CN117551093A - Preparation method of maleic acid atorvastatin (4-chloro-2-thienyl) -2-thiazole amine) as starting material - Google Patents
Preparation method of maleic acid atorvastatin (4-chloro-2-thienyl) -2-thiazole amine) as starting material Download PDFInfo
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- CN117551093A CN117551093A CN202311511998.7A CN202311511998A CN117551093A CN 117551093 A CN117551093 A CN 117551093A CN 202311511998 A CN202311511998 A CN 202311511998A CN 117551093 A CN117551093 A CN 117551093A
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- 239000007858 starting material Substances 0.000 title claims abstract description 42
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 title claims abstract description 32
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 title claims abstract description 32
- 229960005370 atorvastatin Drugs 0.000 title claims abstract description 32
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 title claims abstract description 32
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- -1 4-chloro-2-thienyl Chemical group 0.000 title claims abstract description 20
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 title description 3
- 239000011976 maleic acid Substances 0.000 title description 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 60
- 238000000034 method Methods 0.000 claims abstract description 38
- 150000001875 compounds Chemical class 0.000 claims abstract description 34
- SMBPGSKGPGBYBQ-UHFFFAOYSA-N 4-(4-chlorothiophen-2-yl)-1,3-thiazol-2-amine Chemical compound S1C(N)=NC(C=2SC=C(Cl)C=2)=C1 SMBPGSKGPGBYBQ-UHFFFAOYSA-N 0.000 claims abstract description 32
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims abstract description 31
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims abstract description 20
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims abstract description 18
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 13
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 12
- PGBFYLVIMDQYMS-UHFFFAOYSA-N Methyl thiophene-2-carboxylate Chemical compound COC(=O)C1=CC=CS1 PGBFYLVIMDQYMS-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 11
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000006467 substitution reaction Methods 0.000 claims abstract description 9
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 8
- 238000006482 condensation reaction Methods 0.000 claims abstract description 8
- 230000002140 halogenating effect Effects 0.000 claims abstract description 8
- 239000012670 alkaline solution Substances 0.000 claims abstract description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 3
- 239000011593 sulfur Substances 0.000 claims abstract description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 156
- 239000002904 solvent Substances 0.000 claims description 63
- 239000000243 solution Substances 0.000 claims description 41
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 16
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 12
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical group [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 8
- 239000011592 zinc chloride Substances 0.000 claims description 8
- 235000005074 zinc chloride Nutrition 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 235000019441 ethanol Nutrition 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000000047 product Substances 0.000 abstract description 17
- 239000012535 impurity Substances 0.000 abstract description 14
- 238000009776 industrial production Methods 0.000 abstract description 5
- 238000005660 chlorination reaction Methods 0.000 abstract description 3
- 239000007795 chemical reaction product Substances 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- 239000012071 phase Substances 0.000 description 24
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 16
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 15
- 239000007788 liquid Substances 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000012295 chemical reaction liquid Substances 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 5
- 238000002390 rotary evaporation Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000031709 bromination Effects 0.000 description 4
- 238000005893 bromination reaction Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- FKESGQASARHBDC-UHFFFAOYSA-N 1-(4-chlorothiophen-2-yl)ethanone Chemical compound CC(=O)C1=CC(Cl)=CS1 FKESGQASARHBDC-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000001276 controlling effect Effects 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 102000036693 Thrombopoietin Human genes 0.000 description 2
- 108010041111 Thrombopoietin Proteins 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 208000019423 liver disease Diseases 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- MISPBGHDNZYFNM-BTJKTKAUSA-N (z)-but-2-enedioic acid;1-[3-chloro-5-[[4-(4-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)-1,3-thiazol-2-yl]carbamoyl]pyridin-2-yl]piperidine-4-carboxylic acid Chemical compound OC(=O)\C=C/C(O)=O.C1CC(C(=O)O)CCN1C1=NC=C(C(=O)NC=2SC(=C(C=3SC=C(Cl)C=3)N=2)N2CCN(CC2)C2CCCCC2)C=C1Cl MISPBGHDNZYFNM-BTJKTKAUSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 150000002500 ions Chemical group 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 210000003593 megakaryocyte Anatomy 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 210000003643 myeloid progenitor cell Anatomy 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
Classifications
-
- 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
- C07D417/02—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 two hetero rings
- C07D417/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention provides a preparation method of a starting material 4- (4-chloro-2-thienyl) -2-thiazolamine of atorvastatin maleate. According to the method, thiophene-2-carboxylic acid methyl ester is used as a starting material, and is subjected to chlorination reaction with N-chlorosuccinimide to obtain a compound II, and the compound II is subjected to hydrolysis reaction under the action of an alkaline solution to obtain a compound III; carrying out condensation reaction on the compound III and N, N' -carbonyl diimidazole to obtain a compound IV; reacting the compound IV with trimethyl sulfoxide iodide, and converting the reaction product into a sulfur ylide structure to obtain a compound V; carrying out substitution reaction on the compound V and a halogenating agent to obtain a compound VI; the compound VI and thiourea undergo a ring-closure reaction to obtain 4- (4-chloro-2-thienyl) -2-thiazole amine. The product obtained by the method has high yield and purity, less disubstituted impurity content, mild process reaction conditions and high yield, and is suitable for industrial production.
