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Method for preparing ibrutinib

A technology of ibrutinib and compounds, applied in the field of drug synthesis, can solve problems such as difficult separation, strong irritation, and difficulty in obtaining raw materials, and achieve the effect of simplifying the process and reducing the production of impurities

Active Publication Date: 2016-08-17
SHANGYU JINGXIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The main disadvantages of this route are (1) the use of acryloyl chloride is a poisonous and harmful chemical, which is highly irritating to the human respiratory system, eyes, nose, etc., and has tear gas
(2) The piperazine compound that has not yet participated in the reaction in the last acylation reaction is easy to add a large amount of by-product formula V with the product ibrutinib. The properties of this compound are similar to ibrutinib, and it is difficult to combine with ibrutinib. completely separated
[0010] This route introduces acrylamide at the beginning of the reaction. Although it avoids the generation of dimerization product formula V, it has the disadvantages of difficult acquisition of raw materials, high price, and high requirements for reaction conditions.

Method used

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  • Method for preparing ibrutinib
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  • Method for preparing ibrutinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] 1-(3-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-3- Chloro-propan-1-one

[0036]

[0037] Formula III piperidine compound (8.0g, 20.7mmol) was added in dichloromethane (100ml), diisopropylethylamine (2.95g, 22.8mmol) was added, and under ice-water bath cooling, 3-chloro A solution of propionyl chloride (2.5g, 19.7mmol) in 20ml of dichloromethane (argon protection), after dropping, stirred for 15 minutes, added 50ml of water, stirred until the two phases were clear, separated the water phase, and added the organic phase Wash once with 20 ml of 1N hydrochloric acid, separate the organic phase and spin dry. Column chromatography, eluent (dichloromethane:methanol=30:1), collected the product to obtain 9.6 g of the title compound with a yield of 97%.

[0038] 1 H NMR (400M Hz, CDCl 3 ),δ8.36(s,1H),7.67-7.64(m,2H),7.43-7.38(m,2H),7.29-7.15(m,3H),7.10(d,J=4.0Hz,2H), 5.9(brs,2H),4.88-4.83(m,2H),3.88-3.72(m,3H),3.35-3.33(m,2H),

[0039]...

Embodiment 2

[0042] 1-(3-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)-3- Bromo-propan-1-one

[0043]

[0044] The piperidine compound of formula III (2.0g, 5.18mmol) was added in dichloromethane (20ml, insoluble), diisopropylethylamine (1.47g, 11.4mmol) was added, and under cooling in an ice-water bath, 3 -A solution of bromopropionyl chloride (0.84g, 4.92mmol,) in 10 ml of dichloromethane (argon protection), after dropping, stir for 5 minutes, add 20 ml of water, stir until the two phases are clear, and separate the upper aqueous phase , the organic phase was washed once with 20 ml of 1N hydrochloric acid, the organic phase was separated and spin-dried, column chromatography, eluent (dichloromethane: methanol = 30:1), collected to obtain 2.6 g of the title compound, yield 96.4% .

[0045] 1 H NMR (400M Hz, CDCl 3 ),δ8.36(s,1H),7.60-7.56(m,2H),7.47-7.36(m,2H),7.29-7.15(m,3H),7.08(d,J=3.6Hz,2H), 5.8(brs,2H),4.88-4.83(m,2H),3.76-3.58(m,3H),3.35-3.33(m...

Embodiment 3

[0049] 1-(3-(4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)propan-2 -en-1-one

[0050]

[0051] Formula III piperidine compound (4.0g, 10.35mmol) was added in dichloromethane (40ml), diisopropylethylamine (1.47g, 11.4mmol) was added, and under ice-water bath cooling, 3-chloro A solution of propionyl chloride (1.25g, 9.83mmol) in 10ml of dichloromethane (argon protection), after dropping, stirred for 5 minutes, added 20ml of water, stirred until the two phases were clear, separated the upper aqueous phase, and the organic phase Add 20 ml of 1N hydrochloric acid to wash once, separate the organic phase and spin dry, add 40 ml of acetone, 20 ml of 2.5N sodium hydroxide solution, stir at room temperature for 30 minutes, add 40 ml of ethyl acetate for extraction, and use anhydrous sulfuric acid for the organic phase Sodium-dried and spin-dried to obtain 4.2 g of the title compound, the yield was 92%, and the impurity content of the dimer of formula...

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Abstract

The invention discloses a method for preparing ibrutinib, and relates to an intermediate compound used for preparing the ibrutinib, wherein the intermediate compound has a structural formula shown in a formula II. The invention also discloses a method for preparing an intermediate, which is characterized in that a compound in a formula III and an acyl chloride derivative are subjected to a reaction, and then the ibrutinib is obtained through a further reaction. The impurity content of the ibrutinib prepared by the method is obviously reduced.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of tyrosine kinase inhibitor ibrutinib. Background technique [0002] Ibrutinib (ibrutinib), the chemical name is 1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine-1- base) piperidin-1-yl) prop-2-en-1-one, which has the structure shown in formula I. [0003] [0004] Ibrutinib, a tyrosine kinase inhibitor developed by Pharmacyclics, has efficacy in the treatment of mantle cell lymphoma and chronic cell leukemia. The synthesis method of ibrutinib is disclosed in PCT application WO2008039218, and the specific reaction scheme is as follows: [0005] [0006] The main disadvantage of this route is that (1) adopting acryloyl chloride is a poisonous and harmful chemical, which is highly irritating to the human respiratory system, eyes, nose, etc., and has lachrymatory properties. (2) The piperazine compound that has not yet participated in the re...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
Inventor 徐苗焕
Owner SHANGYU JINGXIN PHARMA
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