- Preparation method of clopidogrel hydrogen sulfate intermediate
-
The present invention relates to a preparation method of a clopidogrel hydrogen sulfate intermediate. (+)-2-chlorophenylglycine methyl ester and alpha-thiopheneethanol p-toluenesulfonate are adopted as raw materials, a reaction solvent and an acid-binding agent are added for a condensation reaction, the condensation reaction process is divided into a first stage and a second stage, and when 60-95% of the condensation reaction is completed, first-stage reaction is completed; after the first-stage reaction is completed, firstly part of the reaction solvent is removed, and then second-stage reaction is carried out; and after the second-stage reaction is completed, a target product is obtained, namely the clopidogrel hydrogen sulfate intermediate. After the first-stage reaction is completed, part of the reaction solvent is removed firstly, and then the second-stage reaction is continued, so that the concentration of the reaction material can be increased in the later stage of the condensation reaction, the use amount of the reaction solvent is reduced, and racemization and side reaction in the reaction process are effectively inhibited, thereby improving the chiral purity of the product, increasing the yield, reducing the use of auxiliary materials greatly, and reducing the production cost.
- -
-
Paragraph 0032; 0035-0073; 0083
(2021/05/15)
-
- Preparation method of clopidogrel hydrogen sulfate
-
The invention relates to a preparation method of clopidogrel hydrogen sulfate. The preparation method comprises the following steps: reacting (S)-o-chlorophenylglycine methyl ester with 1, 1, 1, 3, 3,3-hexamethyldisilazane to obtain trimethylsilyl protected (S)-o-chlorophenylglycine methyl ester; in the presence of acetonitrile, superfine powder potassium carbonate and the trimethylsilyl protected (S)-o-chlorophenylglycine methyl ester, adding 2- (2-bromoethyl) thiophene, evaporating acetonitrile in batches, adding water and methyl acetate, extracting to obtain a methyl acetate solution of (S)-2-thiophene ethylamino-2-chlorophenylmethyl acetate, dropwise adding concentrated hydrochloric acid, carrying out pulping and cooling to obtain (S)-2-thiophene ethylamino methyl-2-chlorophenyl acetate hydrochloride, mixing the (S)-2-thiophene ethylamino methyl-2-chlorophenyl acetate hydrochloride with a formaldehyde aqueous solution for reaction, and carrying out reaction with concentrated sulfuric acid to obtain the clopidogrel hydrogen sulfate. According to the method, the high-purity (S)- 2-thiophene ethylamino-2-chlorophenyl methyl acetate hydrochloride and clopidogrel hydrogen sulfate can be obtained with high efficiency and high yield, and the method is suitable for industrial production.
- -
-
Paragraph 0075; 0078-0079; 0082; 0085-0086; 0089; 0092-0093
(2021/02/10)
-
- Preparation method of sulfonic clopidogrel impurity
-
The invention discloses a preparation method of a sulfonic clopidogrel impurity. The preparation method comprises the following steps: reacting thiophene-2-ethanol with toluenesulfonyl chloride to generate p-toluenesulfonic acid-2-thienylethyl ester; carrying out esterification on o-chlorophenylglycine and methanol to generate o-chlorophenylglycine methyl ester; resolving the o-chlorophenylglycinemethyl ester by using L(+) tartaric acid; converting into free S-(+)-o-chlorophenylglycine methyl ester in dichloromethane; carrying out a condensation reaction on the p-toluenesulfonic acid-2-thienylethyl ester and the S-(+)-o-chlorophenylglycine methyl ester under an alkaline condition; acidifying the obtained product to generate (S)-2-(2-thienylethylamino)(2-chlorphenyl)methyl acetate, carrying out a condensation reaction on the (S)-2-(2-thienylethylamino)(2-chlorphenyl)methyl acetate and formaldehyde to obtain clopidogrel, and carrying out a reaction on the clopidogrel and chlorosulfonicacid to generate sulfonic clopidogrel impurity. The preparation method of the sulfonic clopidogrel impurity has the advantages of mild reaction conditions, accessible raw materials, low cost and highyield and purity.
