A kind of industrial preparation method of Ribociclib

A compound and catalyst technology, applied in the field of medicinal chemistry, can solve the problems of large safety hazards, cumbersome process operation, and large amount of three wastes.

Active Publication Date: 2020-04-28
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The raw materials of this synthetic route are expensive and difficult to obtain. Various precious metal catalysts, manganese dioxide oxidizing agents, and highly toxic cyanides are used. The process operation is cumbersome, the safety hazard is large, the amount of three wastes is large, and it is difficult to industrialize.

Method used

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  • A kind of industrial preparation method of Ribociclib
  • A kind of industrial preparation method of Ribociclib
  • A kind of industrial preparation method of Ribociclib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] Example 1: Preparation of Ribociclib (I)

[0088] Step (1): N,N-Dimethyl-2-{5-[(4-tert-butoxycarbonylpiperazin-1-yl)pyridin-2-yl]}amino-7H-pyrrole[2,3- d] pyrimidine-6-carboxamide (Ⅵ 1 , molecular weight 466.5) preparation

[0089] In a 500 ml four-necked flask, add 300 g of n-butanol, 41.8 g (0.2 moles) of N,N-dimethyl-2,2-dichloro-4-cyano n-butyramide (II), 35.5 g ( 0.3 mol) N,N-dimethylformamide dimethyl acetal (Ⅲ 1 ), 0.5 gram of piperidine, reacted for 4 hours at 115°C to obtain the compound of formula IV, and the gas phase detection reaction was completed (without separation); down to 25-30°C, add 70.5 grams (0.22 moles) of N-[5-(4- tert-butoxycarbonylpiperazin-1-yl)pyridin-2-yl]guanidine (V), react at 90-95°C for 12 hours, and the reaction is completed by liquid phase detection. Cool down to room temperature, filter, filter cake was washed once with 40 grams of ethanol, and dried to obtain 86.3 grams of light yellow solid N,N-dimethyl-2-{5-[(4-tert-butoxycarb...

Embodiment 2

[0096] Example 2: Preparation of Ribociclib (I)

[0097] Step (1): N,N-Dimethyl-2-{5-[(4-tert-butoxycarbonylpiperazin-1-yl)pyridin-2-yl]}amino-7H-pyrrole[2,3- d] pyrimidine-6-carboxamide (Ⅵ 1 ) preparation

[0098] In a 500 ml four-necked flask, add 300 g of n-butanol, 41.8 g (0.2 moles) of N,N-dimethyl-2,2-dichloro-4-cyano n-butyramide (II), 26.5 g ( 0.25 mol) of trimethyl orthoformate, 0.8 g of zinc chloride, reacted at 80-85° C. for 4 hours, and the reaction was completed by gas phase detection. Drop to 25-30°C, add 80.0 g (0.25 moles) of N-[5-(4-tert-butoxycarbonylpiperazin-1-yl)pyridin-2-yl]guanidine, react at 90-95°C for 12 hours, liquid The phase detection reaction is complete. Lowered to room temperature, filtered, and the filter cake was washed with 40 grams of ethanol to obtain 85.7 grams of light yellow solid N,N-dimethyl-2-{5-[(4-tert-butoxycarbonylpiperazin-1-yl)pyridine- 2-yl]}amino-7H-pyrrole[2,3-d]pyrimidine-6-carboxamide, molecular weight 466.5, liquid ph...

Embodiment 3

[0103] Example 3: Preparation of Ribociclib (I)

[0104] Step (1): N,N-Dimethyl-2-{5-[(4-benzylpiperazin-1-yl)pyridin-2-yl]}amino-7H-pyrrole[2,3-d] Pyrimidine-6-carboxamide (Ⅵ 2 , molecular weight 456.5) preparation

[0105] In a 500 ml four-necked flask, add 200 g of N,N-dimethylformamide, 41.8 g (0.2 moles) of N,N-dimethyl-2,2-dichloro-4-cyano n-butyramide ( Ⅱ), 35.5 g (0.3 moles) of N,N-dimethylformamide dimethyl acetal, 0.4 g of DBU, reacted at 110° C. for 4 hours, and the reaction was completed by gas phase detection. Decrease to 25-30°C, add 77.5 g (0.25 moles) N-[5-(4-benzylpiperazin-1-yl)pyridin-2-yl]guanidine, react at 100-105°C for 10 hours, liquid phase detection The reaction is complete. Recover N,N-dimethylformamide by distillation under reduced pressure, then add 50 grams of water and 50 grams of ethanol to the residue, filter, and wash the filter cake with 40 grams of ethanol to obtain 85.6 grams of light yellow solid N,N-dimethylformamide Base-2-{5-[(4-ben...

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Abstract

The invention relates to an industrial preparation method for ribociclib. The method comprises the following steps: carrying out a condensation reaction on N,N-dimethyl-2,2-dihalo-4-cyano-n-butanamide(II) and a methylenenation reagent (III) to prepare a compound of formula IV; condensing the compound of formula IV and a compound of formula V to obtain a compound of formula VI; carrying out an N-substitution reaction on the compound VI and cyclopentane halide to obtain N,N-dimethyl-7-cyclopentyl-2-{5-[(4-PG-substituted)piperazin-1-yl)pyridin-2-yl]}amino-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (VIII), and removing the PG substituent from the compound VIII to obtain the ribociclib. The method of the invention has the advantages of cheap and easily available raw materials, simple process flow, safety in operation, and low cost.

Description

technical field [0001] The invention relates to an industrial preparation method of ribociclib, which belongs to the technical field of medicinal chemistry. Background technique [0002] Ribociclib, whose trade name is Kisqali, is a dual inhibitor of highly specific cell cycle-dependent kinases (CDK4 and CDK6) being developed by Novartis. Studies on 17 neuroblastomas have shown that Ribociclib Sidney (I) can significantly inhibit the growth of 12 types of neurocytoma, and was approved by the US FDA and European EMA in March and August 2017, respectively, for premenopausal hormone receptor-positive and human epidermal growth factor-responsive Treatment of body 2 negative advanced breast cancer. The results of the second clinical phase III of Ribociclib for the treatment of advanced or metastatic breast cancer announced by Novartis showed that the treatment effect is significant. In addition, Ribociclib has high protein binding rate, long physiological half-life, effective o...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04
CPCY02P20/55
Inventor 戚聿新刘月盛王保林范岩森鞠立柱
Owner XINFA PHARMA
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