WO2009077797A1 - Racemization process for the preparation of an intermediate of clopidogrel hydrogen sulphate - Google Patents
Racemization process for the preparation of an intermediate of clopidogrel hydrogen sulphate Download PDFInfo
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- WO2009077797A1 WO2009077797A1 PCT/HU2008/000148 HU2008000148W WO2009077797A1 WO 2009077797 A1 WO2009077797 A1 WO 2009077797A1 HU 2008000148 W HU2008000148 W HU 2008000148W WO 2009077797 A1 WO2009077797 A1 WO 2009077797A1
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- WIPO (PCT)
- Prior art keywords
- acetate
- dihydrothieno
- chlorophenyl
- methyl
- pyridine
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 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 title claims abstract description 13
- 230000006340 racemization Effects 0.000 title claims description 25
- 229950010477 clopidogrel hydrogen sulphate Drugs 0.000 title abstract description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 41
- 239000000203 mixture Substances 0.000 claims abstract description 33
- GKTWGGQPFAXNFI-OAHLLOKOSA-N methyl (2r)-2-(2-chlorophenyl)-2-(6,7-dihydro-4h-thieno[3,2-c]pyridin-5-yl)acetate Chemical compound C1([C@@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-OAHLLOKOSA-N 0.000 claims abstract description 17
- 239000003960 organic solvent Substances 0.000 claims abstract description 13
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000001117 sulphuric acid Substances 0.000 claims abstract description 9
- 235000011149 sulphuric acid Nutrition 0.000 claims abstract description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 51
- 239000002585 base Substances 0.000 claims description 24
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 16
- -1 methyl (R,S) Chemical compound 0.000 claims description 13
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 11
- 238000010992 reflux Methods 0.000 claims description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 8
- 229910052783 alkali metal Inorganic materials 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 235000011181 potassium carbonates Nutrition 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 5
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 5
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 5
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims description 5
- 150000007530 organic bases Chemical class 0.000 claims description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 239000011877 solvent mixture Substances 0.000 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 3
- 239000012038 nucleophile Substances 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 125000001931 aliphatic group Chemical group 0.000 claims description 2
- AYJRCSIUFZENHW-DEQYMQKBSA-L barium(2+);oxomethanediolate Chemical compound [Ba+2].[O-][14C]([O-])=O AYJRCSIUFZENHW-DEQYMQKBSA-L 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- DIBHLCJAJIKHGB-UHFFFAOYSA-N dec-5-ene Chemical compound [CH2]CCCC=CCCCC DIBHLCJAJIKHGB-UHFFFAOYSA-N 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 2
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 2
- 239000001095 magnesium carbonate Substances 0.000 claims description 2
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 229940086066 potassium hydrogencarbonate Drugs 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims 1
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 abstract description 10
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical class C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 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 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- MIOPJNTWMNEORI-MHPPCMCBSA-N [(4r)-7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl]methanesulfonic acid Chemical compound C1C[C@]2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-MHPPCMCBSA-N 0.000 description 4
- 239000012452 mother liquor Substances 0.000 description 4
- DCASRSISIKYPDD-AWEZNQCLSA-N (2s)-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-AWEZNQCLSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- ZKPBAMKYQNMNDK-UHFFFAOYSA-N 2-(3,4-dihydropyridin-5-yl)acetic acid Chemical compound OC(=O)CC1=CN=CCC1 ZKPBAMKYQNMNDK-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 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
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 229960005235 piperonyl butoxide Drugs 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 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
- MMDDFTYVMBRJQA-UQKRIMTDSA-N (2s)-2-(2-chlorophenyl)-2-(6,7-dihydro-4h-thieno[3,2-c]pyridin-5-yl)acetic acid;sulfuric acid Chemical compound OS(O)(=O)=O.C1([C@H](N2CC=3C=CSC=3CC2)C(=O)O)=CC=CC=C1Cl MMDDFTYVMBRJQA-UQKRIMTDSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical class C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- WTLWYLDVLAIHPU-UHFFFAOYSA-N 2-(2-chlorophenyl)-2-(2-thiophen-2-ylethylamino)acetamide Chemical compound C=1C=CC=C(Cl)C=1C(C(=O)N)NCCC1=CC=CS1 WTLWYLDVLAIHPU-UHFFFAOYSA-N 0.000 description 1
- RWOLDZZTBNYTMS-UHFFFAOYSA-N 2-(2-chlorophenyl)-2-hydroxyacetic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1Cl RWOLDZZTBNYTMS-UHFFFAOYSA-N 0.000 description 1
- UCEZSLREZBFKMQ-UHFFFAOYSA-N 2-(3,4-dihydropyridin-5-yl)acetic acid;sulfuric acid Chemical compound OS(O)(=O)=O.OC(=O)CC1=CN=CCC1 UCEZSLREZBFKMQ-UHFFFAOYSA-N 0.000 description 1
- 101000783577 Dendroaspis angusticeps Thrombostatin Proteins 0.000 description 1
- 101000783578 Dendroaspis jamesoni kaimosae Dendroaspin Proteins 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 229960004676 antithrombotic agent Drugs 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 150000007516 brønsted-lowry acids Chemical class 0.000 description 1
- 150000007528 brønsted-lowry bases Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 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 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000002411 thermogravimetry 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
Definitions
- the invention relates to a new industrial process for the preparation of the pharmaceutically applicable methyl (S)-(+)- ⁇ -(2-chlorophenyl)-6,7-dihydrothieno [3,2-c]pyridine-5(4H)-acetate hydrogen sulphate (also known as S-(+)-clopidogrel hydrogen sulphate) of formula (I) comprising racemizing methyl (R)-(-)- ⁇ -(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate (known as (R)-(-)-clopidogrel) or methyl
- the (S)-(+)-clopidogrel hydrogen sulphate of formula (I) is a known valuable pharmaceutical substance used as platelet aggregation inhibitor and anti-thrombotic agent.
