- Method for recycling S - O-chloromandelic acid
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The invention belongs to the technical field of chemical synthesis, and discloses a method for recycling S-o-chloromandelic acid. The o-chloromandelic acid is a clopidogrel hydrogen sulfate starting material. The method is characterized by comprising the following steps: concentrating a lipid solution of S-o-chloromandelic acid to dryness, and adding an alkaline aqueous solution to react at a hightemperature to racemize the S-o-chloromandelic acid; after the reaction is completed, adding a C2-C8 lipid solvent and adjusting the pH of the solution with an inorganic acid to be acidic; separatingan aqueous phase from an organic phase, and allowing the organic phase to be dried and directly reacted with a resolving agent to prepare R-o-chloromandelic acid. The invention provides a method forrecycling clopidogrel hydrogen sulfate intermediate waste, the influence of reaction byproducts on the environment is eliminated, the S-o-chloromandelic acid is converted and then used in the preparation process of clopidogrel hydrogen sulfate, and the economic value is very high.
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Paragraph 0032-0055
(2021/02/09)
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- PROCESS FOR THE PREPARATION OF CLOPIDOGREL POLYMORPHOUS FORM 1 USING SEED CHRYSTALS
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The invention relates to the process for the preparation of hydrogen sulfate salt of dextro rotatory Methyl - α - 5 - (4,5,6,7- tetrahydro - (3,2-c ) thienopyridyl) - (2-chlorophenyl) acetate which is generally referred as clopidogrel hydrogen sulfate ( I
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Page/Page column 3
(2011/02/24)
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- RACEMIZATION PROCESS FOR THE PREPARATION OF AN INTERMEDIATE OF CLOPIDOGREL HYDROGEN SULPHATE
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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.
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Page/Page column 9-10
(2009/07/18)
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- PROCESSES FOR THE PREPARATION OF CLOPIDOGREL
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The invention relates to processes for the preparation of clopidogrel and salts thereof. The inventors have developed a process for preparing racemic clopidogrel by racemizing R(-) clopidogrel. The process includes the step of reacting R(-) clopidogrel with a powered anhydrous base in one or more solvents.
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Page/Page column 6
(2009/01/20)
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- PROCESS FOR PREPARING CLOPIDOGREL
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A process for the preparation of clopidogrel of formula (I) or its pharmaceutically acceptable salts, solvates, hydrates thereof is disclosed. The process comprises treating (+)-(S)-2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2- c]pyridin-5-yl)acetamide of formula (II) with acid to provide novel acid salt of (+)-(S)- 2-Chlorophenyl-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide of formula (III) wherein in S represent acid selected from hydrochloric acid, hydrobromic acid, phosphoric acid, benzoic acid, succinic acid, oxalic acid, malic acid, maleic acid, methanesulfonic acid, ethane sulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid, nephthalene sulfonic acid and converting acid salt of (+)-(S)-2-Chlorophenyl- (6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetamide to Clopidogrel (I) and its pharmaceutically acceptable salts, hydrates, solvates thereof.
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Page/Page column 13-14
(2008/12/07)
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- Procedure for the preparation of methyl (+)-(S)-Alpha-(O-chlorophenyl)-6,7-dihydrothieno-[3,2-C]pyridine-5(4H) acetate
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A process for the preparation of Methyl (+)-(S)-α-(o-chlorophenyl)-6,7-dihydrothieno-[3,2-c]pyridine-5(4H)acetate of formula I: the process comprising: a. reacting 4,5,6,7-tetrahydro[3,2-c]thieno pyridyl methane (II) with 2-halophenyl acetic acid derivative of formula III b. extracting the formed product (+/-) clopidogrel in to solvent from the reaction mixture of step a; c. resolution of (+/-) clopidogrel of step b with levorotatory camphor sulfonic acid and isolation of the (+) clopidogrel camphor sulfonic acid salt; d. purifying (+) clopidogrel camphor salt; and e. neutralization of the camphor salt of step d with aqueous base in solvent and isolation of (+) clopidogrel base by separation and removal solvent.
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Page/Page column 9; 10
(2008/12/04)
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- Process for preparing clopidogrel
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The present invention encompasses processes for the preparation of optically pure clopidogrel camphorsulfonic acid salt without the need to isolate or recover (±) clopidogrel.
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Page/Page column 10
(2008/12/09)
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- PREPARATION OF CLOPIDOGREL AND ITS ANALOGUES METHYL TETRAHYDROTHIENOPYRIDINE ACETATE COMPOUNDS
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The present invention disclosed a preparation method of Clopidogrel (X=2-Cl) and its analogues of methyl tetrahydrothienopyridine acetate (I) by using halogen phenyl acetonitrile (VIII) as starting material and tetrahydrothienopyridine acetonitrile (IV), tetrahydrothienopyridine acetate (V) as key intermediates, and further using kinetic resolution to prepare the optical active Clopidogrel and compounds of methyl tetrahydrothenopridine acetate of formula (XII). The Clopidogrel of present invention is a novel high effective and safety drug for inhibition of platelet aggregation. This invention applied systematic technique of racemization of unwanted optical active enantiomer, recover recycle and reuse of resolution agent etc., with greater economic advantages and suitable for commercial scale industrial production. Wherein: X represents atoms of hydrogen, fluorine, chlorine, bromine or iodine, M represents an alkali metal ion.
