WO2016102438A1 - Process for the preparation of 4-phenyl-5-alkoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidine analogues - Google Patents
Process for the preparation of 4-phenyl-5-alkoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidine analogues Download PDFInfo
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- WO2016102438A1 WO2016102438A1 PCT/EP2015/080750 EP2015080750W WO2016102438A1 WO 2016102438 A1 WO2016102438 A1 WO 2016102438A1 EP 2015080750 W EP2015080750 W EP 2015080750W WO 2016102438 A1 WO2016102438 A1 WO 2016102438A1
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- 0 *[C@@]1N=C(c2ncc[s]2)NC(CBr)=C1C(O*)=O Chemical compound *[C@@]1N=C(c2ncc[s]2)NC(CBr)=C1C(O*)=O 0.000 description 4
- QMZPEPRAOFNSQH-UHFFFAOYSA-N CC(NC(c1ncc[s]1)=NC1c(c(Cl)c2)ccc2F)=C1C(OC)=O Chemical compound CC(NC(c1ncc[s]1)=NC1c(c(Cl)c2)ccc2F)=C1C(OC)=O QMZPEPRAOFNSQH-UHFFFAOYSA-N 0.000 description 1
- WFRGVVPTIMGCOB-AWEZNQCLSA-N CCOC(C1=C(C)NC(c2ncc[s]2)=N[C@H]1c1ccccc1Cl)=O Chemical compound CCOC(C1=C(C)NC(c2ncc[s]2)=N[C@H]1c1ccccc1Cl)=O WFRGVVPTIMGCOB-AWEZNQCLSA-N 0.000 description 1
- FMYUSYPZSFXDSC-WMZOPIPTSA-N CCOC(C1=C(CN(CCOC2)[C@@H]2C(O)=O)NC(c2ncc[s]2)=N[C@H]1c1ccccc1Cl)=O Chemical compound CCOC(C1=C(CN(CCOC2)[C@@H]2C(O)=O)NC(c2ncc[s]2)=N[C@H]1c1ccccc1Cl)=O FMYUSYPZSFXDSC-WMZOPIPTSA-N 0.000 description 1
- IKUXZCKUEVLLMD-UHFFFAOYSA-N N#CCOP1(OC(C=CC2=CCCC=C22)=C2c(c2ccccc2cc2)c2O1)=O Chemical compound N#CCOP1(OC(C=CC2=CCCC=C22)=C2c(c2ccccc2cc2)c2O1)=O IKUXZCKUEVLLMD-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
Definitions
- the present invention relates to a process for the preparation of a compound of formula (la),
- R 1 is phenyl, which is unsubstituted, or once, twice or three times substituted by halogen;
- R 2 is C 1-6 alkyl;
- R 3 is heterocyclyl; or diastereomer, pharmaceutically acceptable salts thereof, which is useful for prophylaxis and treatment of a viral disease in a patient relating to hepatitis B infection or a disease caused by hepatitis B infection.
- One object of this invention is to develop an effective and scalable synthetic process to synthesize compounds of formula (I) or (la). Another object is to simplify purification of the compound of formula (I) or (la) by either formation of MSA salt or acid/base extraction. A further object of this invention is to provide synthetic approach which can be applied on technical scale and allows obtaining the product in good yield, desired purity and stable form.
- Ci_ 6 alkyl signifies a saturated, linear- or branched chain alkyl group containing 1 to 6, particularly 1 to 5 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, ie/ -butyl and the like.
- Particular "Ci_ 6 alkyl” group is methyl.
- halogen signifies fluorine, chlorine, bromine or iodine, particularly fluorine or chlorine.
- diastereomer denotes a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another.
- pharmaceutically acceptable salt refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of formula I and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases.
- Acid-addition salts include for example those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as /7-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like.
- Base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethyl ammonium hydroxide.
- the chemical modification of a pharmaceutical compound into a salt is a technique well known to pharmaceutical chemists in order to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. It is for example described in Bastin R.J., et al., Organic Process Research & Development 2000, 4, 427-435; or in Ansel, H., et al., In: Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th ed. (1995), pp. 196 and 1456-1457.
- heterocycle 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 or more ring atoms.
- Examples of monocyclic heterocyclyl rings containing in particular from 3 to 7 ring atoms include aziridinyl, 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 thio morpholinyl.
- 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.
- heterocyclylamine refers to an amine with nitrogen atom on the heterocyclyl ring, wherein heterocyclyl is defined above.
- the present invention provides a process for preparing the compounds of formula (I) as outlined in the scheme 1 exemplified for the compound with R 1 is phenyl, which is unsubstituted, or once, twice or three times substituted by halogen; R 2 is C 1-6 alkyl; R 3 is heterocyclyl.
- the whole synthesis comprises the following steps:
- Step b) The formation and recrystallization of the enantiomeric salt of formula (VII), or solvate,
- R 1 and R 2 are defined as above;
- Step c) The recovery of enantiomeric compound of formula (VIII) from its enantiomeric salt of formula (VII) or solvate,
- R 1 and R 2 are defined as above;
- R 1 and R 2 are defined as above;
- R 1 ,R2 and R 3 are defined as above;
- Step f The purification and recrystallization of compound of formula (I).
- Step a) Beginelli reaction to form the compound of formula (V) .
- compound of formula (V) is usually performed in the presence of a suitable catalyst and a suitable base in a suitable organic solvent.
- the conversion as a rule is performed under a heating condition.
- the suitable catalyst is selected from TEA, a mixture of TEA and AcOH, Pyridine, a mixture of Pyridine and AcOH, Glycine, ⁇ - Alanine, GAB A, DBU, a mixture of DBU and AcOH, a mixture of AcOH and piperidine, particularly the catalyst is a mixture of AcOH and piperidine.
- the suitable base is selected from TEA, DIPEA, DBU, particularly the base is TEA.
- the suitable organic solvent is selected from MeOH, EtOH, IPA, tBuOH and toluene, particularly the organic solvent is IPA.
