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Method for preparing (S)-4-((2-bromo-6-fluoro-phenyl) hydroxymethyl) piperidine-1-tert-butyl formate

A technology of tert-butyl formate and hydroxymethyl, which is applied in the field of drug synthesis, can solve the problems of unsuitability for large-scale production, high cost, and high toxicity of reagents, and achieve the effects of large-scale production, mild conditions, and simple operation

Active Publication Date: 2018-08-24
SHANGHAI ZAIQI BIO TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The existing synthetic route of imidazoisoindole derivatives is the last step to obtain the final product through chiral preparation and separation, and the final chiral preparation needs to use the method of preparation instead of simple chiral resolution, and The chiral preparation method requires the use of a chiral column and the use of chiral chromatography, the equipment is expensive, the method is not practical, the cost is expensive, and it is not suitable for scale-up production
[0009] In addition, in the synthetic route described above, the synthetic conditions for the intermediate 4-((2-bromo-6-fluorophenyl) hydroxymethyl) piperidine-1-carboxylic acid tert-butyl ester are also relatively harsh, and the reagent toxicity is high For example, lithium diisopropylamide needs to be used in the first process route mentioned above and its preparation temperature needs to be controlled at -78°C, while in the second process route, the preparation temperature needs to be controlled at 110°C, and the produced low rate
[0010] Therefore, expect to be able to develop a kind of compound (S)-4-((2-bromo-6-fluorophenyl) hydroxymethyl) piperidine-1-carboxylic acid tert-butyl ester that more efficient reaction conditions are gentler in this area Preparation method, and solve the problem that the final step of chiral preparation is required in the synthesis of imidazoisoindole derivatives

Method used

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  • Method for preparing (S)-4-((2-bromo-6-fluoro-phenyl) hydroxymethyl) piperidine-1-tert-butyl formate
  • Method for preparing (S)-4-((2-bromo-6-fluoro-phenyl) hydroxymethyl) piperidine-1-tert-butyl formate
  • Method for preparing (S)-4-((2-bromo-6-fluoro-phenyl) hydroxymethyl) piperidine-1-tert-butyl formate

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Experimental program
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Effect test

Embodiment 1

[0047] In this example, (S)-4-((2-bromo-6-fluorophenyl)hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester was prepared by the following preparation method, and the preparation process was as follows:

[0048]

[0049] Concrete preparation method comprises the following steps:

[0050] (1) Preparation of tert-butyl 4-((2-bromo-6-fluorophenyl)(hydroxyl)methyl)piperidine-1-carboxylate

[0051] Prepare a solution of newly prepared Grignard reagent in tetrahydrofuran [from tert-butyl 4-bromopiperidine-1-carboxylate (75.5g, 286mmol), magnesium powder (13.9g, 572mol), a small amount of iodine particles, and tetrahydrofuran (300ml) at 50°C. Obtained] A solution of the aldehyde (58.06 g, 286 mmol) in THF was added slowly over 1 hour at 0°C, and the solution was allowed to warm to room temperature and stirred for 3 hours. Aqueous ammonium chloride solution was used to quench the reaction and extracted with dichloromethane, slurried with n-hexane (500ml) and filtered to obta...

Embodiment 2

[0057] (1) Preparation of tert-butyl 4-((2-bromo-6-fluorophenyl)(hydroxyl)methyl)piperidine-1-carboxylate

[0058] Prepare a fresh ether solution of Grignard reagent [from tert-butyl 4-bromopiperidine-1-carboxylate (75.5g, 286mmol), magnesium powder (13.9g, 572mol), a small amount of iodine particles, and ether (300ml) at 25°C Obtained] To a solution of the aldehyde (48.31 g, 238 mmol) in diethyl ether was slowly added at 0° C. over 1.5 hours, and the solution was allowed to warm to room temperature and stirred for 8 hours. Aqueous ammonium chloride solution was used to quench the reaction and extracted with dichloromethane. The product (80.39 g, yield 87%) was obtained by beating with petroleum ether (500 ml) and filtered. MS = 388.3. 1 H-NMR (400MHz, CDCl3): δ (ppm) 7.36-7.34 (d, J = 7.6Hz, 1H, Ar-H), 7.14-7.08 (dd, J = 13.8Hz, J = 8.6Hz, 1H, ArH ),7.05-7.00(m,1H,Ar-H),4.87(s,1H,CH),4.18-4.04(m,2H,CH 2 ), 2.68-2.55 (m, J=9.4Hz, 2H, CH 2 ),2.46(s,1H,CH),2.15-2.08(m,2H,CH ...

