NO327807B1 - Fremgangsmate for fremstilling av klopidogrel - Google Patents

Fremgangsmate for fremstilling av klopidogrel Download PDF

Info

Publication number: NO327807B1
Authority: NO; Norway
Prior art keywords: formula; compound; acid; salt; thieno
Prior art date: 2001-01-24

Application number

NO20032898A

Other languages

English (en)

Norwegian (no)

Other versions

NO20032898L (no

NO20032898D0 (no

Inventor

Braj Bhushan Lohray

Vidya Bhushan Lohray

Bipin Pandey

Original Assignee

Cadila Healthcare Ltd

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2001-01-24

Filing date

2003-06-24

Publication date

2009-09-28

Family has litigation

First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=26324902&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=NO327807(B1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.

2001-01-24 Priority claimed from IN84MU2001 external-priority patent/IN191030B/en

2003-06-24 Application filed by Cadila Healthcare Ltd filed Critical Cadila Healthcare Ltd

2003-06-24 Publication of NO20032898D0 publication Critical patent/NO20032898D0/no

2003-09-03 Publication of NO20032898L publication Critical patent/NO20032898L/no

2009-09-28 Publication of NO327807B1 publication Critical patent/NO327807B1/no

Links

238000000034 method Methods 0.000 title claims abstract description 79
238000002360 preparation method Methods 0.000 title claims abstract description 21
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 19
239000005552 B01AC04 - Clopidogrel Substances 0.000 title description 10
229960003009 clopidogrel Drugs 0.000 title description 10
150000001875 compounds Chemical class 0.000 claims abstract description 109
150000003839 salts Chemical class 0.000 claims abstract description 107
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 16
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 11
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 11
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 11
229910052794 bromium Inorganic materials 0.000 claims abstract description 11
229910052801 chlorine Inorganic materials 0.000 claims abstract description 11
239000000460 chlorine Substances 0.000 claims abstract description 11
125000005843 halogen group Chemical group 0.000 claims abstract description 11
239000001257 hydrogen Substances 0.000 claims abstract description 10
229910052740 iodine Inorganic materials 0.000 claims abstract description 10
ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 9
239000011630 iodine Substances 0.000 claims abstract description 9
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 7
229910052731 fluorine Inorganic materials 0.000 claims abstract description 7
239000011737 fluorine Substances 0.000 claims abstract description 7
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 135
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 122
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 114
239000002904 solvent Substances 0.000 claims description 74
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 74
239000000203 mixture Substances 0.000 claims description 53
238000006243 chemical reaction Methods 0.000 claims description 50
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 42
239000002253 acid Substances 0.000 claims description 32
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical class CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 31
238000010992 reflux Methods 0.000 claims description 31
-1 anhydrous Chemical class 0.000 claims description 29
KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 26
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 24
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 21
230000003287 optical effect Effects 0.000 claims description 21
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 20
239000003153 chemical reaction reagent Substances 0.000 claims description 19
SRKXAUBVRPEIQR-UHFFFAOYSA-N 2-(2-chlorophenyl)-2-(6,7-dihydro-4h-thieno[3,2-c]pyridin-5-yl)acetamide Chemical compound C1CC=2SC=CC=2CN1C(C(=O)N)C1=CC=CC=C1Cl SRKXAUBVRPEIQR-UHFFFAOYSA-N 0.000 claims description 18
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 17
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
239000002585 base Substances 0.000 claims description 13
DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 12
GKTWGGQPFAXNFI-UHFFFAOYSA-N 2-(2-chlorophenyl)-2-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetic acid methyl ester Chemical compound C1CC=2SC=CC=2CN1C(C(=O)OC)C1=CC=CC=C1Cl GKTWGGQPFAXNFI-UHFFFAOYSA-N 0.000 claims description 10
XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 10
230000006340 racemization Effects 0.000 claims description 10
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
150000007513 acids Chemical class 0.000 claims description 8
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 7
239000007858 starting material Substances 0.000 claims description 7
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
238000004090 dissolution Methods 0.000 claims description 6
QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 6
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
239000003054 catalyst Substances 0.000 claims description 5
