4-bromophenyl) -8-phenyl-2, 2-dimethyl-4H- [1,3] -dioxino [5,4-c ] pyridin-4-one in 62% yield.
1H NMR(400MHz,CDCl3)δ9.15(s,1H),7.35–7.29(m,5H),7.20–7.16(m,2H),7.12–7.07(m,2H),1.72(s,6H).13C NMR(100MHz,CDCl3)δ162.79,160.29,159.82,150.21,137.93,132.31,131.66,131.17,130.56,128.57,128.19,124.59,123.47,108.59,107.70,25.99.
Example 11: 7- (naphthalen-2-yl) -2, 2-dimethyl-4H- [1,3] -dioxino [5,4-c ] pyridin-4-one in 85% yield.
1H NMR(400MHz,CDCl3)δ9.17(s,1H),8.53(s,1H),8.07(dd,J＝8.7,1.7Hz,1H),7.95–7.89(m,2H),7.87–7.82(m,1H),7.55–7.48(m,2H),7.42(s,1H),1.78(s,6H).13CNMR(100MHz,CDCl3)δ164.24,162.90,159.75,151.84,134.99,134.44,133.37,129.15,128.85,127.83,127.78,127.52,126.79,124.29,108.42,108.38,107.75,26.12.
Example 12: 7- (benzofuran-3-yl) -2, 2-dimethyl-4H- [1,3] -dioxino [5,4-c ] pyridin-4-one in 75% yield.
1H NMR(400MHz,CDCl3)δ9.15(s,1H),8.32(s,1H),8.26–8.18(m,1H),7.62–7.54(m,1H),7.44–7.34(m,2H),7.29(s,1H),1.82(s,6H).13C NMR(100MHz,CDCl3)δ162.56,159.57,159.22,156.28,152.01,146.44,125.29,124.84,123.94,121.84,121.28,112.01,108.07,108.00,107.71,26.09.
Example 13: 7- (thien-2-yl) -2, 2-dimethyl-4H- [1,3] -dioxino [5,4-c ] pyridin-4-one in 70% yield.
1H NMR(400MHz,CDCl3)δ9.00(s,1H),7.66(d,J＝3.1Hz,1H),7.51(d,J＝4.8Hz,1H),7.19(s,1H),7.14(t,J＝4.3Hz,1H),1.77(s,6H).13C NMR(100MHz,CDCl3)δ162.66,159.49,159.04,152.01,143.30,130.39,128.61,127.12,108.14,107.66,105.94,26.08.
Example 14: 7- (furan-3-yl) -2, 2-dimethyl-4H- [1,3] -dioxino [5,4-c ] pyridin-4-one.
1H NMR(400MHz,CDCl3)δ9.01(s,1H),8.11(s,1H),7.50(t,J＝1.7Hz,1H),6.99(s,1H),6.84(d,J＝1.6Hz,1H),1.76(s,6H).13C NMR(100MHz,CDCl3)δ162.69,159.56,158.86,152.01,144.50,143.48,126.40,108.49,108.03,107.63,107.29,26.05.
Example 15: 3- (2, 2-dimethyl-4-oxo-4H- [1,3] -dioxino [5,4-c ] pyridin-7-yl) -1H-indole-1-carboxylic acid tert-butyl ester in a yield of 70%.
1H NMR(400MHz,CDCl3)δ9.15(s,1H),8.31(d,J＝7.5Hz,1H),8.25(br,2H),7.45–7.33(m,2H),7.31(s,1H),1.80(s,6H),1.70(s,9H).13C NMR(100MHz,CDCl3)δ162.51,160.64,159.74,151.91,149.38,136.40,127.68,127.51,125.29,123.88,121.57,119.92,115.58,108.13,107.79,107.65,84.90,28.30,26.16.
Example 16: 7- (quinolin-2-yl) -2, 2-dimethyl-4H- [1,3] -dioxino [5,4-c ] pyridin-4-one in 50% yield.
