CN110759915A - Preparation method of ibrutinib - Google Patents
Preparation method of ibrutinib Download PDFInfo
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- CN110759915A CN110759915A CN201910838433.7A CN201910838433A CN110759915A CN 110759915 A CN110759915 A CN 110759915A CN 201910838433 A CN201910838433 A CN 201910838433A CN 110759915 A CN110759915 A CN 110759915A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 51
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 title claims abstract description 31
- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 title claims abstract description 31
- 229960001507 ibrutinib Drugs 0.000 title claims abstract description 31
- 238000002156 mixing Methods 0.000 claims abstract description 17
- 239000003054 catalyst Substances 0.000 claims abstract description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000003756 stirring Methods 0.000 claims abstract description 14
- FFNKBQRKZRMYCL-UHFFFAOYSA-N 5-amino-1h-pyrazole-4-carbonitrile Chemical compound NC1=NNC=C1C#N FFNKBQRKZRMYCL-UHFFFAOYSA-N 0.000 claims abstract description 12
- XPOLVIIHTDKJRY-UHFFFAOYSA-N acetic acid;methanimidamide Chemical compound NC=N.CC(O)=O XPOLVIIHTDKJRY-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 12
- 239000003960 organic solvent Substances 0.000 claims abstract description 12
- 238000001514 detection method Methods 0.000 claims abstract description 8
- 239000000203 mixture Substances 0.000 claims abstract description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 7
- 238000011049 filling Methods 0.000 claims abstract description 4
- 238000007789 sealing Methods 0.000 claims abstract description 4
- 230000001954 sterilising effect Effects 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 41
- 239000000243 solution Substances 0.000 claims description 31
- 239000007787 solid Substances 0.000 claims description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 11
- -1 4-phenoxyphenyl vinylene dicyanomethane compound Chemical class 0.000 claims description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 238000000605 extraction Methods 0.000 claims description 8
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical class O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 4
- 238000007363 ring formation reaction Methods 0.000 claims description 4
- 239000007868 Raney catalyst Substances 0.000 claims description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 3
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 3
- 229960000583 acetic acid Drugs 0.000 claims description 3
- 239000003638 chemical reducing agent Substances 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 238000010790 dilution Methods 0.000 claims description 3
- 239000012895 dilution Substances 0.000 claims description 3
- 239000012362 glacial acetic acid Substances 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 239000007791 liquid phase Substances 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 238000010791 quenching Methods 0.000 claims description 3
- 230000000171 quenching effect Effects 0.000 claims description 3
- 239000011780 sodium chloride Substances 0.000 claims description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 2
- 230000000284 resting effect Effects 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 230000035484 reaction time Effects 0.000 abstract description 3
- 239000000047 product Substances 0.000 description 21
- 239000006227 byproduct Substances 0.000 description 7
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 2
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- AQSCHALQLXXKKC-UHFFFAOYSA-N 4-phenylmethoxybenzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1OCC1=CC=CC=C1 AQSCHALQLXXKKC-UHFFFAOYSA-N 0.000 description 1
- 229940125814 BTK kinase inhibitor Drugs 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 239000012611 container material Substances 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- LKPFBGKZCCBZDK-UHFFFAOYSA-N n-hydroxypiperidine Chemical compound ON1CCCCC1 LKPFBGKZCCBZDK-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
Classifications
-
- 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
Abstract
The invention relates to the technical field of ibrutinib preparation, and discloses a preparation method of ibrutinib, which comprises the following steps: 1) preparing a preparation container, sterilizing the preparation container, performing sealing detection, preheating after detection, filling nitrogen into the preparation container after preheating is completed, pouring an organic solvent along the inner wall of the preparation container, pouring 3-amino-4-cyanopyrazole, mixing and stirring, adding formamidine acetate after stirring is completed, and uniformly mixing to obtain a mixture. According to the preparation method of ibrutinib, in the step 1), the nitrogen is filled in the preparation container, and the organic solvent is poured along the inner wall in the preparation container, so that the phenomenon that air enters the equipment to react and influences the product quality can be effectively avoided, and in the step 2), the catalyst and the cyclizing agent are added, so that the preparation efficiency of the equipment can be effectively improved, the reaction time of the equipment is shortened, and the production efficiency is improved.