150000002431 hydrogen Chemical class 0.000 claims description 5
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 5
LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 5
CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 4
XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
239000007789 gas Substances 0.000 claims description 4
229910052500 inorganic mineral Chemical class 0.000 claims description 4
WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 4
BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Chemical class OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
239000011707 mineral Chemical class 0.000 claims description 4
235000010755 mineral Nutrition 0.000 claims description 4
UWCWUCKPEYNDNV-LBPRGKRZSA-N 2,6-dimethyl-n-[[(2s)-pyrrolidin-2-yl]methyl]aniline Chemical compound CC1=CC=CC(C)=C1NC[C@H]1NCCC1 UWCWUCKPEYNDNV-LBPRGKRZSA-N 0.000 claims description 3
HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 3
FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 3
230000001476 alcoholic effect Effects 0.000 claims description 3
229910052783 alkali metal Inorganic materials 0.000 claims description 3
150000001340 alkali metals Chemical group 0.000 claims description 3
FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical class OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 claims description 3
229940106681 chloroacetic acid Drugs 0.000 claims description 3
238000011065 in-situ storage Methods 0.000 claims description 3
OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical class COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
230000002378 acidificating effect Effects 0.000 claims description 2
239000012736 aqueous medium Substances 0.000 claims description 2
235000019253 formic acid Nutrition 0.000 claims description 2
235000019260 propionic acid Nutrition 0.000 claims description 2
IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
239000008096 xylene Substances 0.000 claims description 2
FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims 4
239000012445 acidic reagent Substances 0.000 claims 4
DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical group C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 claims 2
229930007886 (R)-camphor Natural products 0.000 claims 2
JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 claims 2
229960000846 camphor Drugs 0.000 claims 2
229960001270 d- tartaric acid Drugs 0.000 claims 2
PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims 2
FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 claims 2
VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical class OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims 2
BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims 2
229960001367 tartaric acid Drugs 0.000 claims 2
239000011975 tartaric acid Substances 0.000 claims 2
235000002906 tartaric acid Nutrition 0.000 claims 2
FEWJPZIEWOKRBE-PIKHSQJKSA-N (3s)-2,3-dihydroxybutanedioic acid Chemical compound OC(=O)C(O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-PIKHSQJKSA-N 0.000 claims 1
ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 claims 1
239000003377 acid catalyst Substances 0.000 claims 1
230000014759 maintenance of location Effects 0.000 claims 1
238000004519 manufacturing process Methods 0.000 abstract description 10
229910052799 carbon Inorganic materials 0.000 abstract description 6
239000013067 intermediate product Substances 0.000 abstract description 5
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 4
125000001424 substituent group Chemical group 0.000 abstract description 4
MKYRMMMSZSVIGD-UHFFFAOYSA-N thieno[3,2-c]pyridine Chemical class N1=CC=C2SC=CC2=C1 MKYRMMMSZSVIGD-UHFFFAOYSA-N 0.000 abstract description 4
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 3
239000012467 final product Substances 0.000 abstract description 3
230000002744 anti-aggregatory effect Effects 0.000 abstract description 2
230000002785 anti-thrombosis Effects 0.000 abstract description 2
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract 1
239000000047 product Substances 0.000 description 110
239000011541 reaction mixture Substances 0.000 description 69
DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 47
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 37
239000000243 solution Substances 0.000 description 34
JFDVAYOTONCKQN-UHFFFAOYSA-N 2-(2-chlorophenyl)-2-(6,7-dihydro-4h-thieno[3,2-c]pyridin-5-yl)acetonitrile Chemical compound ClC1=CC=CC=C1C(C#N)N1CC(C=CS2)=C2CC1 JFDVAYOTONCKQN-UHFFFAOYSA-N 0.000 description 30
238000002844 melting Methods 0.000 description 30
230000008018 melting Effects 0.000 description 30
239000012044 organic layer Substances 0.000 description 28
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
239000002244 precipitate Substances 0.000 description 19
238000004949 mass spectrometry Methods 0.000 description 17
238000005160 1H NMR spectroscopy Methods 0.000 description 16
238000003756 stirring Methods 0.000 description 16
239000003480 eluent Substances 0.000 description 15
FPYUJUBAXZAQNL-UHFFFAOYSA-N 2-chlorobenzaldehyde Chemical compound ClC1=CC=CC=C1C=O FPYUJUBAXZAQNL-UHFFFAOYSA-N 0.000 description 14
239000011734 sodium Substances 0.000 description 14
