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Preparation method of precursor of ibrutinib

A system and system technology, applied in the field of preparation of pharmaceutical intermediates, can solve problems such as side reactions, low yields, and restrictions on industrial production, and achieve the effect of reducing the risk of side reactions

Active Publication Date: 2020-04-14
上海柏狮生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] In the study of ibrutinib, we found that there is a significant shortcoming in the method reported by Pharmacyclics: the yield of compound (I) from compound (Ⅲ) and compound (Ⅳ) is not high. Because compound (Ⅲ) has many reaction sites and poor stability, resulting in more side reactions in this step of Mitsunobu reaction with compound (Ⅳ)
This significant defect greatly limits its industrial production and makes the drug more expensive

Method used

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  • Preparation method of precursor of ibrutinib

Examples

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Effect test

Embodiment 1

[0039] Example 1: Precursor (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine Synthesis of -4-amine (I)

[0040]Add 100 g of compound (III), 350 g of triphenylphosphine and 2 L of tetrahydrofuran into the reaction flask. 270g of diisopropyl azodicarboxylate was added dropwise at 0°C. After dropping, the system was reacted at 50°C for 1 hour. HPLC showed that the content of compound (III) was less than 0.5%. Maintained at 50°C, 5 g of tetrabutylammonium bromide was added, followed by dropwise addition of 200 g of compound (IV) in 1 L of tetrahydrofuran. After 20 hours, keep the temperature at 50 degrees, add 250 mL of 30% hydrochloric acid solution dropwise, and stop the reaction after 2 hours. Cool down to room temperature, add 2.5 L of water to the system, and separate to obtain an aqueous layer. The aqueous layer was washed twice with 2 L of ethyl acetate each time. The liquid was separated to obtain the water layer, and solid sodium hydroxide was...

Embodiment 2

[0042] Example 2: (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Ⅰ )Synthesis

[0043] Add 100 g of compound (III), 260 g of triphenylphosphine and 1.8 L of tetrahydrofuran into the reaction flask. 173g of diethyl azodicarboxylate was added dropwise at 0°C. After dropping, the system was reacted at 55°C for 8 hours. HPLC showed that the content of compound (III) was less than 0.5%. Maintaining at 55°C, 11 g of tetrabutylphosphine bromide was added, followed by dropwise addition of a solution of 400 g of compound (IV) in 1.5 L of tetrahydrofuran. After 26 hours, keep the temperature at 55 degrees, add 400 mL of concentrated hydrochloric acid dropwise, and stop the reaction after 1.5 hours. Cool down to room temperature, add 3L of water to the system, and separate to obtain an aqueous layer. The aqueous layer was washed twice with 2 L of ethyl acetate each time. The liquid was separated to obtain the water layer, and solid sodium hydroxide ...

Embodiment 3

[0044] Embodiment three: the synthesis of compound (Ⅲ-C)

[0045] Add 1 g of compound (III), 2 g of triphenylphosphine and 10 mL of tetrahydrofuran into the reaction flask. Diisopropyl azodicarboxylate was added dropwise at 0°C. After dropping, the system was reacted at room temperature for 24 hours. HPLC showed that the content of compound (III) was less than 0.5%. Then 10 mL of water was added and stirred for another 24 hours. Concentrate under reduced pressure to remove the solvent, and the resulting oil is separated by column chromatography to obtain 2g of the oil:

[0046] 1H NMR (500MHz, CDCl3) δ: 7.12-7.15(m, 5H), 7.37-7.42(m, 8H), 7.44-7.47(m, 8H), 7.50-7.55(m, 7H), 7.68-7.72(m , 7H), 7.83-7.87 (m, 5H), 8.19 (s, 1H), 8.53 (d, J=8.5Hz, 2H).

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Abstract

The invention relates to the pharmaceutical industry, in particular to a preparation method of a drug intermediate, and specifically discloses a preparation method of a precursor of ibrutinib. The preparation method comprises the following steps: (1) reacting a compound (III) with triphenylphosphine and azodicarbonic acid diester to obtain an intermediate (III-B); (2) reacting the intermediate (III-B) with a compound (IV) under the action of a catalyst to obtain an intermediate (V-C); and (3) reacting the intermediate (V-C) under the action of hydrochloric acid to obtain (R)-3-(4-phenoxy phenyl)-1-(piperidine-3-yl)-1H-pyrazolo [3, 4-d] pyrimidine-4-amine (I). The method has the advantages of high yield, high purity, convenience in purification, simplicity and convenience in operation and the like, is suitable for industrial production, and contributes to reducing the cost to a certain extent.

Description

technical field [0001] The invention relates to the pharmaceutical industry, in particular to a preparation method of a drug intermediate. Background technique [0002] Ibrutinib, 1-[(3R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1- Base)-1-piperidinyl]-2-propen-1-one (II), is a first-in-class oral Bruton's tyrosine kinase (BTK) inhibitor. Jointly developed by Pharmacyclics and Johnson&Johnson. The trade name is Imbruvica. The specific structure of ibrutinib is as follows: [0003] [0004] Currently, the main industrialized preparation routes are reported by Pharmacyclics, and all of them use compound (I) as the key precursor. For example, the route described in patent US 7514444: [0005] [0006] This route mixes compound (Ⅲ), compound (Ⅳ), triphenylphosphine and DIAD with each other, and uses Mitsunobu reaction to form the condensation product compound (Ⅴ-A), which is the key precursor formed after removing Boc protection in acid (Ⅰ). Compo...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07F9/6561
CPCC07D487/04C07F9/65616
Inventor 陈宇王亚萍彭邱君周艺军张荣于万盛李勤勤路燕
Owner 上海柏狮生物科技有限公司
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