- the Biginelli reaction as a rule is performed at 0°C - 80°C, particularly at 75°C - 80°C.
- Step b) The formation and recrystallization of the enantiomeric salt of formula (VII), or solvate.
- the formation of the enantiomeric salt of formula (VII) or solvate is usually performed in the presence of a suitable organic acid (VI) in a suitable organic solvent.
- a suitable organic acid (VI) 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-
- the suitable organic solvent used in salt formation is selected from tetrahydrofuran, MTBE, isopropyl ether, methoxycyclopentane, MeOH, EtOH, IPA, IP Ac, EtOAc, MEK, DCM, heptane, acetone, ACN, toluene, water, MIBK, trifluoroethanol, cyclohexane, DCM, xylene,
- organic solvent is MIBK, IP Ac or a mixture of ACN and MTBE.
- suitable amount of organic acid (VI) is 0.5 eq - 1.0 eq, particularly the amount is 0.8 eq.
- the salt formation as a rule is performed at 0°C - 80°C, particularly at 60°C - 75°C.
- Recrystallization of the crude enantiomeric salt of formula (VIII) or solvate is 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 c) The recovery of enantiomeric compound of formula (VIII) from its enantiomeric salt of formula (VII) or solvate.
- the recovery of enantiomeric compound of formula (VIII) can be achieved by reacting desired enantiomeric salt of formula (VII) or solvate with a suitable amount of base in a suitable organic solvent, followed by a suitable work up procedure to remove water residual.
- the 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 suitable base amount is selected from 1.0 eq - 1.5 eq, particularly the base amount is
- the suitable work up to remove the water residual was selected by dried through Mg 2 S0 4 , Na 2 S0 4 , and azeotropy, particular the work up is azeotropy.
- Step d) The bromination of compound of formula (VIII) to form a compound of formula (IX).
- the bromination of compound of formula (VIII) to form a compound of formula (IX) is usually performed in the presence of a suitable reagent in a suitable organic solvent and suitable additive.
- the conversion as a rule is performed under a heating condition.
- the suitable bromination reagents is selected from liquid bromine, NBS, pyridine tribromide, l,3-dibromo-5,5-dimethylhydantion, particularly the bromination reagent is NBS.
- the reaction is usually performed in an organic solvent which is selected from carbon tetrachloride, benzene, fluorobenzene, chlorobenzene, cyclohexane and DCM, particularly the organic solvent is DCM.
- organic solvent selected from carbon tetrachloride, benzene, fluorobenzene, chlorobenzene, cyclohexane and DCM, particularly the organic solvent is DCM.
- the bromination as a rule is performed at 0°C - 80°C, particularly at 35°C - 40°C.
- the suitable additive is selected from NH 4 C1, NH 4 Br, NH 4 OAc, V 65 , AuCl 3 , FeCl 3 , A1C1 3 ,
- PBr 3 KBr, ZnBr, MSA, TFA, H 2 S0 4 and AcOH, particularly the additive is PBr 3 .
- substitution of the compound of formula (IX) to form a compound of formula (I) is usually performed in the presence of a suitable base in a suitable organic solvent.
- the conversion as a rule is performed under a heating condition.
- the suitable base is selected from NaOH, KOH, NaOtBu, NaH, NEt 3 , DIPEA, DBU and TMP particularly the base is TMP.
- the suitable organic solvent is selected from THF, IP Ac, MTBE, fluorobenzene, benzene and DCM, particularly the organic solvent is DCM.
- the coupling reaction as a rule is performed at 0°C - 40°C, particularly 35 °C - 40°C.
- Step f The purification and recrystallization of compound of formula (I).
- the purification of compound of formula (I) is performed with a suitable acid in a suitable solvent to form a salt or through an acid-base work-up; and recrystallization of compound of formula (I) is performed with suitable seeding amount in the suitable pH range or a direct recrystallization in a suitable organic solvent.
- the suitable acid used in the purification of compound of formula (I) for salt formation is selected from HCl, HBr, H 2 SO 4 , H 3 PO 4 , MSA, toluene sulfonic acid and camphor sulfonic acid, particularly the acid is MSA.
- the acid used in the purification of compound of formula (I) for acid-base work-up is selected from HCl, HBr, H 2 SO 4 , H 3 PO 4 , MSA, toluene sulfonic acid and camphor sulfonic acid, particularly the acid is H 3 PO 4 .
- the base used in the purification of compound of formula (I) for acid-base work-up is selected from NaOH, KOH, K 2 CO 3 and Na 2 C0 3 , particularly the base is NaOH.
- the suitable organic solvent for purification is selected from THF, IP Ac, MTBE, fluorobenzene, benzene and DCM, particularly the organic solvent is DCM.
- the suitable solvent for recrystallization of compound of formula (I) was selected from acetone, ACN, MeOH, EtOH and IPA, particularly the solvent is acetone.
- the suitable seeding amount is selected from lwt - 100 wt , particularly the seeding amount is lwt .
- the suitable pH range is from 0 to 10, particularly the pH is 7.
- the suitable recrystallization time is from 2 hours to 4 days, particularly the
- recrystallization time is 3 days.
- the suitable organic solvent used in direct recrystallization is selected from acetone, ACN, MeOH, EtOH, IPA and a co-solvent of IPA and heptane, particularly the suitable organic solvent is co-solvent of IPA and heptane.
- reaction mixture was slowly cooled to 40 °C in 6 hours, then the reaction mixture was stirred at 40 °C for another 2 hours. Reaction mixture was filtrated, and the collected solid was rinsed with MIBK (50 L) 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.
- R)-(-)-l,l '-Binaphthyl-2,2'-diyl hydrogenphosphate salt mono MIB solvate (Example 2, 2.50 kg, 3.07 mol) and dichloromethane (25.0 L).