238000004440 column chromatography Methods 0.000 description 13
CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 13
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
239000000543 intermediate Substances 0.000 description 12
SRKXAUBVRPEIQR-CQSZACIVSA-N (2r)-2-(2-chlorophenyl)-2-(6,7-dihydro-4h-thieno[3,2-c]pyridin-5-yl)acetamide Chemical compound C1([C@@H](N2CC=3C=CSC=3CC2)C(=O)N)=CC=CC=C1Cl SRKXAUBVRPEIQR-CQSZACIVSA-N 0.000 description 11
150000001408 amides Chemical class 0.000 description 11
238000002329 infrared spectrum Methods 0.000 description 11
239000007787 solid Substances 0.000 description 11
238000005481 NMR spectroscopy Methods 0.000 description 9
UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
229910000029 sodium carbonate Inorganic materials 0.000 description 8
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 description 7
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
229960000583 acetic acid Drugs 0.000 description 7
FDEODCTUSIWGLK-RSAXXLAASA-N clopidogrel sulfate Chemical compound [H+].OS([O-])(=O)=O.C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl FDEODCTUSIWGLK-RSAXXLAASA-N 0.000 description 7
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 7
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
238000000746 purification Methods 0.000 description 7
FAGCFTXEUBQVEU-UHFFFAOYSA-N 2-(2-chlorophenyl)-2-(6,7-dihydro-4h-thieno[3,2-c]pyridin-5-yl)propanoic acid Chemical compound C1CC=2SC=CC=2CN1C(C)(C(O)=O)C1=CC=CC=C1Cl FAGCFTXEUBQVEU-UHFFFAOYSA-N 0.000 description 6
ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
OGUWOLDNYOTRBO-UHFFFAOYSA-N 4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1NCCC2=C1C=CS2 OGUWOLDNYOTRBO-UHFFFAOYSA-N 0.000 description 6
150000001412 amines Chemical class 0.000 description 6
230000015572 biosynthetic process Effects 0.000 description 6
239000013078 crystal Substances 0.000 description 6
150000002148 esters Chemical class 0.000 description 6
229910052757 nitrogen Inorganic materials 0.000 description 6
229940001593 sodium carbonate Drugs 0.000 description 6
229910052938 sodium sulfate Inorganic materials 0.000 description 6
235000011152 sodium sulphate Nutrition 0.000 description 6
230000009466 transformation Effects 0.000 description 6
XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 5
238000001704 evaporation Methods 0.000 description 5
230000008020 evaporation Effects 0.000 description 5
239000012458 free base Substances 0.000 description 5
238000001819 mass spectrum Methods 0.000 description 5
VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 5
KXKVLQRXCPHEJC-UHFFFAOYSA-N methyl acetate Chemical compound COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 5
229920006395 saturated elastomer Polymers 0.000 description 5
229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
235000017557 sodium bicarbonate Nutrition 0.000 description 5
SRKXAUBVRPEIQR-AWEZNQCLSA-N (2s)-2-(2-chlorophenyl)-2-(6,7-dihydro-4h-thieno[3,2-c]pyridin-5-yl)acetamide Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)N)=CC=CC=C1Cl SRKXAUBVRPEIQR-AWEZNQCLSA-N 0.000 description 4
238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical class S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 4
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 4
DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 4
239000000284 extract Substances 0.000 description 4
ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 4
238000001953 recrystallisation Methods 0.000 description 4
239000004289 sodium hydrogen sulphite Substances 0.000 description 4
235000010267 sodium hydrogen sulphite Nutrition 0.000 description 4
239000000126 substance Substances 0.000 description 4
238000003786 synthesis reaction Methods 0.000 description 4
BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 3
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
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 3
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 3
150000001298 alcohols Chemical class 0.000 description 3
239000012267 brine Substances 0.000 description 3
238000001816 cooling Methods 0.000 description 3
239000006184 cosolvent Substances 0.000 description 3
238000000605 extraction Methods 0.000 description 3
238000001914 filtration Methods 0.000 description 3
239000012362 glacial acetic acid Substances 0.000 description 3
150000004702 methyl esters Chemical class 0.000 description 3
150000002825 nitriles Chemical class 0.000 description 3
239000002798 polar solvent Substances 0.000 description 3
239000003586 protic polar solvent Substances 0.000 description 3
238000004064 recycling Methods 0.000 description 3
238000000926 separation method Methods 0.000 description 3
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
238000003860 storage Methods 0.000 description 3
235000011149 sulphuric acid Nutrition 0.000 description 3
239000000725 suspension Substances 0.000 description 3
ZIQWQDJRKHGOIF-UQKRIMTDSA-N (2S)-2-(2-chlorophenyl)-2-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide (7,7-dimethyl-2-oxo-1-bicyclo[2.2.1]heptanyl)methanesulfonic acid Chemical compound CC1(C)C2CCC1(CS(O)(=O)=O)C(=O)C2.NC(=O)[C@@H](N1CCc2sccc2C1)c1ccccc1Cl ZIQWQDJRKHGOIF-UQKRIMTDSA-N 0.000 description 2