- -
-
Paragraph 0012; 0034-0035
(2020/08/02)
-
- Synthesis of clopidogrel intermediate (S)-2-(2- thiophene ethylamine-)-(2-chlorophenyl)- methyl acetate
-
The invention belongs to the technical field of medicines, and relates to a novel process (S)- 2 - (2 - for synthesizing the intermediate) - (2 - thiophene ethyl amino) - chlorophenyl, methyl acetate and the salt thereof, for the first time, and the inven
- -
-
Paragraph 0050-0133
(2020/03/17)
-
- Method for preparing D-(+)-alpha-(2-thiopheneethylamino)-alpha-(2-chlorophenyl)methyl acetate hydrochloride
-
The invention provides a novel method for preparing D-(+)-alpha-(2-thiopheneethylamino)-alpha-(2-chlorophenyl)methyl acetate hydrochloride, aiming at solving the technical problems of a traditional synthesis technology of the D-(+)-alpha-(2-thiopheneethylamino)-alpha-(2-chlorophenyl)methyl acetate hydrochloride that the technology is complicated, the cost is high and the yield is low. The method comprises the following steps: 1) preparing 2-bromothiophene; 2) preparing 2-thiopheneethanol; 3) preparing 2-thiopheneethanol p-toluenesulfonate; 4) preparing L-(+)-o-chlorophenylglycine methyl esterL-tartrate; 5) preparing the D-(+)-alpha-(2-thiopheneethylamino)-alpha-(2-chlorophenyl)methyl acetate hydrochloride. The preparation method provided by the invention is low in cost, high in yield andhigh in safety and is suitable for industrial production.
- -
-
Paragraph 0011; 0061-0064; 0070-0072; 0079; 0084-0108
(2018/12/14)
-
- The clopidogrel hydrogen sulfate synthesis method (by machine translation)
-
The invention discloses a clopidogrel hydrogen sulfate synthesis method, comprises the following steps: S1, 2 - (2 - thiophene) ethanol tosylates synthetic, S2, (+) - O-chlorobenzene glycine methyl brown oil of synthetic, S3, (S)- 2 - (2 - thiophene ethylamine) (2 - chlorophenyl) acetic acid methyl ester hydrochloride of synthetic, S4, the finished synthetic; the invention with conventional clopidogrel hydrogen sulfate existing synthesis method, the processing operation is more convenient, after treatment is simple, and is suitable for commercial production; high yield, few by-products, impurity removal easier; simple and easy to obtain, the cost is cheap. (by machine translation)
- -
-
Paragraph 0006; 0008
(2018/11/22)
-
- A compound clopidogrel hydrogensulfate method for the preparation of
-
The invention relates to a preparation method of clopidogrel disulfate. The preparation method comprises the following steps of step one. carrying out esterification reaction, namely preparing (+/-) DL-2-Chlorophenylglycine methyl ester; step two. carrying out splitting reaction, namely preparing (+) DL-2-Chlorophenylglycine methyl ester; step three. carrying out activating reaction, namely preparing alpha-thiophene ethanol p-toluenesulfonates; step four. carrying out substitution reaction, namely preparing (+) alpha-(2-thiophene ethylamino)-2-(2-chlorobenzene) methyl acetate hydrochloride; step five. carrying out ring closing reaction, namely preparing clopidogrel; and step six. carrying out salt-forming reaction, namely preparing the clopidogrel disulfate. The preparation method has the advantages that the preparation technology is optimized and improved, reaction conditions are mild, the splitting and the racemization are truly and synchronously carried out, and an obtained crude product has high specific rotation; a catalyst is used in the substitution reaction, so that the reaction time is shortened; the ring closing reaction is carried out at 40 DEG C under the condition of avoiding light, so that the purity of the product is relatively high; and the period of the whole synthetic route is shortened, the aftertreatment operation is simple, and therefore, the preparation method is suitable for mass production.
- -
-
Paragraph 0103-0105
(2017/01/26)
-
- AN IMPROVED PROCESS FOR THE PREPARATION OF CLOPIDOGREL BISULFATE FORM-I
-
The present invention provides an improved process for the preparation of pure Clopidogrel bisulfate Form-I of formula (I), which comprises: reacting S(+)-methyl-2- [2-(thiophen-2-yl)ethylamino]-2-(2-chlorophenyl) acetate hydrochloride (Formula II) with Formaldehyde and R-(-) Camphor sulphonic acid to yield S (+)-Clopidogrel camphor sulfonate salt (Formula III), which is on further treatment with C1-5 carboxylic acid followed by sulphuric acid to get Clopidogrel Form-I.
- -
-
Page/Page column 6; 7
(2014/08/19)
-
- AN IMPROVED PROCESS FOR THE PREPARATION OF CLOPIDOGREL BISULFATE
-
The present invention provides an improved process for the preparation of Clopidogrel of Formula (I) or its pharmaceutically acceptable salts, and its intermediate of Formula (II). Formula (I) Formula (II).
- -
-
Page/Page column 7
(2011/02/24)
-
- PROCESS FOR PREPARING CLOPIDOGREL
-
A process for preparing clopidogrel or a salt thereof.