Description
Technical Field
The invention relates to a preparation method of a starting material 4- (4-chloro-2-thienyl) -2-thiazolamine of atorvastatin maleate, belonging to the technical field of synthesis of pharmaceutical intermediates.
Background
Atorvastatin maleate is an oral Thrombopoietin (TPO) receptor agonist that stimulates megakaryocyte proliferation and differentiation in myeloid progenitor cells, thereby increasing platelet production. The atorvastatin maleate was developed by the Tadali pharmaceutical group of Japan An Si, after which new drug development was completed by AkaRx pharmaceutical company, and was approved by the United states FDA for marketing at 5.23 of 2018 under the trade name Doptelet for adult Chronic Liver Disease (CLD) patients suffering from thrombocytopenia and intended to undergo medical or dental procedures.
4- (4-chloro-2-thienyl) -2-thiazolamine is an important starting material for the synthesis of atorvastatin maleate, and at present, the route in patent WO2021021000A1 is a common route for the synthesis of 4- (4-chloro-2-thienyl) -2-thiazolamine, wherein the process route uses 4-chloro-2-acetylthiophene as a starting material and carries out bromination and thiourea cyclization to obtain 4- (4-chloro-2-thienyl) -2-thiazolamine, and the specific route is shown as follows. The disadvantages of the process route are as follows: (1) The bromine equivalent of the liquid in the bromination step is not well controlled, the disubstituted byproducts are more, and the liquid is difficult to purify and separate in the post-treatment, so that the yield and the purity are low; (2) The liquid bromine has strong pungent smell, the production site environment is bad, the waste liquid is generated more and pollutes the environment, the industrial safety risk is high, and the industrial production is not facilitated; (3) The starting material 4-chloro-2-acetylthiophene has small market scale and high price, and limits the application of the starting material in drug synthesis.
Therefore, a preparation method of 4- (4-chloro-2-thienyl) -2-thiazole amine with mild process reaction conditions, high safety, less impurity of the obtained product and high yield and purity is developed.
Disclosure of Invention
The invention provides a preparation method of a starting material 4- (4-chloro-2-thienyl) -2-thiazolamine of atorvastatin maleate aiming at the defects of the prior art. According to the method, thiophene-2 carboxylic acid methyl ester is used as a starting raw material, and 4- (4-chloro-2-thienyl) -2-thiazole amine is prepared through chlorination, hydrolysis, condensation, thio ylide and bromination ring closure reactions, so that the obtained product has high yield and purity, low content of disubstituted impurities, mild technological reaction conditions and high yield, and is suitable for industrial production.
The technical scheme of the invention is as follows:
a method for preparing a starting material 4- (4-chloro-2-thienyl) -2-thiazolamine of atorvastatin maleate, which comprises the following steps:
(1) Dissolving thiophene-2-carboxylic acid methyl ester I in a solvent A, adding zinc chloride, uniformly stirring, and adding N-chlorosuccinimide to react to obtain a compound II;
(2) In a solvent B, performing hydrolysis reaction on the compound II under the action of an alkaline solution to obtain a compound III; in a solvent C, carrying out condensation reaction on the compound III and N, N' -carbonyl diimidazole to obtain a compound IV;
(3) In a solvent D, under the action of alkali, the compound IV reacts with trimethyl sulfoxide iodide and is converted into a sulfur ylide structure to obtain a compound V; in a solvent E, under the action of acid, carrying out substitution reaction on the compound V and a halogenating agent to obtain a compound VI;
(4) The compound VI and thiourea undergo a ring-closure reaction to obtain the starting material 4- (4-chloro-2-thienyl) -2-thiazolamine of the atorvastatin maleate.
According to a preferred embodiment of the present invention, the solvent a in step (1) is acetonitrile, ethyl acetate or ethanol; the ratio of the volume of the solvent A to the mass of the thiophene-2-carboxylic acid methyl ester I is 5-15 mL/1 g.
According to a preferred embodiment of the invention, the molar ratio of zinc chloride to thiophene-2-carboxylic acid methyl ester I in step (1) is 2-4:1; the zinc chloride is added into the system in 2-4 batches, the time interval of addition is 5-15min, and the temperature of the system is controlled to be 20-25 ℃ when the zinc chloride is added; the stirring time is 0.5-1.5h after adding zinc chloride.
According to a preferred embodiment of the present invention, the molar ratio of N-chlorosuccinimide to methyl thiophene-2 carboxylate I in step (1) is 1-2:1; the N-chlorosuccinimide is added into the system in 2-4 batches equally, the time interval of addition is 5-15min, and the temperature is controlled to be 20-25 ℃ in the process of adding the N-chlorosuccinimide.
According to a preferred embodiment of the present invention, the temperature of the reaction in step (1) is 75-85 ℃; the reaction time is 2-6h.
