CN103848813A - Preparation method of imatinib - Google Patents
Preparation method of imatinib Download PDFInfo
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- CN103848813A CN103848813A CN201210514803.XA CN201210514803A CN103848813A CN 103848813 A CN103848813 A CN 103848813A CN 201210514803 A CN201210514803 A CN 201210514803A CN 103848813 A CN103848813 A CN 103848813A
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- 239000005517 L01XE01 - Imatinib Substances 0.000 title claims abstract description 59
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 title claims abstract description 59
- 229960002411 imatinib Drugs 0.000 title claims abstract description 59
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 69
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 61
- 238000006243 chemical reaction Methods 0.000 claims abstract description 52
- YUUHHSMHLNDBCB-UHFFFAOYSA-N 1-(5-amino-2-methylphenyl)-4-pyridin-3-yl-2h-pyrimidin-2-amine Chemical compound CC1=CC=C(N)C=C1N1C(N)N=C(C=2C=NC=CC=2)C=C1 YUUHHSMHLNDBCB-UHFFFAOYSA-N 0.000 claims abstract description 26
- ZOUYJERDNYMHCS-UHFFFAOYSA-N benzoyl chloride;dihydrochloride Chemical compound Cl.Cl.ClC(=O)C1=CC=CC=C1 ZOUYJERDNYMHCS-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003513 alkali Substances 0.000 claims abstract description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 51
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 48
- 239000000243 solution Substances 0.000 claims description 39
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 27
- 239000007864 aqueous solution Substances 0.000 claims description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- 239000012074 organic phase Substances 0.000 claims description 16
- 125000001931 aliphatic group Chemical group 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 8
- 238000001953 recrystallisation Methods 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 5
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- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 3
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 2
- 239000000920 calcium hydroxide Substances 0.000 claims description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 16
- 239000007810 chemical reaction solvent Substances 0.000 abstract description 6
- 239000007787 solid Substances 0.000 description 22
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 14
- 239000000047 product Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 235000021463 dry cake Nutrition 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- -1 4-methylpiperazine-1-yl Chemical group 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000012535 impurity Substances 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 239000002585 base Substances 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 7
- 150000003839 salts Chemical group 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 229910017053 inorganic salt Inorganic materials 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 238000009413 insulation Methods 0.000 description 5
- 238000012544 monitoring process Methods 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 238000013517 stratification Methods 0.000 description 5
- 238000010792 warming Methods 0.000 description 5
- 238000009835 boiling Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 3
- 239000007790 solid phase Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000003912 environmental pollution Methods 0.000 description 2
- 150000002191 fatty alcohols Chemical class 0.000 description 2
- 231100001261 hazardous Toxicity 0.000 description 2
- 229960003685 imatinib mesylate Drugs 0.000 description 2
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 description 2
- 230000001473 noxious effect Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000004064 recycling Methods 0.000 description 2
- 238000007670 refining Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- TXZFBHYDQGYOIT-UHFFFAOYSA-N 2-(chloromethyl)benzoyl chloride Chemical class ClCC1=CC=CC=C1C(Cl)=O TXZFBHYDQGYOIT-UHFFFAOYSA-N 0.000 description 1
- GDIIPKWHAQGCJF-UHFFFAOYSA-N 4-Amino-2-nitrotoluene Chemical compound CC1=CC=C(N)C=C1[N+]([O-])=O GDIIPKWHAQGCJF-UHFFFAOYSA-N 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- 208000008334 Dermatofibrosarcoma Diseases 0.000 description 1
- 206010057070 Dermatofibrosarcoma protuberans Diseases 0.000 description 1
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 208000014767 Myeloproliferative disease Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- DPNLUUQPOAURBE-UHFFFAOYSA-N [N].CN1CCNCC1 Chemical compound [N].CN1CCNCC1 DPNLUUQPOAURBE-UHFFFAOYSA-N 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention relates to a preparation method of imatinib. The method comprises the following step: performing a reaction on N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-aminopyrimidine and 4-(4-methyl piperazine methyl) benzoyl chloride dihydrochloride by taking methylene dichloride as a reaction solvent and triethylamine as an alkali.
Description
Technical field
The application relates to the preparation method of imatinib.