GAQWDBUWBUOFLS-UHFFFAOYSA-N (7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl)methanesulfonic acid;hydrate Chemical compound O.C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C GAQWDBUWBUOFLS-UHFFFAOYSA-N 0.000 description 2
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
101150041968 CDC13 gene Proteins 0.000 description 2
239000007832 Na2SO4 Substances 0.000 description 2
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
238000007059 Strecker synthesis reaction Methods 0.000 description 2
GAQWDBUWBUOFLS-YZUKSGEXSA-N [(1r,4s)-7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl]methanesulfonic acid;hydrate Chemical compound O.C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C GAQWDBUWBUOFLS-YZUKSGEXSA-N 0.000 description 2
239000000654 additive Substances 0.000 description 2
150000008044 alkali metal hydroxides Chemical class 0.000 description 2
239000007864 aqueous solution Substances 0.000 description 2
238000004296 chiral HPLC Methods 0.000 description 2
239000012069 chiral reagent Substances 0.000 description 2
DCASRSISIKYPDD-UHFFFAOYSA-N clopidogrel carboxylic acid Chemical compound C1CC=2SC=CC=2CN1C(C(=O)O)C1=CC=CC=C1Cl DCASRSISIKYPDD-UHFFFAOYSA-N 0.000 description 2
230000007613 environmental effect Effects 0.000 description 2
238000004128 high performance liquid chromatography Methods 0.000 description 2
125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
239000010410 layer Substances 0.000 description 2
229910052744 lithium Inorganic materials 0.000 description 2
239000000463 material Substances 0.000 description 2
239000002609 medium Substances 0.000 description 2
229940098779 methanesulfonic acid Drugs 0.000 description 2
239000003960 organic solvent Substances 0.000 description 2
239000003444 phase transfer catalyst Substances 0.000 description 2
XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
229910052700 potassium Inorganic materials 0.000 description 2
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
229910052708 sodium Inorganic materials 0.000 description 2
229910000104 sodium hydride Inorganic materials 0.000 description 2
230000002194 synthesizing effect Effects 0.000 description 2
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
238000000844 transformation Methods 0.000 description 2
ZIQWQDJRKHGOIF-YNKLJNJNSA-N (2S)-2-(2-chlorophenyl)-2-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide [(1S)-7,7-dimethyl-2-oxo-1-bicyclo[2.2.1]heptanyl]methanesulfonic acid Chemical compound CC1(C)C2CC[C@@]1(CS(O)(=O)=O)C(=O)C2.NC(=O)[C@@H](N1CCc2sccc2C1)c1ccccc1Cl ZIQWQDJRKHGOIF-YNKLJNJNSA-N 0.000 description 1
DCASRSISIKYPDD-CQSZACIVSA-N (2r)-2-(2-chlorophenyl)-2-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-ium-5-yl)acetate Chemical compound C1([C@@H](N2CC=3C=CSC=3CC2)C(=O)O)=CC=CC=C1Cl DCASRSISIKYPDD-CQSZACIVSA-N 0.000 description 1
ZWRSGQZZKCOSOA-NTISSMGPSA-N (2s)-2-(2-chlorophenyl)-2-(6,7-dihydro-4h-thieno[3,2-c]pyridin-5-yl)propanoic acid;sulfuric acid Chemical compound OS(O)(=O)=O.C1([C@](N2CC=3C=CSC=3CC2)(C(O)=O)C)=CC=CC=C1Cl ZWRSGQZZKCOSOA-NTISSMGPSA-N 0.000 description 1
MIOPJNTWMNEORI-XVKPBYJWSA-N (R)-camphorsulfonic acid Chemical class C1C[C@]2(CS(O)(=O)=O)C(=O)C[C@H]1C2(C)C MIOPJNTWMNEORI-XVKPBYJWSA-N 0.000 description 1
BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
YIWGJFPJRAEKMK-UHFFFAOYSA-N 1-(2H-benzotriazol-5-yl)-3-methyl-8-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carbonyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione Chemical compound CN1C(=O)N(c2ccc3n[nH]nc3c2)C2(CCN(CC2)C(=O)c2cnc(NCc3cccc(OC(F)(F)F)c3)nc2)C1=O YIWGJFPJRAEKMK-UHFFFAOYSA-N 0.000 description 1
JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
RPSNVZNPPVHPBD-UHFFFAOYSA-N 2-(2-chlorophenyl)-2-(6,7-dihydro-4h-thieno[3,2-c]pyridin-5-yl)acetamide;sulfuric acid Chemical compound OS(O)(=O)=O.C1CC=2SC=CC=2CN1C(C(=O)N)C1=CC=CC=C1Cl RPSNVZNPPVHPBD-UHFFFAOYSA-N 0.000 description 1
125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 description 1
COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
230000005526 G1 to G0 transition Effects 0.000 description 1
238000004566 IR spectroscopy Methods 0.000 description 1
229910019213 POCl3 Inorganic materials 0.000 description 1
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
238000002441 X-ray diffraction Methods 0.000 description 1
GAQWDBUWBUOFLS-QPQWKYTISA-N [(4r)-7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl]methanesulfonic acid;hydrate Chemical compound O.C1C[C@]2(CS(O)(=O)=O)C(=O)CC1C2(C)C GAQWDBUWBUOFLS-QPQWKYTISA-N 0.000 description 1
GAQWDBUWBUOFLS-DLGLCQKISA-N [(4s)-7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl]methanesulfonic acid;hydrate Chemical compound O.C1C[C@@]2(CS(O)(=O)=O)C(=O)CC1C2(C)C GAQWDBUWBUOFLS-DLGLCQKISA-N 0.000 description 1
150000001242 acetic acid derivatives Chemical class 0.000 description 1
WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Substances CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 1
WFDIJRYMOXRFFG-XPULMUKRSA-N acetyl acetate Chemical compound [14CH3]C(=O)OC([14CH3])=O WFDIJRYMOXRFFG-XPULMUKRSA-N 0.000 description 1
238000007171 acid catalysis Methods 0.000 description 1
