WO2006042481A1 - Method of obtaining clopidogrel - Google Patents
Method of obtaining clopidogrel Download PDFInfo
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- WO2006042481A1 WO2006042481A1 PCT/CZ2005/000077 CZ2005000077W WO2006042481A1 WO 2006042481 A1 WO2006042481 A1 WO 2006042481A1 CZ 2005000077 W CZ2005000077 W CZ 2005000077W WO 2006042481 A1 WO2006042481 A1 WO 2006042481A1
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- Prior art keywords
- formula
- mixture
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- compound
- solution
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 29
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 title description 30
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 title description 12
- 229960003009 clopidogrel Drugs 0.000 title description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 59
- 239000000203 mixture Substances 0.000 claims abstract description 38
- 239000002904 solvent Substances 0.000 claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- MIOPJNTWMNEORI-XVKPBYJWSA-N (R)-camphorsulfonic acid Chemical compound C1C[C@]2(CS(O)(=O)=O)C(=O)C[C@H]1C2(C)C MIOPJNTWMNEORI-XVKPBYJWSA-N 0.000 claims abstract description 9
- 238000002425 crystallisation Methods 0.000 claims abstract description 5
- 230000008025 crystallization Effects 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 89
- 239000000243 solution Substances 0.000 claims description 48
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 16
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 14
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical class C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 5
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- VSJMYSBFJMOGNQ-UHFFFAOYSA-N 2-[2-(2-chlorophenyl)-6,7-dihydro-4h-thieno[3,2-c]pyridin-5-yl]acetic acid Chemical compound C=1C=2CN(CC(=O)O)CCC=2SC=1C1=CC=CC=C1Cl VSJMYSBFJMOGNQ-UHFFFAOYSA-N 0.000 claims description 2
- -1 aliphatic ethers Chemical class 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims 2
- 238000002156 mixing Methods 0.000 claims 2
- 239000011877 solvent mixture Substances 0.000 claims 2
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims 1
- 150000008041 alkali metal carbonates Chemical class 0.000 claims 1
- 239000002585 base Substances 0.000 claims 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical class C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims 1
- 229940098779 methanesulfonic acid Drugs 0.000 claims 1
- 150000004702 methyl esters Chemical class 0.000 claims 1
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims 1
- 229940090181 propyl acetate Drugs 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 abstract description 5
- 238000000926 separation method Methods 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 239000000047 product Substances 0.000 description 24
- 239000011541 reaction mixture Substances 0.000 description 13
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 238000001704 evaporation Methods 0.000 description 12
- 230000008020 evaporation Effects 0.000 description 12
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropyl acetate Chemical compound CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 12
- 235000019441 ethanol Nutrition 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 7
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000011521 glass Substances 0.000 description 6
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 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 description 3
- OGUWOLDNYOTRBO-UHFFFAOYSA-N 4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1NCCC2=C1C=CS2 OGUWOLDNYOTRBO-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000002744 anti-aggregatory effect Effects 0.000 description 2
- 230000001407 anti-thrombic effect Effects 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 235000011148 calcium chloride Nutrition 0.000 description 2
- 229960002713 calcium chloride Drugs 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 159000000001 potassium salts Chemical class 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- RZNQPADJGNRYGR-UHFFFAOYSA-N 2,3,3a,4-tetrahydrothieno[3,2-b]pyridine;hydrochloride Chemical compound Cl.N1C=CC=C2SCCC21 RZNQPADJGNRYGR-UHFFFAOYSA-N 0.000 description 1
- IUJAAIZKRJJZGQ-UHFFFAOYSA-N 2-(2-chlorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC=C1Cl IUJAAIZKRJJZGQ-UHFFFAOYSA-N 0.000 description 1
- XEENARPWPCQXST-DDJQTTAYSA-N C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C.C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C.C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl XEENARPWPCQXST-DDJQTTAYSA-N 0.000 description 1
- GKTWGGQPFAXNFI-OAHLLOKOSA-N COC([C@@H](c(cccc1)c1Cl)N(CC1)Cc2c1[s]cc2)=O Chemical compound COC([C@@H](c(cccc1)c1Cl)N(CC1)Cc2c1[s]cc2)=O GKTWGGQPFAXNFI-OAHLLOKOSA-N 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- MIOPJNTWMNEORI-MHPPCMCBSA-N [(4r)-7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl]methanesulfonic acid Chemical class C1C[C@]2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-MHPPCMCBSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- 229950010477 clopidogrel hydrogen sulphate Drugs 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000002037 dichloromethane fraction Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 150000002332 glycine derivatives Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- FDEODCTUSIWGLK-UHFFFAOYSA-N hydrogen sulfate;hydron;methyl 2-(2-chlorophenyl)-2-(6,7-dihydro-4h-thieno[3,2-c]pyridin-5-yl)acetate Chemical compound OS(O)(=O)=O.C1CC=2SC=CC=2CN1C(C(=O)OC)C1=CC=CC=C1Cl FDEODCTUSIWGLK-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 208000023589 ischemic disease Diseases 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 235000011182 sodium carbonates Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Definitions
- the invention relates to a new method of preparation of known antithrombic agent, the S(+) isomer of (2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridme-5(4H)-acetic acid, known under the INN name clopidogrel.
