HPLC method for analyzing ibrutinib and ibrutinib-preparation-related substances and usage of impurities as reference standard

A technology of ibrutinib and impurities, applied in the field of drug synthesis, can solve the problems of not being able to truly reflect the quality of the drug, not being able to accurately measure the real content of impurities, and not having qualitative analysis

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

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Problems solved by technology

[0007] (3) The impurity calculation method of this method is the area normalization method. Due to the different structure of each impurity, the ultraviolet absorption is different under the proposed detection wavelength. Therefore, the area normalization method cannot accurately measure each impurity. The actual content in the final product
[0008] (4) No qualitative analysis of specific impurities in ibrutinib
[0009] In summary, the test results of the prior art cannot truly reflect the quality of the drug

Method used

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  • HPLC method for analyzing ibrutinib and ibrutinib-preparation-related substances and usage of impurities as reference standard
  • HPLC method for analyzing ibrutinib and ibrutinib-preparation-related substances and usage of impurities as reference standard
  • HPLC method for analyzing ibrutinib and ibrutinib-preparation-related substances and usage of impurities as reference standard

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0117] Intermediate-1: (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine synthesis

[0118] 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. After the addition was c...

Embodiment 2

[0119] Embodiment 2: Preparation of Ibrutinib

[0120] 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 residue was recrystallized three times with isopropanol to obtain the finished product of ibrutinib: 3.63 g. 1 H-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....

Embodiment 3

[0121] Example 3: Impurity A: (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl Synthesis of ]piperidin-1-yl)-3-chloropropyl-1-one.

[0122] 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 turbid 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 pres...

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Abstract

The invention belongs to the field of medicine synthesis, and particularly relates to impurities appearing in the preparing process of ibrutinib (1-[(3R)-3-[4-amino-3-(4-phenoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidine-1-butyl]-1-piperidyl]) and a method for analyzing an ibrutinib preparation. A method for detecting the impurities includes the following steps that 1, the ibrutinib or medicine with the ibrutinib is dissolved into a solvent to prepare a sample solution; 2, samples of one or more of compounds A to H are dissolved into a solvent to prepare a reference standard solution or a reference substance solution; 3, the chromatographic technique is carried out on the sample solution and the reference standard solution; 4, existence of any one or more of the compounds A to H in the ibrutinib or the medicine with the ibrutinib is detected.

Description

technical field [0001] The invention belongs to the field of medicine synthesis. Specifically, the present invention relates to ibrutinib (1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H pyrazolo[3,4-d]pyrimidine- 1-yl]-1-piperidinyl]-2-propen-1-one) impurities appearing in the preparation process and the method for analyzing ibrutinib preparations. 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 chemical name of Ibrutinib is: 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H pyrazolo[3,4-d]pyrimidine-1- Base]-1-piperidinyl]-2-propene-1-one, the structural formula is: [0003] [0004] Patent WO201384572A discloses HPLC analysis of the chemical purity...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N30/88
Inventor 贾慧娟何学敏王艳鑫李衍李厚全
Owner BEIJING CREATRON INST OF PHARMA RES CO LTD
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