Preparation method of pusaimode (Chinese name)

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: 2020-05-01
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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  • Preparation method of pusaimode (Chinese name)
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  • Preparation method of pusaimode (Chinese name)

Examples

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preparation example Construction

[0016] The technical solution for realizing the purpose of the present invention is to provide a new preparation method of Prosamod, and the synthesis 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 tocoyl group In the second step, compound 2 is esterified with butyrate to generate compound 3, and in the third step, compound 3 is cyclized with butanamide to generate compound 4. In the fourth step reaction, compound 4 is coupled with bis-pinacol borate 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 aluminum oxide in batches under ice bath, and the reaction is completed in about 0.5-3 hours. The reaction solution was poured into a 1mol / L hydrochloric acid mixed solution of ice and water. Extraction, drying ...

preparation example 1

[0043] 2-Propyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazole (compound 5) Synthesis

[0044]

[0045] a. Synthesis of 1-(4-bromophenyl)-2-chloro-1-one (compound 2): 20.0g of bromobenzene was dissolved in dichloromethane (200mL) solution, placed in a three-necked flask for external cooling With stirring, 10.6 mL of chloroacetyl chloride was dissolved in dichloromethane (50 mL), and slowly dropped into the three-necked flask. Keeping the temperature low, 20.4g of anhydrous aluminum chloride was added into the reaction flask in three batches (7.0g was added for the first time, 7.0g was added for the second time, and 6.4g was added 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 turned light yellow-green. Use dichloromethane to extract and separate (200mL×3), wash with saturated brine (200mL×...

preparation example 2

[0050]

[0051] Synthesis of 2-acetylamino-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-bromophenylethanol was dissolved in anhydrous dichloromethane (50 mL), and quickly added dropwise into the reaction flask. The ice bath was removed, and the reaction was carried out at room temperature for about 6 hours. Evaporate dichloromethane, add water-methanol mixed solution (400mL, water:methanol volume ratio is 1:3), transfer to a separatory funnel, add n-heptane for extraction (200mL×3), shake vigorously until the whole system is free The color is transparent, and the organic layers are combined. Dry over anhydrous sodium sulfate, distill off the organic solvent to obtain a colorless transparent solid, which is co...

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Abstract

The invention discloses a preparation method of pusaimode. Bromo-benzene and benzene are used as initial raw materials to prepare pusaimode by adopting a convergent synthesis route. The yield of the preparation method is high, the cost is low, the amount of generated waste water, waste gas, and waste solids is low, the operation is convenient, and the application value is high.

Description

technical field [0001] The invention relates to a new method for preparing Prosamod, which belongs to the technical field of medicine. Background technique [0002] Prosamod is a novel S1P1 receptor immunosuppressant developed by the Institute of Medicine, Chinese Academy of Medical Sciences. As shown in formula 1, it is a new type of drug for the treatment of rheumatoid arthritis and is currently in phase I clinical trials. According to the experimental data obtained earlier, the compound has good pharmacological activity and may be applied in clinical treatment. [0003] [0004] The traditional preparation of Prosamod and its hydrochloride is shown in formula 1, using the method of linear synthesis, with biphenyl as the starting material, through Friedel-Crafts acylation, coupling, reduction, Friedel-Crafts acylation, Esterification, cyclization, reduction, hydrolysis, hydrochloride, finally get the product, Prosimod and its hydrochloride. The route obtained the fina...

Claims

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Application Information

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Patent Type & Authority Applications(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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