According to the invention, in the step (1), after the reaction is completed, the target product can be separated and purified according to a conventional separation and purification method; preferably, the post-treatment step of the reaction liquid obtained after the completion of the reaction is specifically as follows: concentrating the reaction solution obtained by the reaction until no solvent flows out, cooling the concentrate to 10-15 ℃, adding water, extracting by using dichloromethane, washing the obtained organic phase by using saturated sodium chloride solution, drying by using anhydrous sodium sulfate, and removing the solvent to obtain a compound II; the ratio of the volume of water added to the concentrate to the mass of methyl thiophene-2-carboxylate was 3-7mL:1g.
According to a preferred embodiment of the present invention, the solvent B in step (2) is methanol, ethanol or tetrahydrofuran; the ratio of the volume of the solvent B to the mass of the compound II is 3-5 mL/1 g.
According to the invention, preferably, the alkaline solution in the step (2) is a sodium hydroxide aqueous solution with the mass fraction of 20%; the mass ratio of the alkaline solution to the compound II is 1-2:1.
According to the invention, the temperature of the hydrolysis reaction in step (2) is 20-30 ℃ and the time of the hydrolysis reaction is 1-3h.
According to the invention, in the step (2), after the hydrolysis reaction is completed, the target product can be separated and purified according to a conventional separation and purification method; preferably, the post-treatment step of the reaction liquid obtained after the completion of the hydrolysis reaction is specifically as follows: and regulating the pH value of the reaction liquid obtained by the hydrolysis reaction to 1-2 by using a 2mol/L dilute hydrochloric acid solution, cooling to 10-15 ℃, preserving heat for 1-2 hours, filtering, and vacuum drying the obtained filter cake at 50-60 ℃ for 4-8 hours to obtain the compound III.
According to a preferred embodiment of the invention, the solvent C in step (2) is tetrahydrofuran, acetonitrile or dichloromethane; the ratio of the volume of the solvent C to the mass of the compound III is 5-10 mL/1 g.
According to a preferred embodiment of the invention, the molar ratio of N, N' -carbonyldiimidazole to compound III in step (2) is 1-2:1.
According to a preferred embodiment of the present invention, the temperature of the condensation reaction in step (2) is 20-30 ℃; the time of the condensation reaction is 3-5h.
According to the invention, in the step (2), after the condensation reaction is finished, the target product can be separated and purified according to a conventional separation and purification method; preferably, the post-treatment step of the reaction liquid obtained after the completion of the condensation reaction is specifically as follows: the reaction solution obtained by the condensation reaction was concentrated until no solvent flowed out, ethyl acetate and water were added to the residue obtained after the concentration, and the mixture was stirred and separated, and the obtained ethyl acetate phase was washed with water, dried over anhydrous sodium sulfate, filtered, and the solvent was removed to obtain compound IV.
According to a preferred embodiment of the present invention, the solvent D in step (3) is N, N-dimethylformamide, tetrahydrofuran or dimethyl sulfoxide; the ratio of the volume of the solvent D to the mass of the compound IV is 3-7 mL/1 g.
Preferably according to the invention, the base in step (3) is potassium tert-butoxide, sodium ethoxide or sodium tert-butoxide; the molar ratio of the alkali to the compound IV is 1-1.5:1.
According to a preferred embodiment of the invention, the molar ratio of trimethylsulfoxide iodide to compound IV in step (3) is 1-1.5:1.
According to the invention, in step (3), the reaction temperature of the compound IV with trimethylsulfoxide iodide is 0-10deg.C, and the reaction time is 1-3h.
According to a preferred embodiment of the invention, the specific step of reacting compound IV with trimethylsulfoxide iodide in step (3) is: adding alkali into the solvent D, stirring for 0.5-1h, adding trimethyl sulfoxide iodide, stirring for l-2h at 0-10 ℃, controlling the temperature to be 0-10 ℃, and equally dividing the compound IV into 1-3 batches to be added into the system for reaction.
According to the invention, preferably, after the compound IV in the step (3) reacts with trimethyl sulfoxide iodide, the target product can be separated and purified according to a conventional separation and purification method; preferably, the post-treatment step of the reaction liquid obtained after the completion of the reaction is specifically as follows: and (3) dropwise adding a saturated ammonium chloride solution into the reaction solution at the temperature of 0-10 ℃, wherein the mass ratio of the volume of the saturated ammonium chloride solution to the compound IV is 5-10mL:1g, then adding ethyl acetate, the mass ratio of the volume of the ethyl acetate to the compound IV is 3-7mL:1g, separating the solution, extracting the water phase with ethyl acetate, merging the ethyl acetate phases, washing the obtained ethyl acetate phase with the saturated ammonium chloride solution, drying the ethyl acetate phase with anhydrous sodium sulfate, filtering, and removing the solvent to obtain the compound V.
According to a preferred embodiment of the present invention, the solvent E in step (3) is tetrahydrofuran, ethyl acetate or acetonitrile; the ratio of the volume of the solvent E to the mass of the compound V is 4-10 mL/1 g.
Preferably according to the invention, the acid in step (3) is methanesulfonic acid or trifluoroacetic acid; the molar ratio of the acid to the compound V is 1-1.5:1.
