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Preparation method of ribociclib intermediate

A technology of Ribociclib and intermediates, applied in the field of drug synthesis, can solve the problems of unsuitability for industrialized large-scale production, lengthy reaction steps, and low total yield, and achieve great implementation value and social and economic benefits, reasonable cost, and low price low effect

Pending Publication Date: 2022-07-15
HANGZHOU FST PHARMA +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] The reaction steps of this route are lengthy, the raw materials are expensive and difficult to obtain, the process is loaded down with trivial details, and the total yield is low (about 15%), so it is not suitable for industrialized large-scale production

Method used

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  • Preparation method of ribociclib intermediate
  • Preparation method of ribociclib intermediate
  • Preparation method of ribociclib intermediate

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Effect test

preparation example Construction

[0047] As a kind of preferred embodiment, a kind of preparation method of ribociclib intermediate, specifically comprises the steps:

[0048] (1) Using uracil as the starting material and iodine as the iodine reagent, compound I, iodine and ceric ammonium nitrate were added to solvent A, and the temperature was raised to 70-80°C, and the reaction was kept for 5-6h to obtain compound II: 5- Iodine-uracil; molar ratio of compound I, iodine and catalyst A=1.0:0.5-1.0:0.05-0.15.

[0049] (2) Add base B to compound II and phosphorus oxychloride, and heat the temperature to 90-100° C. to obtain compound III: 5-iodo-2,4-dichloropyrimidine; the base B is selected from triethylamine, N , one of N-dimethylaniline and N,N-diisopropylethylamine. Compound II, POCl 3 , the substance ratio of alkali B = 1.0: 3.0-10.0: 2.0-5.0.

[0050] (3) Dissolve compound III and base A in solvent A, cool to -10-0°C, add dropwise a mixture of cyclopentylamine and solvent A, and react for 1 to 5 hours to...

Embodiment approach

[0053] A preparation method of ribociclib intermediate, comprising the following steps:

[0054] (1) Compound I, iodine, catalyst A and solvent A are mixed, the temperature is raised to 70-80° C., and the reaction is incubated for 5-6 hours to generate compound II; the catalyst A is selected from the group consisting of DMAP, hydrogen peroxide, and ceric ammonium nitrate; The solvent A is selected from one or more of tetrahydrofuran, water, acetonitrile, ethanol, isopropanol and tert-butanol. The molar ratio of compound I, iodine and catalyst A=1.0:0.5-1.0:0.05-0.15.

[0055] (2) Compound II, phosphorus oxychloride and base B are mixed and reacted to form compound III; the base B is selected from triethylamine, N,N-dimethylaniline and N,N-diisopropylethylamine one or more of them. In step (2), the molar ratio of compound II, phosphorus oxychloride and base B=1.0:3.0-10.0:1.5-5.0.

[0056] (3) Dissolve compound III and base C in solvent C, cool to -10-0°C, add dropwise the m...

Embodiment 1

[0064] 1) Preparation of Intermediate II:

[0065] The ratio of the amount of the feeding material is uracil: iodine: cerium ammonium nitrate = 1: 0.6: 0.1

[0066] In a 1L there-necked flask, add uracil (112g, 1mol), 336mL of acetonitrile, iodine particles (152g, 0.6mol), ceric ammonium nitrate (54.8g, 0.1mol), turn on stirring, be warming up to 80 DEG C of reflux, insulation reaction , HPLC monitoring the consumption of raw materials, the temperature of the reaction solution was naturally cooled to 50 ° C, the acetonitrile was evaporated under reduced pressure, and recovered for use. Add 200 mL of 5% aqueous sodium thiosulfate solution until the solid color fades, filter, rinse the filter cake with water, and collect the filter cake. Product appearance: white solid, mass: 222 g, reaction yield 93%.

[0067] Hydrogen spectrum characterization of intermediate II;

[0068] 1 H NMR (400MHz, DMSO-d 6 , ppm) δ 11.39 (s, 1H), 11.20 (s, 1H), 7.90 (s, 1H).

[0069] 2) Preparati...

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Abstract

The invention discloses a ribociclib intermediate preparation method, which comprises: (1) mixing a compound I, iodine, a catalyst A and a solvent A, heating to a temperature of 70-80 DEG C, and carrying out a heat preservation reaction for 5-6 h to generate a compound II; (2) mixing the compound II, phosphorus oxychloride and alkali B, and reacting to generate a compound III; (3) dissolving the compound III and alkali C in a solvent C, cooling to-10-0 DEG C, dropwise adding a mixed solution of cyclopentylamine and the solvent C, and reacting for 1-5 hours after dropwise adding to obtain a compound IV; (4) under the protection of inert gas, adding the compound IV, propargyl alcohol, a palladium catalyst, alkali D, a ligand and an activating agent into a solvent D, and carrying out Sonogashira coupling reaction for 5-10 hours to obtain a compound V; the method is mild in reaction condition, high in reaction yield, high in operability, low in production cost, green, environmentally friendly and suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of a ribociclib intermediate. Background technique [0002] Ribociclib, a cyclin-dependent kinase (CDK) 4 / 6 inhibitor developed by Novartis, was approved by the U.S. FDA on March 14, 2017 for the treatment of hormone receptor-positive (HR+) and human Epidermal growth factor receptor 2-negative (HER2-) postmenopausal women with breast cancer. Novartis' Kisqali still has great promise to become a blockbuster drug, and Clarivate Analytics predicts that the sales of ribocoxib will exceed one billion US dollars in 2024. [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, its chemical structure is shown below: [0004] [0005] In the current synthesis methods of ribociclib reported in the literature, the key lies in how to efficiently construct the k...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 刘陆军邵建平张伟伟司体明包戚明钟为慧凌飞
Owner HANGZHOU FST PHARMA
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