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Preparation method of Bruton's tyrosine kinase inhibitor

A tyrosine kinase and inhibitor technology, which is applied in the field of drug synthesis, can solve the problems of high production cost, cumbersome steps, complicated processes, etc., and achieves the effects of low cost, concise steps, and simple operation.

Active Publication Date: 2017-08-01
SHANDONG NEWTIME PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In addition to using the difficult and expensive palladium reagent in this process, column chromatography analysis is also used many times. The steps are cumbersome and the process is complicated, and the production cost is high, which is not conducive to industrial production.

Method used

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  • Preparation method of Bruton's tyrosine kinase inhibitor
  • Preparation method of Bruton's tyrosine kinase inhibitor
  • Preparation method of Bruton's tyrosine kinase inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] 1. Preparation of intermediate Ⅰ

[0036] Add 600g of (S)-tert-butyloxycarbonyl-3-hydroxypiperidine, 780g of triphenylphosphine and 3LDMF into the reaction flask and stir to dissolve, then add 300g of 4-amino-3-(4-benzene Oxyphenyl)-1H-pyrido(3,4-d)pyrimidine, continue to stir for 10-30min, avoid light, start adding diisopropyl azodicarboxylate dropwise at 10-15℃ under temperature control, drop After the addition is complete, raise the temperature to 25-30°C, stir and react for 3-4h; stop the reaction, cool down to 0°C, start to add 1110mL concentrated HCl dropwise, after the dropwise addition, warm up to room temperature, stir for 3-4h; stop the reaction, Add 3L of purified water and stir, then add 1.8L of chloroform for 5 times and 1.8L of ethyl acetate for 2 times. After the extraction, add 1.2L of ethyl acetate, cool down to 0°C, and start adding 25% NaOH solution dropwise , adjust the pH value to 8-9, a large amount of solids are precipitated, stirred and crystall...

Embodiment 2

[0040] 1. Preparation of intermediate Ⅰ

[0041] Add 600g of (S)-tert-butyloxycarbonyl-3-hydroxypiperidine, 780g of triphenylphosphine and 3L of acetone into the reaction flask and stir to dissolve, then add 300g of 4-amino-3-(4- Phenoxyphenyl)-1H-pyrido(3,4-d)pyrimidine, continue to stir for 10-30min, avoid light, start adding diisopropyl azodicarboxylate dropwise at 10-15°C under temperature control, After the dropwise addition, raise the temperature to 25-30°C, stir and react for 3-4h; stop the reaction, cool down to 0°C, start to add 1110mL concentrated HCl dropwise, after the dropwise addition, warm up to room temperature, stir for 3-4h; stop the reaction , add 3L of purified water and stir, then add 1.8L of chloroform for 5 times and 1.8L of ethyl acetate for 2 times, after the extraction, add 1.2L of ethyl acetate, cool down to 0°C, and start adding 25% NaOH dropwise solution, adjust the pH value to 8-9, precipitate a large amount of solids, stir and crystallize, the c...

Embodiment 3

[0045] 1. Preparation of intermediate Ⅰ

[0046] Add 600g of (S)-tert-butyloxycarbonyl-3-hydroxypiperidine, 780g of triphenylphosphine and 3L of ethyl acetate into the reaction flask and stir to dissolve, then add 300g of 4-amino-3-( 4-phenoxyphenyl)-1H-pyrido(3,4-d)pyrimidine, continue to stir for 10-30 minutes, keep away from light, and start adding diisopropyl azodicarboxylate dropwise at 10-15°C under temperature control Esters, after the dropwise addition, raise the temperature to 25-30°C, stir for 3-4 hours; stop the reaction, cool down to 0°C, start adding 1110mL of concentrated HCl dropwise, after the dropwise addition, warm up to room temperature, and stir for 3-4h; Stop the reaction, add 3L of purified water and stir, then add 1.8L of chloroform for 5 times and 1.8L of ethyl acetate for 2 times, after the extraction, add 1.2L of ethyl acetate, cool down to 0°C, and start adding 25 % NaOH solution, adjust the pH value to 8-9, a large amount of solids are precipitated...

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Abstract

The invention relates to the field of drug synthesis, specifically to a preparation method of a Bruton's tyrosine kinase inhibitor. The new method comprises: carrying out a dark reaction between 4-amino-3-(4-phenoxylphenyl)-1H-pyridino(3,4-d)pyrimidine and (S)-tert-butoxycarbonyl-3-hydroxy piperidine in the action of triphenyl phosphine and diisopropyl azodiformate, taking Boc off in an acidic condition to form salt, performing crystallization with 25% NaOH to dissolve salt to prepare an intermediate I in one pot, and reacting the intermediate I with acryloyl chloride in an alkaline condition to generate a target product. The preparation method is simple in production condition, low in cost and high in yield, is eco-friendly and clean, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of a Bruton's tyrosine kinase inhibitor. Background technique [0002] Bruton's Tyrosine Kinase (BTK) Inhibitor 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d] Pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one is jointly developed by Pharmacyclics and Johnson & Johnson. The trade name is Imbruvica and the generic name is Ibrutinib. It is an oral, first-in-class drug called a Bruton's tyrosine kinase (BTK) inhibitor, which is primarily used to treat a rare and aggressive form of blood cancer called mantle cell lymphoma (MCL). The drug irreversibly inhibits BTK by selectively covalently binding to cysteine ​​residues in the active site of the target protein Btk, thereby effectively preventing tumor migration from B cells to lymphoid tissues adapted to the tumor growth environment. [0003] [0004] Patent WO2014022390A1 reports the synthesis of the drug...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/519A61P35/00
CPCA61K31/519C07B2200/07C07B2200/13C07D487/04
Inventor 张贵民张朝花董怀民
Owner SHANDONG NEWTIME PHARMA
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