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Synthesis method of ribociclib intermediate product and intermediate compound thereof

A synthetic method, ribociclib technology, applied in the synthetic method of ribociclib intermediate products and its intermediate compounds, can solve the problems of long route, difficult reaction amplification, expensive raw materials and reagents, etc.

Active Publication Date: 2020-05-05
广安凯特制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the following problems still exist in this route: the raw materials and reagents are expensive, the route is long, and noble metal catalysis is still required, and there are certain difficulties in reaction amplification.

Method used

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  • Synthesis method of ribociclib intermediate product and intermediate compound thereof
  • Synthesis method of ribociclib intermediate product and intermediate compound thereof
  • Synthesis method of ribociclib intermediate product and intermediate compound thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069]

[0070] Add phosphorus oxychloride (153.3g, 1000mmol) into the three-necked flask, stir, cool down to -10~0°C in an ice-salt bath, slowly add N,N-dimethylformamide (36.5g, 500mmol) dropwise, and keep the temperature constant When the temperature is higher than 5°C, after the dropwise addition, the temperature is controlled and stirred for 1 hour, barbituric acid 1 (38.4g, 300mmol) is added, the ice-salt bath is removed, the temperature is naturally returned to room temperature, and then the temperature is raised to 120°C, and stirred overnight. After the completion of the reaction as monitored by TLC, the reaction solution was slowly added to ice water, a large amount of solids precipitated, cold filtered, and the filter cake was washed with water until the effluent was neutral to obtain a light yellow solid, which was dried at 50-60°C by air blast to obtain compound 2 (58.3g , yield 92.5%). ESI m / z = 211.01 (M+1).

Embodiment 2

[0072]

[0073] Methanol (200mL), cyclopentanone (16.8g, 200mmol), glycine methyl ester (17.8g, 200mmol), and acetic acid (0.12g, 2mmol) were sequentially added into the single-port reaction flask. Stir in an ice bath, add sodium triacetate borohydride (63.6 g, 300 mmol) in batches, return to room temperature and stir for 2 hours after the addition, TLC monitors that the reaction is complete, drop water (150 g) to quench the reaction, and concentrate under reduced pressure to remove methanol. Add 1 mol / L hydrochloric acid (200mL), ethyl acetate (200mL), separate liquid, organic layer TLC detects that there is no product, discard it, add solid sodium bicarbonate to the aqueous phase to adjust the pH to about 8, extract three times with ethyl acetate (200mL) , the combined organic phases were concentrated to dryness under reduced pressure to obtain a brown oily compound 3-1 (29.8 g, yield 95.0%). ESI m / z = 158.21 (M+1).

Embodiment 3

[0075]

[0076] Add 2 (31.6g, 150mmol) and dichloromethane (300mL) to the three-necked flask successively, stir in an ice bath, and cool down to 5-15°C; add compound 3-1 (25.9g, 175mmol) and diisopropylethylamine dropwise (38g, 200mmol) in dichloromethane (100mL) solution, control the internal temperature at 10-20°C, remove the ice bath after the dropwise addition, and react at room temperature for 2-5 hours, after TLC monitors the reaction is complete, add 150mL of water, separate the liquid, and extracted with 100 mL of dichloromethane, combined the organic phases, washed once with 200 mL of saturated saline, collected the organic phases, concentrated to dryness to obtain a brown semi-solid, added 50 mL of ethyl acetate and 100 mL of petroleum ether, heated to 50°C and stirred for 1 h, cooled to Filter at 0-5°C, collect the filter cake, and dry under reduced pressure at 40-50°C to obtain a light yellow solid, compound 4-1 (44.3g, yield 89.2%). ESI m / z = 332.12 (M+1). 1 H...

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Abstract

The invention discloses a synthesis method of a ribociclib intermediate product, which comprises the following steps: by using barbituric acid as a starting material, carrying out chlorination and formylation to obtain a compound 2; and performing condensation, cyclization, dechlorination, elimination and other reactions to obtain the rebociclib intermediate 2-chloro-7-cyclopentyl-N, N-dimethyl-7H-pyrrolo [2, 3-d] pyrimidine-6-formamide. In addition, the intermediate compound is also disclosed. The synthesis method can avoid the use of noble metal catalysis, has the advantages of simple process route, accessible raw materials and mild conditions, effectively lowers the production cost, and is suitable for large-scale production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and specifically relates to a method for synthesizing an intermediate product of Ribociclib and an intermediate compound thereof. Background technique [0002] Ribociclib is a new type of highly effective oral anticancer drug developed by Novartis. As a highly specific cell cycle-dependent kinase (CDK4 / 6 dual inhibitor), the drug can significantly inhibit the growth of various neuroblastomas. The results of clinical research show that the drug has a significant curative effect for the treatment of advanced breast cancer, so it has a broad market prospect. [0003] The chemical name of ribociclib is: 7-cyclopentyl-N,N-dimethyl-2-[[5-(1-piperazinyl)-2-pyridyl]amino]-7H-pyrrolo[ 2,3-d]pyrimidine-6-carboxamide, the structure is shown below. [0004] [0005] At present, the preparation of ribociclib is mainly through the key intermediate product, namely 2-chloro-7-cyclopentyl-N,N-d...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D239/30
CPCC07D487/04C07D239/30Y02P20/584
Inventor 张耀春周福委左小勇周旭东刘新军
Owner 广安凯特制药有限公司
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