1H NMR(400MHz,CDCl3)δ9.19(s,1H),8.59(d,J＝8.6Hz,1H),8.32–7.33(m,2H),8.16(d,J＝8.5Hz,1H),7.87(d,J＝8.1Hz,1H),7.76(t,J＝7.6Hz,1H),7.59(t,J＝7.5Hz,1H),1.81(s,6H).13C NMR(100MHz,CDCl3)δ163.20,163.03,159.80,154.45,151.45,148.02,137.22,130.09,130.05,128.87,127.82,127.65,119.38,110.02,109.84,107.81,26.17.
Example 17: 7,7' - (pyridine-2, 6-yl) -bis- (2, 2-dimethyl-4H- [1, 3)]-dioxino [5,4-c]Pyridin-4-one), yield 40%. (POCl for example 17 and example 18 at the time of Synthesis3And DMF doubling in amount)
1H NMR(400MHz,CDCl3)δ9.17(s,2H),8.61(s,1H),8.59(s,1H),8.21(s,2H),8.04(t,J＝7.8Hz,1H),1.83(s,12H).13C NMR(100MHz,CDCl3)δ163.13,162.62,159.65,154.05,151.60,138.58,123.48,109.97,109.09,107.87,26.18.
Crystal data of example 17C23H19N3O6,M＝433.41, α＝88.385(2)°,β＝83.754(2)°,γ＝83.251(2)°,T100. (2) K, space group (space group) P-1, Z2, μ (Cu K α) 0.884mm-117769 repeated measurements, 3959 independent measurements (R)int0.0457). Final R1The value was 0.0417 (I)>2 σ (I)). Final wR (F)2) Value 0.1141 (I)>2 σ (I)). Final R1The value is 0.0466 (all data). Final wR (F)2) The value is 0.1196 (all data). F2The goodness of fit (goodness of fit) of (A) was 1.054. (the structure is shown in FIG. 1)
Example 18: 7,7' - (benzene-1, 3-yl) -bis- (2, 2-dimethyl-4H- [1,3] -dioxino [5,4-c ] pyridin-4-one) in 40% yield.
1H NMR(400MHz,CDCl3)δ9.16(s,2H),8.72(t,J＝1.6Hz,1H),8.14(dd,J＝7.8,1.8Hz,2H),7.62(t,J＝7.8Hz,1H),7.43(s,2H),1.80(s,12H).13C NMR(100MHz,CDCl3)δ163.58,162.98,159.63,151.83,138.52,129.72,129.40,126.56,108.74,108.45,107.84,26.11.
Example 19: 7- (phenethyl) -2, 2-dimethyl-4H- [1,3] -dioxino [5,4-c ] pyridin-4-one in 55% yield.
1H NMR(400MHz,CDCl3)δ9.01(s,1H),7.28–7.22(m,2H),7.20–7.12(m,3H),6.64(s,1H),3.12–3.00(m,4H),1.71(s,6H).13C NMR(100MHz,CDCl3)δ169.60,162.27,159.63,151.41,140.74,128.47,128.41,126.21,110.86,107.96,107.46,40.61,35.26,25.90.
Example 20: ethyl 2, 2-dimethyl-4-oxo-4H- [1,3] -dioxino [5,4-c ] pyridine-7-carboxylate in 45% yield.
1H NMR(400MHz,CDCl3)δ9.15(s,1H),7.70(s,1H),4.46(q,J＝7.0Hz,2H),1.76(s,6H),1.42(t,J＝7.1Hz,3H).13C NMR(100MHz,CDCl3)δ163.93,163.15,158.68,154.36,151.80,114.15,111.89,108.34,62.76,25.99,14.31.
Example 21: 7- (propyl) -2, 2-dimethyl-4H- [1,3] -dioxino [5,4-c ] pyridin-4-one in 60% yield.
