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Method for synthesis of 1-(N-Boc-4-piperidine)-4-pyrazoleboronic acid pinaol ester

A technology of n-boc-4-, pyrazole boronic acid, applied in the field of pharmaceutical intermediate synthesis, can solve the problems of limitation, reaction requiring ultra-low temperature conditions, difficult post-processing, etc., and achieves mild conditions, cheap and easy-to-obtain raw materials, and reproducibility. Good results

Active Publication Date: 2015-12-16
SHANGHAI TBBMED CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The above-mentioned synthetic method has the following defects in practical application: 1) the synthesis of raw materials needs to use the highly toxic methanesulfonyl chloride; 2) during the substitution reaction, N-Boc-4-piperidine mesylate is A large number of by-products are generated, which increases the difficulty of post-processing; 3) the halogen atom at the 4-position of pyrazole is restricted, or the reaction requires ultra-low temperature conditions

Method used

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  • Method for synthesis of 1-(N-Boc-4-piperidine)-4-pyrazoleboronic acid pinaol ester
  • Method for synthesis of 1-(N-Boc-4-piperidine)-4-pyrazoleboronic acid pinaol ester

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Embodiment 1

[0016] Synthesis of N-Boc-4-piperidine hydrazine:

[0017] In a 500 ml reaction bottle equipped with magnetic stirring, after adding 10 g of N-Boc-4-piperidone and 60 ml of methanol, it was dissolved under stirring, and then 32 g of 80% hydrazine hydrate was slowly added dropwise. After the addition was complete, stir at room temperature for about 30 minutes to detect the completion of the reaction. Evaporate the reaction solution to dryness to remove excess hydrazine hydrate and solvent, add 80 milliliters of methanol, stir to dissolve completely, add 2.5 grams of sodium borohydride, stir at room temperature for 2 hours, the reaction is over, add 5-8 milliliters of acetic acid to quench the reaction, distill the solvent Finally, dichloromethane was added for extraction, washed with water, and the organic layer was spin-dried to obtain 9.1 g of N-Boc-4-piperidinylhydrazine crude product with a yield of 85%, which was directly used in the next reaction;

[0018] Synthesis of 1...

Embodiment 2

[0021] Synthesis of N-Boc-4-piperidine hydrazine:

[0022] In a 500 ml reaction bottle equipped with magnetic stirring, after adding 10 g of N-Boc-4-piperidone and 80 ml of ethanol, the solution was dissolved under stirring, and then 37.5 g of 80% hydrazine hydrate was slowly added dropwise. After the addition was complete, stir at room temperature for about 30 minutes to detect the completion of the reaction. Evaporate the reaction solution to dryness to remove excess hydrazine hydrate and solvent, add 80 milliliters of methanol, stir to dissolve completely, add 3.0 grams of sodium borohydride, stir at room temperature for 2 hours, the reaction is over, add 5-8 milliliters of acetic acid to quench the reaction, distill the solvent Finally, dichloromethane was added for extraction, washed with water, and the organic layer was spin-dried to obtain 9.5 g of N-Boc-4-piperidinylhydrazine crude product with a yield of 88%, which was directly used in the next reaction;

[0023] Syn...

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Abstract

The invention discloses a method for synthesis of 1-(N-Boc-4-piperidine)-4-pyrazoleboronic acid pinaol ester. According to the method, N-Boc-4-piperidone serves as the raw material and reacts with hydrazine hydrate, N-Boc-4-piperidine hydrazine is generated through reduction, then dehydration condensation reaction is conducted between N-Boc-4-piperidine hydrazine and 2-halogenate malonaldehyde so that a 1-(N-Boc-4-piperidine)-4-chlorine / bromine pyrazol midbody can be obtained effectively, and in the presence of metallic nickel, metallic nickel catalytic coupling reaction ester forming is conducted on the midbody under a mild condition to obtain the 1-(N-Boc-4-piperidine)-4-pyrazoleboronic acid pinaol ester. The whole process is easy to operate, conditions are mild, and untralow-temperature reaction is not needed; meanwhile, required raw materials are cheap and easy to obtain, reproducibility is high, and the method is suitable for industrialized large-scale production.

Description

technical field [0001] The invention relates to a method for synthesizing 1-(N-Boc-4-piperidine)-4-pyrazoleboronic acid pinacol ester, which belongs to the field of synthesis of pharmaceutical intermediates. Background technique [0002] In recent years, the incidence of cancer, especially lung cancer, has been increasing, which is threatening human health. In 2012, Pfizer of the United States timely launched a new drug for the treatment of lung cancer, crizotinib, which became a major breakthrough drug in this field. [0003] As the important structural unit of medicine crizotinib: the synthetic method of 1-(N-Boc-4-piperidine)-4-pyrazole boronic acid pinacol ester, the synthetic method of published document patent data is as follows: adopt 4-bromo / iodopyrazole is deprotonated with sodium hydride, and then reacted with N-Boc-4-piperidine mesylate to generate 1-(N-Boc-4-piperidine)-4-iodopyrazole intermediate , followed by isopropyl Grignard reagent exchange / borylation or ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F5/02
Inventor 高峰曾赛兰
Owner SHANGHAI TBBMED CO LTD
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