- Compound Vlllb was prepared in analogy to step 1) of Example 3 by using (S)-4-(4-chloro-3- fluoro-phenyl)-6-methyl-2-thiazol-2-yl- l,4-drhydropyrimidine-5-carboxylic acid methyl ester mono (R)-(-)- l, l '-Binaphthyl-2,2'-diyl hydrogenphosphate salt (Example 6, 100 g , 0.14 mol) instead of (R)-4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl- 1 ,4-dihydro-pyrimidine-5- carboxylic acid methyl ester mono (R)-(-)- l,l '-Binaphthyl-2,2'-diyl hydrogenphosphate salt mono MIBK solvate (Example 2).
- Example 7 preparation of (3S)-4-rr(4S)-4-(4-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2- thiazol-2-yl-l,4-dihydropyrimidin-6-yllmethyllmorpholine-3-carboxylic acid (Example 7)
- the compound of Example 7 was prepared in analogy to step 3) of Example 3 by using
- reaction mixture was slowly cooled to room temperature, and stirred at room temperature for another 2 hours. Then the reaction mixture was filtered, and the collected solid was rinsed with ACN/MTBE (0.40 L, v/v 1:1) for 2 times. The collected solid was dried in vacuum oven at 55°C for 24 hours to give 85 g product as a light yellow solid.
- the compound VIIIc was prepared in analogy to step 1) of Example 3 by using (R)-4-(2- chlorophenyl)-6-methyl-2-thiazol-2-yl-l,4-dihydropyrimidine-5-carboxylic acid ethyl ester mono (S)-(-)-l,l '-Binaphthyl-2,2'-diyl hydrogenphosphate salt mono ACN solvate (Example 9) instead of ( R)-4-( 2-chloro-4-fluoro-phen ⁇ )-6-rnethyl-2-thiazol-2-yl- 1 ,4-dihydropyrimidine-5- carboxylic acid methyl ester mono (R)-(-)-l,l '-Binaphthyl-2,2'-diyl hydrogenphosphate salt mono M1BK solvate (Example 2).
Abstract
The present invention relates to a process for synthesizing a compound of formula (I), (I), wherein R1 is phenyl, which is unsubstituted, or once, twice or three times substituted by halogen; R2 is C1
-
6alkyl; R3 is heterocyclyl; and diastereomer, pharmaceutically acceptable salts thereof, which is useful for prophylaxis and treatment of a viral disease in a patient relating to hepatitis B infection or a disease caused by hepatitis B infection.
Description
Process for the preparation of 4-phenyl-5-alkoxycarbonyl-2-thiazol-2-yl-l,4- dihydropyrimidine analogues
The present invention relates to a process for the preparation of a compound of formula (la),
wherein R1 is phenyl, which is unsubstituted, or once, twice or three times substituted by halogen; R 2 is C1-6alkyl; R 3 is heterocyclyl; or diastereomer, pharmaceutically acceptable salts thereof, which is useful for prophylaxis and treatment of a viral disease in a patient relating to hepatitis B infection or a disease caused by hepatitis B infection.
BACKGROUND OF THE INVENTION
Yingxian Zhu / Sep. 23, 2015
The patent WO2014029193 disclosed synthetic approaches to obtain compounds of formula (I) or (la). However, the synthetic approach disclosed in patent WO2014029193 needs to be improved in terms of overall low yield, racemic synthesis and column purification.
One object of this invention is to develop an effective and scalable synthetic process to synthesize compounds of formula (I) or (la). Another object is to simplify purification of the compound of formula (I) or (la) by either formation of MSA salt or acid/base extraction. A further object of this invention is to provide synthetic approach which can be applied on technical scale and allows obtaining the product in good yield, desired purity and stable form.
DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS
As used herein, the term "Ci_6alkyl" signifies a saturated, linear- or branched chain alkyl group containing 1 to 6, particularly 1 to 5 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, ie/ -butyl and the like. Particular "Ci_6alkyl" group is methyl.
The term "halogen" signifies fluorine, chlorine, bromine or iodine, particularly fluorine or chlorine.
The term "diastereomer" denotes a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another.
The term "pharmaceutically acceptable salt" refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of formula I and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Acid-addition salts include for example those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as /7-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethyl ammonium hydroxide. The chemical modification of a pharmaceutical compound into a salt is a technique well known to pharmaceutical chemists in order to obtain improved physical and chemical
stability, hygroscopicity, flowability and solubility of compounds. It is for example described in Bastin R.J., et al., Organic Process Research & Development 2000, 4, 427-435; or in Ansel, H., et al., In: Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th ed. (1995), pp. 196 and 1456-1457.
The term "heterocycle" 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 or more ring atoms. Examples of monocyclic heterocyclyl rings containing in particular from 3 to 7 ring atoms include aziridinyl, 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 thio morpholinyl. 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_6alkyl, cyano, carboxy, carboxy Ci_ 6alkyl, 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.
The term "heterocyclylamine" refers to an amine with nitrogen atom on the heterocyclyl ring, wherein heterocyclyl is defined above.
ABBREVIATION
ACN Acetonitrile eq Equivalent CSA Camphor sulfonic acid
DTTA Di-p-toluoyl-tartaric acid
DBTA Dibenzoyl-tartaric acid
DBU l,8-Diazabicyclo[5.4.0]undec-7-ene
DCM Dichloro methane
DIPEA N,N-Diisopropylethylamine
GABA γ-aminobutyric acid
IPA Isopropanol
IPAc Isopropyl acetate
MEK 2-Butanone
MIBK Methyl isobutyl ketone
MSA Methanesulfonic acid
MTBE Methyl tert-butyl ether
NBS N-Bromosuccinimide
NMM N-methylmorpholine
TEA Triethylamine
TFA Trifluoro acetic acid
THF Tetrahydrofuran TMP 2,2,6,6-Tetramethylpiperidine
V volume
V65 2,2'-Azobis-(2,4-dimethylvaleronitrile) wt% weight percentage
The present invention provides a process for preparing the compounds of formula (I) as outlined in the scheme 1 exemplified for the compound with R1 is phenyl, which is unsubstituted, or once, twice or three times substituted by halogen; R2 is C1-6alkyl; R3 is heterocyclyl.
