Processes for preparing dihydropyrimidine derivatives and intermediates thereof

• US 9,617,252 B2
• Filed: 11/27/2014
• Issued: 04/11/2017
• Est. Priority Date: 11/27/2013
• Status: Active Grant

• Current Assignee: Sunshine Lake Pharma Co Ltd (Shenzhen Dongyangguang Industry Co., Ltd.)
• Original Assignee: Sunshine Lake Pharma Co Ltd (Shenzhen Dongyangguang Industry Co., Ltd.)
• Inventors: Tu, Linjin, Liu, Xinchang, Ren, Qingyun, Zou, Zhifu, Liang, Jinsheng, Goldmann, Siegfried, Zhang, Yingjun
• Primary Examiner(s): Anderson, Rebecca
• Assistant Examiner(s): Cheng, Karen
• Application Number:
  US15/023,676
• Publication Number:
  US 20160264562A1
• Time in Patent Office: 866 Days
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/14 containing three or more hetero rings

Abstract

The present invention refers to processes for preparing a dihydropyrimidine compound having Formula (I), or a tautomer thereof having Formula (1a), as well as a intermediate thereof. The process of the invention has simple operation, high optical purity of product, high yield and convenient work-up, which is suitable for industrial production.

Claims

1. A process for preparing a dihydropyrimidine compound having Formula (I), or a tautomer thereof having Formula (Ia),

2. The process of claim 1, wherein the dihydropyrimidine compound has Formula (I-1), or a tautomer thereof having Formula (Ia-1),

3. The process of claim 2, wherein the dihydropyrimidine compound has Formula (I-2), or a tautomer thereof having Formula (Ia-2),

4. The process of claim 1, wherein

R³ is methyl, ethyl, propyl, isopropyl, tert-butyl, or butyl;

Z is —

O—

, —

S—

, or —

N(CH₃)—

;

Y is —

O—

, —

S—

, —

S(═

O)₂—

, or —

(CH₂)_q—

;

each R⁶ is independently H, halo, C_1-4 alkyl, C_1-4 haloalkyl, amino, C_1-4 alkylamino, C_1-4 alkoxy, nitro, triazolyl, tetrazyl, —

(CR⁷R^7a)_m—

OH, —

(CR⁷R^7a)_m—

C(═

O)O—

R⁸, —

(CR⁷R^7a)_t—

N(R^8a)₂, —

S(═

O)_qOR^8a, —

(CR⁷R^7a)_m—

S(═

O)_qN(R^8a)₂, —

(CR⁷R^7a)_m—

C(═

O)O—

(CR⁷R^7a)_m—

OC(═

O)O—

R⁸, —

(CR⁷R^7a)_m—

C(═

O)O—

(CR⁷R^7a)_m—

OC(═

O)—

R⁸, —

(CR⁷R^7a)_m—

C(═

O)O—

(CR⁷R^7a)_m—

C(═

O)O—

R⁸, —

(CR⁷R^7a)_m—

OC(═

O)—

R⁸, or —

(CR⁷R^7a)_m—

C(═

O)N(R⁸R^8a);

each R^7a and R⁷ is independently H, methyl, ethyl, trifluoromethyl, —

(CH₂)_m—

OH, or —

(CH₂)_m—

C(═

O)O—

R⁸;

each R⁸ and R^8a is independently H, methyl, ethyl, propyl, isopropyl, aminomethyl, methoxy, C_1-4 alkyl-S(═

O)₂—

, phenyl, pyridyl, thiazolyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl, triazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-S(═

O)₂—

, cyclobutyl-S(═

O)₂—

, cyclopentyl-S(═

O)₂—

, cyclohexyl-S(═

O)₂—

, naphthyl-S(═

O)₂—

, phenyl-S(═

O)₂—

, —

(CH₂)_m—

OH, —

(CH₂)_m—

C(═

O)O—

(CH₂)_m—

H, or —

(CH₂)_m—

OC(═

O)—

(CH₂)_m—

H;

R^3b is methoxy or ethoxy; and

R^3a is H, methyl, ethyl, isopropyl, or propyl.

5. The process of claim 1, wherein the reaction in step (A) is performed at a temperature from 25°

C. to 154°

C. or from 60°

C. to 100°

C.

6. The process of claim 1, wherein the step (A) further comprises a step of cooling the resulting compound of Formula (Va) of step (A) to obtain a solid compound of Formula (Va) at a cooling temperature from −

40°

C. to 40°

C. or from 25°

C. to 40°

C.

7. The process of claim 6, wherein the cooling is performed for a period of from 0 hour to 24 hours, or from 1 minute to 24 hours, or from 1 hour to 8 hours.

