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Preparation method for R-benzhydryl thionyl acetic acid

A technology of diphenylmethyl thioacetic acid and benzyl thioacetic acid, which is applied in the field of preparation of R-diphenylmethyl thioacetic acid, can solve the problems of long time, high impurity content, and insufficient starting materials. Stability and other issues, to achieve the effect of prolonging the service life of the equipment, simple preparation process and good product quality

Active Publication Date: 2013-04-24
CHONGQING KANGLE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, the preparation methods of R-diphenylmethylsulfinyl acetic acid are (1) EP528172. In this patent, a large amount of organic solvents are used, especially the carcinogen trichloromethane, and to obtain high-purity products, it is necessary to pass through the column Chromatographic purification has low yield and long time, so it is not conducive to industrial production; (2) US6998490, in this patent, ε phthalimido percaproic acid is used as an oxidant to oxidize diphenylmethylthioacetic acid, due to The starting material is extremely unstable, and the impurity content is high, which is not conducive to quality control. It is difficult to obtain high-purity R-diphenylmethylsulfinyl acetic acid, so it is not conducive to industrialization of production; (3) CN1867544, in this patent, using manual It is a non-toxic metal complexing agent, which oxidizes benzhydryl thioacetic acid into benzhydryl thioacetic acid under alkaline conditions, and then uses α-phenylethylamine resolving agent to resolve the product. Two kinds of products are used in the process Chiral agent, and chiral metal complexing agent is more expensive, not suitable for actual industrialization requirements

Method used

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  • Preparation method for R-benzhydryl thionyl acetic acid
  • Preparation method for R-benzhydryl thionyl acetic acid
  • Preparation method for R-benzhydryl thionyl acetic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] The preparation of R-diphenylmethyl thionyl acetic acid includes the following steps:

[0032] a. Preparation of benzhydryl thionyl acetic acid

[0033] In a 500 mL three-necked round bottom flask, add 100 g of benzhydryl thioacetic acid and 400 ml of glacial acetic acid. Under stirring conditions, the temperature is lowered to 15°C, and 50 g of 27% hydrogen peroxide is slowly dropped. Keep the temperature at 25℃~30℃, stir the reaction for 1.5 hours and monitor the progress of the reaction by thin layer chromatography (TLC). After the reaction is complete, cool the reaction solution to a temperature of 10℃, filter, and wash the filter cake with water at a temperature of 40℃ After vacuum drying, 76.8 g of benzhydryl thionyl acetic acid was obtained, the purity was 99.91%, and the yield was 72.32%;

[0034] b. Preparation of R-Diphenylmethyl Thionyl Acetate·L-Arginine Salt

[0035] In a 500 mL three-neck round bottom flask, add 40 g of benzhydryl thionyl acetic acid obtained in ...

Embodiment 2

[0042] The preparation of R-diphenylmethyl thionyl acetic acid includes the following steps:

[0043] a. Preparation of benzhydryl thionyl acetic acid

[0044] In a 500 mL three-neck round bottom flask, add 100 g of benzhydryl thioacetic acid and 400 ml of glacial acetic acid. Under stirring conditions, the temperature is lowered to 15℃, and 65 g of 27% hydrogen peroxide is slowly added dropwise. After the addition is complete, the reaction solution is heated Keep the temperature at 25℃~30℃, stir the reaction for 1.5 hours and monitor the progress of the reaction by TLC method. After the reaction is complete, cool the reaction solution to a temperature of 10℃, filter, wash the filter cake with water, and dry under vacuum at 40℃ to obtain two 77.5 g of benzyl thionyl acetic acid, purity 99.95%, yield 72.98%;

[0045] b. Preparation of R-Diphenylmethyl Thionyl Acetate·L-Arginine Salt

[0046] In a 500 mL three-neck round bottom flask, add 40 g of benzhydryl thionyl acetic acid obtained...

Embodiment 3

[0053] The preparation of R-diphenylmethyl thionyl acetic acid includes the following steps:

[0054] a. Preparation of benzhydryl thionyl acetic acid

[0055] In a 500 mL three-necked round bottom flask, add 100 g of benzhydryl thioacetic acid and 400 ml of glacial acetic acid. Under stirring conditions, the temperature is lowered to 15℃, and 85 g of 27% hydrogen peroxide is slowly added dropwise. After the addition is complete, the reaction solution is heated Keep the temperature at 25℃~30℃, stir the reaction for 1.5 hours and monitor the progress of the reaction by TLC method. After the reaction is complete, cool the reaction solution to a temperature of 10℃, filter, wash the filter cake with water, and dry under vacuum at 40℃ to obtain two 80.4 g of benzyl thionyl acetic acid, purity 99.95%, yield 75.71%;

[0056] b. Preparation of R-Diphenylmethyl Thionyl Acetate·L-Arginine Salt

[0057] In a 500 mL three-necked round bottom flask, add 40 g of benzhydryl thionyl acetic acid obta...

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Abstract

The invention belongs to the field of synthesis, in particular to a preparation method for R-benzhydryl thionyl acetic acid. The preparation method comprises the following steps of a, performing an oxidation reaction on benzhydryl thioacetic acid served as a starting raw material and hydrogen peroxide to obtain the benzhydryl thionyl acetic acid; b, performing a reaction on the benzhydryl thionyl acetic acid obtained in step a and L-arginine to obtain a R-benzhydryl thionyl acetic acid L-arginine crude product; and c, adding methanol or ethanol into the R-benzhydryl thionyl acetic acid L-arginine obtained in step b, and recrystallizing to obtain a R-benzhydryl thionyl acetic acid L-arginine refined product; and d, performing a hydrolysis reaction on the R-benzhydryl thionyl acetic acid L-arginine refined product obtained in step c and hydrochloric acid to obtain the benzhydryl thionyl acetic acid. The preparation method has the advantages that a preparation process is simple; the quality of products is high; a corrosive reagent is avoided; the service life of equipment can be prolonged; the pollution to environment is less; and the preparation method is more suitable for industrial production.

Description

Technical field [0001] The invention belongs to the field of synthesis, and particularly relates to a method for preparing R-benzyl thionyl acetic acid. Background technique [0002] Modafinil is a new central stimulant drug. Compared with traditional central stimulant drugs such as caffeine, amphetamine, and methylphenidate, it has the advantages of fast onset, less side effects, and no dependence. It is expected to replace Methylphenidate has become the drug of choice for the treatment of narcolepsy. In addition, it is also widely used as an anti-fatigue drug and a sleep regulator, and has a good application prospect. As an important intermediate for the synthesis of modafinil, benzhydryl thioacetamide also has broad market prospects. [0003] In mid-June 2007, the US FDA approved Cephalon's non-amphetamine arousal promoter armodafinil tablets (trade name: Nuvigil) to be marketed for the treatment of obstructive sleep apnea / hypopnea syndrome Drowsiness caused by symptoms (OSAHS...

Claims

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Application Information

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IPC IPC(8): C07C317/44C07C315/06C07C315/02
Inventor 杨继斌陈大海邓远艳
Owner CHONGQING KANGLE PHARMA