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A key intermediate for synthesizing cdk4/6 dual inhibitor and its preparation method and application

A compound and reaction temperature technology, applied in organic chemistry, bulk chemical production, etc., can solve problems such as expensive, difficult to obtain raw material compound XVI, and not environmentally friendly

Active Publication Date: 2021-09-03
PHARMABLOCK SCIENCES (NANJING) INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] This route has the following problems: the price of selected raw materials is relatively expensive, and more precious metal catalysts are used; after 6 steps of reaction, the coupling reaction yield is relatively low; the total yield is 17.28%, the yield is low, and the process cost is higher , heavily polluted
[0010] This route has the following problems: propynyl alcohol is used as the side chain for coupling, the reaction system has many impurities and the yield is low; the impurities produced by the ring-closing reaction of compound XIV are difficult to remove; in the process of preparing VIII from compound XV, a highly toxic Sodium cyanide is not environmentally friendly; and a large amount of manganese dioxide is used as an oxidant; the process is inconvenient to enlarge and operate
[0014] Although this route has improved in yield compared with the above two routes, there are still the following problems: expensive metal catalysts are used; raw material compound XVI is not easy to obtain; the last step uses peroxide, which has certain safety risks
Therefore, it is not suitable for industrial production

Method used

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  • A key intermediate for synthesizing cdk4/6 dual inhibitor and its preparation method and application
  • A key intermediate for synthesizing cdk4/6 dual inhibitor and its preparation method and application
  • A key intermediate for synthesizing cdk4/6 dual inhibitor and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Preparation of compound III-1:

[0059]

[0060] In a 50L double-layer kettle, add compound II (2500g, 13.3mol, 1.0e.q.) into 20L of dichloromethane, add triethylamine (2019g, 19.95mol, 1.5e.q.), after the addition is complete, add benzenesulfonate dropwise at 0°C Acyl chloride (2584g, 14.63mol, 1.1e.q.), temperature controlled 0-10°C, the dropwise addition was completed, stirred at 10°C for 5h, and LC-MS detected that the reaction was complete. Add 25L of water to the reaction solution, stir well and separate the liquids, wash the organic phase with 25L of saturated sodium bicarbonate solution, wash with 25L of water and separate the liquids, add anhydrous magnesium sulfate to dry, filter, evaporate the solvent under reduced pressure, and use Slurry with petroleum ether and dry to obtain 3675.0 g of compound III-1 as a light yellow solid with a yield of 84.2%. 1 HNMR (400MHz, CDCl 3 , δppm) 8.26-8.25 (d, 2H), (7.78-7.58, m, 4H), 6.72-6.71 (d, 1H).

[0061] Prepar...

Embodiment 2

[0073] Preparation of compound III-2:

[0074]

[0075] In a 50L double-layer kettle, compound II (2500g, 13.3mol, 1.0e.q.) was added to 30L THF, and at 0°C, NaH (797.8g, 19.95mol, 1.5e.q.) was added in batches. Add p-toluenesulfonyl chloride (3042g, 15.96mol, 1.2e.q.), control the temperature at 0-10°C, dropwise, stir at 20°C for 6h, and LC-MS detects that the reaction is complete. Add 35L of water to the reaction solution, stir well and separate the liquids, wash the organic phase with 30L of saturated sodium bicarbonate solution, wash with 30L of water and separate the liquids, add anhydrous magnesium sulfate to dry, filter, evaporate the solvent under reduced pressure, and use Slurry with petroleum ether and dry to obtain 3881.3 g of compound III-2 as a light yellow solid with a yield of 85.3%.

[0076] Preparation of Compound IV-2:

[0077]

[0078] Compound III-2 (2000g, 5.84mol, 1.0e.q.) in 10L tetrahydrofuran solution, cooled to -50°C, added dropwise 2.5M NaHMD...

Embodiment 3

[0089] Preparation of compound III-1:

[0090]

[0091] In a 50L double-layer kettle, compound II (2500g, 13.3mol, 1.0e.q.) was added to 20L of dichloromethane, and DBU (3035g, 19.95mol, 1.5e.q.) was added. After the addition was complete, benzenesulfonyl chloride ( 2819g, 15.96mol, 1.2e.q.), the temperature was controlled at 0-10°C, the dropwise addition was completed, the reaction was stirred at 30°C for 5h, and the reaction was detected by LC-MS. Add 25L of water to the reaction solution, stir well and separate the liquids, wash the organic phase with 25L of saturated sodium bicarbonate solution, wash with 25L of water and separate the liquids, add anhydrous magnesium sulfate to dry, filter, evaporate the solvent under reduced pressure, and use Slurry with petroleum ether and dry to obtain 3723.1 g of compound III-1 as a light yellow solid with a yield of 85.3%. 1 HNMR (400MHz, CDCl 3 ), 8.26-8.25 (d, 2H), (7.78-7.58, m, 4H), 6.72-6.71 (d, 1H).

[0092] Preparation of...

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Abstract

The invention discloses a synthetic 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide intermediate (compound I) and its The preparation method and application include the following steps: using 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (compound II) as a starting material, first preparing compound III by applying a protecting group; compound III Compound IV is obtained through carbonyl insertion reaction; compound V is obtained through deprotection group; compound VI is obtained by selective dechlorination; compound I is obtained by cyclopentyl on compound VI; compound VI is obtained by hydrolysis of compound I; -7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (Compound VIII).

Description

technical field [0001] The invention relates to the field of synthesis of pharmaceutical intermediates, in particular to a CDK4 / 6 dual inhibitor key intermediate 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3 -d] Preparation method and application of pyrimidine-6-carboxamide. Background technique [0002] 2-Chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide is an important intermediate in pharmaceutical synthesis. It can be used to prepare a cyclin-dependent kinase (CDK4 / 6 dual inhibitor), which can significantly inhibit the growth of various neuroblastomas, and is used for the treatment of advanced breast cancer. The recent clinical research results show that the curative effect is significant, so it has a wide range of applications. market expectation. [0003] Novartis disclosed the synthesis method of 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide in patent CN102186856(B): [0004] [0005] Reagents and co...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04
CPCC07D471/04Y02P20/55
Inventor 杨光明武帅刘存路朱经伟杨民民吴希罕
Owner PHARMABLOCK SCIENCES (NANJING) INC
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