CN106146516A - The preparation method of Buddhist nun's impurity of the drug is replaced according to Shandong - Google Patents

The preparation method of Buddhist nun's impurity of the drug is replaced according to Shandong Download PDF

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CN106146516A
CN106146516A CN201510188801.XA CN201510188801A CN106146516A CN 106146516 A CN106146516 A CN 106146516A CN 201510188801 A CN201510188801 A CN 201510188801A CN 106146516 A CN106146516 A CN 106146516A
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impurity
shandong
base
pyrimidine
buddhist nun
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CN106146516B (en
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贾慧娟
陈岩
张帆
刘祥伟
李伟
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Beijing Creatron Institute Of Pharmaceutical Research Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention belongs to pharmaceutical synthesis field, relate to impurity in production of raw medicine technique and preparation method thereof, process contaminants replacing Buddhist nun 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H pyrazolo [3,4-d] pyrimidine-1-base]-piperidino]-2-propylene-1-ketone according to Shandong and preparation method thereof particularly to one.

Description

The preparation method of Buddhist nun's impurity of the drug is replaced according to Shandong
Technical field
The invention belongs to pharmaceutical synthesis field, relate to crude drug according to Shandong for process contaminants in Buddhist nun's production process And preparation.Buddhist nun's process contaminants and preparation method thereof is replaced particularly to according to Shandong.
Background technology
First Ibrutinib is developed in 2007 by Celera Genomics company of the U.S., after transfer The Pharmacyclics company exploitation of California, subsidiary's Janssen Pharmaceutica (Jassen) of Johson & Johnson in 2011 Participate in cooperative development.There is no the Chinese translation of standard at present, therefore its transliteration at this is by the applicant " according to Shandong for Buddhist nun ".This medicine obtains FDA approval in November, 2013, for previously accepting at least The treatment of lymphoma mantle cell (MCL) patient of lenalidomide or other drug treatment.Replace according to Shandong Buddhist nun be first once a day, unitary agent, oral bruton's tyrosine kinase (BTK) inhibitor. February 12 in 2014, Yi Lu was increased indication for Buddhist nun by FDA approval, was used for treating chronic lymphatic thin Born of the same parents' leukemia (CLL).On July 28th, 2014, FDA announces again, expands approval according to Shandong for Buddhist nun Indication, uses it for chronic lymphocytic leukemia (CLL) patient of chromosome 17P disappearance.2015 In on January 29, in, extend to treat Waldenstrom macroglobulinemia for the indication of Buddhist nun according to Shandong, In breakthrough treatment, this medicine obtains extension approval, and this is that a first unique example is ratified through FDA Waldenstrom macroglobulinemia is treated.In October, 2014, according to Shandong for Buddhist nun by Europe medication management Office (EMA) approval listing, is used for treating lymphoma mantle cell (MCL) and the white blood of chronic lymphocytic Sick (CLL).
Buddhist nun is replaced to be bruton's tyrosine kinase (BTK) micromolecular inhibitor according to Shandong, with BTK avtive spot Cysteine residues formed covalent bond, cause BTK inhibition of enzyme activity.BTK is B-cellular antigens Receptor (BCR) and the signaling molecule of cytokine receptor path.The effect of BTK is by B-cell Surface receptor sends signal instruction, thus activates the transport of B-cell, chemotactic, and sticks required path. Non-clinical study shows and suppresses malignant B-cells propagation and internal existence according to Shandong for Buddhist nun, simultaneously also suppresses body Outer cell migration and substrate stick.Recurrent B-cell lymphoma patient takes according to Shandong for Buddhist nun, dosage >=2.5mg/kg/day (in terms of body weight 70 kilograms per capita, take and be more than 175 according to Shandong for Buddhist nun per capita by daily dose Mg/day), observe after 24 hours that peripheral blood mononuclear cell BTK avtive spot is occupied more than 90% Neck.
According to Shandong for the chemical name of Buddhist nun it is: 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H pyrrole Azoles also [3,4-d] pyrimidine-1-base]-piperidino]-2-propylene-1-ketone, structural formula is:
Prior art discloses seven kinds of process contaminants or degradation impurity, and they replace the mistake of Buddhist nun in synthesis according to Shandong Journey obtains, but FDA examination & approval report only reported the impurity structure of chiral isomer and internal generation Thank to the structure of thing (PCI-45227), the structure of other impurity is not all described.
Only one document (patent WO2013/184572, the 90-91 page) refer to replace according to Shandong The method of Buddhist nun's A crystal form purity detection, the method is buffer in order to 0.1% trifluoroacetic acid aqueous solution (A), with the acetonitrile of 0.1% trifluoroacetic acid as organic solvent (B), chromatographic column is Gemini-NX C18, 4.6 × 150mm, 3 μm, the HPLC method of gradient elution, the method does not has in preparation technology Specific impurities separates.
Report in Chinese Patent Application No. 201510165869.6 for the feather weight synthetic route of Buddhist nun according to Shandong Road, the strategy of this route is: with commercialization, 3-(4-the Phenoxyphenyl)-1H-of process route maturation Pyrazolo [3,4-d] pyrimidine-4-amine (SM1) and (S)-1-tertbutyloxycarbonyl-3-hydroxy piperidine (SM2) is initial Raw material, under the effect of triphenyl phosphorus and diisopropyl azodiformate, in tetrahydrofuran solution system In carry out Mitsunobu reaction, reaction terminates, directly deprotection under the effect of concentrated hydrochloric acid, then warp In sodium hydroxide and crystallize, obtain intermediate-1:(R)-3-(4-Phenoxyphenyl)-1-(piperidines-3-base)-1H- Pyrazolo [3,4-d] pyrimidine-4-amine.This intermediate is in dichloromethane solvent, with N, N-diisopropyl Base ethamine makees alkali, carries out amidation process, through ethanol/water system recrystallization system with acrylic anhydride condensation Obtain finished product according to Shandong for Buddhist nun.
Above-mentioned process route has the advantage that the total recovery of (1) two-step reaction compared with other routes The yield reported higher than other.(2) intermediate-1 and be recrystallization for the method for purification of Buddhist nun according to Shandong, Make to be possibly realized for the industrialized production of Buddhist nun according to Shandong；(3) Mitsunobu react in use cheap Triphenyl phosphorus replaces the triphenyl phosphorus that polymer connects, and reduces industrial production cost；(4) in The production of mesosome-1 uses " one kettle way ", Mitsunobu reaction is merged with deprotection reaction, Simplify technological operation.(5) amidation reagent is changed into acrylic anhydride by acryloyl chloride, it is to avoid be difficult to The impurity removed by recrystallization is generated.This route is the synthesis strategy with industrial production value. At present, there is no the report to the process contaminants produced in this production line.