Scheme 1
The whole synthesis comprises the following steps:
Step a) Beginelli reaction to form the compound of formula (V),
wherein R 1 and R 2 are defined as above;
Step b) The formation and recrystallization of the enantiomeric salt of formula (VII), or solvate,
Step c) The recovery of enantiomeric compound of formula (VIII) from its enantiomeric salt of formula (VII) or solvate,
Step d) The bromination of compound of formula (VIII) to form a compound of formula
(ix),
Step e) The substitution of the compound of formula (IX) to form a compound of formula
(I),
Step f) The purification and recrystallization of compound of formula (I).
Another embodiment of this invention is that compound of formula (la) can also be synthesized in analogy to Scheme 1 without chiral separation step.
A detailed description of present invention of process steps is as following:
Step a) Beginelli reaction to form the compound of formula (V) .
The formation of compound of formula (V) is usually performed in the presence of a suitable catalyst and a suitable base in a suitable organic solvent. The conversion as a rule is performed under a heating condition.
The suitable catalyst is selected from TEA, a mixture of TEA and AcOH, Pyridine, a mixture of Pyridine and AcOH, Glycine, β- Alanine, GAB A, DBU, a mixture of DBU and AcOH, a mixture of AcOH and piperidine, particularly the catalyst is a mixture of AcOH and piperidine.
The suitable base is selected from TEA, DIPEA, DBU, particularly the base is TEA.
The suitable organic solvent is selected from MeOH, EtOH, IPA, tBuOH and toluene, particularly the organic solvent is IPA.
The Biginelli reaction as a rule is performed at 0°C - 80°C, particularly at 75°C - 80°C.
Step b) The formation and recrystallization of the enantiomeric salt of formula (VII), or solvate.
The formation of the enantiomeric salt of formula (VII) or solvate is usually performed in the presence of a suitable organic acid (VI) 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, EtOAc, 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 suitable amount of organic acid (VI) is 0.5 eq - 1.0 eq, particularly the amount is 0.8 eq.
The salt formation as a rule is performed at 0°C - 80°C, particularly at 60°C - 75°C.
Recrystallization of the crude enantiomeric salt of formula (VIII) or solvate is 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 c) The recovery of enantiomeric compound of formula (VIII) from its enantiomeric salt of formula (VII) or solvate. The recovery of enantiomeric compound of formula (VIII) can be achieved by reacting desired enantiomeric salt of formula (VII) or solvate with a suitable amount of base in a suitable organic solvent, followed by a suitable work up procedure to remove water residual.
The suitable base is selected from TEA, DIPEA, methyldicyclohexylamine, NMM, NaOH, Na2C03, NaHC03 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 suitable base amount is selected from 1.0 eq - 1.5 eq, particularly the base amount is
1.1 eq.
The suitable work up to remove the water residual was selected by dried through Mg2S04, Na2S04, and azeotropy, particular the work up is azeotropy.
Step d) The bromination of compound of formula (VIII) to form a compound of formula (IX).
The bromination of compound of formula (VIII) to form a compound of formula (IX) is usually performed in the presence of a suitable reagent in a suitable organic solvent and suitable additive. The conversion as a rule is performed under a heating condition.
The suitable bromination reagents is selected from liquid bromine, NBS, pyridine tribromide, l,3-dibromo-5,5-dimethylhydantion, particularly the bromination reagent is NBS.
The reaction is usually performed in an organic solvent which is selected from carbon tetrachloride, benzene, fluorobenzene, chlorobenzene, cyclohexane and DCM, particularly the organic solvent is DCM.
The bromination as a rule is performed at 0°C - 80°C, particularly at 35°C - 40°C. The suitable additive is selected from NH4C1, NH4Br, NH4OAc, V65, AuCl3, FeCl3, A1C13,
PBr3, KBr, ZnBr, MSA, TFA, H2S04 and AcOH, particularly the additive is PBr3.
Step e) The substitution of the compound of formula (IX) to form a compound of formula
(I).
The substitution of the compound of formula (IX) to form a compound of formula (I) is usually performed in the presence of a suitable base in a suitable organic solvent. The conversion as a rule is performed under a heating condition.
The suitable base is selected from NaOH, KOH, NaOtBu, NaH, NEt3, DIPEA, DBU and TMP particularly the base is TMP.
The suitable organic solvent is selected from THF, IP Ac, MTBE, fluorobenzene, benzene and DCM, particularly the organic solvent is DCM.
The coupling reaction as a rule is performed at 0°C - 40°C, particularly 35 °C - 40°C.
Step f) The purification and recrystallization of compound of formula (I).
The purification of compound of formula (I) is performed with a suitable acid in a suitable solvent to form a salt or through an acid-base work-up; and recrystallization of compound of formula (I) is performed with suitable seeding amount in the suitable pH range or a direct recrystallization in a suitable organic solvent.
The suitable acid used in the purification of compound of formula (I) for salt formation is selected from HCl, HBr, H2SO4, H3PO4, MSA, toluene sulfonic acid and camphor sulfonic acid, particularly the acid is MSA. The acid used in the purification of compound of formula (I) for acid-base work-up is selected from HCl, HBr, H2SO4, H3PO4, MSA, toluene sulfonic acid and camphor sulfonic acid, particularly the acid is H3PO4. The base used in the purification of compound of formula (I) for acid-base work-up is selected from NaOH, KOH, K2CO3 and Na2C03, particularly the base is NaOH.
The suitable organic solvent for purification is selected from THF, IP Ac, MTBE, fluorobenzene, benzene and DCM, particularly the organic solvent is DCM.
The suitable solvent for recrystallization of compound of formula (I) was selected from acetone, ACN, MeOH, EtOH and IPA, particularly the solvent is acetone.
