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Title:
NOVEL CHIRAL RESOLUTION OF 4-ARYL-2-THIAZOL-2-YL-1,4-DIHYDROPYRIMIDINE-5-CARBOXYLIC ACID ESTERS
Document Type and Number:
WIPO Patent Application WO/2016/016196
Kind Code:
A1
Abstract:
The present invention relates to a process for the preparation of an enantiomerically pure of 4-phenyl-6-methyl-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylic acid ester of formula (la), wherein R1 is phenyl once, twice or more times substituted by halogen; R2 is C1_6alkyl.

Inventors:
WANG, Lin (Building No. 5, Lane 720 Cailun Road, 3, 20120, CN)
DU, Zhengming (Building No. 5, Lane 720 Cailun Road, Shanghai 3, 20120, CN)
YU, Jianhua (Building No. 5, Lane 720 Cailun Road, Shanghai 3, 20120, CN)
CHEN, Junli (Building No. 5, Lane 720 Cailun Road, Shanghai 3, 20120, CN)
ZHANG, Guocai (Building No. 5, Lane 720 Cailun Road, Shanghai 3, 20120, CN)
SHE, Jin (Building No. 5, Lane 720, Shanghai 3, 20120, CN)
Application Number:
EP2015/067173
Publication Date:
February 04, 2016
Filing Date:
July 27, 2015
Export Citation:
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Assignee:
F. HOFFMANN-LA ROCHE AG (Grenzacherstrasse 124, Basel, CH-4070, CH)
HOFFMANN-LA ROCHE INC. (Great Notch, 150 Clove Road8th Floo, Little Falls New Jersey, 07424, US)
International Classes:
C07D417/04; C07B57/00
Domestic Patent References:
WO2014037480A12014-03-13
WO2001068640A12001-09-20
WO2002094807A12002-11-28
Other References:
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 28 September 2007 (2007-09-28), CHEN, YANGUI ET AL: "Process for resolution of dihydropyrimidine derivatives", XP002743935, retrieved from STN Database accession no. 2007:1089447
Attorney, Agent or Firm:
HALBIG, Dirk (Grenzacherstrasse 124, Basel, CH-4070, CH)
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Claims:
CLAIMS

1. Process for the preparation of an enantiomerically pure of 4-phenyl-6-methyl-2-thiazol- 2-yl-l,4-dihydropyrimidine-5-carboxylic acid ester, the compound of formula (la),

wherein R1 is phenyl, which is unsubstituted, or once, twice or more times substituted by halogen;

R2 is Ci_6alkyl;

characterized in that the process herein comprises the following steps:

Step a) The formation and recrystallization of the enantiomeric salt of formula (VIII),

or solvate;

Step b) The recovery of enantiomeric compound formula (I) from its enantiomeric salt of formula (VIII) or solvate.

2. Process according to claim 1 for the preparation of (R)-4-phenyl-6-methyl-2-thiazol-2- yl-l,4-dihydropyrimidine-5-carboxylic acid ester, the compound of formula (I),

(I).

3. Process according to claim 1 or 2, wherein R1 is phenyl, which is once, twice or more times substituted by halogen, particularly R1 is 2-chlorophenyl, 2-chloro-3-fluorophenyl, 4- chloro-3-fluorophenyl or 2-chloro-4-fluorophenyl.

4. Process according to any one of claims 1 to 3, wherein R 2 is Ci 2

_6alkyl, particularly R is methyl or ethyl.

5. Process according to any one of claims 1 to 4, characterized in that the formation of the enantiomeric salt of formula (VIII) or solvate in step a) is performed in the presence of an organic acid, wherein the organic acid is selected from D-(+)-DTTA, L-DTTA, L-Tartaric acid, D-DBTA, (+)-CSA, (S)-(+)-l,l '-Binaphthyl-2,2'-diyl hydrogen phosphate and (R)-(-)-l,l '- Binaphthyl-2,2'-diyl hydrogen phosphate, particularly the organic acid is (R)-(-)-l,l '- Binaphthyl-2,2'-diyl hydrogen phosphate or (S)-(+)-l,l '-Binaphthyl-2,2'-diyl hydrogen phosphate.