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Page/Page column 21
(2008/12/06)
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- Preparation of Clopidogrel and Its Analogues Methyl Tetrahydrothienopyridine Acetate Compuunds
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The present invention disclosed a preparation method of Clopidogrel (X=2-Cl) and its analogues of methyl tetrahydrothienopyridine acetate (I) by using halogen phenyl acetonitrile (VIII) as starting material and tetrahydrothienopyridine acetonitrile (IV), tetrahydrothienopyridine acetate (V) as key intermediates, and further using kinetic resolution to prepare the optical active Clopidogrel and compounds of methyl tetrahydrothenopridine acetate of formula (XII). The Clopidogrel of present invention is a novel high effective and safety drug for inhibition of platelet aggregation. This invention applied systematic technique of racemization of unwanted optical active enantiomer, recover recycle and reuse of resolution agent etc., with greater economic advantages and suitable for commercial scale industrial production. Wherein: X represents atoms of hydrogen, fluorine, chlorine, bromine or iodine, M represents an alkali metal ion.
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Page/Page column 17
(2008/12/08)
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- A PROCESS FOR PREPARING (S)-(+)-CLOPIDOGREL BASE AND ITS SALTS
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The present invention relates to an improved processes for the preparation of Methyl (+)-(S)-(2-chlorophenyl)-(6,7dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetate [Clopidogrel base, (I)] and their various pharmaceutically acceptable salts.
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Page/Page column 4
(2008/12/05)
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- Stereoselective process for the preparation of Clopidogrel
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Preparation of (2-halophenyl)(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl) compounds (Ia) or their salts comprises converting benzene derivatives (II) with an optically active amino alcohol to form a first mixture of diastereomers. Preparation of (2-halophenyl)(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl) compounds of formula (Ia) or its salt comprises converting benzene derivatives of formula (II) with an optically active amino alcohol to a first mixture of diastereomers. X : halo; and Y, Z : leaving groups. Independent claims are also included for the following: (1) a mixture of benzene diastereomers of formulae (IVa) and (IVb); (2) a compound (IVa); (3) a mixture of thiazo piperidine diastereomers of formulae (VIa) and (VIb); (4) compound (VIa); (5) a mixture of thiophene diastereomers of formulae (VIIIa) and (VIIIb); (6) a compound (VIIIa); and (7) preparation of 1-dimethylamino-propan-2-ol compound of formula (a) comprising reacting a diastereomeric mixtures of 1-dimethylamino-propan-2-ol of formulae (b) and (c) with L-(-)-di-O-benzoyl-L-(-)-tartaric acid (L-(-)-DBTA) and separating the L-(-)-DBTA salts of the compounds. A* : 1-30C hydrocarbon (containing 5 heteroatoms of S, O, N or halo and substituted with 5 substituents of OH, oxo, CN or nitro group) or one or more optically active units; and either R 1>, R 2>H, 1-20C hydrocarbon containing 4 heteroatoms of S, O, N or halo and substituted with 5 substituents of OH, oxo, CN or nitro groups); or C+R 1>+R 2> or R 1>+R 2>+heteroatom of A* : 5-10 membered ring (optionally saturated and optionally containing further 1-3 heteroatoms of N, O or S adjacent to the N, then a ring member is substituted with up to 5 substituents of 1-6C alkyl, 1-6C alkenyl, 1-6C alkoxy, 5-10C (hetero)aryl, 3-8C cycloalkyl, 2-8C heterocycloalkyl, halo, OH, oxo, CN or nitro (especially 1-6C alkyl, 5-10C hetero(aryl), 3-8C cycloalkyl or 2-8C heterocycloalkyl or N+R 1>+R 2> forms 3-8C saturated or unsaturated ring optionally with 1-6C alkyl or halo substituted and adjacent to N 1-2 further heteroatom of S, N or O). [Image] [Image] [Image] ACTIVITY : Anticoagulant; Thrombolytic. MECHANISM OF ACTION : Thrombocyte aggregation inhibitor.
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Page/Page column 43
(2008/06/13)
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- PROCESS FOR PREPARATION OF CLOPIDOGREL, ITS SALTS AND PHARMACEUTICAL COMPOSITIONS
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The invention discloses an improved process for racemization of methyl (R)-(-) alpha-(2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate , a stereoisomer formed in the synthesis of clopidogrel i.e. methyl (S)-(+)-alpha- (2-chlorophenyl)-6,7-dihydro-thieno[3,2-c]pyridine-5(4H)-acetate or its salts. The invention is also for an improved process for production of clopidogrel or its pharmaceutically acceptable salts. The invention further discloses novel clopidogrel salts and pharmaceutical compositions comprising them.
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