The suitable seeding amount is selected from lwt - 100 wt , particularly the seeding amount is lwt .
The suitable pH range is from 0 to 10, particularly the pH is 7.
The suitable recrystallization time is from 2 hours to 4 days, particularly the
recrystallization time is 3 days.
The suitable organic solvent used in direct recrystallization is selected from acetone, ACN, MeOH, EtOH, IPA and a co-solvent of IPA and heptane, particularly the suitable organic solvent is co-solvent of IPA and heptane.
EXAMPLES
Example 1
Preparation of 4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-l,4-dihydropyrimidine- 5-carboxylic acid methyl ester:
To a 1000 L glass-lined reactor was charged 2-chloro-4-fluoro-benzaldehyde (30.8 kg,
194 mol) and isopropanol (188.0 kg). To the solution was then added methyl acetoacetate (22.7 kg, 195 mol) followed by piperidine (1.74 kg, 20.4 mol) and acetic acid (1.32 kg, 22.0 mol). The mixture was then heated to 43 °C - 47 °C and stirred under this temperature for 5 hours. To the reaction mixture was then added thiazole-2-carboxamidine hydrochloride salt (19.8 kg, 121.0mol) and triethyl amine (20.0 kg, 198.0 mol). The reaction mixture was heated to 80 °C - 85 °C and stirred for 7 hours.
After reaction completion, the reaction mixture was cooled to 20 °C - 25 °C. To the mixture was then added water (52.0 kg). The resulting suspension was stirred at 20 °C - 25 °C for 2 hours. The suspension was centrifuged and the collected solid was washed with isopropanol/water (42 kg; 10v/3v). The wet solid was dried in vacuum oven to afford 35.05 kg of 4-(2-chloro-4-fluoro- phenyl)-6-methyl-2-thiazol-2-yl-l,4-dihydropyrimidine-5-carboxylic acid methyl ester (Example 1). The purity was 95.8%, the yield was 79.2 %, and MS m/e = 366.2 [M+H] +.
Example 2
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,l'-Binaphthyl-2,2'-diyl hydrogenphosphate salt mono MIBK solvate
To a 1000 L flask was charged with 4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2- yl-l,4-dihydropyrimidine-5-carboxylic acid methyl ester (Example 1, 23.8 kg, 65.06 mol), MIBK (660 L) and purified water (6.6 L) 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 (18.1 kg, 52.05 mol) 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 in 6 hours, then the reaction mixture was stirred at 40 °C for another 2 hours. Reaction mixture was filtrated, and the collected solid was rinsed with MIBK (50 L) 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: (R)-4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2- yl-l,4-dihydropyrimidine-5-carboxylic acid methyl ester: MIBK was 1: 1: 1, and the MS m/e =366.2 [M+H]+.
Example 3
Preparation of (3S)-4-[[(4R)-4-(2-chloro-4-fiuoro-phenyl)-5-methoxycarbonyl-2-thiazol-2- yl-l,4-dihydropyrimidin-6-yl]methyl]morpholine-3-carboxylic acid
The title compound was prepared according to following scheme:
Example 2
Villa
IXa
Example 3
Step 1) preparation of (4R -4-(2-chloro-4-fluoro-phenyl -6-methyl-2-thiazol-2-yl-l,4- dihydropyrimidine-5-carboxylic acid methyl ester (compound Villa)
To a 50 L flask was charged with (R)-4-(2-chloro-4-fluoro-phenyl)-6-meihyl-2-thiazol-2- yl- 1 ,4-dihydropyrimidine-5-carboxylic acid methyl ester mono (R)-(-)-l,l '-Binaphthyl-2,2'-diyl hydrogenphosphate salt mono MIB solvate (Example 2, 2.50 kg, 3.07 mol) and dichloromethane (25.0 L). The mixture was stirred at room temperature for another 20 minutes until all yellow solid dissolved. Aqueous NaOU solution (20 wt%, 3.1 eq., 0.68 kg, 3.38 mol) was added to the previous solution in one portion at room temperature. The reaction mixture was stirred for 2 hours, then filtrated, and the collected solid was rinsed with dichloromethane (5.0 L) twice. The collected organic solution was concentrated till dryness in vacuo. To the left residue was added DCM (7.5 L), the resulting solution was concentrated till dryness in vacuo and this process was repeated one more time. The resulting yellow oil (compound Villa) was used in the next step w ithout further purification.
Step 2) preparation of (4R)-6-(bromomethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2- yl-l,4-dihydropyrimidine-5-carboxylic acid methyl ester (compound IXa)
(4R)-4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-l,4-dihydropyrimidine-5- carboxylic acid methyl ester_(compound Villa, 1.0 eq, 1.12 kg, 3.07 mol ) from last step was dissolved in DCM (12.5 L). The previous solution was then heated to 33 °C - 38 °C. Then NBS (0.63 kg, 3.53 mol) was added to previous solution portionwise with careful monitoring the starting material conversion using HPLC. After reaction completion, NaHC03 aqueous solution (3.5 wt , 5.80 kg) was added to the reaction mixture to quench the reaction. Phase separation and resulting organic solution was used in next step without further purification. Step 3) preparation of (3S)-4-rr(4R)-4-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-
2-thiazol-2-yl-l,4-dihydropyrimidin-6-yllmethyllmorpholine-3-carboxylic acid (Example 3)
The 50 L flask was charged w ith crude (4R)-6-(bromomethyl)-4-(2-chloro-4-fluoro- phenyl)-2-thiazol-2-yl-l,4-dihydropyrimidine-5-carboxylic acid methyl esterjcompound IXa) from last step) in dichloromethane solution , ( 3 S ) - mo rp ho 1 i ne - 3 -carbo x y 1 i c acid hydrochloride salt (1.02 eq, 0.53 kg, 3.14 mol) and 2,2,6,6-tetramethylpiperidine (2.87 eq, 1.24 kg, 8.80 mol) at 25 °C - 28 °C. The resulting solution was stirred at 25 °C - 28 °C for 16 hours.