- INN name clopidogrel is an effective antithrombic agent, indicated especially for prevention of atherosclerotic events in patients after experienced infarction, apoplectic stroke or with the ischemic disease of lower limbs. It is, therefore, fundamental in preventing relapse of these diseases and it prevents fatal consequences of said diseases.
- patent EP 99 802 a group of agents with antiaggregation effect was described, which includes also the compound of formula I.
- optically active isomers of the compounds are also reported.
- Preparation of compounds of the type of clopidogrel (I) was, according to the patent, performed via reaction of 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine with an alpha-chloro-derivative of an ester of alpha-(chlorophenyl)-acetic acid in the presence of a base.
- Further development reported in patent EP 281 459 showed that of the compounds described in the above-mentioned patent, hydrogen sulfate (the HSO 4 " anion) of the compound of formula I is the most advantageous.
- the salt was tested with respect to its antiaggregation effects and compared with some other salts.
- EP 281 459 describes also a method of preparation of this salt. It consists in resolving the racemic mixture of the compound of formula I with the R isomer of formula II
- US patent 6,737,411 describes an improved method of this resolution. It consists in preparation of camphorsulfonic acid in a mixture Of C 1 to C 12 hydrocarbons with a suitable co- solvent, which is selected from the group of dimethylformamide, butanol or acetone.
- camphorsulfonic acid is dissolved in dimethylformamide and added to a solution of a mixture of compounds I and II in toluene. No procedure of further recrystallization, leading to a pure salt of form I, is, however, discussed in the patent.
- the present invention introduces a new solution to resolution of compound I from compound II via a selection of set of solvents, which will ensure the optimal ratio of solubilities of compounds I and II as such, of the diastereoisomeric salt of compound II and of the diastereoisomeric salt of compound I, which is recovered from the solution.
- a method of resolving according to the invention consists in separation of camphorsulfonic salts of the compounds of formulae I and II via one or more crystallizations from a mixture of two solvents, both R(-)-10-camphorsulfonic acid and its salts with the compounds of formulae
- the solvent in which the compounds of formulae I and II are better soluble is used in excess in ratios from 1 : 2 to 1 : 100, usually though more than 1 :4.
- the actual method of resolving the mixture of the compounds of formulae I and II consists in dissolving camphorsulfonic acid or a mixture of its salts with the compounds of formulae I and
- the solution can be further inoculated with several crystals of the respective camphorsulfonic salt or the temperature of the solution can be decreased to 5 to 10 0 C.
- esters, ethers or ketones have turned out as suitable solvents in case of these compounds (esters of substituted glycine).
- the total number of carbons in the molecule of these oxygen derivates ranges from 2 to 10, from 4 to 7 carbons turning out to be preferable.
- the particularly advantageous mixtures generally include those which require as few recrystallizations as possible. With respect to yields, such method turns out as more preferable which allows to obtain, already in the first operation, a practically pure product, which can merely be refined.
- Another aspect of this invention includes the discovery of an appropriate method for obtaining the starting mixture of the compounds of formulae I and II.
- the method having proved as very advantageous starts from the compound of formula V
- reaction which is then converted to a mixture of the compounds of formulae I and II via reaction with tetrahydrothienopyridine hydrochloride in an organic solvent in the presence of an organic or inorganic base.
- This reaction is preferably performed in the two-phase arrangement in a system of a chlorinated solvent and an aqueous solution of an inorganic base, preferably of sodium or potassium carbonates. The reaction is performed at temperatures of 40 to 120 °C.
- Another aspect of the invention includes another method for obtaining a mixture of the compounds of formulae I and II, which starts from the unwanted compound of formula II, or from a mixture of the compounds of formulae I and II enriched with compound II.
- the method uses the indicated reaction of potassium salts II - ⁇ I 5 wherein the equilibrium constant of this reaction is equal to 1.