8. The process of claim 1, wherein the first organic solvent is applied in an amount of 0 equivalent to 80 equivalents, or 1 equivalent to 20 equivalents per 1 equivalent by weight of the amidine compound of Formula (II), or a salt thereof.

9. The process of claim 1, wherein step (A) further comprises a step of purifying the compound of Formula (Va) in a second organic solvent, wherein the compound of Formula (Va) is purified by at least one of the following methods:

(1) trituration, wherein the trituration is carried out at a temperature from −

20°

C. to 50°

C. or from 0°

C. to 40°

C.;

(2) recrystallization, wherein the recrystallization comprises a crystallization process at a temperature from −

30°

C. to 40°

C. or from 0°

C. to 40°

C., and wherein the recrystallization comprises a crystallization process of from 1 hour to 20 hours or from 1 hour to 10 hours;

or

(3) washing, wherein the washing is performed at a temperature from 0°

C. to 30°

C.

10. The process of claim 9, wherein the second organic solvent is applied in an amount of 2 equivalent to 20 equivalents per 1 equivalent by weight of the amidine compound of Formula (II), or a salt thereof.

11. The process of claim 9, wherein each of the first organic solvent and the second organic solvent is independently a C_1-4 alcohol, a C_1-4 alcohol-water mixture, acetone, diethyl ether, isopropyl ether, petroleum ether, tetrahydrofuran, acetonitrile, cyclopentane, cyclohexane, n-hexane, a C_1-4 haloalkane solvent, ethyl acetate, trifluoroethanol, 2-methoxyethanol, 1,2-dimethoxyethane, 2-methoxyethyl ether, N,N-dimethyl formamide, N-methylpyrolidone, or a combination thereof, or wherein each of the first organic solvent and the second organic solvent is independently methanol, ethanol, n-propanol, i-propanol, n-butanol, tert-butanol, an ethanol-water mixture at a volume ratio of from 10:

90 to 90;

10, acetone, tetrahydrofuran, N-methylpyrolidone, trifluoroethanol, 2-methoxyethanol, 1,2-dimethoxyethane, 2-methoxyethyl ether, ethyl acetate, glycol, N,N-dimethyl formamide, or a combination thereof.

12. The process of claim 1, wherein the third organic solvent is one or more C_1-4 alcohols, one or more C_1-4 haloalkanes, acetonitrile, isopropyl ether, petroleum ether, toluene, xylene, tetrahydrofuran, ethyl acetate, acetone, or a combination thereof, or wherein the third organic solvent is dichloromethane, chloroform, tetrachloromethane, acetonitrile, isopropyl ether, petroleum ether, tetrahydrofuran, methanol, ethanol, propanol, i-propanol, n-butanol, tert-butanol, ethyl acetate, acetone, or a combination thereof.

13. The process of claim 1, wherein the halogenating reaction in step (B) is carried out in the presence of a halogenating agent, and wherein the halogenating agent is N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, or 1,3-dichloro-5,5-dimethylhydantoin, or a combination thereof.

14. The process of claim 1, wherein the transesterification in step (C) is performed in the presence of a base, and wherein the base is formed by reacting lithium, sodium, or potassium or a combination thereof with a C_1-4 alcohol.

15. The process of claim 14, wherein the C_1-4 alcohol is methanol, ethanol, propanol, i-propanol, n-butanol, i-butanol, or tert-butanol, and wherein the lithium, sodium or potassium or a combination thereof is applied in an amount of 2 equivalents to 6 equivalents per 1 equivalent by mole of the compound of Formula (VIIa).

16. The process of claim 1, wherein the compound of Formula (IVa) in step (A) is prepared by a process comprising reacting a compound of Formula (VIIIa) with a compound of Formula (IX),

27. The process of claim 10, wherein each of the first organic solvent and the second organic solvent is independently a C_1-4 alcohol, a C_1-4 alcohol-water mixture, acetone, diethyl ether, isopropyl ether, petroleum ether, tetrahydrofuran, acetonitrile, cyclopentane, cyclohexane, n-hexane, a C_1-4 haloalkane solvent, ethyl acetate, trifluoroethanol, 2-methoxyethanol, 1,2-dimethoxyethane, 2-methoxyethyl ether, N,N-dimethyl formamide, N-methylpyrolidone, or a combination thereof, or wherein each of the first organic solvent and the second organic solvent is independently methanol, ethanol, n-propanol, i-propanol, n-butanol, tert-butanol, an ethanol-water mixture at a volume ratio of from 10:

90 to 90;

10, acetone, tetrahydrofuran, N-methylpyrolidone, trifluoroethanol, 2-methoxyethanol, 1,2-dimethoxyethane, 2-methoxyethyl ether, ethyl acetate, glycol, N,N-dimethyl formamide, or a combination thereof.