- -
-
Page/Page column 7
(2008/06/13)
-
- AN IMPROVED PROCESS FOR THE PREPARATION OF CLOPIDOGREL
-
The present invention relates to an improved process for the preparation of Clopidogrel of Formula (I). More particularly, the present invention relates to an improved process for the preparation of Clopidogrel intermediate of formula (III) using triethylamine as an organic base in the absence of an organic solvent. Formula (I), Formula (III).
- -
-
Page/Page column 6
(2008/06/13)
-
- PROCESS FOR PREPARATION OF CLOPIDOGREL BISULPHATE FORM-1
-
Disclosed herein is a cost effective and industrially feasible process for the preparation of (+) Clopidogrel bisulphate. The present invention further discloses a novel method of precipitation of (+) Clopidogrel bisulphate Form I directly from solvent mix of methanol and acetone in presence of sulfuric acid at a temperature of 25-40° C.
- -
-
Page/Page column 4
(2008/06/13)
-
- A PROCESS FOR PREPARATION OF CLOPIDOGREL
-
The present invention provides a process for the preparation of S-isomer of methyl α-(4,5,6,7-tetrahydro-5-thieno[3,2-c]pyridyl)(2-chlorophenyl)acetate, a compound of formula (4), or a salt thereof comprising, (a) resolving racemic α-[(2-thien-2-yl)ethylamino]-a-(2-chlorophenyl)methylacetate, a compound of formula 1 or a salt thereof to obtain S-isomer of a compound of formula (1) or a salt thereof and R-isomer of formula (1) or a salt thereof, (b) racemizing the R-isomer of formula 1 or a salt thereof to obtain a racemic compound of formula (1) and optionally converting it into a salt thereof, (c) optionally repeating steps 'a' and 'b', (d) converting the S-isomer of compound of formula (1) obtained in step 'a' to S-isomer of methyl α-(4,5,6,7-tetrahydro-5-thieno[3,2-c]pyridyl)(2-chlorophenyl) acetate.
- -
-
-
- Process for racemization
-
The invention relates to the racemisation process of the optically active [2-(2-thienyl)ethylamino](2-halogenophenyl)acetamides of general formula (VII) by using basic compounds. The resulting racemic compounds of general formula (VII) can thus be recycle
- -
-
Page column 6
(2010/02/06)
-
- Intermediates and process for the preparation thereof
-
A process for the preparation of [2-(2-thienyl)-ethylamino]-(2-halogenophenyl)-acetonitriles of general formula (I) starting from 2-(2-thienyl)-ethyl-amine, alkalicyanide and o-halogeno-benzaldehyde. Compounds of general formula (I) are valuable intermediates.
- -
-
-
- Intermediates and process for the preparation thereof
-
A process for the preparation of 2-[(2-thienyl)-ethylamino]-(2-halogenophenyl)-acetamides of general formula (VII) starting from the nitriles of general formula (I). Compounds of general formula (VII) are valuable intermediates.
- -
-
-
- Process for the preparation of a pharmacologically active substance
-
The present invention relates to a process for the preparation of the racemic or optically active compounds of general formula (VI): wherein the meaning of X is a halogen atom, or their salts, characterized in that, a racemic or optically active new compound of general formula (VII): wherein the meaning of X is a halogen atom, is transformed into the racemic or optically active compound of general formula (VIII):
- -
-
-
- Method for preparing 2-thienylethylamine derivatives
-
PCT No. PCT/FR98/00441 Sec. 371 Date Sep. 2, 1999 Sec. 102(e) Date Sep. 2, 1999 PCT Filed Mar. 5, 1998 PCT Pub. No. WO98/39322 PCT Pub. Date Sep. 11, 1998The present invention relates to a process for the preparation of 2-thienylethylamine derivatives of general formula: as well as their acid addition salts, in which R represents a halogen atom and R1 represents a C1-C4 alkyl group, characterized in that a thienylglycidic derivative of general formula: in which M represents an alkali metal atom or a fraction of an alkaline-earth metal atom, is reacted with a phenylglycine ester, optionally in the form of a strong acid salt, of general formula: in which R and R1 have the same meaning as above, in the presence of an alkali metal borchydride of general formula: X-YIV in which X represents an alkali metal atom and Y represents a group of formula: -BH3CN or -BH(4-w)Zw in which Z represents a carboxylic acid residue and optionally in the presence of a C1-C4 carboxylic acid, which gives the desired compound in the form of a free base which can be treated, if necessary, with an acid in order to obtain an addition salt of this compound.
- -
-
-