Preferably according to the present invention, the halogenating agent in step (3) is lithium bromide; the molar ratio of the halogenating agent to the compound V is 1-2:1.
According to a preferred embodiment of the invention, in step (3), 10-30% of solvent E is used to dissolve the acid, the remainder of solvent E being used to dissolve compound V and the halogenating agent; the solution E of the acid solvent is dripped into the system, and the dripping temperature is 0-10 ℃.
According to the invention, the temperature of the substitution reaction in step (3) is preferably 40-45℃and the time of the substitution reaction is preferably 8-12 hours.
According to a preferred embodiment of the present invention, the substitution reaction in step (3) comprises the steps of: adding 70-90% of solvent E, compound V and halogenating agent into a reaction bottle, uniformly stirring at 20-25 ℃, and cooling to 0-10 ℃; dissolving acid in the rest 10-30% of solvent E, dropwise adding the solvent E solution of the obtained acid into the system at 0-10 ℃, reacting for 0.5h at a temperature of 40-45 ℃ for reaction for 8-12 h.
According to the invention, in the step (3), after the substitution reaction is completed, the target product can be separated and purified according to a conventional separation and purification method; preferably, the post-treatment step of the reaction liquid obtained after the completion of the substitution reaction is specifically as follows: after the reaction, the obtained reaction solution was concentrated until no solvent flowed out, water was added to the obtained concentrate in a volume ratio of 5 to 10ml to 1g of the mass of the compound V, followed by extraction with ethyl acetate, and the obtained organic phase was washed with water and a saturated sodium chloride solution in this order, dried over anhydrous sodium sulfate, filtered, and the solvent was removed to obtain the compound VI.
According to a preferred embodiment of the invention, the molar ratio of compound VI to thiourea in step (4) is from 1:1 to 3.
According to a preferred embodiment of the present invention, the ring closure reaction in step (4) is carried out in a solvent F, which is absolute ethanol, ethyl acetate or acetonitrile; the ratio of the volume of the solvent F to the mass of the compound VI is 5-15 mL/1 g.
According to a preferred embodiment of the present invention, the temperature of the ring closure reaction in step (4) is 70-90 ℃; the time of the ring closing reaction is 10-15h.
According to the invention, preferably, after the ring closure reaction in the step (4) is completed, the target product can be separated and purified according to a conventional separation and purification method; preferably, the post-treatment step of the reaction liquid obtained after the completion of the ring closure reaction is specifically as follows: after the reaction is finished, filtering, adding the obtained filter cake into water, wherein the ratio of the volume of the water to the mass of a compound VI is 2-5mL to 1g, then using a sodium carbonate solution with the mass fraction of 10% to adjust the pH to 7-8, adding ethyl acetate for extraction, combining ethyl acetate phases, drying by anhydrous sodium sulfate, filtering, removing a solvent, and recrystallizing the obtained solid to obtain 4- (4-chloro-2-thienyl) -2-thiazolamine; the solvent used for recrystallization is a mixed solvent of n-heptane and ethyl acetate, and the volume ratio of the n-heptane to the ethyl acetate is 4:1.
The reaction route of the invention is as follows:
the invention has the technical characteristics and beneficial effects that:
according to the invention, thiophene-2-carboxylic acid methyl ester is used as a starting material, and the maleic acid atorvastatin starting material 4- (4-chloro-2-thienyl) -2-thiazolamine is prepared through chlorination, hydrolysis, condensation, thio ylide, bromination and ring closure reaction. The method has the advantages of high yield of the product, capability of controlling the disubstituted impurity to be less than or equal to 0.1%, capability of solving the problem of overlarge disubstituted impurity, mild process reaction condition, high yield and suitability for industrial production, and simultaneously, the method avoids the use of a large amount of liquid bromine, reduces the process safety risk, reduces the generation of waste liquid and has higher practical application value.
Drawings
FIG. 1 is a high performance liquid chromatogram of the starting material 4- (4-chloro-2-thienyl) -2-thiazolamine from atorvastatin maleate prepared in example 1.
FIG. 2 is a liquid mass spectrum of the starting material 4- (4-chloro-2-thienyl) -2-thiazolamine of atorvastatin maleate prepared in example 1.
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of the starting material 4- (4-chloro-2-thienyl) -2-thiazolamine of atorvastatin maleate prepared in example 1.
Detailed Description
The present invention will be described in detail with reference to the following specific embodiments, but the present invention is not limited thereto.
The methods described in the examples are conventional methods unless otherwise specified. The starting materials are available from published commercial sources unless otherwise specified.
Example 1
A method for preparing a starting material 4- (4-chloro-2-thienyl) -2-thiazolamine of atorvastatin maleate, which comprises the following steps:
the reaction scheme is as follows:
the specific operation steps are as follows:
(1) Thiophene-2-carboxylic acid methyl ester I (100 g) and ethyl acetate (1000 mL) are added into a three-mouth bottle, zinc chloride (287.6 g) is added into three batches at the temperature of 20-25 ℃ in a bisecting way after stirring and dissolving, the adding time interval is 10min, N-chlorosuccinimide (NCS, 140.9 g) is added into 3 batches at the temperature of 20-25 ℃ in a bisecting way after adding for 5min, the temperature is raised to 81 ℃ after adding for reflux reaction for 4h, TLC monitors that the reaction is complete, the reaction solution is concentrated until no solvent flows out, the obtained concentrate is cooled to 10-15 ℃, water (500 mL) is added, dichloromethane is used for extraction (300 mL multiplied by 2), the obtained organic phase is washed by saturated sodium chloride solution, anhydrous sodium sulfate is dried, filtered, and the solvent is removed by rotary evaporation of filtrate, thus obtaining a compound II (120.1 g, the purity is 98.52 percent, and the yield is 96.7%).