6. Process according to any one of claims 1 to 5, characterized in that the formation of the enantiomeric salt of formula (VIII) or solvate in step a) is performed in an organic solvent, wherein the organic solvent is selected from tetrahydrofuran, MTBE, isopropyl ether, methoxycyclopentane, MeOH, EtOH, IPA, IP Ac, EA, MEK, DCM, heptane, acetone, ACN, toluene, water, MIBK, trifluoroethanol, cyclohexane, DCM, xylene, fluorobenzene,

chlorobenzene and a mixture thereof, particularly the organic solvent is MIBK, IP Ac or a mixture of ACN and MTBE.

7. Process according to any one of claims 1 to 6, characterized in that the formation of the enantiomeric salt of formula (VIII) or solvate in step a) is performed at a temperature from 0°C to 80°C, particularly from 60°C to 75°C.

8. Process according to any one of claims 1 to 7, characterized in that the recrystallization of the enantiomeric salt of formula (VIII) or solvate in step a) is performed in an organic solvent, wherein the organic solvent is selected from MIBK, IP Ac, diisopropylether, toluene and tert- butylmethylether, particularly the organic solvent is MIBK, IP Ac or a mixture of ACN and MTBE.

9. Process according to any one of claims 1 to 8, characterized in that the recovery of enantiomeric compound of formula (I) from its enantiomeric salt of formula (VIII) or solvate in step b) is performed with a base, wherein the base is selected from TEA, DIPEA,

methyldicyclohexylamine, NMM, NaOH, Na2C03, NaHC03 and a mixture thereof, particularly the base is NaOH.

10. Process according to any one of claims 1 to 9, characterized in that the recovery of enantiomeric compound of formula (I) from its enantiomeric salt of formula (VIII) or solvate in step b) is performed in an organic solvent, wherein the organic solvent is selected from DCM, methyltetrahydrofuran, tert-butylmethylether and fluorobenzene, particularly the organic solvent is DCM.

11. Process according to any one of claims 1 to 10 for the preparation of an

enantiomerically pure compound of formula (lab),

particularly for the preparation of compound of formula (lb),

wherein R3, R4 and R5 are independently selected from hydrogen and halogen;

R2 is Ci_6alkyl.

12. Process according to claim 11, wherein

R3, R4 and R5 are independently selected from hydrogen, fluoro and chloro;

R is methyl or ethyl.

13. A compound of formula (VIII),

or solvate, wherein R is phenyl, which is unsubstituted, or once, twice or more times substituted by halogen; R is Ci-6alkyl; and the acid is an organic acid.

14. A compound according to claim 13, wherein R1 is 2-chlorophenyl, 2-chloro-3- fluorophenyl, 4-chloro-3-fluorophenyl or 2-chloro-4-fluorophenyl; R is methyl, ethyl or isopropyl.

15. A compound according to claim 13 or 14, wherein the organic acid is selected from D- (+)-DTTA, L-DTTA, L-Tartaric acid, D-DBTA, (+)-CSA, (S)-(+)-l,l '-Binaphthyl-2,2'-diyl hydrogen phosphate and (R)-(-)-l,l '-Binaphthyl-2,2'-diyl hydrogen phosphate, particularly the organic acid is (R)-(-)-l,l '-Binaphthyl-2,2'-diyl hydrogen phosphate or (S)-(+)-l,l '-Binaphthyl- 2,2'-diyl hydrogen phosphate.

16. A compound according to any one of claims 13 to 15, wherein the solvate is formed by compound of formula (VIII) and a solvent, wherein the solvent is selected from tetrahydrofuran, MTBE, isopropyl ether, methoxycyclopentane, MeOH, EtOH, IPA, IP Ac, EA, MEK, DCM, heptane, acetone, ACN, toluene, water, MIBK, trifluo methanol, cyclohexane, DCM, xylene, fluorobenzene, chlorobenzene and a mixture thereof, particularly the solvent is MIBK.

