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Preparation method of ribociclib intermediate

A compound and reaction technology, applied in the field of organic synthesis and drug synthesis, can solve problems such as low product yield, low conversion rate of raw materials, and many impurities

Active Publication Date: 2017-10-20
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
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  • Application Information

AI Technical Summary

Problems solved by technology

[0011] In the synthesis of rebuciclib, the preparation of intermediate 9 is extremely critical, and the disclosed preparation method of intermediate 9 has the following defects: (1) The preparation method disclosed in WO2010020675, compound 3 and compound 4 to prepare compound 5 Reaction system impurities Many, difficult to purify, product yield is low; Compound 5 prepares Compound 8 through 3-step reaction, and product is all oily matter, and step is more and difficult to purify, causes yield to reduce; Compound 8 prepares intermediate 9 raw material conversion rate is low, therefore The total reaction yield of this route is low, the operation is cumbersome, and it is not suitable for industrial production
(2) In the preparation method disclosed in WO2012064805, the reaction system of compound 3 and compound 15 to prepare compound 16 has many impurities, and the product yield is low; the ring-closing reaction of compound 16 produces many impurities, which are difficult to remove, and the product yield is low; the preparation of compound 17 is intermediate In the process of forming 9, highly toxic sodium cyanide is used, and the reaction has high requirements on the activation performance of manganese dioxide, and the reaction reproducibility is poor, which is not conducive to industrial production

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0095] Example 1: 2-Chloro-N-cyclopentyl-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyrimidine-4- Preparation of amine (compound of formula Ⅲ-1)

[0096]

[0097] 5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine (60g, 218mmol), tetrabutylammonium fluoride trihydrate (103g, 326mmol), bis(triphenylphosphine) dichloro Palladium chloride (7.6g, 10.85mmol) and anhydrous tetrahydrofuran (550mL) were added to the reaction flask, under nitrogen protection, 2-(prop-2-yn-1-yloxy)tetrahydro-2H-furan (compound of formula II ) (45.6g, 325.5mmol), after reflux reaction for 24 hours, HPLC analysis showed that the reaction was complete. The reaction solution was cooled to room temperature, tetrahydrofuran was distilled off under reduced pressure, ethyl acetate (500 mL) was added, and washed successively with saturated sodium bisulfate (400 mL×3), water (400 mL×3), and saturated brine (400 mL×1). The organic phase was separated and concentrated under reduced pressure to obtain a cr...

Embodiment 2

[0100] Example 2: 2-Chloro-N-cyclopentyl-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyrimidine-4- Preparation of amine (compound of formula Ⅲ-1)

[0101] 5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine (20g, 72.3mmol), tetrabutylammonium fluoride trihydrate (57g, 180.8mmol), tetrakis (triphenylphosphine) Palladium (4.2g, 3.62mmol) and anhydrous tetrahydrofuran (300mL) were added to the reaction flask, and under nitrogen protection, 2-(prop-2-yn-1-yloxy)tetrahydro-2H-furan (20.3g, 144.6 mmol), after reacting for 20 hours at 75°C, HPLC analysis showed that the reaction was complete. The reaction solution was cooled to room temperature, tetrahydrofuran was distilled off under reduced pressure, ethyl acetate (300 mL) was added, and washed successively with saturated sodium bisulfate (200 mL×3), water (200 mL×3), and saturated brine (200 mL×1). The organic phase was separated and concentrated under reduced pressure to obtain a crude oil, which was separated by silica gel ...

Embodiment 3

[0102] Example 3: 2-Chloro-N-cyclopentyl-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyrimidine-4- Preparation of amine (compound of formula Ⅲ-1)

[0103] 5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine (30g, 108.5mmol), tetrabutylammonium fluoride (70.8g, 271.3mmol), bis(triphenylphosphine) dichloro Palladium chloride (7.6g, 10.85mmol) and anhydrous tetrahydrofuran (300mL) were added to the reaction flask, under nitrogen protection, 2-(prop-2-yn-1-yloxy)tetrahydro-2H-furan (22.8g, 162.8mmol), after reacting at 75°C for 20 hours, HPLC analysis showed that the reaction was complete. The reaction solution was cooled to room temperature, tetrahydrofuran was distilled off under reduced pressure, ethyl acetate (300 mL) was added, and washed successively with saturated sodium bisulfate (200 mL×3), water (200 mL×3), and saturated brine (200 mL×1). The organic phase was separated and concentrated under reduced pressure to obtain a crude oil, which was separated by silica gel ...

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Abstract

The invention belongs to the field of organic synthesis and pharmaceutical synthesis and particularly relates to a preparation method of a ribociclib intermediate. According to the preparation method, after 2-halo-7-cyclopentyl-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-7H-pyrrolo[2,3-d] pyrimidine is obtained, the ribociclib intermediate, namely, 2-halo-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-formamide is obtained through three steps of reactions, and high yield and high purity are realized in each reaction step, so that the total yield of the overall route is high and is remarkably better than that in the prior art; besides, raw materials are easy to obtain, the production cost is low, the preparation is simple and easy to operate, reaction reagents are environmentally friendly, and the preparation method of the ribociclib intermediate is particularly suitable for industrial production.

Description

technical field [0001] The present invention belongs to the field of organic synthesis and drug synthesis, and in particular relates to an intermediate 2-halogenated-7-cyclopentyl-N,N-dimethoxylate of Ribciclib (Ribociclib), a drug for treating advanced breast cancer. A preparation method of methyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide and related intermediates. Background technique [0002] Ribociclib (Ribociclib) is a highly specific CDK4 / CDK6 inhibitor developed by Novartis, Switzerland. It can target and inhibit the D1 / CDK4, D3 / CDK6 cell cycle, and block the cell cycle in the G1 phase, thereby playing a role Inhibition of tumor proliferation. The results of clinical trials show that ribociclib can be used in the treatment of breast cancer, melanoma, non-small cell lung cancer, teratoma, liposarcoma and glioblastoma. The drug is currently in phase III clinical trials for advanced breast cancer. [0003] The chemical name of rebuciclib is: 7-cyclopentyl-2-(5-piperaz...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D405/12
CPCC07D405/12C07D487/04
Inventor 黄雨刘健刘相奎蒋慧娟朱雪焱刘飞王善春
Owner SHANGHAI INST OF PHARMA IND CO LTD
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