1H NMR(400MHz,CDCl3)δ8.94(s,1H),6.71(s,1H),2.73(t,J＝7.6Hz,2H),1.81–1.72(m,2H),1.71(s,6H),0.93(t,J＝7.3Hz,3H).13C NMR(100MHz,CDCl3)δ170.85,162.34,159.71,151.32,110.49,107.82,107.46,40.85,25.97,22.56,13.82.
Example 22: 7- (cyclopropyl) -2, 2-dimethyl-4H- [1,3] -dioxino [5,4-c ] pyridin-4-one in 65% yield.
1H NMR(400MHz,CDCl3)δ8.85(s,1H),6.70(s,1H),2.05–1.96(m,1H),1.72(s,6H),1.16–1.10(m,2H),1.10–1.02(m,2H).13C NMR(100MHz,CDCl3)δ171.92,161.89,159.88,151.57,108.87,107.30,25.99,18.25,11.26.
Example 23: 7- (cyclobutyl) -2, 2-dimethyl-4H- [1,3] -dioxino [5,4-c ] pyridin-4-one in 85% yield.
1H NMR(400MHz,CDCl3)δ8.97(s,1H),6.71(s,1H),3.69–3.56(m,1H),2.37–2.22(m,4H),2.10–1.97(m,1H),1.92–1.81(m,1H),1.71(s,6H).13C NMR(100MHz,CDCl3)δ173.25,162.37,159.75,151.47,108.75,107.72,107.42,42.44,28.18,25.99,18.20.
Example 24: 7- (cyclopentyl) -2, 2-dimethyl-4H- [1,3] -dioxino [5,4-c ] pyridin-4-one in 85% yield.
1H NMR(400MHz,CDCl3)δ8.94(s,1H),6.72(s,1H),3.18–3.05(m,1H),2.08–1.97(m,2H),1.80–1.68(m,10H),1.67–1.61(m,2H).13C NMR(100MHz,CDCl3)δ174.52,162.27,159.72,151.31,109.37,107.72,107.37,48.46,33.32,25.96,25.87.
Example 25: 7- (cyclohexyl) -2, 2-dimethyl-4H- [1,3] -dioxino [5,4-c ] pyridin-4-one in 65% yield.
1H NMR(400MHz,CDCl3)δ8.95(s,1H),6.71(s,1H),2.72–2.62(m,1H),1.92(d,J＝12.5Hz,2H),1.82(d,J＝12.6Hz,2H),1.71(s,7H),1.50–1.30(m,4H),1.29–1.19(m,1H).13C NMR(100MHz,CDCl3)δ175.08,162.53,159.77,151.22,108.81,107.83,107.44,47.07,32.49,26.37,26.01,25.95.
Example 26: 7- (benzyl) -2, 2-dimethyl-4H- [1,3] -dioxino [5,4-c ] pyridin-4-one in 60% yield.
1H NMR(400MHz,CDCl3)δ8.94(s,1H),7.28–7.22(m,2H),7.22–7.15(m,3H),6.59(s,1H),4.08(s,2H),1.64(s,6H).13C NMR(100MHz,CDCl3)δ169.47,162.59,159.58,151.49,137.84,129.35,128.92,127.01,110.93,108.05,107.58,45.11,26.00.
Example 27: 7- (benzyloxy-methyl) -2, 2-dimethyl-4H- [1,3] -dioxino [5,4-c ] pyridin-4-one in 60% yield.
1H NMR(400MHz,CDCl3)δ9.00(s,1H),7.41–7.31(m,5H),7.16(s,1H),4.69(s,4H),1.76(s,6H).13C NMR(100MHz,CDCl3)δ167.30,163.06,159.58,151.17,137.55,128.68,128.14,127.96,109.18,108.81,107.77,73.47,72.45,26.08.
Example 28: 7- (2-Methylpropen-2-yl) -2, 2-dimethyl-4H- [1,3] -dioxino [5,4-c ] pyridin-4-one in 70% yield.
1H NMR(400MHz,CDCl3)δ8.99(s,1H),6.70(s,1H),6.29–6.25(m,1H),2.13(s,3H),1.95(s,3H),1.72(s,6H).13C NMR(100MHz,CDCl3)δ164.47,162.11,159.79,151.15,146.06,124.43,110.80,107.38,107.00,28.06,26.00,20.45.