Description
Technical Field
The invention relates to the technical field of ibrutinib preparation, and particularly relates to a preparation method of ibrutinib.
Background
Ibrutinib, molecular formula C25H24N6O2, molecular weight 440.50, having the structure shown in formula I, chemical name 1- [ (3R) -3- (4-amino-3- (4-phenoxyphenyl) -1H-pyrazolo [3, 4-d ] pyrimidin-1-yl) -1-piperidinyl) -2-propen-1-one, ibrutinib is a pioneer drug of oral bruton's tyrosine kinase inhibitor developed and marketed by us and qiangsheng company in combination, which irreversibly inhibits Btk by selectively covalently binding to the target protein Btk active site cysteine residue (Cys-481), thus effectively preventing tumor migration from B cells to lymphoid tissues adapted to the tumor growth environment, since FDA was obtained for approval on day 11/13 in 2013, ibrutinib has been approved for 5 indications up to now, such as Mantle Cell Lymphoma (MCL), Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL), in the united states.
At present, CN 105859728B in Chinese patent proposes a synthetic method of ibrutinib, which uses 4-benzyloxy benzoic acid as a starting material, and performs acylation to obtain acyl chloride, the acyl chloride reacts with malononitrile to obtain an intermediate 7, the intermediate 7 reacts with TMSCH2N2 to obtain an intermediate 8, the intermediate 8 performs a ring-closing reaction with hydrazine hydrate to obtain an intermediate 9, the intermediate 9 performs a high-temperature reaction in methylamine to obtain an intermediate 4, the intermediate 4 and piperidinol perform Mitsunobu reaction and then perform deprotection to obtain an intermediate 5, and finally the intermediate 5 performs amidation with acryloyl chloride to obtain a target product of ibrutinib.
Disclosure of Invention
Technical problem to be solved
Aiming at the defects of the prior art, the invention provides the preparation method of ibrutinib, which has the advantages of high production efficiency, high product purity and the like, and solves the problems that the existing preparation method is easy to generate a large amount of byproducts, low in total yield and difficult to realize the industrial production requirement.
(II) technical scheme
In order to realize the purposes of high production efficiency and high product purity, the invention provides the following technical scheme: a preparation method of ibrutinib comprises the following steps:
1) preparing a preparation container, sterilizing the preparation container, performing sealing detection, preheating after detection, filling nitrogen into the preparation container after preheating is completed, pouring an organic solvent along the inner wall of the preparation container, pouring 3-amino-4-cyanopyrazole, mixing and stirring, adding formamidine acetate after stirring is completed, and uniformly mixing to obtain a mixture;
2) carrying out thermal reaction on 3-amino-4-cyanopyrazole and formamidine acetate in the step 1), cooling the mixture to room temperature after the reaction is finished to separate out a white solid, filtering out the white solid, mixing the white solid and N-halogenated succinimide in a reaction container, adding a catalyst and a cyclizing agent, adding a PH reagent to neutralize, stirring at room temperature until the reaction is finished, concentrating the solvent, filtering the concentrated solvent, adding anhydrous sodium sulfate into the filtrate to dry, standing for a period of time, drying, and finally obtaining an intermediate 1;
3) dissolving the intermediate 1 in the step 2) in dichloromethane, adding glacial acetic acid and a reducing agent, reacting at room temperature until the reaction is finished, adding a saturated sodium carbonate solution to adjust the pH of the reaction system to be alkaline, finally adding ethyl acetate, adding a catalyst, uniformly mixing, finally extracting, standing the solution obtained by the extraction for a period of time, layering, extracting an upper layer solution, and concentrating to obtain an intermediate 2;
4) putting the intermediate 2 obtained in the step 3) and the 4-phenoxyphenyl vinylene dicyanomethane compound into a reaction kettle for mixing, uniformly stirring, and carrying out cyclization reaction to obtain an intermediate 3;
5) placing the intermediate 3 obtained in the step 4) and a cyclizing agent together into a constant-temperature heating magnetic stirrer or a microwave synthesizer for reaction at 60-120 ℃, adding a protected sodium chloride solution for dilution after the reaction is finished, adding ethyl acetate for extraction, washing, standing and layering, extracting an upper-layer solution by using equipment, washing by using a saturated sodium chloride solution, standing and layering, finally extracting the upper-layer solution, and placing the upper-layer solution into concentration equipment for purification to obtain a white solid, namely ibrutinib.