After reaction completion, water (10.0 L) was added to reaction mixture to quench the reaction. The reaction mixture was adjusted to p l = 2.5 using H3PO4. After phase separation, the organic phase was washed w ith acid solution (using H3PO4 to adjust pH = 2.5) twice to remove
all the TMP. The organic solution was concentrated to dryness in vacuo and the residue was re- dissolved in MIBK (10.0 L). To the solution was then added MSA (0.78 eq, 0.23 kg, 2.39 mol) slowly in 2 hours. After the addition of MSA, the solution was heated to 40 "C - 45 "C and stirred for 2 hours. The result ing suspension was cooled to 23 "C - 25 "C. The reaction mixture was filtered and the collected solid was rinsed with MI B (1.0 L). The resulting solid was dried in v acuum oven at 45 "C for 16 hours to afford the MSA salt of Example 3 (1.45 kg ).
To a 20 L flask was charged with MSA salt of Example 3 ( 1 .45 kg, 2.45 mol), EtOAc (15.0 L) and Nal lCCh aqueous solution (10 wt%, 1 .33 kg ) at room temperature. After phase separation, the organic phase w as washed with water (3.0 L). The organic solution was concentrated to dryness in vacuo and the residue was re-dissolved in acetone (1 .10 L). The resulting acetone solut ion was slowly added into w ater (12.0 L) in 12 hours at 20 "C -
25 "C. The resulting suspension was stirred for an additional 72 hours at 20 "C -25 °C. Reaction mixture was filtered and the collected solid was rinsed with water (5.0 L) for 2 times. The resulting solid was dried under vacuum at 55 "C for 72 hours until the weight was constant to give 1.01 kg product as light yellow solid. The purity was 99.5%, the yield was 66.6% for 3 steps, and the MS m/e =495.1 [M+H]+.
Example 4
Alternative method for preparation of (3S)-4-[[(4R)-4-(2-chloro-4-fluoro-phenyl)-5- methoxycarbonyl-2-thiazol-2-yl-l,4-dihydropyrimidin-6-yl]methyl]morpholine-3- carboxylic acid
The compound IXa in DCM solution was prepared in analogy to Example 3 step 1) and 2). To the previous solution was then added (3S)-morpholine-3-carboxylic acid hydrochloride salt (compound X. 1 .03 eq. 1.06 kg. 6.32 mol), and 2.2.6.6-tetramethylpiperidine ( 2.84 eq, 2.46 kg, 1 7.42 mol). The resulting solution was stirred at 25 "C - 28 "C for 16 hours. After reaction completion, aqueous NaHCO.* (3.5 wt%, 15.0 L) solution was added to quench the reaction. The reaction mixture was adjusted to pl l = 2.5 using H3PO4. After phase separation, the organic phase was washed with acid solution ( using H3PO4 to adjust pl l = 2.5 ) twice to remove all the I MP. Water (15.0 L) was added and the aqueous phase of the mixture was adjust to pH = 0.26 - 0.3 with H3PO4 ( 85 wt%). The solution was stirred for another 30 mins. After phase separation, the aqueous layer was washed with DCM (15.0 L) twice. Then the aqueous layer was adjusted to pH=2.5 with aqueous NaOH solution (40 wt%). The resulting solution was extracted with EtOAc (20.0 L). After phase separation, the organic phase was washed w ith water (3.0 L) and filtered through polish fi lter. The organic solution was
concentrated till dryness in vacuo. The left residue was re-dissolved in acetone (4.0 L). The resulting acetone solut ion was slowly added into water (30.00 L) in 1 hour at 20 "C -
25 °C. The result ing suspension was stirred for another 72 hours at 20 "C -25 °C. Then the previous suspension was filtered and the collected solid was rinsed with water (5.0 L) twice. The resulting solid was dried in vacuum oven at 55 "C for 72 hours until the weight was constant to give 2.29 kg product as a light yellow solid. The purity was 99.5%, the yield was 75.5%, and the MS m/e =495.1 [M+H]+.
Example 5
Preparation of 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 Example 1 by using 4-chloro-3-fluoro- benzaldehyde (94.80g, 0.60mol) instead of 2-chloro-4-fluoro-benzaldehyde. 113.00 g product was obtained as light yellow solid. The purity was 81.0%, the yield was 51.6%, and MS m/e = 366.3 [M+H] +.
Example 6 Preparation of (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
The title compound was prepared in analogy to Example 2 by using 4-(4-chloro-3-fluoro- phenyl)-6-methyl-2-thiazol-2-yl-l,4-dihydropyrimidine-5-carboxylic acid methyl ester (Example
5, 182 g, 0.50 mol) and (R)-(-)-l,l '-Binaphthyl-2,2'-diyl hydrogenphosphate (140 g, 0.40 mol) instead of methyl 4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-l,4-dihydropyrimidine- 5-carboxylate (Example 1) 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 72.0%, and MS m/e = 366.3 [M+H] +.
