PROCESSES FOR PREPARING DIHYDROPYRIMIDINE DERIVATIVES AND INTERMEDIATES THEREOF

• US 20160264563A1
• Filed: 11/27/2014
• Published: 09/15/2016
• 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: SHAN, Yuefeng, LEI, Douxing, GOLDMANN, Slegfried, REN, Qingyun, LIU, Xinchang, ZOU, Zhifu, TU, Linjin, ZHANG, Yingjun
• Granted Patent: US 9,643,962 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• 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 (Ia), 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^8′

);

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 isopropoxy, propoxy, tert-butoxy, n-butoxy, 1-methylpropoxy, n-pentyloxy, n-hexyloxy, methylamino, ethylamino, isopropylamino, propylamino, tert-butylamino, n-butylamino, 1-methylpropylamino, n-pentylamino, n-hexylamino, benzylamino, or benzyloxy; and

R^3b 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.

7. The process of claim 1, wherein 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.

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

11. The process of claim 1, wherein the amidine compound of Formula (II) reacts with the aldehyde compound of Formula (III) and the compound of Formula (IVa) in a first organic solvent, and 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.

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

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

10°

C. to 40°

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 12 hours;

or

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

C. to 30°

C.

15. The process of claim 13, wherein the purification is carried out in a second organic solvent, 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.

24. The process of claim 11, 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, C_1-4 haloalkanes 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 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.

26. The process of claim 1, wherein the halogenating reaction in step (B) is carried out in an third organic solvent, and 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.

28. 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.

29. The process of claim 1, wherein the transesterification in step (C) is performed in the present 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.

30. The process of claim 29, 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).

32. 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 (Villa) with a compound of Formula (IX),

67. The process of claim 15, 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, C_1-4 haloalkanes 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 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.

6. (canceled)

8. (canceled)

10. (canceled)

12. (canceled)

14. (canceled)

16-23. -23. (canceled)

25. (canceled)

27. (canceled)

31. (canceled)

33. A compound having Formula (Va), or a tautomer thereof having Formula (Val), or a salt thereof, or a combination thereof,

34. The compound of claim 33 having Formula (Va-1), or a tautomer thereof having Formula (Val-1), or a salt thereof, or a combination thereof,

35. The compound of claim 33 having Formula (Va-2), or a tautomer thereof having Formula (Val-2), or a salt thereof, or a combination thereof,

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

37. The process of claim 36, wherein the dihydropyrimidine compound has Formula (I-1), or a tautomer thereof having Formula (Ia-1),

38. The process of claim 37, wherein the dihydropyrimidine compound has Formula (I-2), or a tautomer thereof having Formula (Ia-2),

39. The process of claim 36, 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^8′

);

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 isopropoxy, propoxy, tert-butoxy, n-butoxy, 1-methylpropoxy, n-pentyloxy, n-hexyloxy, methylamino, ethylamino, isopropylamino, propylamino, tert-butylamino, n-butylamino, 1-methylpropylamino, n-pentylamino, n-hexylamino, benzylamino, or benzyloxy; and

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

61. The process of claim 36, 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 C1-4 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).

64. The process of claim 36, wherein the halogenating reaction in step (3) is carried out in a forth organic solvent, and wherein the forth 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.

66. The process of claim 36, 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.

40-60. -60. (canceled)

62. (canceled)

63. (canceled)

65. (canceled)