- the reaction proceeds preferably in an alcohol (C 1 to C 5 ), in water or in an aqueous alcoholic solution.
- Esterification is then performed with methyl iodide in solvents of the type of acetone, dimethylformamide, or in a heterogeneous system organics-water under action of a phase- transfer catalyst.
- reaction mixture was then extracted with 5 ml of IN HCl and the dichloromethane solution was added to a previously prepared mixture of 6.9 g K 2 CO 3 (49.84 mmol) in 25 ml of water, 25 ml of dichloromethane and the compound of formula III.
- the resulting reaction mixture was refiuxed for 20.5 hours. After cooling down to room temperature, the aqueous layer was separated from the mixture.
- the organic fraction was extracted with 15 ml of IN HCl, dried with anhydrous magnesium sulfate, and the solvent was evaporated in a rotary vacuum evaporator. The resulting evaporation residue was dissolved in 50 ml of toluene and extracted with 2x10 ml of 4N HCl.
- the combined acidic extracts were alkalized with a 10% solution of NaHCO 3 and extracted with 2x30 ml of dichloromethane.
- the combined dichloromethane fractions were extracted with 10 ml of water and dried with anhydrous magnesium sulfate. After evaporation of the dichloromethane solution, clopidogrel (II) was obtained as a viscous honey-like evaporation residue (11.16 g; 69.6 % of theoretical).
- the unwanted enantiomer was reprocessed into a racemic mixture of compounds I and II.
- Example 16 34.42 g of the compound of formula VII was dissolved in 30 ml of ethyl alcohol and added to a 50% solution of KOH, which was prepared via dissolving 50 g of KOH in 50 ml of water. The reaction mixture was heated to boil and ethyl alcohol was distilled off. Subsequently, the reaction mixture was heated for another 1 hour at 100 0 C. After cooling, the undissolved matter was filtered off on sintered glass and washed with ca 200 ml of acetone. A brownish solid of formula VII was obtained in the amount of 39.8 g.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CZ20041048A CZ20041048A3 (cs) | 2004-10-18 | 2004-10-18 | Způsob výroby klopidogrelu |
| CZPV2004-1048 | 2004-10-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2006042481A1 true WO2006042481A1 (en) | 2006-04-27 |
Family
ID=35265647
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CZ2005/000077 WO2006042481A1 (en) | 2004-10-18 | 2005-10-17 | Method of obtaining clopidogrel |
Country Status (2)
| Country | Link |
|---|---|
| CZ (1) | CZ20041048A3 (cs) |
| WO (1) | WO2006042481A1 (cs) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008046792A1 (de) * | 2006-10-17 | 2008-04-24 | Adamed Sp. Z O.O. | KRISTALLINE FORM DES RAZEMISCHEN METHYL-α-(2-CHLORPHENYL)-2-(6,7-DIHYDROTHIENO[3,2-C]PYRIDIN-5(4H))-ACETATS,VERFAHREN ZU IHRER HERSTELLUNG UND IHRE VERWENDUNG |
| WO2008034912A3 (en) * | 2006-09-22 | 2008-08-07 | Krka Tovarna Zdravil D D Novo | Process for the synthesis of clopidogrel and new forms of pharmaceutically acceptable salts thereof |
| KR100887655B1 (ko) | 2007-08-01 | 2009-03-11 | (주)바이오켐넷 | 클로피도그렐의 제조방법 |
| WO2009006859A3 (en) * | 2007-07-09 | 2009-03-19 | Zentiva As | A method of manufacturing 5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7- tetrahydrothieno[3,2-c]pyridin-2-yl acetate (prasugrel) |
| CN101402556A (zh) * | 2008-11-11 | 2009-04-08 | 上海现代制药股份有限公司 | 新化合物1-环丙基-2-(2-氟苯基)-2-羟基乙酮及其制备方法和用途 |
