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Synthesis method of Trilaciclib

A synthesis method and technology of a condensing agent are applied in the synthesis field of Trilaciclib and can solve the problems of long synthesis route and low yield of Trilaciclib

Active Publication Date: 2021-12-14
SHENZHEN BAY LAB PINGSHAN TRANSLATIONAL MEDICINE CENT
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The purpose of this application is to provide a synthetic method of Trilaciclib, aiming to solve the technical problems of long synthetic route and low yield of Trilaciclib

Method used

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  • Synthesis method of Trilaciclib
  • Synthesis method of Trilaciclib
  • Synthesis method of Trilaciclib

Examples

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preparation example Construction

[0025] The embodiment of the present application provides a synthetic method of Trilaciclib, which comprises the following steps:

[0026] S01: Using 2-(methylthio)-7H-pyrrole[2,3-d]pyrimidine-6-carboxylic acid and 1-aminomethyl-1-cyclohexanol as raw materials, carry out condensation reaction to obtain formula I Intermediate 1 shown:

[0027] S02: subjecting intermediate 1 to an internal cyclization reaction to obtain intermediate 2 shown in formula II;

[0028] S03: Nucleophilic substitution reaction of intermediate 2 with 1-methyl-4-(6-aminopyridin-3-yl)piperazine to obtain Trilaciclib;

[0029]

[0030] The synthetic method of Trilaciclib provided in the Examples of the present application, the specific route is as follows, with 2-(methylthio)-7H-pyrrole[2,3-d]pyrimidine-6-carboxylic acid and 1-aminomethyl-1-cyclohexyl Alcohol is used as a raw material, and the synthesis reaction is carried out to obtain intermediate 1, and then intermediate 1 is subjected to intramole...

Embodiment 1

[0043] Preparation of intermediate 1 shown in formula I

[0044]

[0045] Add DMF 150mL, DCM 150mL, 2-(methylthio)-7H-pyrrole[2,3-d]pyrimidine-6-carboxylic acid 21g (100mmol), 1-aminomethyl-1 - Cyclohexanol 14.3g (110mmoL), HOBt 15.2g (100mmoL), EDC.HCl 19.2g (100mmoL), react at 100°C for 20 hours. After the reaction, add 1N dilute sodium bicarbonate to the system to adjust the pH to 7-8, extract with DCM, combine the organic phases, wash the organic phase with saturated brine, dry with anhydrous magnesium sulfate, and concentrate the obtained filtrate under reduced pressure , a brown crude product was obtained. 300 mL of isopropanol was added to the obtained crude product for recrystallization, and 25.7 g of off-white solid product was obtained, that is, intermediate 1 with a purity of 99% and a yield of 85%.

[0046] The structure of the obtained product was confirmed by mass spectrometry and nuclear magnetic resonance, and the results were: 1 H NMR (400MHz, DMSO-d 6 ...

Embodiment 2

[0048] Preparation of intermediate 1 shown in formula I

[0049] Add DMF 150mL, DCM 150mL, 2-(methylthio)-7H-pyrrole[2,3-d]pyrimidine-6-carboxylic acid 21g (100mmol), 1-aminomethyl-1 - Cyclohexanol 14.3g (110mmoL), TBTU 32.1g (100mmoL), DIPEA 12.9g (100mmoL), react at 120°C for 20 hours. After the reaction, add 1N dilute sodium bicarbonate to the system to adjust the pH to 7-8, extract with DCM, combine the organic phases, wash the organic phase with saturated brine, dry with anhydrous magnesium sulfate, and concentrate the obtained filtrate under reduced pressure , a brown crude product was obtained. 320 mL of isopropanol was added to the obtained crude product for recrystallization to obtain 25.4 g of off-white solid product, that is, Intermediate 1 with a purity of 99% and a yield of 84%.

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Abstract

The invention relates to the technical field of synthetic chemistry, and especially relates to a synthesis method of Trilaciclib. The synthesis method comprises the following steps: carrying out condensation reaction on 2-(methylthio)-7H-pyrrolp[2, 3-d]pyrimidine-6-carboxylic acid and 1-aminomethyl-1-cyclohexanol to obtain an intermediate 1 as shown in a formula I: carrying out internal cyclization reaction on the intermediate 1 to obtain an intermediate 2 as shown in a formula II; and carrying out a nucleophilic substitution reaction on the intermediate 2 and 1-methyl-4-(6-aminopyridine-3-yl) piperazine to obtain the Trilaciclib. Compared with an existing method, the synthesis method has the advantages that the synthesis route is remarkably shortened, the total yield is increased, so the synthesis method has a good application prospect in the field of Trilaciclib preparation.

Description

technical field [0001] The application belongs to the technical field of synthetic chemistry, and in particular relates to a synthetic method of Trilaciclib. Background technique [0002] In February 2021, the Food and Drug Administration (FDA) approved the marketing application for the new CDK4 / 6 inhibitor Cosela (Trilaciclib), which is a subsidiary of G1 Therapeutics, and is a drug that reduces the risk of treatment in patients with extensive-stage small cell cancer. It is the first CDK4 / 6 inhibitor approved for this indication. Cosela (Trilaciclib) can protect bone marrow cells from chemotherapy-induced damage by inhibiting the activity of the target CDK4 / 6. As a short-acting CDK4 / 6 inhibitor, patients use the drug before chemotherapy, allowing bone marrow stem cells to Short-term cell cycle arrest, thereby protecting bone marrow stem cells from chemotherapy drugs. [0003] The structural formula of Trilaciclib is as follows, and the Cas number of its free base is: 1374...

Claims

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Application Information

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IPC IPC(8): C07D487/20
CPCC07D487/20Y02P20/55
Inventor 陈学明刘运尹登蒋晨然李硕陈杰安黄湧
Owner SHENZHEN BAY LAB PINGSHAN TRANSLATIONAL MEDICINE CENT
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