150000008043 acidic salts Chemical class 0.000 description 1
BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
229910000147 aluminium phosphate Inorganic materials 0.000 description 1
150000001413 amino acids Chemical class 0.000 description 1
239000008346 aqueous phase Substances 0.000 description 1
239000003125 aqueous solvent Substances 0.000 description 1
125000005605 benzo group Chemical group 0.000 description 1
150000001558 benzoic acid derivatives Chemical class 0.000 description 1
230000004071 biological effect Effects 0.000 description 1
230000002051 biphasic effect Effects 0.000 description 1
125000004432 carbon atom Chemical group C* 0.000 description 1
KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
238000005660 chlorination reaction Methods 0.000 description 1
150000001805 chlorine compounds Chemical class 0.000 description 1
238000003776 cleavage reaction Methods 0.000 description 1
229960003958 clopidogrel bisulfate Drugs 0.000 description 1
238000007796 conventional method Methods 0.000 description 1
239000012043 crude product Substances 0.000 description 1
238000002425 crystallisation Methods 0.000 description 1
230000008025 crystallization Effects 0.000 description 1
WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
238000000354 decomposition reaction Methods 0.000 description 1
238000004821 distillation Methods 0.000 description 1
VFNGKCDDZUSWLR-UHFFFAOYSA-N disulfuric acid Chemical class OS(=O)(=O)OS(O)(=O)=O VFNGKCDDZUSWLR-UHFFFAOYSA-N 0.000 description 1
238000001035 drying Methods 0.000 description 1
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
238000009472 formulation Methods 0.000 description 1
238000001640 fractional crystallisation Methods 0.000 description 1
229910052736 halogen Inorganic materials 0.000 description 1
150000002367 halogens Chemical class 0.000 description 1
238000010438 heat treatment Methods 0.000 description 1
150000004680 hydrogen peroxides Chemical class 0.000 description 1
230000007062 hydrolysis Effects 0.000 description 1
238000006460 hydrolysis reaction Methods 0.000 description 1
QMXCTKPNQFJZGK-UHFFFAOYSA-N hydron;4,5,6,7-tetrahydrothieno[3,2-c]pyridine;chloride Chemical compound Cl.C1NCCC2=C1C=CS2 QMXCTKPNQFJZGK-UHFFFAOYSA-N 0.000 description 1
230000002209 hydrophobic effect Effects 0.000 description 1
QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 1
239000002085 irritant Substances 0.000 description 1
231100000021 irritant Toxicity 0.000 description 1
238000002955 isolation Methods 0.000 description 1
150000002576 ketones Chemical class 0.000 description 1
JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
239000007788 liquid Substances 0.000 description 1
239000001630 malic acid Substances 0.000 description 1
235000011090 malic acid Nutrition 0.000 description 1
230000002503 metabolic effect Effects 0.000 description 1
150000004972 metal peroxides Chemical class 0.000 description 1
XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical class COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
125000000896 monocarboxylic acid group Chemical group 0.000 description 1
239000012452 mother liquor Substances 0.000 description 1
150000002894 organic compounds Chemical class 0.000 description 1
238000007122 ortho-metalation reaction Methods 0.000 description 1
239000012071 phase Substances 0.000 description 1
229920000137 polyphosphoric acid Polymers 0.000 description 1
239000011736 potassium bicarbonate Substances 0.000 description 1
235000015497 potassium bicarbonate Nutrition 0.000 description 1
229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
229910000027 potassium carbonate Inorganic materials 0.000 description 1
235000011181 potassium carbonates Nutrition 0.000 description 1
TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
239000012264 purified product Substances 0.000 description 1
229910052761 rare earth metal Inorganic materials 0.000 description 1
150000002910 rare earth metals Chemical class 0.000 description 1
239000012429 reaction media Substances 0.000 description 1
238000005185 salting out Methods 0.000 description 1
238000013341 scale-up Methods 0.000 description 1
230000007017 scission Effects 0.000 description 1
150000003335 secondary amines Chemical class 0.000 description 1
239000003579 shift reagent Substances 0.000 description 1
239000002002 slurry Substances 0.000 description 1
235000015424 sodium Nutrition 0.000 description 1
239000011780 sodium chloride Substances 0.000 description 1
MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
239000012312 sodium hydride Substances 0.000 description 1
239000012265 solid product Substances 0.000 description 1
238000001228 spectrum Methods 0.000 description 1
WBWWGRHZICKQGZ-HZAMXZRMSA-N taurocholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@@H](O)C1 WBWWGRHZICKQGZ-HZAMXZRMSA-N 0.000 description 1
XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
238000002834 transmittance Methods 0.000 description 1
LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
238000005406 washing Methods 0.000 description 1
238000010626 work up procedure Methods 0.000 description 1
238000002424 x-ray crystallography Methods 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