- the (S)-(+)-clopidogrel hydrogen sulphate and a process for the preparation thereof was originally disclosed in EP 281 459.
- WO 2000/027840 published patent application is directed to a racemization process of the optically active (-)-[2-(2-thienyl)-ethylamino]-(2-chlorophenyl)-acetamide.
- the R(-)-amide is converted to racemic amide ⁇ another named to [2-(2-thienil)-ethylamino]-(2-chlorophenyl)-acetamide ⁇ by using organic or inorganic basic compounds (alkali metal hydroxides, alkali metal alcoholates).
- WO 2004/074215 published patent application discloses a process for the racemization of methyl (R)-(-)- ⁇ -(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]-pyridine-5(4H)- acetate.
- the base is liberated from the camphor-sulphonic acid salt of methyl (R)-(-)- ⁇ -(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]-pyridine-5(4H)-acetate then the so obtained base is treated with an acid (hydrochloric acid, sulphuric acid, acetic acid, phosphoric acid) to obtain methyl (R,S)-( ⁇ )- ⁇ -(2chlorophenyl)-6,7-dihydrothieno[3,2-c] pyridine-5(4H)-acetate.
- an acid hydrochloric acid, sulphuric acid, acetic acid, phosphoric acid
- WO 2003/000636 published patent application discloses a process for the preparation of racemic 2-hydroxy-2(2-chlorophenyl) acetic acid by racemizing its S-(+) isomer with an alkali metal hydroxide.
- the racemic 2-hydroxi-2(2-chlorophenyl)acetic acid is one of the starting materials of the S-(+)-clopidogrel hydrogen sulphate. According to the process disclosed in US 6 737 411 patent specification methyl (R)-
- racemization of (R)-(-)- ⁇ -(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate is also carried out with a base (potassium-fert-butoxide, lithium diisopropylamide, potassium hydroxide, sodium hydroxide, sodium methoxide, potassium hydride, sodium hydride).
- the invention relates to a new process for the preparation of the pharmaceutically applicable methyl (S)-(+)- ⁇ -(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate hydrogen sulphate of formula (I) comprising racemizing methyl (R)-(-)- ⁇ -(2-chlorophenyl)- 6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate or methyl (S)-(+)- ⁇ -(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate, or a mixture thereof in any proportion with a weak base in the presence of an organic solvent, converting the (R,S)-( ⁇ )- ⁇ -(2-chlorophenyl)- 6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate of fomula (II) obtained
- Bronsted-Lowry acids or bases in the racemization step results in other catalytic actions (ester hydrolysis, condensation reactions, etc.) therefore the product obtained requires further purifying actions.
- the procedures are also disadvantageous from the environmental point of view due to use of strong acids or bases.
- the racemization procedure can be carried out by using weak bases (alkali metal hydrogen carbonates, alkali earth metal hydrogen carbonates, alkali metal carbonates, alkali earth metal carbonates, organic bases with non-nucleophile character, particularly cyclic organic bases) instead of strong bases.
- weak bases alkali metal hydrogen carbonates, alkali earth metal hydrogen carbonates, alkali metal carbonates, alkali earth metal carbonates, organic bases with non-nucleophile character, particularly cyclic organic bases
- room temperature refers to temperatures between about 20 and 25°C.
- DSC differential scanning calorimetric test.
- TG thermogravimetric analysis.
- IR infrared spectra.