Example 7
Preparation of (3S)-4-[[(4S)-4-(4-chloro-3-fiuoro-phenyl)-5-methoxycarbonyl-2-thiazol-2- yl-l,4-dihydropyrimidin-6-yl]methyl]morpholine-3-carboxylic acid
The title compound was prepared according to following scheme:
Step 1) preparation of (4S -4-(4-chloro-3-fluoro-phenyl -6-methyl-2-thiazol-2-yl- l,4- dihydropyrimidine-5-carboxylic acid methyl ester (compound VHIb
Compound Vlllb was prepared in analogy to step 1) of Example 3 by using (S)-4-(4-chloro-3- fluoro-phenyl)-6-methyl-2-thiazol-2-yl- l,4-drhydropyrimidine-5-carboxylic acid methyl ester mono (R)-(-)- l, l '-Binaphthyl-2,2'-diyl hydrogenphosphate salt (Example 6, 100 g , 0.14 mol) instead of (R)-4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl- 1 ,4-dihydro-pyrimidine-5- carboxylic acid methyl ester mono (R)-(-)- l,l '-Binaphthyl-2,2'-diyl hydrogenphosphate salt mono MIBK solvate (Example 2). The resulting yellow solid (compound Vlllb ) was used in next step without further purification. Step 2) preparation of (4S -6-(bromomethyl -4-(4-chloro-3-fluoro-phenyl -2-thiazol-2-yl- l,4-dihydropyrimidine-5-carboxylic acid methyl ester mono methane sulfonic acid salt (compound IXb
To a 5 L flask was charged with the (4S)-4-(4-chloro-3-fluoro-phenyl)-6-methyl-2- thiazol-2-yl- 1 .4-dihydropyrimidine-5-carboxylic acid methyl ester (compound Vlllb, 127 g, 0.35 mol) and DCM (3.0 L). The solution was heated to 35 "C -38 "C and to the solution was added PBr; (4.71 g, 17.4 mmol). Then NBS (71.13 g, 0.40 mol ) was added to the reaction mixture portionwise with careful monitoring the starting material conversion using HPLC. After reaction
completion. NaHCOs (3.5 wt%, 700 g) was added to quench the reaction. After phase separation, the organic phase was dried with NajSO.*. The DCM was removed under vacuum. IP Ac (500 mL) was added to the residue followed by addition of MSA (1.0 eq; 33.36 g, 0.35 mol). The result ing solution was heated to 55 "C - 58 "C and the agitation was maintained for 2 hours. The
suspension was then cooled to 25 "C - 28 "C and stirred for 2 hours. Reaction mixture was filtered and the collected solid was rin ed with IP Ac (100 mL) twice. The resulted solid was dried in vacuum oven at 55 "C for 72 hours to afford 114.00 g product as a white solid. The purity was 91.4%, the yield was 55.1%, and the MS m/e =444.0 [M+H]+.
Step 3) preparation of (3S)-4-rr(4S)-4-(4-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2- thiazol-2-yl-l,4-dihydropyrimidin-6-yllmethyllmorpholine-3-carboxylic acid (Example 7) The compound of Example 7 was prepared in analogy to step 3) of Example 3 by using
(4S)-6-(bromomethyl)-4-(4-chloro-3-fluoro-phenyl)-2-thiazol-2-yl-l,4-dihydropyrimidine-5- carboxylic acid methyl ester mono methane sulfonic acid salt (compound IXb, 114g, 0.21mol) instead of (4R)-6-(bromomethyl)-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-l,4- dihydropyrimidine-5-carboxylic acid methyl ester (compound IXa). 105 g product was obtained as a light yellow solid. The chiral purity was 99.88%, purity was 99.1%, the yield was 97.9%, and MS m/e = 494.3 [M+H] +
Example 8
Preparation of 4-(2-chlorophenyl)-6-methyl-2-thiazol-2-yl-l,4-dihydropyrimidine-5- carboxylic acid ethyl ester
The title compound was prepared in analogy to Example 1 by using 2-chlorobenzaldehyde (140 g, 1.00 mol) and ethyl 3-oxobutanoate (130 g, 1.00 mol) instead of 2-chloro-4-fluoro-
benzaldehyde and methyl 3-oxobutanoate. 224 g product was obtained as a light yellow solid. The purity was 99.0%, the yield was 62.2% and MS m/e = 362.3 [M+H] +.
Example 9
Preparation of (R)-4-(2-chlorophenyl)-6-methyl-2-thiazol-2-yl-l,4-dihydropyrimidine-5- carboxylic acid ethyl ester mono (S)-(-)-l,l'-Binaphthyl-2,2'-diyl hydrogenphosphate salt mono ACN solvate
To a 2 L flask was charged with 4-(2-chlorophenyl)-6-methyl-2-thiazol-2-yl-l,4- dihydropyrimidine-5-carboxylic acid ethyl ester (Example 8,120 g, 0.33 mol), ACN (0.60 L), MTBE (0.60 L) and purified water (120 mL) at room temperature. (S)-(-)-l,l '-Binaphthyl-2,2'- diyl hydrogen phosphate (115 g, 0.33 mol) was added to the previous reaction mixture in one portion at room temperature. The reaction mixture was heated to 75 °C and agitation was maintained for 16 hours. After that, the reaction mixture was slowly cooled to room temperature, and stirred at room temperature for another 2 hours. Then the reaction mixture was filtered, and the collected solid was rinsed with ACN/MTBE (0.40 L, v/v 1:1) for 2 times. The collected solid was dried in vacuum oven at 55°C for 24 hours to give 85 g product as a light yellow solid. The chiral purity was 99.3%, the yield was 72.0%, the mol ratio of Acid: (R)-4-(2-chlorophenyl)-6- methyl-2-thiazol-2-yl-l,4-dihydropyrimidine-5-carboxylic acid ethyl ester : ACN was 1: 1: 1, and MS m/e = 362.3 [M+H] +.
Example 10
Preparation of (3S)-4-[[(4S)-4-(4-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2- yl-l,4-dihydropyrimidin-6-yl]methyl]morpholine-3-carboxylic acid
IXc Example 10
Step 1) preparation of (R -4-(2-chlorophenyl -6-methyl-2-thiazol-2-yl-l,4- dihydropyrimidine-5-carboxylic acid ethyl ester (compound VIIIc)
The compound VIIIc was prepared in analogy to step 1) of Example 3 by using (R)-4-(2- chlorophenyl)-6-methyl-2-thiazol-2-yl-l,4-dihydropyrimidine-5-carboxylic acid ethyl ester mono (S)-(-)-l,l '-Binaphthyl-2,2'-diyl hydrogenphosphate salt mono ACN solvate (Example 9) instead
of ( R)-4-( 2-chloro-4-fluoro-phen\ )-6-rnethyl-2-thiazol-2-yl- 1 ,4-dihydropyrimidine-5- carboxylic acid methyl ester mono (R)-(-)-l,l '-Binaphthyl-2,2'-diyl hydrogenphosphate salt mono M1BK solvate (Example 2). The chiral purity was 99.2%, the yield was 98.0%, and MS m/e = 362.3 [M+H] +.
