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Synthesis method of pyrotinib

A technology of pyrotinib and synthetic method, applied in the field of pharmaceutical chemical synthesis, can solve the problems of high cost, easy oxidation and deterioration, low industrial production value and significance

Active Publication Date: 2020-12-22
SUZHOU FUSHILAI PHARMA CO LTD
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  • Summary
  • Abstract
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  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Route 3 (WO2011029265A1, WO2012122865A2) has the following reaction steps, (2R)-1-methylpyrrolidine-2-carbaldehyde is unstable and easy to oxidize and deteriorate, and there is no commercially available product available, which needs to be synthesized in advance because of its difficulty in synthesis Larger, its cost is higher, on the other hand, the Wittig-Honner reaction between (2R)-1-methylpyrrolidine-2-carbaldehyde and formula 2 needs to be carried out at ultra-low temperature (<-50°C) The yield is low, so the cost of this route is high, and the value and significance of industrial production are low

Method used

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  • Synthesis method of pyrotinib
  • Synthesis method of pyrotinib
  • Synthesis method of pyrotinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] (A) Preparation of [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]boronic acid:

[0030] Dissolve 2-[(4-bromo-2-chlorophenoxy)methyl]pyridine (5.0g, 17mmol) as formula I in tetrahydrofuran (80mL), cool to -78°C, and slowly add 1.6M n- Butyl lithium in n-hexane solution (12mL), the reaction mixture was stirred at -78°C for 2h, then trimethyl borate (2.5g, 24mmol) was slowly added, the reaction mixture was stirred at -78°C for 1h, then naturally raised to 20°C and stirred for 10h , slowly add methanol (50mL), add dropwise dilute hydrochloric acid to adjust pH = 3, cool and crystallize for 3h, filter with suction, and dry in vacuo to obtain [3-chloro-4-(pyridin-2-ylmethoxy) as formula II Phenyl] boronic acid (4.0g), yield 91%, the reaction formula of this step is:

[0031]

[0032] (B) preparation of pyrotinib:

[0033] (2E)-N-(4-amino-3-cyano-7-ethoxyquinolin-6-yl)-3-[(2R)-1-methylpyrrolidin-2- Base] acrylamide (5.0g, 14mmol) and [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]bor...

Embodiment 2

[0036] (A) Preparation of [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]boronic acid:

[0037]First, 2-[(4-bromo-2-chlorophenoxy)methyl]pyridine (12.5g, 42mmol) was dissolved in tetrahydrofuran (200mL), cooled to -78°C, and slowly added dropwise with 1.6M n-butyllithium n-Hexane solution (33mL,), the reaction mixture was stirred at -78°C for 2h, then slowly added triethyl borate (10.0g, 69mmol), the reaction mixture was stirred at -78°C for 1h, naturally raised to 25°C and stirred for 8h, slowly added Methanol (60mL), dilute hydrochloric acid was added dropwise to adjust pH=3, cooled and crystallized for 3h, suction filtered, and vacuum dried to obtain [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]boronic acid (10.0g ), yield 91%;

[0038] (B) preparation of pyrotinib:

[0039] (2E)-N-(4-amino-3-cyano-7-ethoxyquinolin-6-yl)-3-[(2R)-1-methylpyrrolidin-2-yl]acrylamide ( 11.0g, 30mmol), [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]boronic acid (10.0g, 38mmol), copper acetate (2.0g, 10mmol) and...

Embodiment 3

[0041] (A) Preparation of [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]boronic acid:

[0042] Dissolve 2-[(4-bromo-2-chlorophenoxy)methyl]pyridine (30.0g, 0.10mol) in tetrahydrofuran (400mL), cool to -78°C, and slowly add 1.6M n-butyl lithium dropwise n-hexane solution (90mL), the reaction mixture was stirred at -78°C for 2h, then triisopropyl borate (35.0g, 0.19mol) was slowly added, the reaction mixture was stirred at -78°C for 1h, then naturally raised to 25°C and stirred for 6h, Add methanol (80mL) slowly, add dilute hydrochloric acid dropwise to adjust pH=3, cool and crystallize for 3h, filter with suction, and dry in vacuo to obtain [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]boronic acid ( 24.0g), yield 91%;

[0043] (B) preparation of pyrotinib:

[0044] (2E)-N-(4-amino-3-cyano-7-ethoxyquinolin-6-yl)-3-[(2R)-1-methylpyrrolidin-2-yl]acrylamide ( 24.0 g, 66 mmol), [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]boronic acid (24.0 g, 91 mmol), copper sulfate (5.0 g, 31 mmol) and pyridi...

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Abstract

The invention discloses a synthesis method of pyrotinib, which belongs to the technical field of chemical synthesis of medicines. The preparation method comprises the following steps of firstly, reacting 2-[(4-bromo-2-chlorophenoxy)methyl]pyridine with n-butyllithium at a low temperature, and then carrying out a boronation reaction with an organic boron reagent to obtain [3-chloro-4-(pyridine-2-ylmethoxy)phenyl]boric acid, enabling (2E)-N-(4-amino-3-cyano-7-ethoxy quinoline-6-yl)-3-[(2R)-1-methyl pyrrolidine-2-yl] acrylamide and the obtained [3-chloro-4-(pyridine-2-yl methoxy)phenyl]boric acid to be subjected to a catalytic coupling reaction in a system of a copper catalyst, a base catalyst and a solvent, and acquiring pyrotinib. The method has the characteristics of readily available rawmaterials, simple process, economy, environmental protection and the like, is beneficial to quality control and improvement of final product raw material medicines, is suitable for industrial production and is beneficial to promoting cheap development of the raw material medicines.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to a synthetic method of pyrotinib. Background technique [0002] Pyrotinib is an irreversible human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR) dual-target tyrosine kinase inhibitor independently developed by China Jiangsu Hengrui Pharmaceutical Company The mechanism of action is to covalently bind to the adenosine triphosphate (ATP) binding site of the HER2 and EGFR kinase domain in the cell, prevent the formation of homogeneous and heterogeneous dimers of HER2 and EGFR in tumor cells, and inhibit its own phosphorylation, Block the activation of downstream signaling pathways, thereby inhibiting tumor cell growth. Pyrrotinib maleate tablets were officially approved by the China Food and Drug Administration (CFDA) in August 2018 for the treatment of epidermal growth factor receptor 2 (HER2) positive pat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14
CPCC07B2200/07C07D401/14
Inventor 王永兴张晓红何旭曾陵
Owner SUZHOU FUSHILAI PHARMA CO LTD
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