- the starting material of our invention is methyl (R)-(-)- ⁇ -(2-chlorophenyl)-6,7- dihydrothieno[3,2-c] ⁇ yridine-5(4H)-acetate or methyl (S)-(+)- ⁇ -(2-chloro ⁇ henyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate or a mixture thereof in any ratio remained in the mother liquor after resolution with (R)-(-)-camphor-10-sulphonic acid is racemized using a weak base in the presence of an organic solvent to obtain (R,S)-( ⁇ )- ⁇ -(2 ⁇ chlorophenyl)-6,7- dihydrothieno[3.2-c]pyridine-5(4H)-acetate of formula (II).
- This compound is converting to its sulphuric acid addition salt methyl (R,S)-( ⁇ )- ⁇ -(2-chlorophenyl)-6,7-dihydrothieno [3,2-c]pyridine-5(4H)-acetate hydrogen sulphate (also known as racemic clopidogrel hydrogen sulphate) and converting it to methyl (S)-(+)- ⁇ -(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate hydrogen sulphate of formula (I) by known manner.
- the camphor- 10-sulphonic acid salt of methyl (R)-(-)- ⁇ -(2-chlorophenyl)-6,7-dihydrothieno [3,2-c]pyridine-5(4H)-acetate or the camphor- 10-sulphonic acid salt of methyl (S)-(+)- ⁇ - (2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate or a mixture thereof in any ratio remained in the mother liquor is extracted with aqueous alkali hydrogen carbonate or alkali earth metal hydrogen carbonate to liberate the acetate compounds.
- racemization process affords the possibility of further resolution steps to give further amounts of (S)-(+)- ⁇ -(2-chlorophenyl)-6,7-dihydrothieno [3,2-c]pyridine-5(4H)-acetate hydrogen sulphate of formula (I).
- Suitable weak base which can be used in the racemization process according to the invention include alkali metal hydrogen carbonates, alkali earth metal hydrogen carbonates, or a mixture thereof, particularly sodium hydrogen carbonate, potassium hydrogen carbonate, preferably sodium hydrogen carbonate.
- Suitable weak base which can be used in the racemization process according to the invention include alkali metal carbonates, alkali earth metal carbonates, or a mixture thereof, particularly lithium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, barium carbonate, preferably potassium carbonate.
- Suitable weak base which can be used in the racemization process according to the invention include organic bases with non-nucleophile character, particularly cyclic organic bases, or a mixture thereof, particularly l,5,7-triazabicyclo[4.4.0]dec-5-ene, l,8-diazabicyclo[5.4.0]undec-7-ene, l,5-diazabicyclo[4.3.0]non-5 ⁇ ene, preferably l,8-diazabicyclo[5.4.0]undec-7-ene.
- organic bases with non-nucleophile character particularly cyclic organic bases, or a mixture thereof, particularly l,5,7-triazabicyclo[4.4.0]dec-5-ene, l,8-diazabicyclo[5.4.0]undec-7-ene, l,5-diazabicyclo[4.3.0]non-5 ⁇ ene, preferably l,8-diazabicyclo[5.4.0]undec-7
- Suitable weak base which can be used in the racemization process according to the invention include also a mixture of the above listed alkali metal hydrogen carbonates, alkali earth metal hydrogen carbonates, alkali metal carbonates, alkali earth metal carbonates, organic bases with non-nucleophilic character, particularly cyclic organic bases.
- 0,1-1,0 mol equivalents preferably 0,1 mol equivalents of the weak base is applied per one mol of methyl (R)-(-)- ⁇ -(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate or methyl
- organic solvent for the racemization process according to the invention one or more straight or branched chain aliphatic or cyclic saturated or unsaturated mono- or polisubstituted primary, secondary or tertiary C 1 -C 6 alcohol, preferably methanol can be used.
- the solvent is applied in 1-20 fold, preferably in 10 fold amount based on the weight of the methyl (R)-(-)- ⁇ - (2-chloro ⁇ henyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate or methyl (S)-(+)- ⁇ -
- the reaction is carried out between 0° C and the reflux temperature of the solvent or solvent mixture applied, preferably at the reflux temperature of the solvent or solvent mixture.
- the advantage of the invention appears in that the racemization process according to the invention is suitable for the economical preparation of methyl (S)-(+)- ⁇ -(2-chlorophenyl)- 6,7-dihydrothieno[3,2c]pyridine-5(4H)-acetate hydrogen sulphate of formula (I) in industrial scale.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention relates to a process for the preparation of the pharmaceutically applicable methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)- acetate hydrogen sulphate (also known as S-(+)-clopidogrel hydrogen sulphate) of formula (I) comprising racemizing methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine- 5(4H)-acetate or methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)- acetate, or a mixture thereof in any proportion with a weak base in the presence of an organic solvent, converting the methyl (R,S)-(±)-α-(2-chlorophenyl)-6,7-dihydrothieno [3,2-c]pyridine-5(4H)-acetate of fomula (II) obtained to its sulphuric acid addition salt methyl (R,S)-(±)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate hydrogen sulphate and converting it to methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c] pyridine-5(4H)-acetate hydrogen sulphate of formula (I) by known manner.