Background technology
Imatinib mesylate is developed by Novartis company of Switzerland, is used for the treatment of various tumours, for example acute transformation of chronic myelocytic leukemia phase, acceleration period, the chronic phase patient after alpha-interferon therapy failure, and gastrointestinal stromal tumors.At present, known imatinib mesylate can also be used for the treatment of the various diseases such as acute lymphoblastic leukemia, high eosinophilic granulocyte syndromes, dermatofibrosarcoma, mastocytosis, melanoma, myeloproliferative disease, pulmonary fibrosis, renal cell carcinoma, pulmonary hypertension disease, rheumatic arthritis, prostate cancer.Imatinib is the important as precursors of synthesizing methanesulfonic acid imatinib.
The chemical name of imatinib is:
4-[(4-methylpiperazine-1-yl) methyl]-N-[4-methyl-3-[[4-(pyridin-3-yl) pyrimidine-2-base] amino] phenyl] benzamide; Its structural formula is:
The open CN1077713A of Chinese patent and CN101899035A all disclose preparation method's (scheme 1) of imatinib: N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-aminopyrimidine and 4-(4-methylpiperazine methyl) Benzoyl chloride are carried out to condensation reaction under alkaline condition, make imatinib.
In CN1077713A, use pyridine as reaction solvent, and the consumption of pyridine is very large, up to volume/mass=40/1.Be difficult to be recovered utilization because pyridine boiling point is high, therefore cause serious environmental pollution, production cost is high and product purity is low, the residual quantity of solvent is large in product.In CN101899035A, use acetonitrile as solvent and triethylamine as alkali.Due to acetonitrile good water solubility, and boiling point and triethylamine approach, therefore high for the cost compare of purification and recover.
Chinese patent CN1630648A discloses another preparation method (scheme 2) of imatinib: be to make imatinib taking 4-methyl-3-nitro aniline as starting raw material through polystep reaction.This preparation method need to pass through multiple midbody compounds, and synthetic route is long, and total recovery is low, and production cost is high.
Patent WO2004108699 discloses another preparation method (scheme 3) of imatinib: make N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-aminopyrimidine first with to chloromethyl benzoic acid chlorides condensation, then react generation imatinib with nitrogen methylpiperazine.The method has increased single step reaction than the method for the open CN1077713A of Chinese patent and CN101899035A, and reaction yield also correspondingly reduces.
Therefore, still need the method for new synthetic imatinib badly.
Summary of the invention
The application relates to imatinib (4-[(4-methylpiperazine-1-yl) methyl]-N-[4-methyl-3-[[4-(pyridin-3-yl) pyrimidine-2-base] amino] phenyl] benzamide, formula I) preparation method, the method comprises the steps: taking methylene dichloride as organic solvent, taking triethylamine as alkali, N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-aminopyrimidine is reacted with 4-(4-methylpiperazine methyl) Benzoyl chloride dihydrochloride, form imatinib.
The application's the method for preparing imatinib has following one or more advantages: production cost is low, simple to operate, low for equipment requirements, reaction temperature and, environmentally friendly, do not use and produce hazardous and noxious substances, yield is high and purity is high, can be applicable to large-scale industrialization produce requirement.
Brief description of the drawings
High performance liquid chromatography (HPLC) collection of illustrative plates of the refining imatinib that accompanying drawing 1: embodiment 1 obtains
High performance liquid chromatography (HPLC) collection of illustrative plates of the refining imatinib that accompanying drawing 2: embodiment 2 obtains
Embodiment
Following description comprises some detail so that the various disclosed embodiments of thorough.But various equivalent modifications should be appreciated that can be without one or more these details, or can use other method, composition, material etc. to put into practice embodiment.
In whole specification sheets, mentioned " embodiment ", " embodiment ", " in another embodiment ", " some embodiment " or " in certain embodiments " refers to that the described feature that be specifically related to, structure or the characteristic relevant to described embodiment are included at least one embodiment.Therefore, local phrase " in one embodiment ", " in embodiments ", " in another embodiment " or " in certain embodiments " occurring of each in whole specification sheets needn't all refer to identical embodiment.In addition, specific features, structure or characteristic can combine in any suitable manner in one or more embodiments.
The application relates to the preparation method of imatinib (I), described method comprises the steps: taking methylene dichloride as organic solvent, taking triethylamine as alkali, N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-aminopyrimidine is reacted with 4-(4-methylpiperazine methyl) Benzoyl chloride dihydrochloride, form imatinib.
Reaction scheme is:
Wherein TEA represents triethylamine.