Preferably, the raw materials comprise 3-amino-4-cyanopyrazole, N-halogenated succinimide, acrylic ester, 4-phenoxyphenyl vinylene dicyanomethane compound, formamidine acetate, cyclizing agent, catalyst and organic solvent.
Preferably, the catalyst is one of palladium carbon or raney nickel.
Preferably, anhydrous sodium sulfate is added into the filtrate in the step 2) for drying, and the rest time is twenty-five to thirty-five minutes.
Preferably, the 3-amino-4-cyanopyrazole is thermally reacted with the formamidine acetate in the step 2), and the thermal reaction temperature is one hundred ℃.
Preferably, the reagent for adjusting the PH in step 2) and step 3) is one of halogenated acid and trifluoroacetic acid.
Preferably, the volume ratio of the white solid mixed with the N-halogenated succinimide in the step 2) is one to one.
Preferably, the treatment method for filtering out the white solid in the step 2) comprises quenching the reaction, separating solid from liquid, and concentrating and recrystallizing the liquid phase to obtain the white solid.
Preferably, the organic solvent in step 1) is dimethyl sulfoxide.
(III) advantageous effects
Compared with the prior art, the invention provides a preparation method of ibrutinib, which has the following beneficial effects:
1. according to the preparation method of ibrutinib, in the step 1), nitrogen is filled in the preparation container, and an organic solvent is poured along the inner wall in the preparation container, so that air can be effectively prevented from entering the interior of equipment to react, the product quality is influenced, in the step 2), a catalyst and a cyclizing agent are added, the preparation efficiency of the equipment can be effectively improved, the reaction time of the equipment is shortened, the production efficiency is improved, the phenomenon of excessive reaction in the reaction process of the product during long-time reaction is avoided, the purity of the product can be effectively improved by performing two extraction and washing in the steps 3) and 5), and impurities generated by the reaction are effectively provided.
2. According to the preparation method of ibrutinib, in the preparation process of the product, the temperature of the product is below one hundred ℃, the phenomenon that a large number of byproducts are generated at high temperature can be effectively avoided, the purity of the product is effectively improved, the production efficiency of the product is improved, the reagent for adjusting the pH value in the step 2) and the step 3) is one of halogenated acid and trifluoroacetic acid, the influence on the product quality when the pH reagent is adjusted can be effectively reduced, the saturated sodium chloride solution is used for washing, the upper-layer solution is extracted after standing and layering, the incomplete phenomenon when the lower-layer solution is discharged can be effectively avoided, the phenomenon of byproducts generated in the preparation of the product can be further avoided, and the problems that the existing preparation method easily generates a large number of byproducts, the total yield is low, and the requirement of industrial production is difficult to achieve are solved.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
A preparation method of ibrutinib comprises the following steps:
1) preparing a preparation container and raw material medicaments, wherein the raw materials comprise 3-amino-4-cyanopyrazole, N-halogenated succinimide, acrylic ester, a 4-phenoxyphenyl vinylidene dicyanomethane compound, formamidine acetate, a cyclizing agent, a catalyst and an organic solvent, sterilizing the preparation container, performing sealing detection, preheating after the detection is finished, filling nitrogen into the equipment after the preheating is finished, pouring the organic solvent which is dimethyl sulfoxide into the preparation container along the inner wall, pouring 3-amino-4-cyanopyrazole into the preparation container, mixing and stirring, adding formamidine acetate after the stirring is finished, and uniformly mixing to obtain a mixture;