Summary of the invention
Impurity research is the important content of drug research and development, through drug research and development all the time, directly affects The safety of medicine, effectiveness and quality controllability.There is provided for the quality research of Buddhist nun according to Shandong to give There is related substance reference substance, improve the quality standard replacing Buddhist nun according to Shandong, for providing for the safe medication of Buddhist nun according to Shandong Important guidance, the present invention by according to Shandong for Buddhist nun's technical study process sampling carry out HPLC and LC-MS analyzes, and studies, synthesizes and confirms according to Shandong for the process contaminants in Buddhist nun's production line.
The synthetic method and the city that replace Buddhist nun according to Shandong of Chinese Patent Application No. 201510165869.6 report Sell according to Shandong for Buddhist nun's capsule (Imbruvica purchased from Pharmacyclics Janssen company, 140mg, Lot number: L0404951) in, a series of process contaminants can be related to, confirm its chemical name through inventor Claim and structural formula see table
The way of production of above impurity is as follows:
Impurity A: this impurity is impurity in commercially available capsule, it should grind process contaminants for former, in this work Never detect during skill is multiple batches of.
Impurity B: in the synthesis replacing Buddhist nun according to Shandong of Chinese Patent Application No. 201510165869.6 report In method second step amidation process, amidatioon occurs (be expressed as Buddhist nun's intermediate-1 according to Shandong YLTN-1) two positions, the nitrogen on piperidines nuclear nitrogen and pyrimidine ring, produce bisamideization and produce Thing impurity B-1, due to Thermodynamic effect, there is intramolecular cyclization in the latter, generates more stable pair Pyrimidine ring impurity B.
Impurity C: in the synthesis replacing Buddhist nun according to Shandong of Chinese Patent Application No. 201510165869.6 report In method second step amidation process, containing a small amount of acetic anhydride impurity in initiation material acrylic anhydride, with YLTN-1 occurs amidation process to generate impurity C.
Impurity D: in the synthesis replacing Buddhist nun according to Shandong of Chinese Patent Application No. 201510165869.6 report In method second step amidation process, according to Shandong for Buddhist nun (YLTN) and by-product acrylic acid urging at alkali (it is probably DIPEA, is likely to as replacing the nitrogen heterocyclic ring of Buddhist nun self according to Shandong) under change and occur Baylis-Hillman reacts and produces impurity D.
Impurity E, F, G are or to comprise according to Shandong for pharmaceutical preparation strong of Buddhist nun for Buddhist nun's active component according to Shandong Principal degradation impurity in system degraded sample, wherein impurity E is to replace Buddhist nun or according to Shandong for Buddhist nun's preparation system according to Shandong The primary product of oxidative degradation during Bei, impurity F, G are to replace Buddhist nun or according to Shandong for Buddhist nun's preparation system according to Shandong Catabolite during Bei, is also for forcing degraded or the main fall of hydrolysis under the conditions of Buddhist nun's alkalescence according to Shandong Hydrolysis products.
Impurity H: in the synthesis replacing Buddhist nun according to Shandong of Chinese Patent Application No. 201510165869.6 report In method second step amidation process, initiation material acrylic anhydride contains a small amount of propionic andydride impurity, can be with Intermediate-1 reactsGeneration impurity H:
Thus, in one aspect, the present invention relates to following compound:
Compound A, chemical name is: (R)-1-(3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base] piperidin-1-yl)-3-chloropropyl-1-ketone, and have a structure that
Compound B, chemical name is: (R)-8-(1-acryloylpiperidine-3-base)-10-(4-phenoxy group benzene Base)-3,4-dihydro-pyrazolo [4,3-e] pyrimido [1,2-c] pyrimidine-2 (8H)-one, and have a structure that
Compound C, chemical name is: (R)-1-3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base] piperidin-1-yl)-ethyl ketone, and have a structure that
Compound D, chemical name is: (R)-4-(3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base)-piperidines-1-carbonyl) amylene-4-acid, and have a structure that
Compound E, chemical name is: 1-((R)-1-acryloylpiperidine-3-base)-4-amino-3-(4-benzene Phenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-oxide, and have a structure that
Compound F, chemical name is: 1,3-bis-((R)-3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrrole Azoles [3,4-d] pyrimidine-1-base) piperidin-1-yl) propane-1-ketone, and have a structure that
Compound G, chemical name is: 1-((R)-3-(4-((3-((R)-3-(4-amino-3-(4-phenoxy group benzene Base)-1H-pyrazoles [3,4-d] pyrimidine-1-base) piperidin-1-yl)-3-oxopropyl) ammonia)-3-(4-phenoxy group benzene Base)-1H-pyrazoles [3,4-d] pyrimidine-1-base) piperidin-1-yl) propyl group-2-alkene-1-ketone, and have a structure that
Compound H, chemical name is: (R)-1-(3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base)-piperidin-1-yl)-propyl group-1-ketone, and have a structure that
In particular embodiments, above-claimed cpd A-H is unpack format, is preferably the purest Form, more preferably has the purity of greater than about 95%.
On the other hand, the present invention relates to one or more of above-claimed cpd A-H in detection according to Shandong for Buddhist nun Or contain in the sample purity of the pharmaceutical preparation replacing Buddhist nun according to Shandong as reference standard or the application of reference substance, It is wherein 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H pyrrole according to Shandong for the chemical name of Buddhist nun Azoles also [3,4-d] pyrimidine-1-base]-piperidino]-2-propylene-1-ketone, structural formula is:
Accompanying drawing explanation
-3-(4-Phenoxyphenyl)-1-(piperidines-3-base)-1H-pyrazolo [3,4-d] Fig. 1: intermediate-1:(R) Pyrimidine-4-amine1H-NMR；
-3-(4-Phenoxyphenyl)-1-(piperidines-3-base)-1H-pyrazolo [3,4-d] Fig. 2: intermediate-1:(R) The high resolution mass spectrum of pyrimidine-4-amine；
Fig. 3: according to Shandong for Buddhist nun: 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H pyrazolo [3,4-d] Pyrimidine-1-base]-piperidino]-2-propylene-1-ketone1H-NMR；
Fig. 4: according to Shandong for Buddhist nun: 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H pyrazolo [3,4-d] Pyrimidine-1-base]-piperidino] high resolution mass spectrum of-2-propylene-1-ketone.