Description
RACEMIZATION PROCESS FOR THE PREPARATION OF AN INTERMEDIATE OF CLOPIDOGREL HYDROGEN SULPHATE
Field of the invention
The invention relates to a new industrial process for the preparation of the pharmaceutically applicable methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno [3,2-c]pyridine-5(4H)-acetate hydrogen sulphate (also known as S-(+)-clopidogrel hydrogen sulphate) of formula (I) comprising racemizing methyl (R)-(-)-α-(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate (known as (R)-(-)-clopidogrel) or methyl
(S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate (known as
(S)-(+)-clopidogrel), or a mixture thereof in any proportion with a weak base in the presence of an organic solvent, converting the methyl (R,S)-(±)-α-(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate of fomula (II) obtained to its sulphuric acid addition salt methyl (R,S)-(±)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)- acetate hydrogen sulphate (also known as racemic clopidogrel hydrogen sulphate) and converting it to methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)- acetate hydrogen sulphate of formula (I) by known manner.
II
Background of the invention
The (S)-(+)-clopidogrel hydrogen sulphate of formula (I) is a known valuable pharmaceutical substance used as platelet aggregation inhibitor and anti-thrombotic agent. The (S)-(+)-clopidogrel hydrogen sulphate and a process for the preparation thereof was originally disclosed in EP 281 459.
A large number of chemical processes have been developed for the preparation of the racemic clopidogrel hydrogen sulphate by racemization.
In EP 281 459 patent specification the methyl (R,S)-( ±)- α -(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate is formed with (R)-(-)-camphor-10-sulphonic acid to obtain camphor- 10-sulphonie acid salt of methyl (S)-(+)-α-(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate. After separation the so obtained salt is treated with sodium hydrogen carbonate to obtain methyl (S)-(+)-α-(2-chlorophenyl-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate. Then addition of sulphuric acid to the methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate results in S-(+> clopidogrel hydrogen sulphate.
The camphor- 10-sulphonic acid salt of methyl (R)-(-)-α-(2-chlorophenyl)-6,7- dihydrothieno[3,2c]pyridine-5(4H)-acetate or the mixture in any proportion of camphor-10- sulphonic acid salt of methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydrotieno[3,2-c]pyridine- 5(4H)-acetate and camphor- 10-sulphonic acid salt of methyl (S)-(+)-α-(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate that remained in the mother liquor is converted to methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate or a mixture of methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate and methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]ρyridine-5(4H)-acetate.
From the so obtained composition the methyl (R,S)-(±)-α-(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate may be synthetized by racemization to give a further mass of S-(+)clopidogrel hydrogen sulphate.
WO 2000/027840 published patent application is directed to a racemization process of the optically active (-)-[2-(2-thienyl)-ethylamino]-(2-chlorophenyl)-acetamide. In this racemization procedure the R(-)-amide is converted to racemic amide {another named to [2-(2-thienil)-ethylamino]-(2-chlorophenyl)-acetamide} by using organic or inorganic basic compounds (alkali metal hydroxides, alkali metal alcoholates).
WO 2004/074215 published patent application discloses a process for the racemization of methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]-pyridine-5(4H)- acetate. Accordingly, the base is liberated from the camphor-sulphonic acid salt of methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]-pyridine-5(4H)-acetate then the so obtained base is treated with an acid (hydrochloric acid, sulphuric acid, acetic acid, phosphoric acid) to obtain methyl (R,S)-(±)-α-(2chlorophenyl)-6,7-dihydrothieno[3,2-c] pyridine-5(4H)-acetate.
WO 2003/000636 published patent application discloses a process for the preparation of racemic 2-hydroxy-2(2-chlorophenyl) acetic acid by racemizing its S-(+) isomer with an alkali metal hydroxide. The racemic 2-hydroxi-2(2-chlorophenyl)acetic acid is one of the starting materials of the S-(+)-clopidogrel hydrogen sulphate. According to the process disclosed in US 6 737 411 patent specification methyl (R)-
(-)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate is racemized using a strong base (potassium-tert-butoxide, sodium-fe/Y-butoxide, diizopropylamide, potassium hydroxide, sodium hydroxide, potassium methoxide, sodium methoxide) similarly to those written in US 6 800 759 patent specification.
According to WO 2002/059128 published international patent specification racemization of (R)-(-)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate is also carried out with a base (potassium-fert-butoxide, lithium diisopropylamide, potassium hydroxide, sodium hydroxide, sodium methoxide, potassium hydride, sodium hydride).