17. A compound according to any one of claims 13 to 16, selected from: (R)-4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-l,4-dihydropyrimidine-5- carboxylic acid methyl ester mono (R)-(-)-l,l '-Binaphthyl-2,2'-diyl hydrogenphosphate salt mono MIBK solvate;

(R)-4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-l,4-dihydropyrimidine-5- carboxylic acid methyl ester mono (R)-(-)-l,l '-Binaphthyl-2,2'-diyl hydrogenphosphate salt;

(S)-4-(4-chloro-3-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-l,4-dihydropyrimidine-5- carboxylic acid methyl ester mono (R)-(-)-l,l '-Binaphthyl-2,2'-diyl hydrogenphosphate salt;

(R)-4-(2-chloro-3-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-l,4-dihydropyrimidine-5- carboxylic acid methyl ester mono (R)-(-)-l,l '-Binaphthyl-2,2'-diyl hydrogenphosphate salt; and

(R)-4-(2-chlorophenyl)-6-methyl-2-thiazol-2-yl- 1 ,4-dihydropyrimidine-5-carboxylic acid ethyl ester mono (S)-(-)-l,l '-Binaphthyl-2,2'-diyl hydrogenphosphate salt mono ACN solvate.

18. Process according to any one of the claims 1 to 16 for the preparation of a compound of formula (II),

wherein R1 is phenyl, which is unsubstituted, or once, twice or more times substituted by halogen; R 2 is C1-6alkyl; R 3 is heterocycle.

19. The invention as hereinbefore described.

Description:
Novel chiral resolution of 4-aryl-2-thiazol-2-yl-l,4-dihydropyrimidine-5-carboxylic acid esters

The present invention relates to a process for the preparation of an enantiomerically pure 4- phenyl-6-methyl-2-thiazol-2-yl-l,4-dihydropyrimidine-5-carbo xylic acid ester, the compound of formula (la),

particularly of (R)-4-phenyl-6-methyl-2-thiazol-2-yl- 1 ,4-dihydropyrimidine-5-carboxylic acid ester, the compound of formula (I),

wherein R 1 is phenyl, which is unsubstituted, or once, twice or more times substituted by halogen; R is C h alky!

The (R)-4-phenyl-6-methyl-2-thiazol-2-yl-l,4-dihydropyrimidine-5 -carboxylic acid esters of formula (I) are chiral building blocks for the synthesis of dihydropyrimidine derivatives which have the potential to be useful in treatment or prophylaxis of a viral disease in a patient relating to hepatitis B infection or a disease caused by hepatitis B infection. Such dihydropyrimidine derivatives are for example disclosed in the PCT publication WO2014/037480 Al.

Access to enantiomerically pure of (R)-4-phenyl-6-methyl-2-thiazol-2-yl-l,4- dihydropyrimidine-5-carboxylic acid ester of formula (I) is disclosed in Chinese patent

CN101041658(A), however the yield disclosed is less than 30% and experimental procedure is complicated and unfit for large scale process. The technical problem is solved by the process of Yingxian Zhu / April 20, 2015 the present invention with significant recovery improvement and more simple experimental procedure which enables the application on large scale process. Furthermore, high chiral purity is also maintained, and different substrates, such as methyl ester and ethyl ester, are disclosed as well in present invention.

Therefore, one object of the invention is to provide a more simple process with

significantly improved recovery while maintaining high chiral purity, which is suitable for large scale process.

The present invention relates to the process which comprises the chiral resolution of 4- phenyl-6-methyl-2-thiazol-2-yl-l,4-dihydropyrimidine-5-carbo xylic acid ester of formula (la),

wherein R 1 and R 2 are defined above.

Another embodiment of present invention relates to the process for the preparation of an enantiomerically pure compound of formula (lab),

particularly of compound of formula (lb),

wherein R 2 is C 1-6 alkyl; R 3 , R 4 and R 5 are independently selected from hydrogen and halogen.

The synthesis and chiral resolution process in present invention of dihydropyrimidine derivatives of formula (la) can be manufactured for example as outlined in scheme 1 exemplified for the compounds that form salts with acid.

Scheme 1

Mil

Synthesis of racemic compound of formula (la) can be performed according to

WO2014/037480 Al by Biginilli reaction with the presence of a catalyst such as the mixture of acetic acid and piperidine in an organic solvent such as isopropyl alcohol under a heating condition.