2) performing thermal reaction on 3-amino-4-cyanopyrazole and formamidine acetate in the step 1), wherein the thermal reaction temperature is one hundred ℃, cooling the mixture to room temperature after the reaction is finished to separate out white solid, filtering out the white solid, and the white solid is treated by quenching the reaction, performing solid-liquid separation, concentrating and recrystallizing a liquid phase to obtain the white solid, placing the white solid and N-halogenated succinimide in a reaction container for mixing, adding a catalyst and a cyclizing agent, wherein the catalyst is one of palladium carbon or Raney nickel, adding a PH reagent for neutralization, the reagent for regulating the PH value is one of halogenated acid and trifluoroacetic acid, stirring at room temperature until the reaction is finished, concentrating the solvent, and filtering the concentrated solvent, adding anhydrous sodium sulfate into the filtrate for drying, standing for a period of time, adding anhydrous sodium sulfate into the filtrate for drying, wherein the standing time is twenty-five to thirty-five minutes, and drying to obtain an intermediate 1;
3) dissolving the intermediate 1 in the step 2) in dichloromethane, adding glacial acetic acid and a reducing agent, reacting at room temperature until the reaction is finished, adding a saturated sodium carbonate solution to adjust the pH of the reaction system to be alkaline, finally adding ethyl acetate, adding a catalyst, uniformly mixing, finally extracting, standing the solution obtained by the extraction for a period of time, layering, extracting an upper layer solution, and concentrating to obtain an intermediate 2;
4) putting the intermediate 2 obtained in the step 3) and the 4-phenoxyphenyl vinylene dicyanomethane compound into a reaction kettle for mixing, uniformly stirring, and carrying out cyclization reaction to obtain an intermediate 3;
5) placing the intermediate 3 obtained in the step 4) and a cyclizing agent together into a constant-temperature heating magnetic stirrer or a microwave synthesizer for reaction at 60-120 ℃, adding a protected sodium chloride solution for dilution after the reaction is finished, adding ethyl acetate for extraction, washing, standing and layering, extracting an upper-layer solution by using equipment, washing by using a saturated sodium chloride solution, standing and layering, finally extracting the upper-layer solution, and placing the upper-layer solution into concentration equipment for purification to obtain a white solid, namely ibrutinib.
The invention has the beneficial effects that: according to the preparation method of ibrutinib, in the step 1), nitrogen is filled in the preparation container, and an organic solvent is poured along the inner wall in the preparation container, so that air can be effectively prevented from entering the interior of equipment to react, the product quality is influenced, in the step 2), a catalyst and a cyclizing agent are added, the preparation efficiency of the equipment can be effectively improved, the reaction time of the equipment is shortened, the production efficiency is improved, the phenomenon of excessive reaction in the reaction process of the product during long-time reaction is avoided, the purity of the product can be effectively improved by performing two extraction and washing in the steps 3) and 5), and impurities generated by the reaction are effectively provided.
In addition, the preparation method of the ibrutinib can effectively avoid the phenomenon that a large amount of byproducts are generated at high temperature, effectively improve the purity of the product and the production efficiency of the product by keeping the temperature of the product below one hundred ℃ in the preparation process of the product, by setting the pH value adjusting reagent in the steps 2) and 3) as one of halogenated acid and trifluoroacetic acid, the pH value adjusting reagent can be effectively reduced, the influence on the product quality is that the saturated sodium chloride solution is used for washing, and the upper solution is extracted after standing and layering, so that the phenomenon that the lower solution is not completely discharged can be effectively avoided, the phenomenon of byproducts generated in the preparation of the product can be further avoided, and the problems that a large amount of byproducts are easily generated in the existing preparation method, the total yield is low, and the industrial production requirement is difficult to realize are solved.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (9)
1. A preparation method of ibrutinib is characterized by comprising the following steps:
1) preparing a preparation container, sterilizing the preparation container, performing sealing detection, preheating after detection, filling nitrogen into the preparation container after preheating is completed, pouring an organic solvent along the inner wall of the preparation container, pouring 3-amino-4-cyanopyrazole, mixing and stirring, adding formamidine acetate after stirring is completed, and uniformly mixing to obtain a mixture;