(2) Methanol (200 mL) and compound II (50 g) are added into a 500mL three-necked flask, the mixture is stirred and dissolved, then 20% sodium hydroxide aqueous solution (67.9 g) is added, the mixture is stirred and reacted for 2 hours at 20-25 ℃, TLC monitors that the reaction is complete, 2mol/L dilute hydrochloric acid solution is used for adjusting the pH of the reaction solution to 2, the temperature is reduced to 10-15 ℃, the temperature is kept for 1 hour, the filtration is carried out, and a filter cake is dried for 6 hours at 55 ℃ through a vacuum drying oven to obtain compound III (45.0 g, purity 98.18% and yield 97.9%).
(3) Compound III (45 g) was dissolved in (270 mL) of tetrahydrofuran at 20-25℃and N, N' -carbonyldiimidazole (53.8 g) was added thereto, the reaction was monitored by TLC under stirring at 20-25℃for 4h, the reaction solution was directly concentrated until no solvent was eluted, ethyl acetate (400 mL) and water were added to the residue obtained after concentration and stirred (300 mL), the mixture was separated, the ethyl acetate phase was washed with water, dried over anhydrous sodium sulfate, and then filtered and the solvent was removed by rotary evaporation to give Compound IV (58.9 g, purity 98.55%, yield 100%).
(4) DMF (200 mL), potassium tert-butoxide (23.2 g) and trimethylsulfoxide iodide (49.6 g) are added into a 500mL three-necked flask, stirred for 0.5h, stirred for lh at the temperature of 0-10 ℃; dividing 3 batches of compound IV (40 g) at the temperature of 0-10 ℃ and evenly adding the mixture for 5min at the time interval, keeping the temperature for 2h, monitoring the reaction to be complete by TLC, dropwise adding saturated ammonium chloride solution (300 mL) into the reaction liquid at the temperature of 0-10 ℃, then adding ethyl acetate (200 mL), separating the liquid, extracting the water phase with ethyl acetate (200 mL multiplied by 2), combining the ethyl acetate phases, washing the obtained ethyl acetate phases with saturated ammonium chloride solution, drying the ethyl acetate phases with anhydrous sodium sulfate, filtering the dried ethyl acetate phases, and rotationally evaporating the filtrate to remove the solvent to obtain white solid compound V (41.1 g, purity 99.27% and yield 92.3%).
(5) Tetrahydrofuran (240 mL) and compound V (40 g), lithium bromide (17.6 g) are added into a reaction bottle, the mixture is stirred uniformly at 20-25 ℃, the temperature is reduced to 0-10 ℃, the temperature is controlled to 0-10 ℃, a solution of methanesulfonic acid (17.8 g) in tetrahydrofuran (60 mL) is added dropwise, the reaction is carried out for 0.5h under the condition of heat preservation, the temperature is slowly increased to 40-45 ℃ for reaction for 10 h. After the completion of the reaction, the resultant reaction solution was concentrated in vacuo until no solvent was eluted, water (300 mL) was added, extraction was performed using ethyl acetate (200 ml×3), the resultant organic phase was successively washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate and then filtered, and the resultant filtrate was distilled off to remove the solvent, whereby compound VI (38.5 g, purity 98.85%, yield 95.1%) was obtained.
(6) To a 500mL three-necked flask was added absolute ethyl alcohol (300 mL), compound VI (30 g), after stirring and dissolution, thiourea (19.0 g) was added, the temperature was raised to 80℃and the reaction was continued under reflux for 12 hours, after the completion of the reaction, the precipitate was gradually precipitated, filtration was performed, the cake was added to 100mL of water, the pH was adjusted to 7 with a 10% sodium carbonate solution by mass fraction, ethyl acetate was added for extraction (200 mL. Times.3), the ethyl acetate phases were combined, the ethyl acetate phases were dried over absolute sodium sulfate, filtration was performed, the filtrate was distilled off to remove the solvent, and the resulting solid was recrystallized from n-heptane: ethyl acetate=4:1 (v/v, 150 mL) to give atorvastatin maleate starting material 4- (4-chloro-2-thienyl) -2-thiazolamine (25.8 g, purity 99.89%, yield 95.0%).
Fig. 1, fig. 2, and fig. 3 are respectively a high performance liquid chromatogram, a liquid mass chromatogram, and a nmr hydrogen chromatogram prepared in this example, and as can be seen from fig. 1, the purity of the liquid phase of the target product obtained in this example is 99.89%; fig. 2 shows the resulting target product liquid positive ion signal, m+1= 216.97.