Step 2) preparation of (R)-4-(2-chlorophenyl)-6-bromomethyl-2-thiazol-2-yl-l,4- di ydropyrimidine-5-carboxylic acid ethyl ester (compound IXc)
The compound IXc was prepared in analogy to step 2) of Example 3 by using (R)-4-(2- chlorophenyl)-6-methyl-2-thiazol-2-yl-l,4-dihydropyrimidine-5-carboxylic acid ethyl ester (compound VIIIc) instead of (4R)-4-(2-chloro-4-fluoro-phenyl)-6-methyl-2-thiazol-2-yl-l,4- dihydropyrimidine-5-carboxylic acid methyl ester (compound VIIIa)._The purity was 81.0%, the yield was 79.3%, and MS m/e =440.0 [M+H] +.
Step 3) preparation of (3S)-4-rr(4R)-4-(2-chlorophenyl)-5-emoxycarbonyl-2-thiazol-2- yl-1.4-dihydropyrimidin-6-yllmethyllmorpholine-3-carboxylic acid (Example 10)
To the 100 ml, flask was charged w ith (R)-4-(2-chlorophenyl)-6-bromomethyl-2-thiazol- 2-yl-l,4-dihydropyrimidine-5-carboxylic acid ethyl ester (compound IXc, 8. 14g, 18.50 mmol) in DCM solution, ( 3 S )- mo rpho 1 i ne-3-carbo y 1 ic acid hydrochloride salt (compound X, 1.50 eq., 4.64 g. 27.70 mmol) and 2,2,6,6-tetramethylpiperidine (5.10 eq, 13.03 g, 94. 16 mmol). The reaction mixture was stirred at 25 °C - 28 "C for 16 hours. After reaction completion, the reaction mixture was adjusted to pH = 2.5 using H3PO4. After phase separation, the organic phase was washed with acid water ( using H3PO4 to adjust to pH = 2.5) twice to remove all the I MP and concentrated till dryness in vacuo. The residue was dissolved in EtOAc (30 ml.) at 25 °C -28 °C. To the previous solution was then slowly added n-heptane (50 mL) while maintain at 25 °C -28 "C. The resulted suspension was stirred for another 0.5 hour at 25 "C -28 "C. After vacuum filtration, the collected solid was dried in vacuum oven at 55 °C for 16 hours until the weight was constant to give 7.40 g product (Example 10) as a yellow solid. The purity was 99.0%, the yield was 80.7%, and MS m/e =491.3 [M+H] +.
Claims
1. Process for the preparation of a compound of the formula (I),
wherein R is phenyl, which is unsubstituted, or once, twice or three times substituted by halogen; R 2 is C1-6alkyl; R 3 is heterocyclyl; and pharmaceutically acceptable addition salts thereof; comprising the following steps:
Step a) Beginelli reaction to form the compound of formula (V),
Step b) The formation and recrystallization of the enantiomeric salt of formula (VII), or solvate,
(VII),
wherein R1 and R2 are defined as above;
Step c) The recovery of enantiomeric compound of formula (VIII) from its enantiomeric salt of formula (VII) or solvate,
Step d) The bromination of compound of formula (VIII) to form a compound of formula
Step e) The substitution of the compound of formula (IX) to form a compound of formula (I),
2. A process according to claim 1, wherein R 1 is chloro fluorophenyl or chlorophenyl; R 2 is methyl or ethyl; R is carboxymorpholinyl.
3. A process according to claim 1 or 2, wherein the bromination of compound of formula (VIII) in step d) is performed in the presence of a reagent in an organic solvent and additive, wherein the additive is selected from NH4C1, NH4Br, NH4OAc, V65, AuCl3, FeCl3, A1C13, PBr3, KBr, ZnBr, MSA, TFA, H2S04 and AcOH, particularly the additive is PBr3.
4. A process according to any one of claims 1 to 3, wherein the product of bromination of compound of formula (VIII) in step d) is followed by a salt formation between the product and MSA.
5. A process according to any one of claims 1 to 4, wherein the substitution of the compound of formula (IX) in step e) is performed in the presence of a base in an organic solvent, wherein the base is selected from NaOH, KOH, NaOtBu, NaH, TEA, DIPEA, DBU and TMP, particularly the base is TMP.
6. A process according to any one of claims 1 to 5, wherein the purification of compound of formula (I) in step f) is performed with an acid in a solvent to form a salt or through an acid-base work-up; wherein the acid used in the purification of compound of formula (I) for salt formation is selected from HC1, HBr, H2S04, H3P04, MSA, toluene sulfonic acid and camphor sulfonic acid, particularly the acid is MSA.
7. A process according to any one of claims 1 to 6, wherein the acid used in the purification of compound of formula (I) for acid-base work-up in step f) is selected from HC1, HBr, H2S04,
H3P04, MSA, toluene sulfonic acid and camphor sulfonic acid, particularly the acid is H3P04; the base used in the purification of compound of formula (I) for acid-base work-up in step f) is selected from NaOH, KOH, K2C03 and Na2C03, particularly the base is NaOH.
8. A process according to claim 6 or 7, wherein and recrystallization of compound of formula (I) in step f) is performed with seeding amount in the pH range or a direct recrystallization in a suitable organic solvent; wherein the suitable seeding amount is selected from 1 wt - 100 wt , particularly the seeding amount is 1 wt% .
9. A process according to claim 8, wherein the suitable pH range is from 0 to 10, particularly the pH is 7.
10. A process according to claim 8 or 9, wherein the suitable recrystallization time is from 2 hours to 4 days, particularly the recrystallization time is 3 days.
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