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The preparation method of ibrutinib

A pyrazolo, phenoxyphenyl technology, applied in the field of pharmaceutical synthesis, can solve the problems of low total yield, severe conditions, low total reaction yield and the like, and achieves avoiding the generation of impurities, reducing production costs, and simplifying process operations. Effect

Active Publication Date: 2018-07-17
BEIJING CREATRON INST OF PHARMA RES CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Still do not avoid the following disadvantages: (1) yield is low (only 18.9%); (2) purification means is not suitable for industrialized production (silica gel column chromatography); (3) production cost is high (using polymer linked triphenyl base phosphorus)
The disadvantages of this route include: (1) the starting material 1-(3R-hydrazino-1-piperidinyl)-2-propen-1-one is not currently on the market and cannot be purchased; (2) the route is easy to use Combustible reagent sodium hydride is used as alkali, and highly toxic dimethyl sulfate is used as methylating reagent, (3) the reaction temperature of the last step is 105-110 ℃, and the conditions are severe, which increases the difficulty for industrialized production; (4) the three-step total The rate is low, only 37.3%
[0013] To sum up, the currently reported routes have disadvantages such as low total reaction yield, complicated separation means, unavailable raw materials, use of flammable substances, highly toxic substances, etc., which are not conducive to industrial production.

Method used

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  • The preparation method of ibrutinib
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  • The preparation method of ibrutinib

Examples

Experimental program
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Effect test

Embodiment 1

[0040] Example 1: Ibrutinib: 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H pyrazolo[3,4-d]pyrimidine-1- Synthesis of ]-1-piperidinyl]-2-propen-1-one

[0041] According to the synthesis method of ibrutinib route 1 (US7514444), the experiment was repeated, wherein the polymer-linked triphenylphosphine used in route 1 was not easily available in the Chinese market, and the polymer link of route 1 was replaced by triphenylphosphine of triphenylphosphine.

[0042] (1) Intermediate: (R)-tert-butyl 3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl) Synthesis of piperidine-1-carbonate Add 250mL of tetrahydrofuran into a 500mL reaction flask, and add 5g of 3-(4-phenoxyphenyl)-1H-pyrazol[3,4-D]pyrimidine-4- Amine (SM1), (S)-1-tert-butoxycarbonyl-3-hydroxypiperidine (SM2) (6.63g, 2.0eq), triphenylphosphine (6.5g, 1.5eq), slowly add azobis Diisopropyl formate (5 mL, 1.5 eq). The reaction mixture was stirred overnight at room temperature, the reaction mixture was concentrated...

Embodiment 2

[0046] Example 2: Intermediate-1: (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine- Synthesis of 4-amine

[0047] Add 155mL tetrahydrofuran to a 500mL reaction flask, and add 3-(4-phenoxyphenyl)-1H-pyrazol[3,4-D]pyrimidin-4-amine (SM1) (5g, 1eq) sequentially under stirring , (S)-1-tert-butoxycarbonyl-3-hydroxypiperidine (SM2) (4.97g, 1.5eq), triphenylphosphine (13g, 3.0eq). Under the condition of temperature control at 25°C, a solution of diisopropyl azodicarboxylate in tetrahydrofuran (dissolve 10 g, 3.0 eq of diisopropyl azodicarboxylate in 10 mL of tetrahydrofuran) was added dropwise within 30 minutes. After the dropwise addition was completed, the temperature was controlled at 25° C., and the reaction was continued for 5 hours (TLC monitoring: ethyl acetate:methanol=10:1). Stirring and distillation under reduced pressure. The temperature was controlled at 15°C, and 30 mL of concentrated hydrochloric acid was added dropwise to the residue for 30 mi...

Embodiment 3

[0048] Example 3: Intermediate-1: (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine- Synthesis of 4-amine

[0049] Add 155mL tetrahydrofuran to a 500mL reaction flask, and add 3-(4-phenoxyphenyl)-1H-pyrazol[3,4-D]pyrimidin-4-amine (SM1) (5g, 1eq) sequentially under stirring , (S)-1-tert-butoxycarbonyl-3-hydroxypiperidine (SM2) (6.63g, 2eq), triphenylphosphine (13g, 3.0eq). Under temperature control at 25°C, a solution of diisopropyl azodicarboxylate in tetrahydrofuran (dissolve 10 g, 3.0 eq of diisopropyl azodicarboxylate in 10 mL of tetrahydrofuran) was added dropwise within 30 minutes. After the dropwise addition was completed, the temperature was controlled at 25° C., and the reaction was continued for 1 hour (TLC monitoring: ethyl acetate:methanol=10:1). Stirring and distillation under reduced pressure. The temperature was controlled at 15°C, and 30 mL of concentrated hydrochloric acid was added dropwise to the residue for 30 minutes. After the add...

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Abstract

The invention belongs to the field of drug synthesis and relates to preparation of a crude drug and an intermediate, in particular to a preparation method of ibrutinib 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one. The method is characterized in that (1) 3-(4-Phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (SM1) and (S)-1-Boc-3-hydroxypiperidine (SM2) are adopted as starting materials and subjected to a Mitsunobu reaction, and an intermediate (-1): (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine is obtained and condensed with acrylic anhydride for an amidation reaction, and the finished product ibrutinib is prepared through recrystallization.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and relates to the preparation of raw materials and intermediates, in particular to a preparation method of ibrutinib. Background technique [0002] Ibrutinib was first developed by Celera Genomics of the United States in 2007, and then transferred to Pharmacyclics in California for development. In 2011, Janssen, a subsidiary of Johnson & Johnson, participated in the joint development. There is no standard Chinese translation at present, so the applicant hereby transliterates it as "Ibrutinib". The drug was approved by the FDA in November 2013 for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior treatment with lenalidomide or other drugs. Ibrutinib is the first once-daily, single-agent, oral Bruton's tyrosine kinase (BTK) inhibitor. On February 12, 2014, Ibrutinib was approved by the FDA to add indications for the treatment of chronic lymphocytic leuke...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 贾慧娟陈岩张帆李伟刘祥伟
Owner BEIJING CREATRON INST OF PHARMA RES CO LTD