FIG. 3 shows the nuclear magnetic resonance hydrogen spectrum of the obtained target product, and the data are as follows:
1 H-NMR(d6-DMSO，600MHz)：δ＝7.40(d,1H)，δ＝7.38(d,1H)，δ＝7.22(s,2H)，δ＝6.98(s,1H)。
example 2
A method for preparing a starting material 4- (4-chloro-2-thienyl) -2-thiazolamine of atorvastatin maleate, which comprises the following steps:
the reaction scheme is as follows:
the specific operation steps are as follows:
(1) Thiophene-2-carboxylic acid methyl ester I (50 g) and acetonitrile (500 mL) are added into a three-mouth bottle, zinc chloride (143.8 g) is added into three batches at the temperature of 20-25 ℃ in a bisecting way after stirring and dissolving, the adding time interval is 10min, N-chlorosuccinimide (NCS, 70.5 g) is added into 3 batches at the temperature of 20-25 ℃ in a bisecting way after adding for 5min, the temperature is raised to 77 ℃ after adding for reflux reaction for 6h, TLC monitors that the reaction is complete, the reaction solution is concentrated until no solvent flows out, the obtained concentrate is cooled to 10-15 ℃, water (250 mL) is added, dichloromethane (150 mL multiplied by 2) is used for extraction, the obtained organic phase is washed by saturated sodium chloride solution, anhydrous sodium sulfate is dried, then filtered, the solvent is removed by rotary evaporation of filtrate, and the compound II (58.9 g, the purity is 97.92% and the yield is 94.9%).
(2) To a 500mL three-necked flask, ethanol (100 mL) and compound II (25 g) were added, and after stirring and dissolution, a 20% by mass aqueous sodium hydroxide solution (33.9 g) was added, and the reaction was stirred at 20-25℃for 2 hours, and TLC was monitored to complete the reaction, and the pH of the reaction solution was adjusted to 2 with a 2mol/L diluted hydrochloric acid solution, cooled to 10-15℃and kept at that temperature for 1 hour, and filtered, and the cake was dried at 55℃for 6 hours in a vacuum oven to give compound III (21.8 g, purity 98.87%, yield 94.9%).
(3) Compound III (20 g) was dissolved in (120 mL) of acetonitrile at 20-25℃and N, N' -carbonyldiimidazole (23.9 g) was added thereto, the reaction was monitored by TLC at 20-25℃under stirring for 4h, the reaction solution was directly concentrated until no solvent was eluted, ethyl acetate (200 mL) and water were added to the residue obtained after the concentration under stirring (150 mL), the solution was separated, the ethyl acetate phase was washed with water, dried over anhydrous sodium sulfate, and then, the solvent was removed by rotary evaporation to give compound IV (25.9 g, purity 98.12%, yield 98.9%).
(4) DMF (100 mL), sodium tert-butoxide (10.0 g) and trimethylsulfoxide iodide (29.8 g) are added into a 250mL three-necked flask, stirred for 0.5h, stirred for lh at the temperature of 0-10 ℃; dividing 3 batches of compound IV (20 g) at the temperature of 0-10 ℃ and evenly adding the mixture for 5min at the time interval, keeping the temperature for 2h, monitoring the reaction to be complete by TLC, dropwise adding saturated ammonium chloride solution (150 mL) into the reaction liquid at the temperature of 0-10 ℃, adding ethyl acetate (100 mL), separating the liquid, extracting the water phase with ethyl acetate (100 mL multiplied by 2), merging the ethyl acetate phases, washing the obtained ethyl acetate phases with saturated ammonium chloride solution, drying the ethyl acetate phases with anhydrous sodium sulfate, filtering the dried ethyl acetate phases, and rotationally evaporating the filtrate to remove the solvent to obtain white solid compound V (19.6 g, purity 99.15% and yield 88.1%).
(5) Tetrahydrofuran (120 mL), compound V (20 g), lithium bromide (8.8 g) and stirring uniformly at 20-25 ℃, cooling to 0-10 ℃, controlling the temperature to 0-10 ℃, dropwise adding tetrahydrofuran (30 mL) solution of trifluoroacetic acid (8.9 g), reacting for 0.5h under heat preservation, and slowly heating to 40-45 ℃ for reacting for 10 h. After the completion of the reaction, the reaction mixture was concentrated in vacuo until no solvent was eluted, water (150 mL) was added, ethyl acetate (100 mL. Times.3) was extracted, the obtained organic phase was successively washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate and then filtered, and the solvent was removed by rotary evaporation from the obtained filtrate to give compound VI (15.8 g, purity 98.72%, yield 78.1%).
(6) To a 250mL three-necked flask was added ethyl acetate (150 mL), compound VI (15 g), and after stirring and dissolution, thiourea (9.5 g) was added, and after the reaction was gradually precipitated by refluxing at 80℃for 12 hours, after the completion of the reaction, the filter cake was filtered, 50mL of water was added, pH was adjusted to 7 with a 10% by mass sodium carbonate solution, ethyl acetate was added for extraction (100 mL. Times.3), the ethyl acetate phases were combined, the ethyl acetate phases were dried over anhydrous sodium sulfate, and after filtration, the filtrate was distilled off to remove the solvent, and the resulting solid was recrystallized from n-heptane: ethyl acetate=4:1 (v/v, 75 mL) to give atorvastatin maleate starting material 4- (4-chloro-2-thienyl) -2-thiazolamine (11.8 g, purity 99.72%, yield 86.9%).
