Method for preparing high-purity palbociclib and reaction intermediate of palbociclib

A reaction and purity technology, applied in the field of preparation of high-purity palbociclib and its reaction intermediate, palbociclib, can solve the problem of high production equipment requirements, harsh reaction conditions, Problems such as low utilization rate, to overcome the low utilization rate of raw materials, strong operability and controllability, and good application prospects

Inactive Publication Date: 2016-03-23
重庆莱美隆宇药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0023] In order to overcome the defects of low raw material utilization rate, cumbersome operation, harsh reaction conditions, high production equipment requirements, low yield and high cost of preparing pal...

Method used

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  • Method for preparing high-purity palbociclib and reaction intermediate of palbociclib
  • Method for preparing high-purity palbociclib and reaction intermediate of palbociclib
  • Method for preparing high-purity palbociclib and reaction intermediate of palbociclib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] At room temperature, compound D1(C) was added to the dry reaction flask 30 H 39 N 7 O 4 5.6g, 10mmol, purity ≥99.5%), HCl (7.3g, 200mmol), CH 3 OH (56.1 ml) was slowly mixed, and the reaction was stirred at 80 °C for 12 h. After the reaction was completed, the mixture was cooled and crystallized, and a small amount of CH was added. 3 The mixed solvent of OH and petroleum ether was recrystallized to obtain light yellow solid E. Solid E is then suspended in C 2 H 5In OH (57.0ml), HCl (7.3g, 200mmol) was added dropwise, and the reaction was stirred at 80°C for 6h. After the reaction was completed, NaOH was added to adjust the pH to 11, cooling and crystallization, suction filtration, and drying to obtain pure Pabbu. 3.5 g of corybine free base, yield 78%; mass spectrum (EI): m / z 448 (M+H).

Embodiment 2

[0058] At room temperature, compound D2 (C 33 H 45 N 7 O 4 7.2g, 12mmol, purity ≥99.5%), HCl (12.0g, 600mmol), CH 3 OH (217.0 ml) was slowly mixed, and the reaction was stirred at 60 ° C for 18 h. After the reaction was completed, the mixture was cooled and crystallized, and a small amount of CH was added. 3 The mixed solvent of OH and petroleum ether was recrystallized to obtain yellow solid E. Solid E is then suspended in C 2 H 5 In OH (220.0ml), HCl (12.0g, 600mmol) was added dropwise, and the reaction was stirred at 80°C for 6h. After the reaction was completed, cooling and crystallization, suction filtration, and drying were to obtain pure Palbociclib free base. 4.2 g, 79% yield; mass spectrum (EI): m / z 448 (M+H).

Embodiment 3

[0060] At room temperature, compound D3 (C 31 H 40 ClN 7 O 4 6.1g, 10mmol, purity ≥99.5%), CH 3 COOH (12.0 g, 200 mmol), CH 3 OH (91.4ml) was slowly mixed, and the reaction was stirred at 60°C for 12h. After the reaction was completed, the mixture was cooled and crystallized, and a small amount of CH was added. 3 The mixed solvent of OH and petroleum ether was recrystallized to obtain light yellow solid E. Solid E is then suspended in C 2 H 5 OH (92.0ml) was added dropwise with HCl (7.3g, 200mol), and the reaction was stirred at 80°C for 3h. After the reaction was completed, cooling and crystallization, suction filtration and drying were performed to obtain pure Palbociclib free base. 3.4 g, 76% yield; mass spectrum (EI): m / z 448 (M+H).

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Abstract

The invention relates to a method for preparing compound palbociclib (shown as the formula I). A compound D (shown as the formula II) serves as a raw material, and a compound E (shown as the formula III) is obtained through a rearrangement reaction of alkenyl ether; then the compound E is subjected to t-butyloxycarboryl protection group removal under the acidic condition, and target product palbociclib is obtained; an R group in a compound D is selected from any one of a C1-C6 alkyl group, a C1-C6 halogenate alkyl group, C1-C6 hydroxyalkyl and a C1-C6 naphthenic base. The process procedure and operation steps are easy and convenient, prepared palbociclib is high in purity, and good popularization prospects are achieved.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to a method for preparing palbociclib, in particular to a method for preparing high-purity palbociclib and a reaction intermediate thereof. Background technique [0002] Breast cancer is not a single disease. The results of immunohistochemical detection of ER, PR, HER2 and Ki67 divided breast cancer into 4 types. But no matter which type, it is actually related to the dysregulation of the cell cycle. Cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor, which is closely related to the cell cycle, can inhibit the binding of serine / threonine kinase and cyclin D, and block cells from G1 phase to S phase transition. CDK4 / 6 inhibitors, as small molecule targeted drugs for anti-tumor, have the advantages of selectively inhibiting CDK4 / 6 without showing the cytotoxicity of "pan-CDK inhibitors", such as bone marrow suppression and intestinal reactions; The level of cyclin D is higher than that...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCY02P20/55C07D471/04
Inventor 黄文峰黄胜陈进许辉川
Owner 重庆莱美隆宇药业有限公司
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