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Method for synthesizing S-3-(piperidine-2-yl)-azacyclo-azetidine-3-alcohol

A technique for the synthesis of azetidine and its synthesis method, which is applied in the field of synthesis of S-3--azetidine-3-ol, and can solve problems such as difficulty in realizing industrialized mass production, non-compliance with environmental protection requirements, and complex process schemes, etc. problem, to achieve the effect of good methodological significance, easy operation, and short process route

Active Publication Date: 2016-12-14
CHENGDU BAISHIXING SCI & TECH IND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0019] The above process schemes all have disadvantages such as complex process scheme, high cost, cumbersome operation, difficulty in realizing industrial mass production, and failure to meet environmental protection requirements.

Method used

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  • Method for synthesizing S-3-(piperidine-2-yl)-azacyclo-azetidine-3-alcohol
  • Method for synthesizing S-3-(piperidine-2-yl)-azacyclo-azetidine-3-alcohol
  • Method for synthesizing S-3-(piperidine-2-yl)-azacyclo-azetidine-3-alcohol

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Effect test

Embodiment 1

[0050] Embodiment 1: A kind of specific synthetic method of S-3-(piperidin-2-yl)-azetidin-3-alcohol

[0051] S1. Formula A compound S-N-Boc-piperidine-2-carboxylic acid is condensed with CDI to obtain a formula B compound; the molar mass ratio of the formula A compound S-N-Boc-piperidine-2-carboxylic acid to CDI is 1:1; reaction The solvent used in the system is tetrahydrofuran; the reaction temperature is 0°C;

[0052] S2. The compound of formula B and nitromethane are condensed under alkaline conditions to obtain the compound of formula C; the molar mass ratio of the compound of formula B, nitromethane and alkali is 1:1:1; the alkali is alkoxy Sodium salt; the solvent used in the reaction system is tetrahydrofuran; the temperature of the reaction is 0°C, and the reaction time is 1h;

[0053] S3. The compound of formula C reacts with the halomethyl Grignard reagent to obtain the compound of formula D; the molar mass ratio of the compound of formula C to the halomethyl Grigna...

Embodiment 2

[0057] Embodiment 2: A kind of specific synthetic method of S-3-(piperidin-2-yl)-azetidin-3-alcohol

[0058] S1. Formula A compound S-N-Boc-piperidine-2-carboxylic acid is condensed with CDI to obtain a formula B compound; the molar mass ratio of the formula A compound S-N-Boc-piperidine-2-carboxylic acid to CDI is 1:2; reaction The solvent used in the system is DMF; the reaction temperature is 60°C;

[0059] S2. The compound of formula B and nitromethane are condensed under alkaline conditions to obtain the compound of formula C; the molar mass ratio of the compound of formula B, nitromethane and base is 1:2:2; the base is alkoxy Potassium salt; the solvent used in the reaction system is dioxane; the temperature of the reaction is 60°C, and the reaction time is 48h;

[0060] S3. The compound of formula C reacts with the halomethyl Grignard reagent to obtain the compound of formula D; the molar mass ratio of the compound of formula C and the halomethyl Grignard reagent is 1:2...

Embodiment 3

[0064] Embodiment 3: A kind of specific synthetic method of S-3-(piperidin-2-yl)-azetidin-3-alcohol

[0065] S1. Formula A compound S-N-Boc-piperidine-2-carboxylic acid is condensed with CDI to obtain a formula B compound; the molar mass ratio of the formula A compound S-N-Boc-piperidine-2-carboxylic acid to CDI is 1:1.2; reaction The solvent used in the system is DMAc; the reaction temperature is 8°C;

[0066] S2. The compound of formula B and nitromethane are condensed under alkaline conditions to obtain the compound of formula C; the molar mass ratio of the compound of formula B, nitromethane and alkali is 1:1.1:1.2; the alkali is an alkali metal hydride ; The solvent used in the reaction system is DMF; the temperature of the reaction is 10°C, and the reaction time is 5h;

[0067] S3. The compound of formula C reacts with the halomethyl Grignard reagent to obtain the compound of formula D; the molar mass ratio of the compound of formula C to the halomethyl Grignard reagent...

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Abstract

The invention discloses a method for synthesizing S-3-(piperidine-2-yl)-azacyclo-azetidine-3-alcohol. The method comprises the following steps: condensing a compound S-N-Boc-piperidine-2-formic acid of a formula A and CDI so as to obtain a compound of a formula B; condensing the compound of the formula B and nitromethane under an alkali condition so as to obtain a compound C; enabling the compound C and a halogen methyl Grignard reagent to react so as to obtain a compound D; performing nitro reduction and cyclization on the compound D so as to obtain a compound I; condensing a compound of a formula I and a compound of a formula II in the alkali environment so as to obtain a compound of a formula III; performing deprotection on the compound of the formula III under an acid condition, thereby obtaining the S-3-(piperidine-2-yl)-azacyclo-azetidine-3-alcohol. The method disclosed by the invention is cheap and easily obtainable in raw material, simple and convenient in process operation, small in waste pollution, green and economic and easy in industrialization; by adopting the method disclosed by the invention, use of a conventional chiral resolution method is avoided, and a feasible technical scheme is provided for large-scale production of Cobimetinib.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a synthesis method of S-3-(piperidin-2-yl)-azetidin-3-ol. Background technique [0002] Cobimetinib (Filmtabletten) / It is a small molecule MEK inhibitor approved by Swissmedic on August 27, 2015, and approved by the US FDA on November 10, 2015. The key intermediate for the synthesis of Cobimetinib is the compound of formula A. The structural formula is as follows: [0003] [0004] The drug was discovered by Exelixis. In 2006, Genentech (Roche) and Exelixis reached a global agreement to obtain authorization to develop the drug for the treatment of multiple solid tumors. Exelixis receives a 50% profit share in the U.S. market and royalties on sales in stores outside the U.S. Approved with Vemurafini In combination for the treatment of unresectable or metastatic melanoma with BRAF V600E mutation. [0005] Cobimetinib is a selective MEK (also known...

Claims

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Application Information

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IPC IPC(8): C07D401/04A61P35/00C07B53/00
CPCC07B53/00C07B2200/07C07D401/04
Inventor 石常青
Owner CHENGDU BAISHIXING SCI & TECH IND
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