Compound of formula (lab) can also be synthesized by Scheme 1 accordingly.

The chiral resolution usually comprises the following steps:

Step a) The formation and recrystallization of the enantiomeric salt of formula (VIII),

or solvate;

Step b) The recovery of enantiomeric compound formula (I) from its enantiomeric salt of formula (VIII) or solvate.

A detailed description of present invention of process steps is as following:

Step a) The formation and recrystallization of the enantiomeric salt of formula (VIII) or solvate.

The formation of the enantiomeric salt of formula (VIII) or solvate is usually performed in the presence of a suitable organic acid (VII) in a suitable organic solvent. The conversion as a rule is performed under a heating condition.

The suitable organic acid used in salt formation is selected from D-(+)-DTTA, L-DTTA, L- Tartaric acid, D-DBTA, (+)-CSA, (S)-(+)-l,l '-Binaphthyl-2,2'-diyl hydrogen phosphate and (R)- (-)-l,l '-Binaphthyl-2,2'-diyl hydrogen phosphate, particularly the organic acid is (R)-(-)-l,l '- Binaphthyl-2,2'-diyl hydrogen phosphate or (S)-(+)-l,l '-Binaphthyl-2,2'-diyl hydrogen phosphate.

The suitable organic solvent used in salt formation is selected from tetrahydrofuran, MTBE, isopropyl ether, methoxycyclopentane, MeOH, EtOH, IPA, IP Ac, EA, MEK, DCM, heptane, acetone, ACN, toluene, water, MIBK, trifluoroethanol, cyclohexane, DCM, xylene,

fluorobenzene, chlorobenzene and a mixture thereof, particularly the organic solvent is MIBK, IP Ac or a mixture of ACN and MTBE.

The salt formation as a rule is performed at a temperature from 0°C to 80°C, particularly from 60°C to 75°C.

Recrystallization of the crude enantiomeric salt of formula (VIII) or solvate can be achieved by selective crystallization in a suitable solvent. The other enantiomeric salt as a rule remains in the mother liquor.

The suitable solvent used in recrystallization is selected from MIBK, IP Ac,

diisopropylether, toluene and tert-butylmethylether, particularly the organic solvent is MIBK, IP Ac or a mixture of ACN and MTBE. Step b) The recovery of enantiomeric compound of formula (I) from its enantiomeric salt of formula (VIII) or solvate.

This recovery of enantiomeric compound of formula (I) can be achieved by reacting desired enantiomeric salt of formula (VIII) or solvate with a suitable base in a suitable organic solvent.

Suitable base is selected from TEA, DIPEA, methyldicyclohexylamine, NMM, NaOH, Na 2 C0 3 , NaHC0 3 and a mixture thereof, particularly the base is NaOH.

The reaction is usually performed in an organic solvent which is selected from DCM, methyltetrahydrofuran, tert-butylmethylether and fluorobenzene, particularly the organic solvent is DCM.

The process of the present invention is also particularly useful in the synthesis of dihydropyrimidine compounds of the formula (II),

wherein R 1 is phenyl, which is unsubstituted, or once, twice or more times substituted by halogen; R 2 is C 1-6 alkyl; R 3 is heterocycle.

The term "Ci_ 6 alkyl" signifies a saturated, linear- or branched chain alkyl group containing 1 to 6, particularly 1 to 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, 1 -butyl, 2- butyl, tert-butyl and the like. Particular "Ci_ 6 alkyl" groups are methyl and ethyl.

The term "halogen" signifies chlorine, fluorine, bromine or iodine. Particular halogen are chorine and fluorine.