17. A compound having Formula (Va), or a tautomer thereof having Formula (Va1), or a salt thereof, or a combination thereof,

18. The compound of claim 17 having Formula (Va-1), or a tautomer thereof having Formula (Va1-1), or a salt thereof, or a combination thereof,

19. The compound of claim 17 having Formula (Va-2), or a tautomer thereof having Formula (Va1-2), or a salt thereof, or a combination thereof,

20. A process for preparing a dihydropyrimidine compound having Formula (I), or a tautomer thereof having Formula (Ia),

21. The process of claim 20, wherein the dihydropyrimidine compound has Formula (I-1), or a tautomer thereof having Formula (Ia-1),

22. The process of claim 21, wherein the dihydropyrimidine compound has Formula (I-2), or a tautomer thereof having Formula (Ia-2),

23. The process of claim 20, wherein

R³ is methyl, ethyl, propyl, isopropyl, tert-butyl, or butyl;

Z is —

O—

, —

S—

, or —

N(CH₃)—

;

Y is —

O—

, —

S—

, —

S(═

O)₂—

, or —

(CH₂)_q—

;

each R⁶ is independently H, halo, C_1-4 alkyl, C_1-4 haloalkyl, amino, C_1-4 alkylamino, C_1-4 alkoxy, nitro, triazolyl, tetrazyl, —

(CR⁷R^7a)_m—

OH, —

S(═

O)_qOR^8a, —

(CR⁷R^7a)_m—

S(═

O)_qN(R^8a)₂, —

(CR⁷R^7a)_t—

N(R^8a)₂, —

(CR⁷R^7a)_m—

C(═

O)O—

R⁸, —

(CR⁷R^7a)_m—

C(═

O)O—

(CR⁷R^7a)_m—

OC(═

O)O—

R⁸, —

(CR⁷R^7a)_m—

C(═

O)O—

(CR⁷R^7a)_m—

OC(═

O)—

R⁸, —

(CR⁷R^7a)_m—

C(═

O)O—

(CR⁷R^7a)_m—

C(═

O)O—

R⁸, —

(CR⁷R^7a)_m—

OC(═

O)—

R⁸, or —

(CR⁷R^7a)_m—

C(═

O)—

N(R⁸R^8a);

each R^7a and R⁷ is independently H, methyl, ethyl, trifluoromethyl, or —

(CH₂)_m—

C(═

O)O—

R⁸;

each R⁸ and R^8a is independently H, methyl, ethyl, propyl, isopropyl, aminomethyl, methoxy, C_1-4 alkyl-S(═

O)₂—

, phenyl, pyridyl, thiazolyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrimidinyl, pyridazinyl, diazolyl, triazolyl, tetrazolyl, thienyl, pyrazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, pyranyl, triazinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-S(═

O)₂—

, cyclobutyl-S(═

O)₂—

, cyclopentyl-S(═

O)₂—

, cyclohexyl-S(═

O)₂—

, naphthyl-S(═

O)₂—

, phenyl-S(═

O)₂—

, —

(CH₂)_m—

OH, —

(CH₂)_m—

C(═

O)O—

(CH₂)_m—

H, or —

(CH₂)_m—

OC(═

O)—

(CH₂)_m—

H;

R^3b is methoxy or ethoxy; and

R^3a is H, methyl, ethyl, isopropyl, or propyl.

24. The process of claim 20, wherein the transesterification in step (2) is performed in the present of a base, wherein the base is formed by reacting lithium, sodium, or potassium or a combination thereof with a C_1-4 alcohol, wherein the C_1-4 alcohol is methanol, ethanol, propanol, i-propanol, n-butanol, i-butanol, or tert-butanol, and wherein the lithium, sodium, potassium or a combination thereof is applied in an amount of 2 equivalents to 8 equivalents per 1 equivalent by mole of the compound of Formula (Va).

25. The process of claim 20, wherein the fourth organic solvent is one or more C_1-4 alcohols, one or more C_1-4 haloalkanes, ethyl acetate, acetonitrile, isopropyl ether, petroleum ether, toluene, xylene, tetrahydrofuran, acetone, or a combination thereof, or the forth organic solvent is methanol, ethanol, propanol, i-propanol, n-butanol, tert-butanol, dichloromethane, chloroform, tetrachloromethane, ethyl acetate, acetonitrile, isopropyl ether, petroleum ether, tetrahydrofuran, acetone, or a combination thereof.

26. The process of claim 20, wherein the halogenating reaction in step (3) is carried out in the presence of a halogenating agent, and wherein the halogenating agent is N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, 1,3-dichloro-5,5-dimethylhydantoin, or a combination thereof.