Fig. 5: impurity A: ((4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] is phonetic for 3-for (R)-1- Pyridine-1-base] piperidin-1-yl)-3-chloropropyl-1-ketone1H-NMR；
Fig. 6: impurity A: ((4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] is phonetic for 3-for (R)-1- Pyridine-1-base] piperidin-1-yl) high resolution mass spectrum of-3-chloropropyl-1-ketone；
Fig. 7: impurity B: (R)-8-(1-acryloylpiperidine-3-base)-10-(4-Phenoxyphenyl)-3,4-bis- Hydrogen pyrazolo [4,3-e] pyrimido [1,2-c] pyrimidine-2 (8H)-one1H-NMR；
Fig. 8: impurity B: (R)-8-(1-acryloylpiperidine-3-base)-10-(4-Phenoxyphenyl)-3,4-bis- The high resolution mass spectrum of hydrogen pyrazolo [4,3-e] pyrimido [1,2-c] pyrimidine-2 (8M)-one；
-1-3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] phonetic Fig. 9: impurity C:(R) Pyridine-1-base] piperidin-1-yl)-ethyl ketone1H-NMR；
-1-3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] phonetic Figure 10: impurity C:(R) Pyridine-1-base] piperidin-1-yl) high resolution mass spectrum of-ethyl ketone.
-4-(3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] Figure 11: impurity D:(R) Pyrimidine-1-base)-piperidines-1-carbonyl) amylene-4-acid1H-NMR；
-4-(3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] Figure 12: impurity D:(R) Pyrimidine-1-base)-piperidines-1-carbonyl) amylene-4-acid high resolution mass spectrum；
-1-(3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] Figure 13: impurity H:((R) Pyrimidine-1-base)-piperidin-1-yl)-propyl group-1-ketone1H-NMR；
-1-(3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] Figure 14: impurity H:(R) Pyrimidine-1-base)-piperidin-1-yl) high resolution mass spectrum of-propyl group-1-ketone；
Figure 15: impurity E: 1-((R)-1-acryloylpiperidine-3-base)-4-amino-3-(4-phenoxy group benzene Base)-1H-pyrazolo [3,4-d] pyrimidine-1-oxide1H-NMR。
Figure 16: impurity E: 1-((R)-1-acryloylpiperidine-3-base)-4-amino-3-(4-phenoxy group benzene Base) high resolution mass spectrum of-1H-pyrazolo [3,4-d] pyrimidine-1-oxide.
Figure 17: impurity F: 1,3-bis-((R)-3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazoles [3,4-d] Pyrimidine-1-base) piperidin-1-yl) propane-1-ketone1H-NMR。
Figure 18: impurity F: 1,3-bis-((R)-3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazoles [3,4-d] Pyrimidine-1-base) piperidin-1-yl) high resolution mass spectrum of propane-1-ketone.
Figure 19: impurity G:1-((R)-3-(4-((3-((R)-3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrrole Azoles [3,4-d] pyrimidine-1-base) piperidin-1-yl)-3-oxopropyl) ammonia)-3-(4-Phenoxyphenyl)-1H-pyrazoles [3,4-d] pyrimidine-1-base) piperidin-1-yl) propyl group-2-alkene-1-ketone1H-NMR。
Figure 20: impurity G:1-((R)-3-(4-((3-((R)-3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrrole Azoles [3,4-d] pyrimidine-1-base) piperidin-1-yl)-3-oxopropyl) ammonia)-3-(4-Phenoxyphenyl)-1H-pyrazoles [3,4-d] pyrimidine-1-base) piperidin-1-yl) high resolution mass spectrum of propyl group-2-alkene-1-ketone；
Detailed description of the invention
In order to the present invention will be described further, will be illustrated by specific embodiment below, but It is that protection scope of the present invention is not constituted any limitation by below example.
Embodiment 1: intermediate-1:(R)-3-(4-Phenoxyphenyl)-1-(piperidines-3-base)-1H-pyrazolo [3, 4-d] synthesis of pyrimidine-4-amine (YLTN-1)
In the reaction bulb of 500mL, add 155mL oxolane, under stirring, be sequentially added into 3-(4- Phenoxyphenyl)-1H-pyrazoles [3,4-D] pyrimidine-4-amine (SM1) (5g, 1eq), (S)-1-tertiary fourth oxygen Carbonyl-3-hydroxy piperidine (SM2) (4.97g, 1.5eq), triphenylphosphine (13g, 3.0eq).Temperature control Under the conditions of 25 DEG C, in 30 minutes, the tetrahydrofuran solution of dropping diisopropyl azodiformate (will 10g, 3.0eq diisopropyl azodiformate is dissolved in the oxolane of 10mL).After being added dropwise to complete, Temperature control 25 DEG C, continues reaction 5 hours (TLC monitors: ethyl acetate: methanol=10: 1).Stirring Lower decompression distillation.Temperature control 15 DEG C, drips 30mL concentrated hydrochloric acid, time for adding 30 points in residue Clock, after being added dropwise to complete, temperature control 25 DEG C, continues reaction 2 hours.By dichloromethane aqueous phase extracted three Secondary (each 75mL), retains aqueous phase.Extract once by 50mL ethyl acetate.Residue aqueous phase fills Divide stirring, temperature control 15 DEG C, drip the sodium hydrate aqueous solution of about 45g 20%, use pH reagent paper prison Measured reaction liquid, pH=5～6 (time for adding about 30 minutes) obtains light yellow solid.Above-mentioned solid is led to Cross ethyl alcohol recrystallization twice, obtain off-white powder 2.87g, yield: 45%.1H-NMR (400Mz, DMSO-d6) δ: 8.226 (s, 1H), 7.656～7.634 (m, 2H), 7.435～7.395 (m, 2H), 7.185～7.094 (m, 5H), 4.689～4.635 (m, 1H), 3.081～3.043 (m, 1H), 2.957～2.930 (m, 1H), 2.901～2.873 (m, 1H), 2.490～2.457 (m, 1H), 2.125～2.015 (m, 2H), 1.750～1.717 (m, 1H), 1.589～1.518 (m, 1H) (referring to Fig. 1)；ESI-HRMS spectrogram shows Molecular ion peak m/z=387.19449 [MW+H]+, corresponding molecular weight and the structural formula of offer Calculated value (387.19279) is consistent.Absolute error is 4.41ppm, in high resolution mass spectrum error Within the scope of.(referring to Fig. 2)
Embodiment 2: replace the preparation of Buddhist nun according to Shandong
Under nitrogen protection, in 100mL there-necked flask, it is sequentially added into 50mL dichloromethane, intermediate-1 (5 G, 1eq), DIPEA (2g, 1.2eq).Under the conditions of temperature control-10 DEG C, start dropping The dichloromethane solution of acrylic anhydride (1.96g, 1.2eq), time for adding 30 minutes, it is added dropwise to complete After, solution is become clarification by muddiness, is incubated-10 DEG C, and (TLC examines completely to be stirred well to raw material reaction Survey, methanol: ethyl acetate: triethylamine=1: 5: 0.05).Reactant liquor 200mL 5% citric acid Solution washing, removes aqueous phase, concentrates and dichloromethane is evaporated off.Get Yi Lu replaces Buddhist nun's crude product: 3.63g.1H-NMR (400Mz, DMSO-d6) δ: 8.259 (s, 1H), 7.654～7.674 (m, 2H), 7.405～7.444 (m, 2H), 7.109～7.195 (m, 5H), 6.676～6.743 (m, 1H), 6.046～6.152 (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 (m, 1H) (referring to Fig. 3)； ESI-HRMS spectrogram display molecular ion peak: 441.20366 [MW+H]+, according to Shandong for Buddhist nun's molecule from The calculated value at sub-peak is: 441.20335 [M+H]+, absolute error is 0.71ppm, meets height Resolution Mass Spectrometry range of error, measured value is consistent with theoretical value.(referring to Fig. 4).