Summary of the invention
The invention relates to a new process for the preparation of the pharmaceutically applicable methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate hydrogen sulphate of formula (I) comprising racemizing methyl (R)-(-)-α-(2-chlorophenyl)- 6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate or methyl (S)-(+)-α-(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate, or a mixture thereof in any proportion with a weak base in the presence of an organic solvent, converting the (R,S)-(±)-α-(2-chlorophenyl)- 6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate of fomula (II) obtained to its sulphuric acid addition salt methyl (R,S)-(±)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)- acetate hydrogen sulphate and converting it to methyl (S)-(+)-α-(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate hydrogen sulphate of formula (I) by known manner.
Drawback of the procedures described in the foregoing is that the use of strong
Bronsted-Lowry acids or bases in the racemization step results in other catalytic actions (ester hydrolysis, condensation reactions, etc.) therefore the product obtained requires further purifying actions. The procedures are also disadvantageous from the environmental point of view due to use of strong acids or bases.
In the course of our experience we have surprisingly found that performing the racemization procedure described in the aforesaid patent applications the racemization
procedure can be carried out by using weak bases (alkali metal hydrogen carbonates, alkali earth metal hydrogen carbonates, alkali metal carbonates, alkali earth metal carbonates, organic bases with non-nucleophile character, particularly cyclic organic bases) instead of strong bases. The so obtained (R,S)-(±)-α-(2-chlorophenyl)-6,7-dihydrothieno[3.2-c] pyridine-5(4H)-acetate of formula (II) can be converted to (S)-(+)-clopidogrel hydrogen sulphate without further purifying procedure.
In the new process according to the invention the starting methyl (R)-(-)-α- (2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate or methyl (S)-(+)~α- (2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate or a mixture thereof can be obtained according to the resolvation process described in EP 281 459 .
Detailed description of the invention
Definitions of terms and abbreviations as used herein have the following meanings: As used herein the term ,,room temperature" refers to temperatures between about 20 and 25°C.
As used herein the abbreviation "DSC" means differential scanning calorimetric test. As used herein the abbreviation ,,TG" means thermogravimetric analysis. As used herein the term abbreviation ,,IR" means infrared spectra.
Using the EP 281 459 procedure for the preparation of methyl (S)-(+)-α-
(2-chlorophenyl)-6,7-dyhidrothieno[3,2-c]pyridine-5(4H)-acetate hydrogen sulphate of formula (I), the starting material of our invention is methyl (R)-(-)-α-(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]ρyridine-5(4H)-acetate or methyl (S)-(+)-α-(2-chloroρhenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate or a mixture thereof in any ratio remained in the
mother liquor after resolution with (R)-(-)-camphor-10-sulphonic acid is racemized using a weak base in the presence of an organic solvent to obtain (R,S)-(±)-α-(2~chlorophenyl)-6,7- dihydrothieno[3.2-c]pyridine-5(4H)-acetate of formula (II). This compound is converting to its sulphuric acid addition salt methyl (R,S)-(±)-α-(2-chlorophenyl)-6,7-dihydrothieno [3,2-c]pyridine-5(4H)-acetate hydrogen sulphate (also known as racemic clopidogrel hydrogen sulphate) and converting it to methyl (S)-(+)-α-(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate hydrogen sulphate of formula (I) by known manner.
Performing the new process according to the invention for the preparation of methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate hydrogen sulphate of formula (I) the starting methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydrothieno [3,2-c]pyridine-5(4H)-acetate or methyl (S)-(+)-α-(2-chloroρhenyl)-6,7-dihydrothieno [3,2-c]pyridine-5(4H)-acetate or a mixture thereof is prepared according to the EP 281 459 procedure. Accordingly, after resolving with (R)-(-)-camphor-10-sulphonic acid the camphor- 10-sulphonic acid salt of methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydrothieno [3,2-c]pyridine-5(4H)-acetate or the camphor- 10-sulphonic acid salt of methyl (S)-(+)-α- (2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate or a mixture thereof in any ratio remained in the mother liquor is extracted with aqueous alkali hydrogen carbonate or alkali earth metal hydrogen carbonate to liberate the acetate compounds. Then the so obtained methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate or methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate or a mixture thereof in any ratio is racemized with a weak base as catalyst in the presence of an organic solvent. The methyl (R,S)-(±)-α-(2-chlorophenyl)-6,7-dihydrothieno[3.2-c]pyridine-
5(4H)-acetate of formula (II) obtained is treated with sulphuric acid to obtain the racemic clopidogrel hydrogen sulphate.
The racemization process according to the invention affords the possibility of further resolution steps to give further amounts of (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno [3,2-c]pyridine-5(4H)-acetate hydrogen sulphate of formula (I).
Suitable weak base which can be used in the racemization process according to the invention include alkali metal hydrogen carbonates, alkali earth metal hydrogen carbonates, or a mixture thereof, particularly sodium hydrogen carbonate, potassium hydrogen carbonate, preferably sodium hydrogen carbonate. Suitable weak base which can be used in the racemization process according to the invention include alkali metal carbonates, alkali earth metal carbonates, or a mixture thereof, particularly lithium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, barium carbonate, preferably potassium carbonate.
