Synthetic method of loratinib intermediate

A synthetic method, the technology of lorlatinib, applied in the field of medicine, can solve the problems of unfavorable industrial production, unavailable raw materials, high cost, etc., and achieve the effect of short steps, low cost and simple operation

Active Publication Date: 2021-08-24
安徽联创生物医药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] The raw materials of this synthetic method are not easy to get, the yield is low, th

Method used

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  • Synthetic method of loratinib intermediate
  • Synthetic method of loratinib intermediate
  • Synthetic method of loratinib intermediate

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Embodiment 1

[0049] A synthetic method of lorlatinib intermediate, comprising the following steps:

[0050] (1) Preparation of ethyl 1,3-dimethyl-1H-pyrazole-5-carboxylate (Ⅱ)

[0051]

[0052] Add 50ml of absolute ethanol to a 250ml three-neck flask, add 12.2g (84.5mmol) of methylhydrazine sulfate, cool down to 0-5°C, and dropwise add a mixed solution of 16.7g (245.9mmol) of sodium ethoxide and 50ml of absolute ethanol After dropping, keep the temperature at 0-5°C, add 10.0 g (76.8 mmol) of acetone ethyl oxalate dropwise, and react at 0-5°C for 4 hours after dropping. Post-reaction treatment, add 100ml of water, evaporate ethanol under reduced pressure, add dichloromethane for extraction, dry and concentrate to obtain 13g of light yellow liquid, distill under reduced pressure to obtain 11.5g of colorless liquid, yield 89.0%, the purity of the product by HPLC 99.0%.

[0053] (2) Preparation of ethyl 4-bromo-1,3-dimethyl-1H-pyrazole-5-carboxylate (Ⅲ)

[0054]

[0055] Add 100ml of ...

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Abstract

The invention provides a synthetic method of a loratinib intermediate, the synthetic method comprises the following steps: taking acetone ethyl oxalate which is simple and easy to obtain as an initial raw material, and sequentially carrying out seven steps of reactions of cyclization, bromination, amide formation, bromination, methylamination, upper protection and dehydration to obtain (4-bromo-5-cyano-1-methyl-1H-pyrazol-3-yl) methyl methyl tert-butyl carbamate. The synthetic method of the loratinib intermediate has the characteristics of easily available raw materials, simplicity in operation, low cost, short steps and high yield.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a method for synthesizing a lorlatinib intermediate. Background technique [0002] Lorlatinib is a novel, reversible, potent small molecule ALK and ROS1 inhibitor developed by Pfizer. 3rd generation ALK inhibitors. The drug entered clinical trials in 2014 for the treatment of lung cancer. [0003] Patent EP3415518A1 discloses the following two synthetic routes of lorlatinib intermediate (4-bromo-5-cyano-1-methyl-1H-pyrazol-3-yl)methylmethylcarbamate tert-butyl ester: [0004] Route 1: [0005] [0006] Route two: [0007] [0008] These two methods all have the characteristics that the raw materials are not easy to get, the synthesis yield is low, the operation is inconvenient, and it is unfavorable to realize the characteristics of industrialized production. [0009] Patent CN104169286A discloses macrocyclic derivatives for the treatment of proliferative diseases, an...

Claims

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Application Information

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IPC IPC(8): C07D231/16
CPCC07D231/16Y02P20/55
Inventor 吴其华葛德培李强韩明超
Owner 安徽联创生物医药股份有限公司
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