Embodiment 3: impurity A: ((4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] is phonetic for 3-for (R)-1- Pyridine-1-base 1 piperidin-1-yl) synthesis of-3-chloropropyl-1-ketone.
Under nitrogen protection, in the there-necked flask of 100mL, add 50ml dichloromethane, depend under stirring Secondary addition intermediate-1:(R)-3-(4-Phenoxyphenyl)-1-(piperidines-3-base)-1H-pyrazoles [3,4-d] pyrimidine -4-amine (YLTN-1) (1.00g, 1eq), DIPEA (0.40g, 1.2eq), fall Temperature, to-20～-10 DEG C, starts to drip 3-chlorpromazine chloride (1.46g, 1eq), drips complete, solution by Muddy change is clarified, and continues stirring 20～30 minutes, and LC-MS detects, and raw material disappears, distillation of reducing pressure, Dichloromethane being evaporated off extremely steam without fraction, obtain crude product column chromatography method and purify, eluting ratio is: Methanol: ethyl acetate=1: 10, collects eluent 400mL altogether, decompression distillation, solvent is evaporated off to nothing Fraction steams.Obtaining off-white powder 830mg is (R)-1-(3-(4-amino-3-(4-Phenoxyphenyl)-1H- Pyrazolo [3,4-d] pyrimidine-1-base] piperidin-1-yl)-3-chloropropyl-1-ketone.1H-NMR (400Mz, CDCl3) δ: 8.382 (d, J=13.2Hz, 1H), 7.660～7.638 (m, 2H), 7.419～7.380 (m, 2H), 7.200～7.083 (m, 5H), 5.751 (m, 2H), 4.891～4.853 (m, 1H), 4.842～4.812 (m, 0.5H), 4.558 (m, 0.5H), 4.066～4.033 (m, 0.5H), 3.844～3.833 (m, 1H), 3.773～3.746 (m, 0.5H), 3.355 (m, 0.5H), 3.191 (m, 0.5H), 2.877～2.843 (m, 2H), 2.812～2.795 (m, 1H), 2.434～2.270 (m, 2H), 2.048～1.955 (m, 1H), 1.756～1.689 (m, 1H).(referring to Fig. 5) ESI-HRMS spectrogram display molecular ion peak m/z =477.17930 [MW+H]+, corresponding molecular weight and the structural formula calculated value of offer (476.17275) it is consistent.Absolute error is 1.52ppm, within high resolution mass spectrum range of error. (referring to Fig. 6).Impurity A replaces when relatively retaining of Buddhist nun relative to main constituent according to Shandong on HPLC spectrogram Between (RRT) be about 1.06.
Embodiment 4: impurity B: (R)-8-(1-acryloylpiperidine-3-base)-10-(4-Phenoxyphenyl)-3,4-bis- The synthesis of hydrogen pyrazolo [4,3-e] pyrimido [1,2-c] pyrimidine-2 (8H)-one.
Nitrogen is protected, and adds 100ml dichloromethane, under stirring successively in the there-necked flask of 250mL Add intermediate-1:(R)-3-(4-Phenoxyphenyl)-1-(piperidines-3-base)-1H-pyrazoles [3,4-d] pyrimidine-4- Amine (YLTN-1) (2.00g, 1eq), DIPEA (1.30g, 2.0eq) is cooled to -20 DEG C～10 DEG C.Start to drip acrylic anhydride (1.33g, 2eq), dropping process temperature control-10 DEG C with Under；Dripping and finish, continue stirring 20～30 minutes, LC-MS detects, and has target product to generate, temperature control 30～40 DEG C, vacuum :-0.08MPa, decompression distillation, dichloromethane is evaporated off to steaming without fraction； Obtaining crude product column chromatography method to purify, eluting ratio is: methanol∶Ethyl acetate=1: 5, collects eluting Liquid, temperature control 30～40 DEG C, vacuum :-0.08MPa, decompression distillation, solvent is evaporated off and steams to without fraction Go out.Obtaining off-white powder 531mg is (R)-8-(1-acryloylpiperidine-3-base)-10-(4-phenoxy group benzene Base)-3,4-dihydro-pyrazolo [4,3-e] pyrimido [1,2-c] pyrimidine-2 (8H)-one.1H-NMR (400Mz, CDCl3) δ: 8.352 (m, 2H), 7.874 (m, 2H), 7.367～7.328 (m, 2H), 7.144～7.050 (m, 5H), 6.591～6.558 (m, 1H), 6.335～6.293 (m, 1H), 5.747～5.658 (m, 1H), 4.803 (m, 1H), 4.649～4.622 (m, 0.5H), 4.300 (m, 0.5H), 4.333～4.300 (m, 2H), 4.153 (m, 0.5H), 4.051～4.019 (m, 0.5H), 3.751～3.680 (m, 0.5H), 3.354～3.217 (m, 1H), 2.902 (m, 0.5H), 2.789～2.770 (m, 2H), 2.397～2.223 (m, 2H), 2.194 ～2.022 (m, 1H), 2.005～1.718 (m, 1H) (referring to Fig. 7).ESI-HRMS spectrogram display molecule Quasi-molecular ions m/z=495.21580 [MW+H]+, corresponding molecular weight is theoretical with the structural formula of offer Value of calculation (494.20664) is consistent.Absolute error is 3.82ppm, in high resolution mass spectrum range of error Within (referring to Fig. 8).Impurity B is protected for the relative of Buddhist nun according to Shandong relative to main constituent on HPLC spectrogram The time (RRT) is stayed to be about 0.97.
