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Method for synthesizing tyrosine kinase inhibitor PCI-32765

A PCI-32765, tyrosine kinase technology, applied in the field of medicinal chemistry, can solve the problems of dangerous reaction, difficult purification, many side reactions, etc., and achieve the effects of mild reaction conditions, environmental friendliness and low cost

Inactive Publication Date: 2013-05-29
SUZHOU DEVI PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] In short, the raw materials of this route are uncommon, expensive, long steps, high cost, dangerous reaction, many side reactions, and difficult purification, which limits the possibility of industrial production of this route

Method used

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  • Method for synthesizing tyrosine kinase inhibitor PCI-32765
  • Method for synthesizing tyrosine kinase inhibitor PCI-32765
  • Method for synthesizing tyrosine kinase inhibitor PCI-32765

Examples

Experimental program
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preparation example Construction

[0020] A synthetic method of tyrosine kinase inhibitor PCI-32765 comprises the following steps:

[0021] 1. Compound 10 and compound 15 undergo a coupling reaction to obtain compound 6;

[0022] 2. During the reaction of compound 6 and compound 16 to obtain compound 11, we chose a more ideal catalyst;

[0023] 3. Compound 11 was protected to obtain compound 12;

[0024] 4. Selective deprotection of compound 12 to obtain compound 13;

[0025] 5. Compound 13 has only the only position available for compound 17 to attack, and a very pure compound 14 is obtained;

[0026] 6. Take off the protecting group to get PCI-32765

[0027]

[0028] Among them, compounds 10, 15, 16, and 17 can be synthesized using reagents or industrial grade compounds, or using related methods and techniques.

[0029] In step 1) of the present invention, compound 10 and compound 15 undergo a Suzuki coupling reaction in a suitable solvent in the presence of an alkaline reagent and a catalyst to genera...

Embodiment 1

[0034] Preparation of compound 6

[0035] Under nitrogen protection, add 0.1 moL of compound 10, 1.5 equivalents of compound 15 and 800 mL of dioxane into a 2L reaction flask, then add 1.5 equivalents of sodium acetate and 0.2 equivalents of catalyst PdCl2(PPh3)2, and react at 50-60°C for 5 hour, filtered while hot, and the filter residue was washed three times with ethanol, and the combined filtrate was concentrated to obtain a solid, which was rinsed with ethanol to obtain 16.2 grams of pure product, yield 60%

Embodiment 2

[0037] Preparation of compound 6

[0038] Under nitrogen protection, add 0.1 moL of compound 10, 1.5 equivalents of compound 15 and 800 mL of DMF into a 2L reaction flask, then add 1.5 equivalents of sodium acetate and 0.2 equivalents of catalyst PdCl2(PhCN)2, and react at 50-60°C for 5 hours. Filtrate hot, wash the filter residue three times with ethanol, combine the filtrates, concentrate to obtain a solid, rinse with ethanol to obtain 21.5 g of pure product, and the yield is 71%.

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Abstract

The invention discloses a method for synthesizing tyrosine kinase inhibitor PCI-32765. The method comprises the following steps of: 1) carrying out a coupled reaction between a compound 10 and a compound 15 to obtain a compound 6; 2) reacting the compound 6 with a compound 16 to obtain a compound 11 in the presence of a more ideal catalyst; 3) protecting the compound 11 to obtain a compound 12; 4) carrying out selective de-protection on the compound 12 to obtain a compound 13; 5) attacking the compound 13 which has only one position which can be attacked by a compound 17 to obtain a very pure compound 14; and 6) removing protecting groups, thus obtaining the PCI-32765. By the method, tyrosine kinase which serves as a main receptor signal of B cells can be inhibited, and the tyrosine kinase inhibitor PCI-32765 is not only capable of inhabiting the generation of hemocyte with little toxicity and side effects, but also is moderate in reaction conditions, simple to operate, convenient to purify, low in cost, environment-friendly, and suitable for large scale production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a synthesis method of tyrosine kinase inhibitor PCI-32765. Background technique [0002] PCI-32765 (Ibrutinib), chemical name: 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine- 1-yl]-1-piperidinyl]-2-propene-1-one, its structural formula is as follows: [0003] [0004] PCI-32765 is an orally administered drug that inhibits tyrosine kinases that act as the main receptor for signaling on B cells, promoting programmed cell death, preventing cell migration, and adhesion to malignant B cells. [0005] The basic patent US20080108636 has disclosed a synthetic route: [0006] This synthetic route uses 4-phenoxybenzoic acid as a raw material, and obtains the final product through eight-step reactions. The reaction steps are as follows: [0007] [0008] There is following shortcoming in above-mentioned this method: [0009] ⅰ, eight-step single-line reactio...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCY02P20/55
Inventor 叶锋方华详
Owner SUZHOU DEVI PHARMA TECH CO LTD
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