Suitable weak base which can be used in the racemization process according to the invention include organic bases with non-nucleophile character, particularly cyclic organic bases, or a mixture thereof, particularly l,5,7-triazabicyclo[4.4.0]dec-5-ene, l,8-diazabicyclo[5.4.0]undec-7-ene, l,5-diazabicyclo[4.3.0]non-5~ene, preferably l,8-diazabicyclo[5.4.0]undec-7-ene.
Suitable weak base which can be used in the racemization process according to the invention include also a mixture of the above listed alkali metal hydrogen carbonates, alkali earth metal hydrogen carbonates, alkali metal carbonates, alkali earth metal carbonates, organic bases with non-nucleophilic character, particularly cyclic organic bases. hi the racemization process according to the invention 0,1-1,0 mol equivalents, preferably 0,1 mol equivalents of the weak base is applied per one mol of methyl
(R)-(-)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate or methyl
(S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2c]pyridine-5(4H)-acetate or a mixture thereof at any rate.
As organic solvent for the racemization process according to the invention one or more straight or branched chain aliphatic or cyclic saturated or unsaturated mono- or polisubstituted primary, secondary or tertiary C1-C6 alcohol, preferably methanol can be used.
In the racemization process according to the invention the solvent is applied in 1-20 fold, preferably in 10 fold amount based on the weight of the methyl (R)-(-)-α- (2-chloroρhenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate or methyl (S)-(+)-α-
(2-chlorophenyl)-6,7-dihydrothieno[3,2c]pyridine-5(4H)-acetate or a mixture thereof at any rate.
In the racemization process according to the invention the reaction is carried out between 0° C and the reflux temperature of the solvent or solvent mixture applied, preferably at the reflux temperature of the solvent or solvent mixture.
The advantage of the invention appears in that the racemization process according to the invention is suitable for the economical preparation of methyl (S)-(+)-α-(2-chlorophenyl)- 6,7-dihydrothieno[3,2c]pyridine-5(4H)-acetate hydrogen sulphate of formula (I) in industrial scale. The specific rotation, IR5 DSC, TG data of methyl (R,S)-(±)-α-(2-chlorophenyl)-
6,7-dihydrothieno[352c]pyridine-5(4H)-acetate hydrogen sulphate obtained in the procedure according to the invention correspond with data described in the literature.
The invention is illustrated by the following non-limiting Examples. Example 1
Preparation of camphor-sulfonic acid salt of methyl (S)-(+)-α-(2-chIorophenvD- 6,7-dihydrothienof3,2-c]pyridine-5(4H)-acetate by resolution of methyl (R1S)-(J-Va- (2-chlorophenyl)-6,7-dihydrothienor3,2-clpyridine-5(4H)-acetate of formula (II)
123.53 g of compound of formula (II) was dissolved in 560.0 ml of acetone at room temperature during stirring and 40.6 g of (R)-(-)-camphor-10-sulphonic acid was added to this mixture. After dissolution of the compound of formula (II) the solution obtained was seeded with (R)-(-)-carnphor-10-sulphonic acid salt of (S)-(+)-α-(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate. The reaction mixture was stirred for further 22 hours at room temperature and the crystals precipitated were filtered washed with acetone and dried.
In this manner 43.7 g of the camphor-sulphonic acid salt of (S)-(+)-α- (2-chlorophenyl)-6,7-dihydrothieno[3 ,2-c]pyridine-5(4H)-acetate was obtained. Yield: 22.5%
Specific rotation: [α]D2°=(24.71°) (C=I, in methanol)
Example 2 Preparation of a mixture of methyl (R)-(-)-α-(2-chlorophenyl)-6,7- dihydrothienof3,2-clpyridine-5(4H)-acetate and methyl (SH+)-q-(2-chlorophenyl)-6,7- dihydrothieno [3,2-d pyridine-5(4HV acetate
The acetonic mother liquor, obtained according to Example 1, was evaporated in vacuum. 280.0 ml of ethyl acetate was added to the oil obtained above and the mixture was
extracted with 90.0 ml of eight percent aqueous sodium hydrogen carbonate. The organic phase was washed with aqueous sodium chloride and dried on sodium sulphate. The dried organic phase was evaporated in vacuum. hi this manner, 76.5 g of product was obtained as a mixture of methyl (R)-(-)-α-(2-chloroρhenyl)-6,7-dihydrothieno[3,2-c]ρyridine-5(4H)-acetate and methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate. Specific rotation: [α]D 20=(-15o)-(-16°) (C=I, in methanol)
Example 3
Preparation of methyl (R,SV(±Vα-(2-chlorophenyl)-6,7-dihydrothieno [3,2-clpyridine-5(4H)-acetate of formula (ID
15.8 g of a mixture of methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydrothieno [3,2-c]pyridine-5(4H)-acetate and methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno [3,2-c]pyridine-5(4H)-acetate obtained in Example 2 was dissolved in 158,0 ml of methanol and 0.41 g of sodium hydrogen carbonate was added. The reaction mixture was heated to reflux temperature for 3 hours then the organic solvent was evaporated in vacuum. To the residue obtained 40.0 ml of ethyl acetate was added and the mixture was extracted with 40 ml of water. The organic phase was dried on sodium sulphate then evaporated in vacuum. hi this manner 14.8 g of compound of formula (II) was obtained.