The term "hererocycle" or "heterocyclyl" refers to a saturated or partly unsaturated monocyclic or bicyclic ring containing from 3 to 10 ring atoms which can comprise one, two or three atoms selected from nitrogen, oxygen and/or sulfur. Bicyclic means consisting of two cycles having two ring atoms in common, i.e. the bridge separating the two rings is either a single bond or a chain of one or two ring atoms. Examples of monocyclic heterocyclyl rings containing in particular from 3 to 7 ring atoms include azirinyl, azetidinyl, oxetanyl, piperidinyl, piperazinyl, azepinyl, diazepanyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyridinyl, pyridazinyl, pyrimidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, thiadiazolidinyl, dihydrofuryl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl, l,l-dioxo-hexahydro-l,6-thiopyranyl and thiomorpholinyl. Examples of bicyclic heterocyclyl rings containing in particular from 5 to 12 ring atoms include 3-oxa-9- azabicyclo[3.3.1]nonan-9-yl and 6,6-difluoro-8-azabicyclo[3.2.1]octan-8-yl. Monocyclic and bicyclic heterocyclyl rings can be further substituted by Ci_ 6 alkyl, cyano, carboxy, carboxy Ci_ 6 alkyl, for example carboxymorpholinyl, 7-(carboxymethyl)-3-oxa-9-azabicyclo[3.3.1]nonan-9- yl, 3-(carboxymethyl)-6,6-difluoro-8-azabicyclo[3.2.1]octan-8-yl .

ABBREVIATION

ACN Acetonitrile

DTTA Di-p-toluoyl-tartaric acid

CSA Camphor sulfonic acid

DBTA Dibenzoyl-tartaric acid

DCM Dichloro methane

DIPEA N,N-Diisopropylethylamine

EA Ethyl acetate

EtOH Ethanol

hr or hrs Hour or hours

IPA Isopropanol

IPAc Isopropyl acetate

L Liter

MEK 2-Butanone

MeOH Methanol

MIBK Methyl isobutyl ketone

mmol Millimole

MTBE Methyl tert-butyl ether

NMM N- methylmorpho line

TEA Triethylamine

EXAMPLES

The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention.

Example 1 (R)-4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-l,4 -dihydropyrimidine-5- carboxylic acid methyl ester

Step a) preparation of (R)-4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-l,4 - dihydropyrimidine-5-carboxylic acid methyl ester mono (R)-(-)-l J '-Binaphthyl-2,2'-diyl hydro genphosphate salt mono MIBK solvate

To a 1000 L flask was charged with racemic 4-(2-chloro-4-fluoro-phenyl)-6-methyl-2- thiazol-2-yl-l,4-dihydropyrimidine-5-carboxylic acid methyl ester (23.8kg,650.6mol), MIBK (660L) and purified water (6.6L) at room temperature. The mixture was stirred at room temperature for another 20 minutes until all yellow solid was dissolved. (R)-(-)-l,l '-Binaphthyl- 2,2'-diyl hydrogen phosphate (18.1kg,520.5mol) was added in one portion at room temperature. The reaction mixture was heated to 75°C and the agitation was maintained for 14 hours. The mixture was slowly cooled to 40°C over 6 hours, then the mixture was stirred at 40°C for another

2 hours. Reaction mixture was filtrated, and the collected solid was rinsed with MIBK (50L) for

3 times. The resulting solid was dried under vacuum at 55°C for 24 hours until the weight was constant to give 21.75 kg product as light yellow solid. The chiral purity was 99.45%, the yield was 87%, the mol ratio of Acid: Example 1:MIBK was 1: 1: 1, and the MS m/e =366.3 [M+H] + .

Step b preparation of (R -4-(2-chloro-4-fluoro-phenyl -6-methyl-2-thiazol-2-yl-l,4- dihydropyrimidine-5-carboxylic acid methyl ester

(R)-4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-l,4 -dihydro-pyrimidine-5- carboxylic acid methyl ester mono (R)-(-)-l,l '-Binaphthyl-2,2'-diyl hydrogenphosphate salt mono MIBK solvate (2.5kg,3.07mol) was dissolved in DCM (25L) at room temperature. 20% NaOH solution (0.675kg, 3.37mol) was added dropwise to previous reaction mixture at room temperature over 60 minutes. The mixture was stirred at room temperature for another 2 hours. The solid was filtrated and washed with DCM (12L). The organic layer was washed with water (15L) and 15% brine (15L). The organic layer was concentrated under reduced pressure to give 1.13kg desired product as yellow oil. The chiral purity was 99.2%, the yield was 99%, and MS m/e = 366.3 [M+H] + .

