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A kind of preparation method of ibrutinib

A technology of ibrutinib and intermediates, applied in the field of drug synthesis, can solve the problems of difficulty in industrialized production, many amidation by-products, low yield, etc. good rate

Active Publication Date: 2018-06-08
南京红太阳医药研究院有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It is difficult to operate with microwave in the reaction. In addition, there are many by-products in the last step of amidation, and the yield is low. The cost of the whole route is high and it is difficult to realize industrial production.

Method used

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  • A kind of preparation method of ibrutinib
  • A kind of preparation method of ibrutinib
  • A kind of preparation method of ibrutinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045]Preparation of Intermediate 1

[0046] 54.05g (0.5mol) of 3-amino-4-cyanopyrazole was added to a 1L reaction flask, 540mL of ethylene glycol monomethyl ether was added, and 52.06g (0.5mol) of formamidine acetate was added under the protection of nitrogen at room temperature, and the system was protected by nitrogen. React at 90°C for 48h. After the reaction was complete, the temperature was lowered to room temperature. At this time, a large amount of solids were precipitated in the system, filtered, and the filter cake was rinsed twice with 100 mL of methanol to obtain 61.9 g of the crude product intermediate. The crude product was recrystallized with 250 mL of toluene and 250 mL of acetic acid, filtered to obtain a ≥99% white solid 55.40 g, yield: 82.0%, HPLC: 99.9%.

[0047] Preparation of intermediate 2

[0048] Add 40.54g (0.3mol) of intermediate 1 and 360mL of DMF to a 1L reaction flask, and at the same time add 101.24g (0.45mol) of N-iodosuccinimide, and the syst...

Embodiment 2

[0059] Preparation of Intermediate 1

[0060] Add 54.05g (0.5mol) of 3-amino-4-cyanopyrazole to 1L reaction flask, 540mL of ethylene glycol monomethyl ether, add 62.47g (0.6mol) of formamidine acetate under nitrogen protection at room temperature, and nitrogen protection of the system, Reaction at 100°C for 46h. After the reaction was complete, the temperature was lowered to room temperature. At this time, a large amount of solids were precipitated in the system, filtered, and the filter cake was rinsed twice with 100mL methanol to obtain 63.8g of the crude intermediate. ≥99% white solid 56.41 g, yield: 83.5%, HPLC: 99.93%.

[0061] Preparation of Intermediate 2

[0062] Add 40.54g (0.3mol) of intermediate 1 and 360mL of DMF to a 1L reaction flask, and add 80.1g (0.45mol) of N-bromosuccinimide at the same time. The system is heated to 80°C for 22-24h, controlled by TLC, The raw material reacted completely. 360 mL of water was added to the system to quench the reaction, and...

Embodiment 3

[0070] Preparation of Intermediate 1

[0071] Add 54.05g (0.5mol) 3-amino-4-cyanopyrazole to 1L reaction flask, 540mL ethylene glycol monomethyl ether, add 67.68g (0.65mol) formamidine acetate at room temperature under nitrogen protection, and nitrogen protection system, Reaction at 120°C for 45h. After the reaction was complete, the temperature was lowered to room temperature. At this time, a large amount of solids were precipitated in the system, filtered, and the filter cake was rinsed twice with 100mL methanol to obtain 62.2g of the crude intermediate. ≥99% white solid 56.82g, yield: 84.1%, HPLC: 99.91%.

[0072] Preparation of Intermediate 2

[0073] Add 40.54g (0.3mol) of intermediate 1 and 360mL of DMF to a 1L reaction flask, and at the same time add 101.24g (0.45mol) of N-iodosuccinimide, and the system is heated to 80°C for 22-24h, controlled by TLC. The raw material reacted completely. 360 mL of water was added to the system to quench the reaction, and a large am...

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Abstract

The invention discloses a preparation method for ibrutinib and belongs to the technical field of drug synthesis. The preparation method specifically includes the steps that 3-amino-4-cyano pyrazol and formamidine acetate serve as initial raw materials, and ibrutinib is obtained through a cyclization reaction, a halogenating reaction, a nucleophilic substitution reaction, a Mitsunobu reaction and an amidation reaction. According to the method, the raw materials are easy to obtain, conditions are mild, the process operability and controllability are high, cost is low, the yield is high, fewer side products are generated, purification is easy, and the high-quality product is obtained.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a synthesis method of ibrutinib. Background technique [0002] Ibrutinib (English name Ibrutinib, trade name IMBRUVICA), chemical name: 1-[3(R)-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3 , 4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one. The drug is a Bruton's tyrosine kinase (BTK) inhibitor jointly developed by Johnson & Johnson of the United States and Pharmacyclics Inc. of the United States. It is the second new drug approved by the FDA breakthrough drug channel (the first is obinutuzumab), and also enjoys two other buffs from the FDA, as well as 7 years of administrative protection after listing. On November 13, 2013, the US Food and Drug Administration (FDA) approved Imbruvica (Ibrutinib-Ibrutinib) for the treatment of mantle cell lymphoma (MCL). MCL is a rare type of non-Hodgkin lymphoma that accounts for approximately 6 percent of all non-Hodgki...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04C07F7/12
CPCC07D487/04C07F7/122
Inventor 李维思黄双吴小刚杨健陈国萍刘力萍
Owner 南京红太阳医药研究院有限公司
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