Embodiment 3

[0065] (1) Preparation of tert-butyl 4-((2-bromo-6-fluorophenyl)(hydroxyl)methyl)piperidine-1-carboxylate

[0066] The 2-methyltetrahydrofuran solution of the newly prepared Grignard reagent [from tert-butyl 4-bromopiperidine-1-carboxylate (75.5g, 286mmol), magnesium powder (13.9g, 572mol), a small amount of iodine particles, 2-methyl Prepared by heating tetrahydrofuran (300ml) at 50°C] at 5°C for 0.5 hours was slowly added to a solution of aldehyde (29.03g, 143mmol) in 2-methyltetrahydrofuran, the solution was warmed to room temperature and stirred for 1 hour. Aqueous ammonium chloride solution was used to quench the reaction and extracted with dichloromethane, slurried with n-hexane (500ml) and filtered to obtain the product (49.41g, yield 89.0%). MS = 388.4. 1 H-NMR (400MHz, CDCl3): δ (ppm) 7.38-7.36 (d, J = 7.6Hz, 1H, Ar-H), 7.16-7.10 (dd, J = 13.8Hz, J = 8.6Hz, 1H, ArH ),7.07-7.02(m,1H,Ar-H),4.89(s,1H,CH),4.121-4.06(m,2H,CH 2 ),2.70-2.57(m, J=9.4Hz, 2H, CH 2 ),2.48(s,...

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Abstract

The invention provides a method for preparing (S)-4-((2-bromo-6-fluoro-phenyl) hydroxymethyl) piperidine-1-tert-butyl formate. The method comprises the steps that 2-bromo-6-fluorobenzaldehyde and Grignard reagent are taken as raw materials, Grignard reaction and deprotection reaction are carried out to prepare the 4-((2-bromo-6-fluoro-phenyl) hydroxymethyl) piperidine-1-tert-butyl formate, then through the resolution of chiral resolution reagent, chiral compound (S)-4-((2-bromo-6-fluoro-phenyl) hydroxymethyl) piperidine-1-tert-butyl formate of which optical activity ee value reaches up to 99%is prepared, the intermediate with chirality is subsequently used to prepare imidazo isoindoles ramification conveniently, so that it is avoided that chirality preparation is carried out at the last step of the preparation; in the preparation course, organolithium and other substances with high danger and high toxicity are not used, conditions in the whole preparation processes are mild, the operation is simple, the implementation is easy, and large-scale production is facilitated.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and relates to a preparation method of a chiral compound (S)-4-((2-bromo-6-fluorophenyl)hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester. Background technique [0002] WO2016169421A1 discloses imidazoisoindole derivatives, which can be used as IDO inhibitors for the treatment of diseases with pathological characteristics of ΠX-mediated tryptophan metabolic pathways, including cancer, Alzheimer's disease , autoimmune diseases, depression, anxiety, cataracts, psychological disorders and AIDS. [0003] 4-((2-bromo-6-fluorophenyl)hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester can be used as a key intermediate for the synthesis of such imidazoisoindole derivatives, such as the imidazole Isoindole derivatives are compounds with the following structures: where R 1 selected from hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl; M is inorganic acid or...

Claims

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Application Information

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IPC IPC(8): C07D211/22
CPCC07B2200/07C07D211/22
Inventor 王治国宋艳红马秀娟田贝贝孙鹏李超李涛张欣
Owner SHANGHAI ZAIQI BIO TECH
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