Example 2

(R)-4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-l,4 -dihydropyrimidine-5- carboxylic acid methyl ester

Step a) preparation of (R -4-(2-chloro-4-fluoro-phenyl -6-methyl-2-thiazol-2-yl-l,4- dihydropyrimidine-5-carboxylic acid methyl ester mono (R -(- -l. -Binaphthyl-2.2'-diyl hydrogenphosphate salt

To a 25 mL flask was charged with racemic 4-(2-chloro-4-fluoro-phenyl)-6-methyl-2- thiazol-2-yl-l,4-dihydropyrimidine-5-carboxylic acid methyl ester (365mg, lmmol), IP Ac (lOmL) and (R)-(-)-l,l '-Binaphthyl-2,2'-diyl hydrogen phosphate (350mg, lmmol) at room temperature. The reaction mixture was shaken at room temperature for 40 hours. After filtration, the collected solid was rinsed with IP Ac (lOmL) for 3 times. The collected solid was dried under vacuum until the weight was constant to give 300 mg product as light yellow solid. The chiral purity was 94%, the yield was 74%, and MS m/e = 366.3 [M+H] + .

Step b preparation of (R -4-(2-chloro-4-fluoro-phenyl -6-methyl-2-thiazol-2-yl-l,4- dihydropyrimidine-5-carboxylic acid methyl ester

The title compound was prepared in analogy to step b) of Example 1 by using (R)-4-(2- chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl- l,4-dihydropyrimidine-5-carboxylic acid methyl ester mono (R)-(-)-l,l '-Binaphthyl-2,2'-diyl hydrogenphosphate salt instead of (R)-4-(2-chloro- 4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-l,4-dihydro-pyrimid ine-5-carboxylic acid methyl ester mono (R)-(-)-l,l '-Binaphthyl-2,2'-diyl hydrogenphosphate salt mono MIBK solvate. The chiral purity was 94%, the yield was 98%, and MS m/e = 366.3 [M+H] + .

Example 3 (S)-4-(4-chloro-3-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-l,4 -dihydropyrimidine-5- carboxylic acid methyl ester

Step a) preparation of Compound 3a, (S)-4-(4-chloro-3-fluoro-phenyl)-6-methyl-2-thiazol- 2-yl-l,4-dihydropyrimidine-5-carboxylic acid methyl ester mono (R)-(-)-lJ '-Binaphthyl-2,2'- diyl hydrogenphosphate salt

Compound 3a was prepared in analogy to step a) of Example 1 by using 4-(4-chloro-3- fluoro-phenyl)-6-methyl-2-thiazol-2-yl- l,4-dihydropyrimidine-5-carboxylic acid methyl ester (182g, 0.5mol) and (R)-(-)-l,l '-Binaphthyl-2,2'-diyl hydrogenphosphate(140g, 0.4mol) instead of methyl 4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl- 1 ,4-dihydropyrimidine-5- carboxylate and (R)-(-)-l,l '-Binaphthyl-2,2'-diyl hydrogenphosphate. 110 g product was obtained as light yellow solid. The chiral purity was 99.3%, the yield was 72%, and MS m/e = 366.3 [M+H] + .

Step b preparation of (S -4-(4-chloro-3-fluoro-phenyl -6-methyl-2-thiazol-2-yl-l,4- dihydropyrimidine-5-carboxylic acid methyl ester

The title compound was prepared in analogy to step b) of Example 1 by using (S)-4-(4- chloro-3-fluoro-phenyl)-6-methyl-2-thiazol-2-yl- l,4-dihydropyrimidine-5-carboxylic acid methyl ester mono (R)-(-)-l,l '-Binaphthyl-2,2'-diyl hydrogenphosphate salt instead of (R)-4-(2-chloro- 4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-l,4-dihydro-pyrimid ine-5-carboxylic acid methyl ester mono (R)-(-)-l,l '-Binaphthyl-2,2'-diyl hydrogenphosphate salt mono MIBK solvate. The chiral purity was 99.3%, the yield was 97%, and MS m/e = 366.3 [M+H] + .