Embodiment 5: impurity C:(R) (4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] is phonetic for-1-3- Pyridine-1-base] piperidin-1-yl) synthesis of-ethyl ketone
By intermediate-1:(R)-3-(4-Phenoxyphenyl)-1-(piperidines-3-base)-1H-pyrazoles [3,4-d] pyrimidine -4-amine (YLTN-1) (2.00g, 1eq) is dissolved in dichloromethane (50ml), adds N, N- Diisopropyl ethyl amine (0.80g, 2eq), is cooled to-10 DEG C, and nitrogen is protected, and drips acetic anhydride (0.53 G, 1eq), finish, react 30 minutes, LC-MS monitors, and reaction completes, by system concentrating under reduced pressure To dry, residue passes through silica gel column chromatography, eluent: ethyl acetate: methanol=10: 1, obtains off-white color Powder 1.38g be (R)-1-3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base] Piperidin-1-yl)-ethyl ketone.1H-NMR (400Mz, CDCl3) δ: 8.352 (d, J=16Hz, 1H), 7.657～7.623 (m, 2H), 7.402～7.364 (m, 2H), 7.187～7.069 (m, 5H), 5.971 (m, 2H), 4.849～4.841 (m, 0.5H), 4.841～4.821 (m, 1H), 4.574～4.541 (m, 0.5H), 4.045～4.005 (m, 0.5H), 3.864～3.831 (m, 0.5H), 3.744～3.685 (m, 0.5H), 3.318～3.253 (m, 0.5H), 3.201～3.141 (m, 0.5H), 2.802～2.745 (m, 0.5H), 2.403～2.249 (m, 2H), 1.962～1.697 (m, 2H) (referring to Fig. 9)；ESI-HRMS spectrogram shows Show molecular ion peak m/z=429.20416 [MW+H]+, corresponding molecular weight and the structure of offer Formula calculated value (428.19607) is consistent.Absolute error is 1.89ppm, at high resolution mass spectrum by mistake (Figure 10 is referred to) within the scope of difference.Impurity C replaces Buddhist nun's relative to main constituent according to Shandong on HPLC spectrogram Relative retention time (RRT) is about 0.96.
Embodiment 6: impurity D:(R) ((4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] is phonetic for 3-for-4- Pyridine-1-base)-piperidines-1-carbonyl) amylene-4-acid synthesis
Under nitrogen protection, will be according to Shandong for Buddhist nun 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H pyrrole Azoles also [3,4-d] pyrimidine-1-base]-piperidino]-2-propylene-1-ketone (2g, 1eq) is dissolved in dichloromethane (50ml), in, it is sequentially added into N, N-diisopropyl ethyl amine (0.70g, 2eq), acrylic acid (0.98 G, 3eq), reaction is warming up to 35 DEG C, stirs 36 hours, is evaporated to do by system, residue By silica gel column chromatography, eluent: ethyl acetate: methanol=8: 1, obtain off-white powder 103mg For (R)-4-(3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base)-piperidines-1- Carbonyl) amylene-4-acid,1H-NMR (400Mz, DMSO-d6) δ: 12.309 (br, 1H), 8.263 (S, 1H), 7.687～7.666 (m, 2H), 7.422～7.461 (m, 2H), 7.122～7.211 (m, 5H), 6.009～6.072 (m, 0.5H), 5.570～5.660 (m, 0.5H), 4.647～4.772 (m, 1H), 4.516～4.547 (m, 0.5H), 4.200-4.232 (m, 0.5H), 4.069-4.101 (m, 0.5H), 3.913～3.945 (m, 0.5H), 3.629-3.655 (m, 0.5H), 3.129～3.157 (m, 1H), 2.878 (m, 0.5H), 2.445-2.513 (m, 4H), 2.206～2.264 (m, 1H), 2.085～2.125 (m, 1H), 1.861～1.936 (m, 1H), 1.522～1.666 (m, 1H) (referring to Figure 11)；ESI-HRMS spectrogram shows Show molecular ion peak m/z=513.22606 [MW+H]+, corresponding molecular weight and the structure of offer Formula calculated value (512.21720) is consistent.Absolute error is 3.09ppm, at high resolution mass spectrum by mistake (Figure 12 is referred to) within the scope of difference.Impurity D replaces Buddhist nun's relative to main constituent according to Shandong on HPLC spectrogram Relative retention time (RRT) is about 1.02.
Embodiment 7: impurity H:(R) ((4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] is phonetic for 3-for-1- Pyridine-1-base)-piperidin-1-yl) synthesis of-propyl group-1-ketone
Under nitrogen protection, by intermediate-1:(R)-3-(4-Phenoxyphenyl)-1-(piperidines-3-base)-1H-pyrrole Azoles [3,4-d] pyrimidine-4-amine (YLTN-1) (2.00g, 1eq) dissolves in dichloromethane (50mL), Adding N, N-diisopropyl ethyl amine (0.80g, 2eq), be cooled to-10 DEG C, nitrogen is protected, and drips third Anhydride (0.67g, 1eq), finishes, and reacts 30 minutes, and LC-MS monitors, and reaction completes, by system Be evaporated to do, residue pass through silica gel column chromatography, eluent: ethyl acetate: methanol=10: 1, Obtaining lightpink powder 1.72g is (R)-1-(3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] Pyrimidine-1-base)-piperidin-1-yl)-propyl group-1-ketone.1H-NMR (400Mz, CDCl3) δ: 8.338～8.302 (m, 2H), 7.658～7.627 (m, 2H), 7.440～7.400 (m, 2H), 7.224～7.097 (m, 5H), 4.881～4.634 (m, 1H), 4.881～4.826 (m, 1H), 4.108～3.094 (m, 1H), 2.762 (m, 1H), 3.310～3.167 (m, 1H), 2.452～2.315 (m, 4H), 1.213～1.157 (m, 3H), 2.069～1.691 (m, 2H) (referring to Figure 13)；ESI-HRMS Spectrogram display molecular ion peak m/z=443.25380 [MW+H]+, corresponding molecular weight and offer Structural formula calculated value (442.21172) be consistent.Absolute error is 3.66ppm, at high-resolution (Figure 14 is referred to) within mass spectrum range of error.Impurity H on HPLC spectrogram relative main constituent according to Shandong Relative retention time (RRT) for Buddhist nun is about 1.04.