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Organic Chemistry (AREA)
Chemical & Material Sciences (AREA)
Health & Medical Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Diabetes (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Life Sciences & Earth Sciences (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Hematology (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)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

NO20032898A 2001-01-24 2003-06-24 Fremgangsmate for fremstilling av klopidogrel NO327807B1 (no)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
IN84MU2001 IN191030B (fr)	2001-01-24	2001-01-24
US10/054,101 US6635763B2 (en)	2001-01-24	2001-10-22	Process to prepare clopidogrel
PCT/IN2002/000012 WO2002059128A2 (fr)	2001-01-24	2002-01-21	Procede de preparation de clopidogrel

Publications (3)

Publication Number	Publication Date
NO20032898D0 NO20032898D0 (no)	2003-06-24
NO20032898L NO20032898L (no)	2003-09-03
NO327807B1 true NO327807B1 (no)	2009-09-28

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NO20032898A NO327807B1 (no)	2001-01-24	2003-06-24	Fremgangsmate for fremstilling av klopidogrel

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Country	Link
EP (1)	EP1353928B1 (fr)
JP (1)	JP5000841B2 (fr)
KR (1)	KR20060040758A (fr)
CN (1)	CN100338068C (fr)
AT (1)	ATE349451T1 (fr)
AU (1)	AU2002228325B2 (fr)
BR (1)	BR0207064A (fr)
CA (1)	CA2436323C (fr)
CY (1)	CY1106346T1 (fr)
DE (1)	DE60217062T2 (fr)
DK (1)	DK1353928T3 (fr)
EA (1)	EA006198B2 (fr)
ES (1)	ES2278010T3 (fr)
MX (1)	MXPA03006133A (fr)
NO (1)	NO327807B1 (fr)
PL (1)	PL365281A1 (fr)
WO (1)	WO2002059128A2 (fr)

