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Preparation method of Ibrutinib drug impurity

A technology of ibrutinib and compound, applied in the field of drug synthesis, can solve the problems such as no process impurity report yet

Active Publication Date: 2016-11-23
BEIJING CREATRON INST OF PHARMA RES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Currently, no process impurities have been reported in this production route

Method used

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  • Preparation method of Ibrutinib drug impurity
  • Preparation method of Ibrutinib drug impurity
  • Preparation method of Ibrutinib drug impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] Example 1: Intermediate-1: (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine- Synthesis of 4-amine (YLTN-1)

[0067] 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 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 minutes....

Embodiment 2

[0068] Embodiment 2: Preparation of Ibrutinib

[0069] Under nitrogen protection, 50 mL of dichloromethane, Intermediate-1 (5 g, 1 eq), and N, N-diisopropylethylamine (2 g, 1.2 eq) were sequentially added into a 100 mL three-necked flask. Under the condition of temperature control at -10°C, start to add the dichloromethane solution of acrylic anhydride (1.96g, 1.2eq) dropwise for 30 minutes. Until the reaction of the raw materials was complete (TLC detection, methanol: ethyl acetate: triethylamine = 1:5:0.05). The reaction solution was washed with 200 mL of 5% citric acid aqueous solution, the water phase was removed, concentrated and evaporated to remove dichloromethane. The crude product of Ibrutinib: 3.63g. 1H-NMR (400Mz, DMSO-d 6 ( m, 1H), 5.570~5.713(m, 1H), 4.690~4.716(m, 1H), 4.554~4.583(m, 0.5H), 4.208(m, 1H), 4.052~4.085(m, 0.5H), 3.674~3.731(m, 0.5H), 3.184~3.214(m, 1H), 2.972~3.027(m, 0.5H), 2.245~2.282(m, 1H), 2.128(m, 1H), 1.903~1.937(m , 1H), 1.577~1.605(...

Embodiment 3

[0070] Example 3: Impurity A: (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl Synthesis of 1-piperidin-1-yl)-3-chloropropyl-1-one.

[0071] Under nitrogen protection, 50ml of dichloromethane was added to a 100mL three-necked flask, and Intermediate-1 was added sequentially under stirring: (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl )-1H-pyrazol[3,4-d]pyrimidin-4-amine (YLTN-1) (1.00g, 1eq), N, N-diisopropylethylamine (0.40g, 1.2eq), cooled to -20~-10°C, start to add 3-chloropropionyl chloride (1.46g, 1eq) dropwise. After the dropwise addition, the solution turns from cloudy to clear. Continue to stir for 20-30 minutes. LC-MS detects that the raw materials disappear, and distills under reduced pressure. , dichloromethane was distilled until no fraction was distilled off, and the crude product was purified by column chromatography, the elution ratio was: methanol: ethyl acetate=1:10, a total of 400 mL of the eluent was collected, distilled under reduced pre...

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Abstract

The invention belongs to the field of pharmaceutical synthesis, and relates to an impurity in the bulk pharmaceutical chemical production process and a preparation method of the impurity, in particular to a process impurity of Ibrutinib 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1Hpyrazole [3,4-d]pyrimidine-1-yl]-1-piperidyl]-2-propylene-1-ketone and a preparation method of the process impurity.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and relates to process impurities in the production process of crude drug ibrutinib and its preparation. In particular, it relates to ibrutinib process impurities and a preparation method thereof. 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 approv...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07D487/14C07D519/00
CPCC07D487/04C07D487/14C07D519/00
Inventor 贾慧娟陈岩张帆刘祥伟李伟
Owner BEIJING CREATRON INST OF PHARMA RES CO LTD
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