Example 29: 3- (2, 2-dimethyl-4-oxo-4H- [1,3] -dioxino [5,4-c ] pyridin-7-yl) -tetrahydropyrrole-1-carboxylic acid tert-butyl ester in 50% yield.
1H NMR(400MHz,CDCl3)δ8.98(s,1H),6.76(s,1H),3.84–3.72(m,1H),3.65–3.33(m,5H),2.30–2.10(m,2H),1.73(s,6H),1.43(s,9H).13C NMR(100MHz,CDCl3)δ169.32,162.58,159.45,154.53,151.62,109.95,108.45,107.69,79.49,50.93,50.64,46.71,45.88,45.59,31.99,31.20,28.60,26.03.
Example 30: 7- (3-buten-1-yl) -8-allyl-2, 2-dimethyl-4H- [1,3] -dioxino [5,4-c ] pyridin-4-one in 70% yield.
1H NMR(400MHz,CDCl3)δ8.93–8.87(m,1H),5.91–5.75(m,2H),5.08–4.99(m,2H),4.99–4.92(m,1H),4.92–4.84(m,1H),3.42–3.30(m,2H),2.91–2.82(m,2H),2.45(dt,J＝14.6,7.2Hz,2H),1.71(s,6H).13C NMR(100MHz,CDCl3)δ167.85,160.33,160.04,148.98,137.49,134.34,120.92,116.16,115.42,107.80,107.29,34.92,33.01,28.72,25.99.
Example 31: 3- (2, 2-dimethyl-4-oxo-4H- [1,3] -dioxino [5,4-c ] pyridine-7-methyl) -1H-indole-1-carboxylic acid tert-butyl ester in 60% yield.
1H NMR(400MHz,CDCl3)δ9.03(s,1H),8.13(d,J＝7.4Hz,1H),7.53(s,1H),7.41(d,J＝7.7Hz,1H),7.34–7.27(m,1H),7.23–7.16(m,1H),6.73(s,1H),4.24(s,2H),1.69(s,6H),1.66(s,9H).13C NMR(100MHz,CDCl3)δ168.49,162.68,159.57,151.50,149.73,135.75,130.13,124.74,124.42,122.77,119.30,116.77,115.47,110.68,108.22,107.62,83.89,34.72,28.31,26.01.
Example 32: 7- (4-methoxyphenyl) -2, 2-dimethyl-5- (trifluoromethyl) -4H- [1,3] -dioxino [5,4-c ] pyridin-4-one
1H NMR(400MHz,CDCl3)δ8.07(d,J＝8.2Hz,2H),7.41(s,1H),7.01(d,J＝8.1Hz,2H),3.88(s,3H),1.79(s,6H).13C NMR(100MHz,CDCl3)δ164.54,162.38,161.07,155.72,148.83(q,2J＝3.6Hz),129.14,128.60,120.55(q,1J＝274.0Hz),114.49,109.21,106.84,106.35,55.48,25.69.
The following documents (g) to (j) can be referred to as a method for producing compound 1 (i.e., a raw material for producing a polysubstituted pyridine derivative) in the present application:
(g)Huang,Z.Y.；Zhang,M.；Wang,Y.；Qin,Y.Synlett 2005,8,1334-1336.
(h)Liu,G.；Cogan,D.A.；Owens,T.D.；Tang,T.P.；Ellman,J.A.J.Org.Chem.1999,64,1278.
(i)Li,G.J.；Xu,X.L.；Tian,H.C.；Liu,X.T.；Chen,W.；Yang,X.D.；Zhang,H.B.RSC Adv.,2017,7,50822–50828.
(j)Chen,W.；Yang,X.D.；Tan,W.Y.；Zhang,X.Y.；Liao,X.L.；Zhang,H.B.Angew.Chem.Int.Ed.2017,56,12327–12331。
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