Yield: 94% Specific rotation: [α]D 20=(0°)-(-lo) (Ol , in methanol)
Example 4
Preparation of methyl (R,SH±Vα-(2-chlorophenvi)-6,7-dihydrothieno f3,2-c1pyridine-5(4ϊDacetate of formula (IB
15.78 g of a mixture of methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydrothieno [3,2c]pyridine-5(4H)-acetate and methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno [3 ,2-c]pyridine-5 (4H) acetate prepared in Example 2 was dissolved in 158.0 ml of methanol and 0.63 g of potassium carbonate was added. The reaction mixture was heated to reflux temperature for additional 3 hours then the organic solvent was evaporated in vacuum. 40.0 ml of ethyl acetate was added to the residue obtained and the mixture was extracted with 40 ml of water. The organic phase was dried on sodium sulphate then evaporated in vacuum, hi this manner 15.1 g of compound of formula (II) was obtained. Yield: 96% Specific rotation: [α]D 20=(0°)-(-lo) (O=I, in methanol)
Example 5
Preparation of methyl (R,SV(±Vα-(2-chlorophenylV6J-dihydrothieno [3.,2-c1pyridine-5(4H)acetate of formula (ID
10.54 g of a mixture of methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydrothieno [3,2c]pyridine-5(4H)-acetate and methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno [3,2-c]pyridine-5(4H)acetate prepared in Example 2 was dissolved in 105.4 ml of methanol and 0.49 ml of l,8-diazabicyclo[5.4.0]undec-7-ene was added. The reaction mixture was heated to reflux temperature for additional 3 hours then the organic solvent was evaporated in vacuum. 40.0 ml of ethyl acetate was added to the residue obtained and
the mixture was extracted with 40 ml of water. The organic phase was dried on sodium sulphate then evaporated in vacuum.
In this manner 9.7 g of compound of formula (II) was obtained.
Yield: 92%. Specific rotation: [α]D 20=(0°)-(-l °) (C=I , in methanol)
Example 6
Preparation of methyl (R,SV(±Vα-(2-chIorophenylV6,7-dihvdrothieno r3.2-clpyridine-5(4EDacetate of formula (ID
15.8 g of methyl (R)-(-)-α-(2-chloroρhenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)- acetate {Specific rotation: [α]D 20=(-47.1°) (C=I, in methanol)} was dissolved in 158.0 ml of methanol and 0.41 g of sodium hydrogen carbonate was added. The reaction mixture was heated to reflux temperature for additional 3 hours then the organic solvent was evaporated in vacuum. 40.0 ml of ethyl acetate was added to the residue obtained and the mixture was extracted with 40 ml of water. The organic phase was dried on sodium sulphate then evaporated in vacuum.
In this manner 15.0 g of compound of formula (II) was obtained. Yield: 95% Specific rotation: [α]D 20=(0oH-P) (C=I , in methanol)
Example 7
Preparation of methyl rR-SH±Vα-(2-chIorophenyiy6,7-dihydrothieno [3,2-c1pyridine-5(4H)acetate of formula (ID
15.78 g of methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine- 5(4H)-acetate {Specific rotation: [α]D 20=(-47,l°) (C=I, in methanol)} was dissolved in 158.0 ml of methanol and 0.63 g of potassium carbonate was added. The reaction mixture was heated to reflux temperature then the organic solvent was evaporated in vacuum. To the residue obtained 40.0 ml of ethyl acetate was added and the mixture was exacted with 40 ml of water. The organic phase was dried on sodium sulphate and evaporated in vacuum. In this manner 15.0 g of compound of formula (II) was obtained.