2) carrying out thermal reaction on 3-amino-4-cyanopyrazole and formamidine acetate in the step 1), cooling the mixture to room temperature after the reaction is finished to separate out a white solid, filtering out the white solid, mixing the white solid and N-halogenated succinimide in a reaction container, adding a catalyst and a cyclizing agent, adding a PH reagent to neutralize, stirring at room temperature until the reaction is finished, concentrating the solvent, filtering the concentrated solvent, adding anhydrous sodium sulfate into the filtrate to dry, standing for a period of time, drying, and finally obtaining an intermediate 1;
3) dissolving the intermediate 1 in the step 2) in dichloromethane, adding glacial acetic acid and a reducing agent, reacting at room temperature until the reaction is finished, adding a saturated sodium carbonate solution to adjust the pH of the reaction system to be alkaline, finally adding ethyl acetate, adding a catalyst, uniformly mixing, finally extracting, standing the solution obtained by the extraction for a period of time, layering, extracting an upper layer solution, and concentrating to obtain an intermediate 2;
4) putting the intermediate 2 obtained in the step 3) and the 4-phenoxyphenyl vinylene dicyanomethane compound into a reaction kettle for mixing, uniformly stirring, and carrying out cyclization reaction to obtain an intermediate 3;
5) placing the intermediate 3 obtained in the step 4) and a cyclizing agent together into a constant-temperature heating magnetic stirrer or a microwave synthesizer for reaction at 60-120 ℃, adding a protected sodium chloride solution for dilution after the reaction is finished, adding ethyl acetate for extraction, washing, standing and layering, extracting an upper-layer solution by using equipment, washing by using a saturated sodium chloride solution, standing and layering, finally extracting the upper-layer solution, and placing the upper-layer solution into concentration equipment for purification to obtain a white solid, namely ibrutinib.
2. The preparation method of ibrutinib according to claim 1, comprising the following raw materials in parts by weight: 3-amino-4-cyanopyrazole, N-halogenated succinimide, acrylic ester, 4-phenoxyphenyl vinylidene dicyanomethane compound, formamidine acetate, cyclizing agent, catalyst and organic solvent.
3. The method according to claim 1, wherein the catalyst is one of palladium on carbon or Raney nickel.
4. The preparation method of ibrutinib according to claim 1, wherein the filtrate obtained in step 2) is dried by adding anhydrous sodium sulfate, and the resting time is twenty-five to thirty-five minutes.
5. The method for preparing ibrutinib according to claim 1, wherein the 3-amino-4-cyanopyrazole in step 2) is thermally reacted with formamidine acetate at a temperature of one hundred degrees celsius.
6. The method for preparing ibrutinib according to claim 1, wherein the reagent for adjusting pH in steps 2) and 3) is one of halogenated acid and trifluoroacetic acid.
7. The method for preparing ibrutinib according to claim 1, wherein the volume ratio of the white solid mixed with the N-halogenated succinimide in the step 2) is one to one.
8. The preparation method of ibrutinib according to claim 1, wherein the white solid filtered out in step 2) is obtained by quenching the reaction, separating solid from liquid, and concentrating and recrystallizing the liquid phase.
9. The method for preparing ibrutinib according to claim 1, wherein the organic solvent in step 1) is dimethyl sulfoxide.
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| CN201910838433.7A CN110759915A (en) | 2019-09-05 | 2019-09-05 | Preparation method of ibrutinib |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103626774A (en) * | 2013-11-20 | 2014-03-12 | 苏州明锐医药科技有限公司 | Preparation method of Ibrutinib |
| CN105859728A (en) * | 2016-05-26 | 2016-08-17 | 江苏中邦制药有限公司 | Preparation method for ibrutinib |
| CN106608877A (en) * | 2015-10-21 | 2017-05-03 | 新发药业有限公司 | Preparation method of Ibrutinib intermediate 4-amino-3-(4-phenoxy) phenyl-1H-pyrazol [3,4-d] pyrimidine |
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- 2019-09-05 CN CN201910838433.7A patent/CN110759915A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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