Embodiment 8: impurity E: 1-((R)-1-acryloylpiperidine-3-base)-4-amino-3-(4-phenoxy group benzene Base) preparation of-1H-pyrazolo [3,4-d] pyrimidine-1-oxide
(1) preparation of impurity E
Prepared by Example 2 replaces Buddhist nun about 5.17g according to Shandong, puts in 500ml reaction bulb, adds 150ml 80% Acetonitrile-water dissolves, then adds 30% hydrogen peroxide 30ml, stirred overnight at room temperature, and reaction terminates, to reaction Adding sodium thiosulfate in liquid, produce to bubble-free, 35 DEG C are evaporated to no liquid and flow out, then add The ethyl acetate of 3 times of aqueous phase volumes, extraction, collect organic facies, merge, 35 DEG C are evaporated to do, Get Yi Lu replaces Buddhist nun impurity E crude product 2.65g.LC-MS detection crude product purity is 51.26%, liquid chromatograph On relative to being 0.98 according to Shandong for the relative retention time of Ni Feng, mass-to-charge ratio [MW+H]+It is 457.2.Miscellaneous Matter E1H-NMR figure sees Figure 15, and high resolution mass spectrum sees Figure 16.
(2) purification of impurity E crude product
The impurity E crude product DMSO of above-mentioned for 2.95g preparation is dissolved into concentration and is about 150mg/ml Solution, use following preparative chromatography to be further purified:
Chromatographic column (purchased from Ai Jieer science and technology): use the C18 filler of particle diameter 10 μm, use isopropanol Post (50mm × 250mm) is filled after homogenate；
Flowing phase: water and acetonitrile
Flow velocity: 120ml/min；
Detection wavelength: 254nm；
Sample size: 10ml
Gradient elution, elution program is:
Time (min) Mobile phase A (%) Mobile phase B (%)
0 65 35
10 65 35
30 45 55
50 45 55
50.01 20 80
55 20 80
55.01 65 35
60 65 35
Collect the fraction corresponding to peak that retention time is 30～37min；LC-MS or HPLC detects The purity of impurity E.
Fraction collected by 35 DEG C of concentrating under reduced pressure flows out to no liquid, adds the ethyl acetate of 3 times of volumes Extraction, collects organic facies, merges, adds anhydrous sodium sulfate and be dried, and filters, 30 DEG C of concentrating under reduced pressure of filtrate To dry, obtaining 2.06g light pink solid, measure through HPLC, purity is 98.97%, and total recovery is 36.6%.
(3) Structural Identification of impurity E
The high resolution mass spectrum (ESI source) of impurity E shows its mass-to-charge ratio [M+H]+It is 457.19930, Corresponding molecular weight is 2.27 with the absolute error of the structural formula calculated value 456.19099 of offer Ppm, meets the range of error of high resolution mass spectrum.The structure of Buddhist nun is replaced according to Shandong, in conjunction with miscellaneous with reference to formula (2) Matter E1H-NMR、13C-NMR spectrum identifies that its structural formula is as shown in following formula E.
Impurity E high resolution mass spectrum shows its molecular weight and is consistent completely with the molecular formula provided；
The nuclear magnetic resonance, NMR of table 1 impurity E1H-NMR、13C-NMR analysis result
Information shown by the proton nmr spectra of impurity E, carbon spectrum can be to the formula E chemical combination provided On thing molecular structural formula, hydrogen, carbon all belong to.Therefore, according to Shandong for Buddhist nun's impurity E and formula E provided Molecular structural formula is consistent.
Embodiment 9: impurity F: 1,3-bis-((R)-3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazoles [3,4-d] Pyrimidine-1-base) piperidin-1-yl) propane-1-ketone and impurity G:1-((R)-3-(4-((3-((R)-3-(4-amino-3-(4- Phenoxyphenyl)-1H-pyrazoles [3,4-d] pyrimidine-1-base) piperidin-1-yl)-3-oxopropyl) nitrogen)-3-(4-benzene Phenyl)-1H-pyrazoles [3,4-d] pyrimidine-1-base) piperidin-1-yl) preparation of propyl group-2-alkene-1-ketone.
(1) impurity F and the preparation of impurity G
Add the preparation of about 20g embodiment 2 in 1000ml reaction bulb replaces Buddhist nun according to Shandong, adds 250ml Acetonitrile and 200ml 5M sodium hydrate aqueous solution, 80 DEG C of heating in water bath for reaction 40min, it is cooled to room Temperature, adds 5M HCl and is neutralized to neutrality, and 35 DEG C are evaporated to no liquid and reserve, and adds 5 times of aqueous phases The ethyl acetate extraction of volume, collects upper organic phase, merges, and 35 DEG C are evaporated to do, obtain According to Shandong for Buddhist nun's impurity F, G crude product 18.72g, LC-MS detects crude product purity, according to corresponding MS ion Peak, relative to replacing the relative retention time of Ni Feng to be about 0.94 (impurity F) and 1.15 according to Shandong in liquid chromatograph The peak of (impurity G) is object, and the content in its crude product is respectively 16.9% (impurity F) and 18.4% (impurity G).Impurity F1H-NMR figure sees Figure 17, and high resolution mass spectrum sees Figure 18.Impurity G 's1H-NMR figure sees Figure 19, and high resolution mass spectrum sees Figure 20.
(2) impurity F and the purification of impurity G crude product
The 18.72g impurity F of above-mentioned preparation, the crude product of G are added DMSO and are dissolved into the solution of 10ml, Loading；
Middle compacting is for post (purchased from Agela company): Agela XBP C18 filler, 480g, filler grain Footpath: 20～35 μm
Flowing phase: water (0.05%TFA) and pure acetonitrile
Flow velocity: 40ml/min
Detection wavelength: 254nm
Applied sample amount :～5g
Gradient elution, elution program is:
Time (min) Mobile phase A (%) Mobile phase B (%)
0 75 25
5 75 25
30 65 35
40 65 35
50 50 50
55 50 50
55.01 75 25
60 75 25
Collecting the fraction at all peaks respectively, LC-MS or HPLC confirms target product.Collect The fraction (impurity F) of 30～33min and the fraction (impurity G) of 40～44min, merge identical fraction, Concentrating under reduced pressure respectively, flows out to no liquid, adds the ethyl acetate extraction of 3 times of volumes, receive in aqueous phase Collection organic facies, adds anhydrous sodium sulfate and is dried, and filters, and collects filtrate.It is evaporated to do, respectively Buddhist nun impurity G secondary separation crude product 2.57g is replaced for Buddhist nun's impurity F sterling 2.21g and Yi Lu according to Shandong.Warp LC-MS or HPLC detects analysis, and the purity replacing Buddhist nun's impurity F according to Shandong is 98.15%, according to Shandong for Buddhist nun The purity of impurity G secondary separation crude product is 85.32%.