Yield: 95% Specific rotation: [α]D 20=(0°)-(-l°) (C=I, in methanol)
Example 8
Preparation of methyl (R.SV(±)-α-(2-chlorophenyl)-6J-dihydrothieno[3.,2-c1 pyridine-5(4H)acetate hydrogen sulphate
16.6 g of compound of formula (II) was dissolved in 48.0 ml of acetone and 2.17 ml of 98 % sulphuric acid was added under stirring. The suspension obtained was stirred for additional 2 hours at room temperature then filtered and washed with acetone. hi this manner 15.17 g of methyl (R,S)-(±)-α-(2-chloroρhenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)acetate hydrogen sulphate was obtained. Yield: 91% Specific rotation: [α]D 20=(0°)-(-P) (C=I, in methanol)
Claims
1. Process for the preparation of the pharmaceutically applicable methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate hydrogen sulphate of formula (I) comprising racemizing methyl (R)-(-)-α-(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]pyridine-5(4H)-acetate or methyl (S)-(+)-α-(2-chlorophenyl)-6,7- dihydrothieno[3,2-c]piridine-5(4H)-acetate, or a mixture thereof in any proportion with a weak base in the presence of an organic solvent, converting the methyl (R,S)(±)-α- (2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate of fomula (II) obtained to its sulphuric acid addition salts and converting the so obtained methyl (R,S)(±)-α- (2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate hydrogen sulphate to methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3 ,2-c]pyridine-5(4H)-acetate hydrogen sulphate of formula (I).
II
2. The process according to claim 1 characterized in that in the racemization reaction alkali metal hydrogen carbonates or alkali earth metal hydrogen carbonates are used as a weak base.
3. The process according to claim 2 characterized in that sodium hydrogen carbonate, potassium hydrogen carbonate, preferably sodium hydrogen carbonate is employed as hydrogen carbonate.
4. The process according to claim 1 characterized in that in the racemization process alkali metal carbonates or alkali earth metal carbonates are employed as a weak base.
5. The process according to claim 4 characterized in that lithium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, barium carbonate, preferably potassium carbonate is employed as carbonate.
6. The process according to claim 1 characterized in that as the weak base an organic base with non-nucleophile character, particularly a cyclic organic base is employed in the racemization reaction.
7. The process according to claim 6 characterized in that as the organic base l,5,7-triazabicyclo[4.4.0]dec-5-ene, l,8-diazabicyclo[5.4.0]undec-7-ene, l,5-diazabicyclo[4.3.0]non-5-ene, preferably l,8-diazabicyclo[5.4.0]undec-7-ene is employed.
8. The process according to any one of claims 1-7. characterized in that in the racemization process a mixture of the above listed alkali metal hydrogen carbonates, alkali earth metal hydrogen carbonates, alkali metal carbonates, alkali earth metal carbonates, bases with non-nucleophil character, particularly cyclic organic bases is employed as a weak base.
9. The process according to any one of claims 1-8. characterized in that 0,1-1,0 mol equivalents, preferably 0,1 mol equivalents of the weak base is applied per one mol of methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]ρyridine-5(4H)-acetate or methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2c]pyridine-5(4H)-acetate or a mixture thereof at any rate.
10. The process according to any one of claims 1-9. characterized in that as organic solvent one or more straight or branched chain aliphatic or cyclic saturated or unsaturated mono- or polisubstituted primary, secondary or tertiary C1-C6 alcohol, preferably methanol is employed in the racemizing process.
11. The process according to any one of claims 1-10. characterized in that the solvent is applied in 1-20 fold, preferably in 10 fold amount based on the weight of the methyl (R)-(-)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate or methyl (S)-(+)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2c]pyridine-5(4H)-acetate or a mixture thereof at any rate in the racemizing process.
12. The process according to any one of claims 1-11. characterized in that the reaction is carried out between O° C and the reflux temperature of the solvent or solvent mixture applied, preferably at the reflux temperature of the solvent or solvent mixture in the racemizing process.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU0700809A HUP0700809A2 (en) | 2007-12-14 | 2007-12-14 | Racemisation process for producing methyl (r,s)-(+)-alpha-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridin-5(4h)-acetate hydrogene sulfate intermediate |
| HUP0700809 | 2007-12-14 |
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| WO2009077797A1 true WO2009077797A1 (en) | 2009-06-25 |
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| WO (1) | WO2009077797A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111166745A (en) * | 2020-01-19 | 2020-05-19 | 成都施贝康生物医药科技有限公司 | Composition containing racemic oxypyramine or salt thereof and application |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004013147A1 (en) * | 2002-08-02 | 2004-02-12 | Teva Pharmaceutical Industries Ltd. | Racemization and enantiomer separation of clopidogrel |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004013147A1 (en) * | 2002-08-02 | 2004-02-12 | Teva Pharmaceutical Industries Ltd. | Racemization and enantiomer separation of clopidogrel |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111166745A (en) * | 2020-01-19 | 2020-05-19 | 成都施贝康生物医药科技有限公司 | Composition containing racemic oxypyramine or salt thereof and application |
Also Published As
| Publication number | Publication date |
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| HU0700809D0 (en) | 2008-02-28 |
| HUP0700809A2 (en) | 2009-11-30 |
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