Method of synthesizing (S)-3-(4-bromophenyl)-piperidine or salt thereof with chiral induction

A synthesis method and bromophenyl technology are applied in the field of chiral induced synthesis of -3--piperidine or its salts, and can solve the problems of large three wastes, long synthesis steps, large amount of raw materials and the like

Active Publication Date: 2019-03-12
SHANGHAI VASTPRO TECH DEV CO LTD
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Problems solved by technology

[0010] The intermediate (S)-3-(4-bromophenyl)-piperidine was used for the synthesis of niraparib for the first time, avoiding the use of sodium azide, but this route has long synthesis steps and many technical problems (For example, the amount of raw materials is large, the operation is cumbersome and complicated, and the three wastes generated are large, etc.) to be solved

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  • Method of synthesizing (S)-3-(4-bromophenyl)-piperidine or salt thereof with chiral induction
  • Method of synthesizing (S)-3-(4-bromophenyl)-piperidine or salt thereof with chiral induction
  • Method of synthesizing (S)-3-(4-bromophenyl)-piperidine or salt thereof with chiral induction

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preparation example Construction

[0088] The invention provides a method for preparing (S)-3-(4-bromophenyl)-piperidine or a salt thereof, the method comprising the following steps (1)-(6).

[0089] Step (1): Condensation reaction between compound 1 and (S)-(-)-tert-butylsulfinamide in the presence of a catalyst under solvent-free conditions. After the reaction, concentrate the reaction mixture and collect the concentrate , so as to obtain compound 2 or a product containing compound 2;

[0090]

[0091] In step (1), the function of the concentration is generally to remove the unreacted by-product (methanol) and recover the raw material compound 1 (trimethyl-4-bromophenylacetate). The concentration is preferably concentration under reduced pressure. The pressure of the reduced-pressure concentration is preferably 0.5 mmHg. The concentration temperature is preferably 60 to 100°C, more preferably 70 to 75°C.

[0092] In step (1), the condensation reaction is a solvent-free reaction.

[0093] In step (1), t...

Embodiment 1

[0162]

[0163]In a dry three-necked round bottom flask of 100ml, the reactant ortho-4-bromobenzoic acid trimethyl ester 1 (41.3g, 150mmol, 1.5eq) was dropped, followed by the raw material (S)-(-)-tert-butylsulfinic acid Amide (11.2g, 100mmol, 1.0eq) and catalyst p-toluenesulfonic acid (0.34g, 2mmol, 0.02eq), magnetically stirred. Heat the internal temperature of the system to 90-95 degrees and reflux for 3 hours. After the reaction is complete, distill the fraction below 75 degrees under reduced pressure (0.5mm Hg) for subsequent batches. Cool the remaining system to room temperature to obtain 49.3g of Crude Compound 2. The yield was 99.0%, and it was directly carried out to the next reaction without further purification. 1 H NMR (400MHz, CDCl 3 ): δ1.21(9H,s),3.74(3H,s),3.98(2H,dd),7.21-7.23(2H,m),7.42-7.44(2H,m).

Embodiment 2

[0165]

[0166] The crude compound 2 (33.2 g, 100 mmol, 1.0 eq) obtained in Example 1 and 250 ml of anhydrous tetrahydrofuran as a reaction solvent were put into a 1000 ml dry three-neck round bottom flask. After 3 nitrogen replacements, cool to -70~-65 degrees, add 1 mol / L LiHMDS solution (200ml, 200mmol, 2eq) dropwise at this temperature, drop it within 1 hour, and continue to stir and react at this temperature for 1 hour. 1-Chloro-3-iodopropane (26.6g, 130mmol, 1.3eq) was added dropwise at this temperature, and after the dropwise addition was completed for 1 hour, it was stirred at -70~-65°C for 2 hours. Then the internal temperature of the system was heated to -20°C, and 250 ml of saturated ammonium chloride aqueous solution was added dropwise, and the dropping temperature was controlled at -20 to -15°C. After the dropwise addition, stir for 15 minutes, add 100 ml of ethyl acetate for extraction three times, combine the organic phases, and wash the organic phases once w...

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Abstract

The invention relates to a method of synthesizing (S)-3-(4-bromophenyl)-piperidine or salt thereof with chiral induction. Particularly, the method comprises the following steps of by taking methyl ortho-4-bromophenylacetate and (S)-(-)-2-methyl-2-propanesulfinamide as starting materials, sequentially performing reactions including condensation, replacement, reduction, ring closure, removal of chiral induced groups and the like, and the (S)-3-(4-bromophenyl)-piperidine or the salt thereof can be obtained, wherein after the reduction reaction, a high-purity single diastereoisomer can be obtainedwith recrystallization; and after the ring closure reaction, a high-purity single diastereoisomer can be further obtained with recrystallization. The method provided by the invention has the advantages of cheap and available raw material, simple operation, high yield, and low cost and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of synthesis of pharmaceutical intermediates. Specifically, the invention relates to a method for synthesizing (S)-3-(4-bromophenyl)-piperidine or a salt thereof by chiral induction. Background technique [0002] With the change of human living environment, living standard and lifestyle and the advancement of medicine, the spectrum of diseases has undergone significant changes. General infectious diseases are gradually being controlled, and cancer has become one of the important diseases that are increasingly common and seriously threaten human life and quality of life. At present, in China and even in the world, cancer has become the second leading cause of human death. In recent years, molecular oncology and molecular pharmacology have continuously clarified the nature of tumors. Malignant tumors are diseases in which the body's own cells become uncontrolled proliferation and spread, and are a type of disease in wh...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/18
CPCC07D211/18
Inventor 赖亮冯亚兵郭朋朱文峰
Owner SHANGHAI VASTPRO TECH DEV CO LTD
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