Example 4

(R)-4-(2-chloro-3-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-l,4 -dihydropyrimidine-5- carboxylic acid methyl ester

Step a) preparation of compound 4a, (R)-4-(2-chloro-3-fluoro-phenyl)-6-methyl-2-thiazol- 2-yl-l,4-dihydropyrimidine-5-carboxylic acid methyl ester mono (R)-(-)-l,r-Binaphthyl-2,2'- diyl hydrogenphosphate salt

Compound 4a was prepared in analogy to step a) of Example 1 by using 4-(2-chloro-3- fluoro-phenyl)-6-methyl-2-thiazol-2-yl- l,4-dihydropyrimidine-5-carboxylic acid methyl ester (18g, 50mmol) instead of methyl 4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-l,4- dihydropyrimidine-5-carboxylic methyl ester. 11 g product was obtained as light yellow solid. The chiral purity was 99.2%, the yield was 71%, and MS m/e = 366.3 [M+H] + .

Step b preparation of (R -4-(2-chloro-3-fluoro-phenyl -6-methyl-2-thiazol-2-yl-l,4- dihydropyrimidine-5-carboxylic acid methyl ester

The title compound was prepared in analogy to step b) of Example 1 by using (R)-4-(2- chloro-3-fluoro-phenyl)-6-methyl-2-thiazol-2-yl- l,4-dihydropyrimidine-5-carboxylic acid methyl ester mono (R)-(-)-l,l '-Binaphthyl-2,2'-diyl hydrogenphosphate salt instead of (R)-4-(2-chloro- 4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-l,4-dihydro-pyrimid ine-5-carboxylic acid methyl ester mono (R)-(-)-l,l '-Binaphthyl-2,2'-diyl hydrogenphosphate salt mono MIBK solvate. The chiral purity was 99.2%, the yield was 98%, and and MS m/e = 366.3 [M+H] + .

Example 5

(R)-4-(2-chlorophenyl)-6-methyl-2-thiazol-2-yl-l,4-dihydropy rimidine-5-carbox lic acid ethyl ester

Step a) preparation of compound 5a, (R)-4-(2-chlorophenyl)-6-methyl-2-thiazol-2-yl-l,4- dihydropyrimidine-5-carboxylic acid ethyl ester mono (S)-(-)-lJ '-Binaphthyl-2,2'-diyl hydro genphosphate salt mono ACN solvate

To a 2 L flask was charged with racemic 4-(2-chlorophenyl)-6-methyl-2-thiazol-2-yl-l,4- dihydropyrimidine-5-carboxylic acid ethyl ester (120g,0.33mol), ACN (0.6L), MTBE (0.6L) and purified water (120mL) at room temperature. (S)-(-)-l,l '-Binaphthyl-2,2'-diyl hydrogen phosphate (115g, 0.33mol) was added to previous reaction mixture in one portion at room temperature. Then the reaction mixture was stirred under reflux for 16 hours. After that, the reaction mixture was slowly cooled to room temperature, and stirred at room temperature for another 2 hours. Reaction mixture was filtrated, and the collected solid was rinsed with

ACN/MTBE (0.4L,v/v 1: 1) for 2 times. The collected solid was dried under vacuum at 55°C for 24 hrs until the weight was constant to give 85g product as light yellow solid. The chiral purity was 99.3%, the yield was 72%, the mol ratio of Acid: Example 5:ACN was 1:1: 1, and MS m/e = 362.3 [M+H] + .

Step b) preparation of (R)-4-(2-chlorophenyl)-6-methyl-2-thiazol-2-yl-l,4- dihydropyrimidine-5-carboxylic acid ethyl ester

Compound 5a (85g, O. l lmol) was dissolved in DCM(l.OL) at room temperature, 20% NaOH (22mL, 0.116mol) was added dropwise to previous reaction mixture at room temperature over 10 minutes. The reaction mixture was stirred at room temperature for another 2 hours. Reaction mixture was filtrated and the solid was washed with DCM (0.6L). The organic layer was washed with water (1L) and 15% brine (1L). The organic layer was concentrated under reduced pressure to give 37g product as yellow oil. The chiral purity was 99.2%, the yield was 98%, and MS m/e = 362.3 [M+H] + .