(3) secondary separation of impurity G
The 2.57g of above-mentioned preparation adds 10ml DMSO according to Shandong for Buddhist nun's impurity G secondary separation crude product and dissolves The condition used for Buddhist nun's impurity G secondary separation according to Shandong is:
Chromatographic column: Waters XBridge C830mm × 100mm, 5 μm
Flowing phase: water and acetonitrile
Detection wavelength: 254nm
Flow velocity: 25ml/min
Gradient elution, elution program is as follows:
Time (min) Mobile phase A (%) Mobile phase B (%)
0 75 25
5 75 25
15 35 65
25 35 65
25.01 75 25
30 75 25
Sampling volume: 2ml/ time every time；
Collect retention time 26min～the fraction of 30min, and confirm object purity with LC-MS. Merge identical fraction, 35 DEG C be evaporated to without acetonitrile flow out, add 3 times of volumes ethyl acetate extraction, Merge organic facies, add anhydrous sodium sulfate and be dried, filter, be evaporated to do, obtain according to Shandong miscellaneous for Buddhist nun Matter G sterling 1.64g, off-white color pressed powder, LC-MS detection purity is 95.13%.
(4) Structural Identification of impurity F
The high resolution mass spectrum (ESI source) of impurity F shows its mass-to-charge ratio [M+H]+It is 827.39065, Corresponding molecular weight with the absolute error of the structural formula calculated value 826.34520 of offer is 2.16ppm, meets the range of error of high resolution mass spectrum.The high resolution mass spectrum of sample shows its molecular weight It is consistent completely with the molecular formula provided.Reference replaces the structure of Buddhist nun according to Shandong, in conjunction with this product1H-NMR、13C-NMR, H-HCOSY, HMBC, HSQC, DEPT spectrum identifies its structure Formula is as shown in following formula F.
Table 2 is impurity F1H-NMR, H-HCOSY and HMBC resolve data
Table 3 impurity F13C-NMR, DEPT, HSQC, HMBC data parsing
By sample1H-NMR, H-HCOSY and HMBC spectrum understands, Hydrogen Proton in its structure Number is consistent with the structure of formula F compound.By sample13C-NMR, DEPT, HSQC and HMBC Spectrum understands, and the carbon number in its structure is consistent with the structure of formula F compound.Nucleus magnetic hydrogen spectrum, carbon spectrum with And the hydrogen on structural formula can rationally be belonged to carbon and associate by two-dimensional spectrum data.
(5) Structural Identification of impurity G
The high resolution mass spectrum (ESI source) of impurity G shows its mass-to-charge ratio [M+H]+It is 881.40140, Corresponding molecular weight with the absolute error of the structural formula calculated value 880.39215 of offer is 1.43ppm, meets the range of error of high resolution mass spectrum.The high resolution mass spectrum of sample shows its molecular weight It is consistent completely with the molecular formula provided.In conjunction with according to Shandong for the structure of Buddhist nun, in conjunction with this product1H-NMR、13C-NMR, DEPT, H-HCOSY, HMBC and hsqc spectrum identify its structure As shown in following formula G.
Table 4 is impurity G's1H-NMR, H-HCOSY and HMBC data and hydrogen ownership
Table 5 is impurity G's13C-NMR, DEPT, HSQC and HMBC data and carbon ownership
According to sample1H-NMR composes, combines knowable to H-HCOSY, HMBC two-dimensional spectrum, its knot In structure, Hydrogen Proton number is consistent with the structure of formula G compound.By sample13C-NMR、DEPT、 HSQC and HMBC spectrum understands, and the carbon number in its structure is consistent with the structure of formula G compound.
Embodiment 10: impurity A-H according to Shandong for application as reference substance in Buddhist nun's defects inspecting
(1) preparation of impurity A-H contrast solution:
Impurity A-the H taking above-mentioned preparation is appropriate, accurately weighed, puts respectively in 100ml volumetric flask, adds Acetonitrile (wherein impurity F and G add 2～4ml DMSO) is ultrasonic in right amount makes dissolving, then adds acetonitrile constant volume To scale, shake up, be respectively prepared the solution of each about 10 μ g of the impure A-H of every 1ml, more accurate amount Take this solution 1.0ml, put in 10ml volumetric flask, add 80% acetonitrile-water and be diluted to scale, shake up, Both respectively containing according to Shandong for the reference substance solution of Buddhist nun impurity A-H.
(2) preparation of need testing solution:
Above-mentioned preparation according to Shandong for the preparation of Buddhist nun's crude product need testing solution: take prepared by above-described embodiment depends on Buddhist nun sample crude product about 10mg is replaced in Shandong, accurately weighed, puts in 10ml volumetric flask, adds 80% acetonitrile-water Dissolve and be settled to scale, shaking up, making every 1ml and contain the solution replacing Buddhist nun about 1mg according to Shandong, as depending on Buddhist nun's crude drug need testing solution is replaced in Shandong.
According to Shandong for the preparation of Buddhist nun's capsule need testing solution: take according to Shandong that (Imbruvica is purchased from for Buddhist nun's capsule Pharmacyclics Janssen company, 140mg, lot number: L0404951) content fine powder (contains in right amount According to Shandong for Buddhist nun about 10mg), accurately weighed, put in 10m1 volumetric flask, add 80% acetonitrile-water and dissolve also It is settled to scale, shakes up, filter, discard just filtrate 2ml, take subsequent filtrate and replace Buddhist nun's capsule as according to Shandong Need testing solution.
(3) chromatographic condition is as follows:
With octyl group silane group silica gel C8 post (4.6 × 250mm, 5 μm) as chromatographic column (purchased from Ai Jieer Science and technology), flowing is mutually: water (0.05%TFA) and acetonitrile, and flow velocity is 1.2ml/min, detects wavelength 254nm, column temperature 35 DEG C, gradient elution, elution program is as follows:
Time (min) Mobile phase A (%) Mobile phase B (%)
0 80 20
3 80 20
15 20 80
22 20 80
22.01 80 20
30 80 20
(4) test procedure: take above-mentioned impurity contrast solution and need testing solution 10 μ l, be injected separately into liquid phase color Spectrometer (purchased from Agilent company of the U.S., model 1260) or LC-MS instrument (Agilent company of the U.S., Agilent 6120), record chromatogram, retain for the relative of Buddhist nun according to Shandong relative to main constituent according to each impurity Time carries out qualitative, according to external standard method (Chinese Pharmacopoeia version in 2010, two, annex V D) meter Calculate the content of impurity A-H.