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IN191030B (fr) *	2001-01-24	2003-09-13	Cadila Healthcare Ltd
GB0125708D0 (en) *	2001-10-26	2001-12-19	Generics Uk Ltd	Novel compounds and processes
US6767913B2 (en)	2001-12-18	2004-07-27	Teva Pharmaceutical Industries Ltd.	Crystal forms iii, iv, v, and novel amorphous form of clopidogrel hydrogensulfate, processes for their preparation, processes for the preparation of form i, compositions containing the new forms and methods of administering the new forms
US7074928B2 (en)	2002-01-11	2006-07-11	Teva Pharmaceutical Industries, Ltd.	Polymorphs of clopidogrel hydrogensulfate
IL166593A0 (en)	2002-08-02	2006-01-15		Racemization and enantiomer separation of clopidogrel
US6800759B2 (en)	2002-08-02	2004-10-05	Teva Pharmaceutical Industries Ltd.	Racemization and enantiomer separation of clopidogrel
WO2004074215A1 (fr) *	2003-02-03	2004-09-02	Sunil Sadanand Nadkarni	Procede de preparation de clopidogrel, ses sels et compositions pharmaceutiques
DE602004026059D1 (de) *	2003-07-02	2010-04-29	Egis Gyogyszergyar Nyilvanosan	Prozess zur herstellung eines kristallinen polymorphs eines die plättchen aggregation hemmenden arzneistoffs
PL378711A1 (pl)	2003-07-02	2006-05-15	Egis Gyorgyszergyar Rt.	Proces wytwarzania bezpostaciowej formy leku inhibitującego agregację płytek krwi
PL1680430T3 (pl)	2003-11-03	2010-06-30	Cadila Healthcare Ltd	Sposoby wytwarzania postaci i (s)-(+)-wodorosiarczanu klopidogrelu
CA2457459A1 (fr) *	2004-02-11	2005-08-11	Brantford Chemicals Inc.	Resolution de melanges racemiques d'acetate de methyl alpha-5-(4,5,6,7- tetrahydro(3,2-c)thienopyridyle)-(2-chlorophenyle)
KR100553398B1 (ko)	2004-03-12	2006-02-16	한미약품 주식회사	티에노[3,2-ｃ]피리딘 유도체의 제조 방법 및 이에사용되는 중간체
AU2004318214B2 (en)	2004-04-09	2007-12-06	Hanmi Holdings Co., Ltd.	Crystalline clopidogrel naphthalenesulfonate or hydrate thereof, method for preparing same and pharmaceutical composition containing same
CZ295920B6 (cs) *	2004-10-18	2005-11-16	Zentiva, A. S	Způsob výroby klopidogrelu
CN100406568C (zh) *	2005-02-18	2008-07-30	淮北市辉克药业有限公司	氯吡格雷新生产工艺
CZ299213B6 (cs)	2005-03-08	2008-05-21	Zentiva, A. S	Zpusob racemizace R(-) izomeru methylesteru kyseliny (2-chlorfenyl)-6,7-dihydro-thieno[3,2-c]pyridin-5(4H)-octové
KR100678287B1 (ko) *	2005-06-23	2007-02-02	한미약품 주식회사	클로피도그렐의 제조방법 및 이에 사용되는 중간체
CN100463909C (zh) *	2005-09-08	2009-02-25	浙江华海药业股份有限公司	一种噻吩并四氢吡啶乙腈化合物的合成方法
CN100417653C (zh) *	2005-09-08	2008-09-10	浙江华海药业股份有限公司	噻吩并四氢吡啶乙酸及其盐的制备方法
EP1942110A4 (fr) *	2005-09-08	2010-08-04	Zhejiang Huahai Pharm Co Ltd	Préparation de clopidogrel et ses composés analogues à base d'acétate de méthyl tétrahydrothiénopyridine
CN100390180C (zh) *	2005-12-15	2008-05-28	上海应用技术学院	氯吡格雷及其盐的制备方法
KR101235117B1 (ko)	2005-12-26	2013-02-20	에스케이케미칼주식회사	광학분리에 의한 (ｓ)-(＋)-클로피도그렐의 제조방법
CN100396687C (zh) *	2006-05-26	2008-06-25	浙江海翔药业股份有限公司	(+)-(s-)-氯吡格雷硫酸氢盐(i型)的制备方法
WO2007144895A1 (fr) *	2006-06-12	2007-12-21	Cadila Healthcare Limited	Procédé de préparation du (s)-(+)-clopidogrel
SI22383A (sl) *	2006-09-22	2008-04-30	Krka, Tovarna Zdravil, D.D., Novo Mesto	Nov postopek sinteze klopidogrela in nove oblike njegovih farmacevtsko sprejemljivih soli
PL380849A1 (pl) *	2006-10-17	2008-04-28	Adamed Spółka Z Ograniczoną Odpowiedzialnością	Krystaliczna postać racemicznego -(2-chlorofenylo)-6,7-dihydrotieno[3,2-c]pirydylo-5(4H)-octanu metylu, sposób jej wytwarzania i zastosowanie
WO2008146249A1 (fr) *	2007-05-30	2008-12-04	Wockhardt Research Centre	Procédé d'élaboration de clopidogrel
AU2008337304A1 (en) *	2007-12-14	2009-06-25	Generics [Uk] Limited	HPLC method for analysing clopidogrel
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CN101812071A (zh) *	2010-05-10	2010-08-25	杭州和素化学技术有限公司	硫酸氢氯吡格雷中间体拆分后的母液处理方法
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Publication number	Publication date
JP5000841B2 (ja)	2012-08-15
NO20032898L (no)	2003-09-03
CN1487943A (zh)	2004-04-07
DE60217062T2 (de)	2007-06-21
KR20060040758A (ko)	2006-05-10
NO20032898D0 (no)	2003-06-24
DE60217062D1 (de)	2007-02-08
EA006198B1 (ru)	2005-10-27
CA2436323C (fr)	2012-02-21
ES2278010T3 (es)	2007-08-01
DK1353928T3 (da)	2007-03-26
AU2002228325B2 (en)	2006-05-04
WO2002059128A2 (fr)	2002-08-01
EA200300831A1 (ru)	2003-12-25
JP2004522744A (ja)	2004-07-29
EA006198B2 (ru)	2007-10-26
BR0207064A (pt)	2004-03-30
WO2002059128A3 (fr)	2002-12-19
EP1353928B1 (fr)	2006-12-27
CN100338068C (zh)	2007-09-19
EP1353928A2 (fr)	2003-10-22
CA2436323A1 (fr)	2002-08-01
CY1106346T1 (el)	2011-10-12
MXPA03006133A (es)	2004-05-04
PL365281A1 (en)	2004-12-27
ATE349451T1 (de)	2007-01-15

