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Preparation method of BTK kinase inhibitor key intermediate

A technology of intermediates and reagents, applied in the field of medicine, can solve problems such as poor amplification feasibility, difficult purification, and low total yield, and achieve the effects of reducing pollution, simple reaction operation, and improving yield

Active Publication Date: 2022-07-15
SHANGHAI ZAIQI BIO TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Example 1 of WO2016007185A1 discloses the key intermediate (R)-1-(1-(tert-butoxyacyl)pyrrolidin-3-yl)-3-cyano-4-(4-(2,6 - the preparation method of ethyl difluorophenoxy) phenyl) -1H-pyrrole-2-carboxylate, this method is only 22.8% in the preparation target compound 93C yield, and the whole method needs eight-step reactions, and there are multiple reaction steps The yield is low and purification is difficult, which makes the total yield of this route low and the scale-up feasibility is poor, and palladium catalyst is used in the method, and the cost is high

Method used

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  • Preparation method of BTK kinase inhibitor key intermediate
  • Preparation method of BTK kinase inhibitor key intermediate
  • Preparation method of BTK kinase inhibitor key intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] first step:

[0044] Under nitrogen protection, N,N-dimethylformamide 10kg, 2,6-difluorophenol (0.85kg, 6.53mol) and p-fluoroacetophenone (1kg, 7.24mol) were added successively in the reactor, stirring Wait for the system to dissolve. Next, sodium carbonate (1.53 kg, 14.48 mol) was added, and the temperature of the oil bath was raised to 150-155° C. and stirring was continued for 16 hours. After the detection reaction was completed, the material was cooled to 60° C., poured into 10 L of ice water, filtered and washed to obtain 1.46 kg of Intermediate B with a yield of 90.2%. Step 2:

[0045] Under nitrogen protection, in the reactor, intermediate B (1.46kg, 5.88mol) and glacial acetic acid 0.50kg were added in dioxane 15L, and the reaction was stirred after adding dibromohydantoin (0.86kg, 3.00mol) in 3 batches Overnight, the reaction was poured into 15 L of water with stirring at room temperature, filtered, and recrystallized to obtain 1.61 kg of Intermediate C, wit...

Embodiment 2

[0054] The first three steps are the same as those in Example 1.

[0055] the fourth step:

[0056] A 2.5M n-butyllithium / n-hexane solution (20L, 50mol) was cooled to -60 to -78°C, and acetonitrile (2.05kg, 50mol) was slowly added dropwise. After the mixture was stirred at -60 to -78°C for 1 hour, ethyl oxalate (7.30 kg, 50 mol) / n-hexane (21 L) solution was slowly added dropwise. After the mixture was stirred at -60 to -78°C for 1 hour, the dry ice bath was removed and slowly returned to ambient temperature. The mixture was poured into 70 L of ice water, and extracted three times with methyl tert-butyl ether. The aqueous phase was cooled to 0°C and adjusted to pH=3-4 with 6M hydrochloric acid. It was extracted three times with ethyl acetate, and the organic phases were combined, dried and concentrated to obtain Intermediate F (5.74 kg, yield: 81.30%).

[0057] the fifth step:

[0058] Under nitrogen protection, in the reactor, add intermediate D (18.02kg, 41.66mol), inter...

Embodiment 3

[0060] The first three steps are the same as those in Example 1.

[0061] the fourth step:

[0062] 1M KHMDS / tetrahydrofuran solution (154L, 154mol) was cooled to -60~-78°C, and acetonitrile (6.31kg, 154mol) was slowly added dropwise. The mixture was stirred at -60 to -78°C for 1 hour, followed by the slow dropwise addition of a solution of ethyl oxalate (17.54 kg, 140 mol) / 2-methyltetrahydrofuran (50 L). After the mixture was stirred at -60 to -78°C for 1 hour, the dry ice bath was removed and slowly returned to ambient temperature. The mixture was poured into 180 L of ice water and extracted three times with methyl tert-butyl ether. The aqueous phase was cooled to 0°C and adjusted to pH=3-4 with 6M hydrochloric acid. It was extracted three times with ethyl acetate, and the organic phases were combined, dried and concentrated to obtain Intermediate F (16.36 kg, yield: 82.79%).

[0063] the fifth step:

[0064] Under nitrogen protection, in the reactor, add intermediate D...

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Abstract

The invention relates to a preparation method of a BTK kinase inhibitor key intermediate, and belongs to the technical field of medical intermediates. The preparation method comprises the following steps: starting from p-fluoroacetophenone, carrying out substitution reaction on p-fluoroacetophenone and 2, 6-difluorophenol to obtain an intermediate B; brominating the intermediate B to obtain an intermediate C; carrying out substitution reaction on the intermediate C and (R)-1-Boc-3-aminopyrrolidine to obtain an intermediate D; the intermediate D and 3-cyano-2-oxo ethyl propionate F are subjected to a ring closing reaction, and a target compound I is obtained. Compared with the prior art, the method provided by the invention shortens the steps, improves the yield, avoids the use of a heavy metal catalyst, is beneficial to industrial expanded production, and reduces the pollution to the environment.

Description

technical field [0001] The invention relates to a preparation method of a key intermediate of a BTK kinase inhibitor, in particular to (R)-1-(1-(tert-butoxyacyl)pyrrolidin-3-yl)-3-cyano-4-( A preparation method of 4-(2,6-difluorophenoxy)phenyl)-1H-pyrrole-2-carboxylic acid ethyl ester belongs to the technical field of medicine. Background technique [0002] Immune cells can usually be divided into two categories: T cells and B cells. The main function of B cells is to secrete various antibodies to help the body resist various foreign invasions. Bruton tyrosine kinase (BTK) is a member of the tyrosine protein kinase subfamily, belonging to the Tec family of kinases, mainly expressed in hematopoietic cells and distributed in the lymphatic system, hematopoietic and blood systems. Bruton's tyrosine kinase (BTK) is a key protein kinase in the BCR signaling pathway. It can regulate the maturation and differentiation of normal B cells, and is also closely related to a variety of ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/34
CPCC07D207/34C07B2200/07Y02P20/55
Inventor 张欣熊锋代少先范涛时秋燕凌超魏菱
Owner SHANGHAI ZAIQI BIO TECH
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