141109-14-0Relevant articles and documents
Asymmetric Hydrocyanation of N-Phosphinoyl Aldimines with Acetone Cyanohydrin by Cooperative Lewis Acid/Onium Salt/Br?nsted Base Catalysis
Junge, Thorsten,Titze, Marvin,Frey, Wolfgang,Peters, René
, p. 1509 - 1512 (2021/02/09)
α-Amino acids are of fundamental importance for life. Both natural and artificial α-amino acids also play a crucial role for pharmaceutical purposes. The catalytic asymmetric Strecker reaction still provides one of the most attractive strategies to prepare scalemic α-amino acids. Here we disclose a new concept for Strecker reactions, in which an achiral Br?nsted base cooperates with a Lewis acid and an aprotic ammonium salt, which are both arranged in the same chiral catalyst entity. The described method could successfully address various long-standing practical issues of this reaction type. The major practical advantages are that (1) the N-protecting group is readily removable, (2) acetone cyanohydrin is attractive as cyanation reagent in terms of atom economy and cost efficiency, (3) an excess of the cyanation reagent is not necessary, (4) the new method does not require additives and (5) is performed at ambient temperature.
Preparation method of clopidogrel hydrogen sulfate intermediate
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Paragraph 0032, (2021/05/15)
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.
Preparation method of sulfonic clopidogrel impurity
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Paragraph 0012; 0032-0033, (2020/08/02)
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.
Preparation method of clopidogrel hydrogen sulfate crystal form II
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Paragraph 0034; 0054; 0070, (2020/02/29)
The invention discloses a preparation method of a clopidogrel hydrogen sulfate crystal form II. The method includes: preparation of (+)o-chlorophenylglycine methyl ester; preparation of (+)alpha-(2-thiophene ethylamino)-alpha-(2-chlorphenyl)methyl acetate hydrochloride; preparation of (+)clopidogrel free alkali; preparation of (+)clopidogrel camphorsulfonic acid double salt; hydrolysis of (+)clopidogrel camphorsulfonic acid double salt; and preparation of clopidogrel hydrogen sulfate. The preparation method of the clopidogrel hydrogen sulfate crystal form II provided by the invention optimizesthe synthesis process of clopidogrel hydrogen sulfate, selects cheap and easily available materials, adopts mild reaction conditions, and can achieve safe and environment-friendly production of a high-purity product.
Synthesis process of anti-cancer drug (glycinate methyl ester)
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Paragraph 0010-0011, (2019/10/10)
The invention provides a synthesis process of an anti-cancer drug (glycinate methyl ester). The process includes the steps of firstly, adding methyl alcohol into a flask with a stirrer, a thermometer and a constant-pressure dropping funnel, controlling the temperature at 0-5 DEG C, and slowly dropwise adding acetyl chloride into the flask for thermal insulation reaction for 1.5 hours; secondly, adding o-chlorophenylglycine to be heated to 45 DEG C for reaction for 15 hours; thirdly, conducting depressurized rotary evaporating to remove most of solvent, and conducting separation and suction-filtration to obtain a product (hydrochloride solid); fourthly, dissolving the obtained solid in water, adding dichloromethane, adjusting the pH value to be 7.5 through ammonium hydroxide, extracting a water layer through dichloromethane, combining an organic layer, conducting washing through saturated table salt until the neutral state is reached, conducting drying and suction filtration on anhydrous magnesium sulfate, and conducting depressurized rotary evaporating to remove a solvent to obtain a colorless transparent oily substance. Through the improvement, the synthesis method has the advantages that the process is green and free of pollution, the reaction conditions are mild, the operation is simple, the product can be easily extracted, and the yield is high; thus, the problems and defects in the background are effectively solved and overcome.
The clopidogrel hydrogen sulfate synthesis method (by machine translation)
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Paragraph 0006; 0008, (2018/11/22)
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)
SYNTHESIS OF ARYL CYCLOHEXANE CARBOXAMIDE DERIVATIVES USEFUL AS SENSATES IN CONSUMER PRODUCTS
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Paragraph 0060; 0151; 0152, (2017/03/21)
Synthesis methods to produce a series of carboxamides built off of an (S)-2-amino acid backbone or an (R)-2-amino acid backbone, depending upon the desired diastereomer of the end product.
A compound clopidogrel hydrogensulfate method for the preparation of
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Paragraph 0093-0095, (2017/01/26)
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.
An asymmetric synthesis of clopidogrel hydrogen sulfate
Sashikanth, Suthrapu,Raju, Veeramalla,Somaiah, Sripathi,Rao, Peddisrinivasa,Reddy, Karnativenugopal
, p. 621 - 624 (2013/04/23)
An asymmetric synthesis of (S)-(+)-clopidogrel hydrogen sulfate has been developed through application of a Strecker reaction with [(1S)-1-(4- methoxyphenyl)ethyl]amine hydrochloride as a chiral auxiliary. Addition of 2-chlorobenzaldehyde to a solution of sodium cyanide and [(1S)-1-(4- methoxyphenyl)ethyl]amine hydrochloride gave diastereoisomerically pure (2S)-(2-chlorophenyl){[(1S)-1-(4-methoxyphenyl)ethyl]amino}acetonitrile hydro chloride. Cleavage of the chiral auxiliary and concomitant hydrolysis of the nitrile group then gave enantiomerically pure (2S)-2-(2-chlorophenyl)glycine hydrochloride, a key intermediate for (S)-(+)-clopidogrel. Georg Thieme Verlag Stuttgart. New York.
Pasteur's Tweezers revisited: On the mechanism of attrition-enhanced deracemization and resolution of chiral conglomerate solids
Hein, Jason E.,Huynh Cao, Blessing,Viedma, Cristobal,Kellogg, Richard M.,Blackmond, Donna G.
supporting information; scheme or table, p. 12629 - 12636 (2012/09/05)
Insights into the mechanism of attrition-enhanced deracemization and resolution of solid enantiomorphic chiral compounds are obtained by crystal size and solubility measurements and by isotopic labeling experiments. Together these results help to deconvolute the various chemical and physical rate processes contributing to the phenomenon. Crystal size measurements highlight a distinct correlation between the stochastic, transient growth of crystals and the emergence of a single solid enantiomorph under attrition conditions. The rapid mass transfer of molecules between the solution and solid phases under attrition is demonstrated, and the concept of a crystal-size-induced solubility driving force is exploited to overcome the stochastic nature of the crystal growth and dissolution processes. Extension to non-racemizing conditions provides a novel methodology for chiral resolution. Implications both for practical chiral separations and for the origin of biological homochirality are discussed.