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Publication	Publication Date	Title
EP1353928B1 (fr)	2006-12-27	Procede de preparation de clopidogrel
US6635763B2 (en)	2003-10-21	Process to prepare clopidogrel
AU2002228325A1 (en)	2003-02-06	Process for preparing clopidogrel
US7482453B2 (en)	2009-01-27	Process for the manufacture of (+)-(S)-clopidogrel bisulfate form-1
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NO323613B1 (no)	2007-06-18	Fremgangsmate for fremstilling av 2-tienyletylamin-derivater
US20070191609A1 (en)	2007-08-16	Process for preparation of clopidogrel bisulphate form-1
US20050049415A1 (en)	2005-03-03	Process for preparing enantiomerically pure alpha phenyl-alpha (6,7-dihydro-4h-thieno[3,2-c]pyridin-5-yl)-acetic acid derivatives
NO167922B (no)	1991-09-16	Imidazolderivater
EP1907397B1 (fr)	2011-06-29	Procédé de préparation de clopidogrel et intermédiaires utilisés dans ce procédé
AU2009264395B2 (en)	2013-12-05	Process for the preparation of clopidogrel hydrogen sulfate crystalline form I
EP2146993B1 (fr)	2015-08-05	Procédé de préparation de mirtazapine
US7754883B2 (en)	2010-07-13	Method of racemization of the R(−) isomer of the (2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetic acid methyl ester
WO2009080469A1 (fr)	2009-07-02	Procédé de préparation de bisulfate de clopidogrel de forme i
KR20090086903A (ko)	2009-08-14	개선된 클로피도그렐의 제조 방법
KR100834967B1 (ko)	2008-06-03	여액의 라세미화 반응에 의한 ｓ-(＋)-클로피도그렐의고수율 제조방법
EP2064217B1 (fr)	2011-01-19	Procédé amélioré de préparation de clopidogrel et ses sels pharmaceutiquement acceptables
EP2128161A1 (fr)	2009-12-02	Procédé d'obtention de 4-hydroxy-6-méthyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-7,7-dioxide et ses enantiomères, ainsi qu'applications correspondantes