| CN101402593A (zh) * | 2008-11-11 | 2009-04-08 | 上海现代制药股份有限公司 | 用于制备普拉格雷的中间体及其制备方法 |
| WO2008130642A3 (en) * | 2007-04-18 | 2009-06-04 | Teva Pharma | Improved process for preparing clopidogrel |
| CN101402643B (zh) * | 2008-11-11 | 2012-11-28 | 上海现代制药股份有限公司 | 一种适于工业生产的普拉格雷的制备方法 |
| CN101402642B (zh) * | 2008-11-11 | 2013-01-09 | 上海现代制药股份有限公司 | 一种新型环保制备普拉格雷的方法 |
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| WO2002059128A2 (en) * | 2001-01-24 | 2002-08-01 | Cadila Healthcare Ltd. | Process for preparing clopidogrel |
| US6573381B1 (en) * | 1997-10-06 | 2003-06-03 | Sanofi-Synthelabo | Hydroxyacetic ester derivatives, preparation method and use as synthesis intermediates |
| WO2004074215A1 (en) * | 2003-02-03 | 2004-09-02 | Sunil Sadanand Nadkarni | Process for preparation of clopidogrel, its salts and pharmaceutical compositions |
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| US4847265A (en) * | 1987-02-17 | 1989-07-11 | Sanofi | Dextro-rotatory enantiomer of methyl alpha-5 (4,5,6,7-tetrahydro (3,2-c) thieno pyridyl) (2-chlorophenyl)-acetate and the pharmaceutical compositions containing it |
| US6573381B1 (en) * | 1997-10-06 | 2003-06-03 | Sanofi-Synthelabo | Hydroxyacetic ester derivatives, preparation method and use as synthesis intermediates |
| WO2002059128A2 (en) * | 2001-01-24 | 2002-08-01 | Cadila Healthcare Ltd. | Process for preparing clopidogrel |
| WO2004074215A1 (en) * | 2003-02-03 | 2004-09-02 | Sunil Sadanand Nadkarni | Process for preparation of clopidogrel, its salts and pharmaceutical compositions |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008034912A3 (en) * | 2006-09-22 | 2008-08-07 | Krka Tovarna Zdravil D D Novo | Process for the synthesis of clopidogrel and new forms of pharmaceutically acceptable salts thereof |
| WO2008046792A1 (de) * | 2006-10-17 | 2008-04-24 | Adamed Sp. Z O.O. | KRISTALLINE FORM DES RAZEMISCHEN METHYL-α-(2-CHLORPHENYL)-2-(6,7-DIHYDROTHIENO[3,2-C]PYRIDIN-5(4H))-ACETATS,VERFAHREN ZU IHRER HERSTELLUNG UND IHRE VERWENDUNG |
| WO2008130642A3 (en) * | 2007-04-18 | 2009-06-04 | Teva Pharma | Improved process for preparing clopidogrel |
| JP2009532508A (ja) * | 2007-04-18 | 2009-09-10 | テバ ファーマシューティカル インダストリーズ リミティド | クロピドグレルの改良された調製方法 |
| WO2009006859A3 (en) * | 2007-07-09 | 2009-03-19 | Zentiva As | A method of manufacturing 5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7- tetrahydrothieno[3,2-c]pyridin-2-yl acetate (prasugrel) |
| CZ302135B6 (cs) * | 2007-07-09 | 2010-11-10 | Zentiva, A. S. | Zpusob výroby 5-[2-cyklopropyl-1-(2-fluorfenyl)-2-oxoethyl]-4, 5, 6, 7-tetrahydrothieno[3,2-c]pyridin-2-yl acetátu (prasugrelu) |
| EA016207B1 (ru) * | 2007-07-09 | 2012-03-30 | ЗЕНТИВА, а.с. | СПОСОБ ПОЛУЧЕНИЯ 5-[2-ЦИКЛОПРОПИЛ-1-(2-ФТОРФЕНИЛ)-2-ОКСОЭТИЛ]-4,5,6,7-ТЕТРАГИДРОТИЕНО[3,2-с]ПИРИДИН-2-ИЛА АЦЕТАТА (ПРАСУГРЕЛЯ) |
| KR100887655B1 (ko) | 2007-08-01 | 2009-03-11 | (주)바이오켐넷 | 클로피도그렐의 제조방법 |
| CN101402556A (zh) * | 2008-11-11 | 2009-04-08 | 上海现代制药股份有限公司 | 新化合物1-环丙基-2-(2-氟苯基)-2-羟基乙酮及其制备方法和用途 |
| CN101402593A (zh) * | 2008-11-11 | 2009-04-08 | 上海现代制药股份有限公司 | 用于制备普拉格雷的中间体及其制备方法 |
| CN101402643B (zh) * | 2008-11-11 | 2012-11-28 | 上海现代制药股份有限公司 | 一种适于工业生产的普拉格雷的制备方法 |
| CN101402642B (zh) * | 2008-11-11 | 2013-01-09 | 上海现代制药股份有限公司 | 一种新型环保制备普拉格雷的方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| CZ295920B6 (cs) | 2005-11-16 |
| CZ20041048A3 (cs) | 2005-11-16 |
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