(4) result of the test:
The most commercially available according to Shandong for impurity analysis of spectrum in Buddhist nun's capsule:
Sequence number Content (%) [MW+H]+ Impurity belongs to Relative retention time
The impurity 1 detected 0.01 429.2 C 0.96
The impurity 2 detected 0.05 495.2 B 0.97
The impurity 3 detected 0.05 443.2 H 1.04
The impurity 4 detected 0.12 477.2 A 1.06
The impurity 5 detected 0.13 414.2/827.4 F 0.94
The impurity 6 detected 0.04 441.3/881.3 Unknown impuritie 1.03
The impurity 7 detected 0.08 441.3/881.6 G 1.15
The impurity analysis of spectrum replacing Buddhist nun's crude product according to Shandong of the most above-mentioned preparation
Sequence number Content (%) [MW+H]+ Impurity belongs to Relative retention time
The impurity 1 detected 0.01 429.2 C 0.96
The impurity 2 detected 0.41 495.2 B 0.97
The impurity 3 detected 0.70 443.2 H 1.04
The impurity 4 detected 0.06 513.2 D 1.02
The impurity 5 detected 0.14 414.2/827.4 F 0.94
The impurity 6 detected 0.07 441.3/881.3 Unknown impuritie 1.03
The impurity 7 detected 0.03 441.3/881.6 G 1.15
The impurity 8 detected 0.07 457.2 E 0.98
It should be noted that all documents mentioned in the present invention are incorporated as reference in this application, It is individually recited as with reference to like that just as each document.In addition, it is to be understood that above-described it is The present invention is embodied as row and the know-why used, after having read present disclosure, this Skilled person the present invention can be made various change or amendment without departing from the present invention spirit with Scope, these equivalent form of values also fall within the scope of the present invention.

Claims (10)

1. compound A, chemical name is: (R)-1-(3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base] piperidin-1-yl)-3-chloropropyl-1-ketone, and have a structure that
2. compound B; chemical name is: (R)-8-(1-acryloylpiperidine-3-base)-10-(4-Phenoxyphenyl)-3,4-dihydro-pyrazolo [4,3-e] pyrimido [1; 2-c] pyrimidine-2 (8H)-one, and have a structure that
3. compound C, chemical name is: (R)-1-3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base] piperidin-1-yl)-ethyl ketone, and have a structure that
4. compound D, chemical name is: (R)-4-(3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base)-piperidines-1-carbonyl) amylene-4-acid, and have a structure that
5. compound E, chemical name is: 1-((R)-1-acryloylpiperidine-3-base)-4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-oxide, and has a structure that
6. compound F, chemical name is: 1,3-bis-((R)-3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazoles [3,4-d] pyrimidine-1-base) piperidin-1-yl) propane-1-ketone, and have a structure that
7. compound G, chemical name is: 1-((R)-3-(4-((3-((R)-3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazoles [3,4-d] pyrimidine-1-base) piperidin-1-yl)-3-oxopropyl) ammonia)-3-(4-Phenoxyphenyl)-1H-pyrazoles [3,4-d] pyrimidine-1-base) piperidin-1-yl) propyl group-2-alkene-1-ketone, and have a structure that
8. compound H, chemical name is: (R)-1-(3-(4-amino-3-(4-Phenoxyphenyl)-1H-pyrazolo [3,4-d] pyrimidine-1-base)-piperidin-1-yl)-propyl group-1-ketone, and have a structure that
。
9., according to the compound according to any one of claim 1～8, for unpack format, it is preferably the purest form, more preferably there is the purity of greater than about 95%.
10. according to the compound according to any one of claim 1～9 one or more detection according to Shandong for Buddhist nun or containing according to Shandong for Buddhist nun pharmaceutical preparation sample purity in as reference standard or the application of reference substance, it is wherein 1-[(3R)-3-[4-amino-3-(4-Phenoxyphenyl)-1H pyrazolo [3 according to Shandong for the chemical name of Buddhist nun, 4-d] pyrimidine-1-base]-piperidino]-2-propylene-1-ketone, structural formula is:
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CN107014943A (en) * 2017-06-07 2017-08-04 福建省微生物研究所 It is a kind of according to Shandong replace Buddhist nun's enantiomter detection method
CN108440540A (en) * 2018-05-16 2018-08-24 杭州中美华东制药有限公司 A kind of her cloth is for Buddhist nun's compound and preparation method thereof
CN108623602A (en) * 2018-05-31 2018-10-09 厦门医学院 A method of prepare and purify and replaces Buddhist nun according to Shandong
CN115716832A (en) * 2021-08-25 2023-02-28 深圳鼎邦化学品有限公司 Preparation method and application of ibrutinib impurity
CN116120346A (en) * 2022-12-30 2023-05-16 浙江美诺华药物化学有限公司 Synthesis method of ibrutinib impurity compound
CN116217594A (en) * 2022-12-30 2023-06-06 浙江美诺华药物化学有限公司 Synthesis method of ibrutinib dimer impurity

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CN104407067A (en) * 2014-11-17 2015-03-11 广东东阳光药业有限公司 Ibrutinib and test method of isomer of ibrutinib

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107014943A (en) * 2017-06-07 2017-08-04 福建省微生物研究所 It is a kind of according to Shandong replace Buddhist nun's enantiomter detection method
CN108440540A (en) * 2018-05-16 2018-08-24 杭州中美华东制药有限公司 A kind of her cloth is for Buddhist nun's compound and preparation method thereof
CN108623602A (en) * 2018-05-31 2018-10-09 厦门医学院 A method of prepare and purify and replaces Buddhist nun according to Shandong
CN108623602B (en) * 2018-05-31 2020-07-17 厦门医学院 Method for preparing and purifying ibrutinib
CN115716832A (en) * 2021-08-25 2023-02-28 深圳鼎邦化学品有限公司 Preparation method and application of ibrutinib impurity
CN116120346A (en) * 2022-12-30 2023-05-16 浙江美诺华药物化学有限公司 Synthesis method of ibrutinib impurity compound
CN116217594A (en) * 2022-12-30 2023-06-06 浙江美诺华药物化学有限公司 Synthesis method of ibrutinib dimer impurity

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