The preparation method of Prosymod

A synthesis method and intermediate technology, applied in the field of medicine, can solve the problems of low yield, long synthesis route, large environmental pollution and the like

Active Publication Date: 2022-06-21
渐宽(苏州)生物科技有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The synthesis route of Prosamod and its hydrochloride disclosed in the above literature adopts a "linear" synthesis method, the synthesis route is long and the yield is low, and in the synthesis process, column chromatography is required, which increases the cost
And use a lot of solvents and Lewis acids, causing great environmental pollution

Method used

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  • The preparation method of Prosymod
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preparation example Construction

[0016] The technical scheme that realizes the object of the present invention is to provide the new preparation method of Procymod, and the synthetic steps are as follows: the preparation route of the key intermediate 5 is shown in formula 3, starting from bromobenzene, the first step is to pass the bromobenzene through the pyridoxyl group. In the second step, compound 2 is esterified with butyrate to form compound 3, and in the third step, compound 3 is cyclized with butyramide to form compound 4. In the fourth step of reaction, compound 4 is coupled with double pinacol boronate under the catalysis of palladium catalyst to generate compound 5.

[0017]

[0018] a. Dissolve bromobenzene (compound 1) and chloroacetyl chloride in anhydrous dichloromethane, add anhydrous alumina in batches under an ice bath, and finish the reaction in about 0.5-3 hours. The reaction solution was poured into a 1 mol / L hydrochloric acid ice-water mixture. Extraction, drying, and solvent removal...

preparation example 1

[0043] 2-propyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)phenyl)oxazole (Compound 5) Synthesis

[0044]

[0045] a. Synthesis of 1-(4-bromophenyl)-2-chloro-1-one (compound 2): Dissolve 20.0 g of bromobenzene in a solution of dichloromethane (200 mL) and place it in a three-necked flask to cool at external temperature Under stirring, 10.6 mL of chloroacetyl chloride was dissolved in dichloromethane (50 mL) and slowly dropped into a three-necked flask. Keeping the low temperature, 20.4 g of anhydrous aluminum chloride was added to the reaction flask in three batches (7.0 g for the first time, 7.0 g for the second time, and 6.4 g for the third time). After 1 hour, the reaction was basically completed, and the reaction solution was poured into 250 mL of dilute hydrochloric acid-ice-water mixture and stirred for half an hour until the reaction became light yellow-green. Dichloromethane was used for extraction and separation (200 mL × 3), washed with saturated brine (2...

preparation example 2

[0050]

[0051] Synthesis of 2-acetamido-2-(4-bromophenethyl) diethyl malonate (key intermediate 6):

[0052] a. Synthesis of 1-bromo-4-(2-iodoethyl)benzene (compound 11): 31.6 g of iodine, 33.9 g of triphenylphosphine and 22.4 mg of imidazole were dissolved in anhydrous dichloromethane (100 mL), After cooling in an ice bath for 30 minutes, 20.0 g of p-bromophenethyl alcohol was dissolved in anhydrous dichloromethane (50 mL), and quickly added dropwise to the reaction flask. The ice bath was removed, and the reaction was carried out at room temperature for about 6 hours. Dichloromethane was evaporated, water-methanol mixed solution (400mL, the volume ratio of water:methanol was 1:3) was added to a separatory funnel, n-heptane was added for extraction (200mL×3), and the whole system was shaken vigorously The color is transparent, and the organic layers are combined. It was dried over anhydrous sodium sulfate, and the organic solvent was evaporated to obtain a colorless and...

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Abstract

The invention discloses a preparation method of prosamod, which uses bromobenzene and benzene as starting materials to prepare prosamod by adopting a convergent synthesis route. The method has high yield, low cost, less pollution of three wastes, and is easy to operate. It has high application value.

Description

technical field [0001] The invention relates to a new method for preparing procymod, belonging to the technical field of medicine. Background technique [0002] Procymod is a new type of S1P1 receptor immunosuppressant developed by the Institute of Materia Medica, Chinese Academy of Medical Sciences. As shown in formula 1, it is a new drug for the treatment of rheumatoid arthritis and is currently in the phase I clinical trial stage. From the experimental data obtained in the early stage, the compound has good pharmacological activity and may be used in clinical treatment. [0003] [0004] The traditional preparation of Procymod and its hydrochloride is shown in formula 1, using the method of linear synthesis, using biphenyl as the starting material, and undergoing Fructus acylation, coupling, reduction, Fructus acylation, Esterification, cyclization, reduction, hydrolysis, hydrochloride, and finally the product, procymod and its hydrochloride. This route obtained the ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D263/32C07F5/04
CPCC07D263/32C07F5/04
Inventor 石泽玉陈思肖琼张翔田育林尹大力
Owner 渐宽(苏州)生物科技有限公司
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