The experimental results of each step of example 1 and example 2 are compared as follows:
by contrast, the reagents, solvents used in the procedure described in example 1 gave intermediates and products of higher purity and yield, optimal conditions.
Comparative example 1
4- (4-chloro-2-thienyl) -2-thiazolamine was prepared according to the method in WO2021021000A 1.
To the reaction flask was added 2-acetyl-4 chlorothiophene (20 g,125 mmol), diethyl ether (150 mL), stirred, solution bromine (22 g,38 mmol) was slowly added at 0deg.C and the reaction mixture stirred for 2 hours after the addition was completed in 20 minutes. After the reaction, ethyl acetate (150 mL) was added, water was 100mL, the solution was separated, the aqueous phase was extracted 2 times with 150mL of ethyl acetate, the ethyl acetate phases were combined, washed 2 times with 50mL of saturated sodium chloride solution, and the ethyl acetate phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oil.
To the oil was added 150mL of ethanol, dissolved with stirring, thiourea (9.5 g,125 mmol) was added, the temperature was raised to reflux, the solid was gradually precipitated, after 5 hours, the temperature was lowered to 25℃and filtered, and the residue was dissolved in 300mL of ethyl acetate/n-heptane (1:1, v/v) mixture and heated to reflux for 1 hour. The temperature was then reduced to 25℃and the shed hydrobromide amine was filtered, the solid was dried in vacuo, the product was suspended in 500mL of aqueous solution, potassium carbonate (40 g,0.3 mol) was added and stirred for 1h, then the precipitate was filtered, rinsed with water and dried in vacuo to give 4- (4-chloro-2-thienyl) -2-thiazolamine (13.6 g, 83.51% purity, 59.1% yield).
The products obtained in example 1 and comparative example 1 were compared, and the experimental results were compared as follows:
| examples of the examples | Yield is good | Purity of | Disubstituted impurities | Reaction conditions |
| Comparative example 1 | 59.1％ | 83.51％ | 8.77％ | Liquid bromine |
| Example 1 | 78.9％ | 99.89％ | 0.06％ | No special reagent |
By contrast, we find that the route yield of the invention is improved by about 20%, and the disubstituted impurity can be controlled to be less than or equal to 0.1%, but the method in patent WO2021021000A1 can not effectively control the disubstituted impurity, and the disubstituted impurity is strictly controlled to ensure the quality of the atorvastatin maleate, so that the invention solves the problem of overlarge disubstituted impurity, and the method has mild process reaction condition and high yield, is suitable for industrial production, and simultaneously avoids the use of a large amount of liquid bromine, reduces the process safety risk, reduces the production of waste liquid and has higher practical application value.
Example 3
The preparation of the starting material 4- (4-chloro-2-thienyl) -2-thiazolamine, atorvastatin maleate, was as described in example 1, except that: the molar ratio of potassium tert-butoxide to compound IV in step (4) is 1:1.
Example 4
The preparation of the starting material 4- (4-chloro-2-thienyl) -2-thiazolamine, atorvastatin maleate, was as described in example 1, except that: the molar ratio of potassium tert-butoxide to compound IV in step (4) was 1.5:1.
Example 5
The preparation of the starting material 4- (4-chloro-2-thienyl) -2-thiazolamine, atorvastatin maleate, was as described in example 1, except that: the molar ratio of methanesulfonic acid to compound IV in step (5) was 1.5:1.
Example 6
The preparation of the starting material 4- (4-chloro-2-thienyl) -2-thiazolamine, atorvastatin maleate, was as described in example 1, except that: the molar ratio of methanesulfonic acid to compound IV in step (5) was 1:1.
Comparative example 2
The preparation of the starting material 4- (4-chloro-2-thienyl) -2-thiazolamine maleate was as described in example 1, except that: the molar ratio of potassium tert-butoxide to compound IV in step (4) was 0.8:1.
Comparative example 3
The preparation of the starting material 4- (4-chloro-2-thienyl) -2-thiazolamine maleate was as described in example 1, except that: the molar ratio of potassium tert-butoxide to compound IV in step (4) was 2:1.
Comparative example 4
The preparation of the starting material 4- (4-chloro-2-thienyl) -2-thiazolamine maleate was as described in example 1, except that: the reaction temperature in the step (4) is 20-30 ℃.
Comparative example 5
The preparation of the starting material 4- (4-chloro-2-thienyl) -2-thiazolamine maleate was as described in example 1, except that: the molar ratio of methanesulfonic acid to compound IV in step (5) was 0.8:1.
Comparative example 6
The preparation of the starting material 4- (4-chloro-2-thienyl) -2-thiazolamine maleate was as described in example 1, except that: the molar ratio of methanesulfonic acid to compound IV in step (5) was 2:1.
Comparative example 7
The preparation of the starting material 4- (4-chloro-2-thienyl) -2-thiazolamine maleate was as described in example 1, except that: the dropping temperature of the methanesulfonic acid in the step (5) is 20-25 ℃.
The products obtained in example 1, examples 3 to 6 and comparative examples 1 to 7 were compared, and experimental results were compared as follows:
by comparison, when the equivalent weight of the potassium tert-butoxide in the step V is 0.8, the reaction raw materials are remained, the purity and the yield are reduced, when the equivalent weight of the potassium tert-butoxide is 2.0, the impurity is increased, the purity is reduced, the optimal equivalent weight of the potassium tert-butoxide is 1.0-1.5, when the reaction temperature is increased to 20-30 ℃, the impurity is increased, the purity and the yield are reduced, and the optimal reaction temperature is 0-10 ℃;
when the equivalent weight of methanesulfonic acid in the step of the compound VI is 0.8, the reaction raw materials remain, the purity and the yield are reduced, when the equivalent weight of methanesulfonic acid is 2.0, the impurity is increased, the purity is reduced, the optimal equivalent weight of methanesulfonic acid is 1.0-1.5, when the dropping temperature is increased to 20-25 ℃, the impurity is increased, the purity and the yield are reduced, and the optimal dropping temperature is 0-10 ℃.
Claims (9)
1. A method for preparing a starting material 4- (4-chloro-2-thienyl) -2-thiazolamine of atorvastatin maleate, which comprises the following steps:
(1) Dissolving thiophene-2-carboxylic acid methyl ester I in a solvent A, adding zinc chloride, uniformly stirring, and adding N-chlorosuccinimide to react to obtain a compound II;
(2) In a solvent B, performing hydrolysis reaction on the compound II under the action of an alkaline solution to obtain a compound III; in a solvent C, carrying out condensation reaction on the compound III and N, N' -carbonyl diimidazole to obtain a compound IV;
(3) In a solvent D, under the action of alkali, the compound IV reacts with trimethyl sulfoxide iodide and is converted into a sulfur ylide structure to obtain a compound V; in a solvent E, under the action of acid, carrying out substitution reaction on the compound V and a halogenating agent to obtain a compound VI;
(4) The compound VI and thiourea undergo a ring-closure reaction to obtain the starting material 4- (4-chloro-2-thienyl) -2-thiazolamine of the atorvastatin maleate.
2. The process for the preparation of the starting material 4- (4-chloro-2-thienyl) -2-thiazolamine from atorvastatin maleate according to claim 1 wherein in step (1) the solvent a is acetonitrile, ethyl acetate or ethanol.
3. The process for the preparation of the starting material 4- (4-chloro-2-thienyl) -2-thiazolamine maleate according to claim 1 wherein the temperature of the reaction in step (1) is 75-85 ℃.
4. The process for the preparation of the starting material 4- (4-chloro-2-thienyl) -2-thiazolamine of atorvastatin maleate according to claim 1 wherein in step (2) the solvent B is methanol, ethanol or tetrahydrofuran; the temperature of the hydrolysis reaction is 20-30 ℃.
5. The process for the preparation of the starting material 4- (4-chloro-2-thienyl) -2-thiazolamine from atorvastatin maleate according to claim 1 wherein in step (2) the solvent C is tetrahydrofuran, acetonitrile or dichloromethane.
6. The process for the preparation of the starting material 4- (4-chloro-2-thienyl) -2-thiazolamine from atorvastatin maleate according to claim 1 wherein in step (3) the solvent D is N, N-dimethylformamide, tetrahydrofuran or dimethylsulfoxide;
the alkali is potassium tert-butoxide, sodium ethoxide or sodium tert-butoxide; the molar ratio of the alkali to the compound IV is 1-1.5:1; the molar ratio of the trimethyl sulfoxide iodide to the compound IV is 1-1.5:1;
the temperature of the reaction of the compound IV and the trimethyl sulfoxide iodide is 0-10 ℃.
7. The process for the preparation of the starting material 4- (4-chloro-2-thienyl) -2-thiazolamine from atorvastatin maleate according to claim 1 wherein in step (3) the solvent E is tetrahydrofuran, ethyl acetate or acetonitrile;
the acid is methanesulfonic acid or trifluoroacetic acid; the molar ratio of the acid to the compound V is 1-1.5:1;
the acid is dripped into the system in the form of an acid solvent E solution, and the dripping temperature is 0-10 ℃.
8. The process for the preparation of the starting material 4- (4-chloro-2-thienyl) -2-thiazolamine from atorvastatin maleate according to claim 1 wherein in step (3) the halogenating agent is lithium bromide; the temperature of the substitution reaction is 40-45 ℃.
9. The process for the preparation of the starting material 4- (4-chloro-2-thienyl) -2-thiazolamine from atorvastatin maleate according to claim 1 wherein the molar ratio of compound VI to thiourea in step (4) is 1:1-3;
the ring closure reaction is carried out in a solvent F, wherein the solvent F is absolute ethyl alcohol, ethyl acetate or acetonitrile.
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