In some embodiment of the application, N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-aminopyrimidine is 0.9-2.0:1.0 with the mol ratio of reacting of 4-(4-methylpiperazine methyl) Benzoyl chloride dihydrochloride, is preferably 0.9:1.0-1.0:1.0.
Those skilled in the art can be according to the consumption that need to select organic solvent dichloromethane in suitable reaction of practice, and for example, its consumption can be the conventional amount used in organic synthesis.In some embodiment of the application, the mass ratio of organic solvent dichloromethane and N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-aminopyrimidine is preferably 15-25:1, more preferably 20:1.
Those skilled in the art can also be according to the consumption that need to select triethylamine in suitable reaction of practice, and for example, its consumption can be the conventional amount used in organic synthesis.In some embodiment of the application, the mol ratio of triethylamine and N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-aminopyrimidine is preferably 2.5-4.0:1.0, more preferably 3:1.
In some embodiment of the application, the temperature of reaction of preparing imatinib is 10 DEG C-40 DEG C; Preferably 20 DEG C-40 DEG C; More preferably 30 DEG C.
The reaction times of preparing imatinib that those skilled in the art can understand the application changes with charging capacity (, the consumption of reactant), and the little required time that reacts of charging capacity is few, and it is long that charging capacity is greatly reacted required time.Conventionally, the reaction times is for till detecting that with thin-layer chromatography (TLC) or high performance liquid chromatography (HPLC) reaction raw materials no longer reduces or reacts completely, and the seldom remaining or HPLC detection display material content of for example TLC detection display raw material institute is less than 1%.Taking the reaction scale described in following embodiment as example, preparing the required reaction times of imatinib is 3 hours-8 hours.
The application's the method for preparing imatinib also comprises the steps:
After reaction finishes, in reaction solution, add alkaline aqueous solution to the pH value of reaction solution to be greater than 14; After being separated, steam except the organic solvent in organic phase; In residuum, add ethyl acetate, filter, obtain highly purified imatinib.
Preferably, the application's the method for preparing imatinib also comprises the steps:
After reaction finishes, reaction solution is cooled to 0 DEG C, adds subsequently alkaline aqueous solution to the pH value of reaction solution to be greater than 14; After being separated, use dichloromethane extraction water, merge organic phase, with after saturated common salt aqueous solution washing organic phase, steam except organic solvent dichloromethane; In residuum, add ethyl acetate, stir after 3 hours, filter, dry cake, obtains highly purified imatinib.
More preferably, the application's the method for preparing imatinib also further comprises the steps:
Saturated aliphatic monobasic alcohol recrystallization for the imatinib that filtration is obtained, obtains more highly purified imatinib.
Even more preferably, the application's the method for preparing imatinib also further comprises the steps:
The imatinib that filtration is obtained adds in saturated aliphatic monobasic alcohol, and heating for dissolving, to refluxing, is cooled to room temperature after heat filtering, and crystallization filters, dry, obtains more highly purified imatinib.
In some embodiment of the application, the limiting examples of described alkaline aqueous solution includes, but not limited to the aqueous solution of sodium hydroxide, potassium hydroxide, lithium hydroxide and calcium hydroxide, be preferably the aqueous solution of sodium hydroxide and potassium hydroxide, more preferably the aqueous solution of sodium hydroxide.
Those skilled in the art can, in practice according to the reacting liquid pH value after needed adjusting, select concentration and the consumption of other suitable alkaline aqueous solution and alkaline aqueous solution.
In some embodiment of the application, the concentration of described alkaline aqueous solution is 1-4mol/L, is preferably 2mol/L; More preferably, the concentration of described aqueous sodium hydroxide solution or potassium hydroxide aqueous solution is 1-4mol/L, is preferably 2mol/L.
In some embodiment of the application, the mass ratio of alkaline aqueous solution consumption and N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-aminopyrimidine consumption is 3-15:1, preferably 10:1; Preferably, the mass ratio of the alkaline aqueous solution consumption of 2mol/L and N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-aminopyrimidine consumption is 8-15:1.Be preferably 10:1; More preferably, the mass ratio of the consumption of the aqueous sodium hydroxide solution of 2mol/L or the consumption of potassium hydroxide aqueous solution and N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-aminopyrimidine is 8-15:1, more preferably 10:1.
Those skilled in the art can be according to the needs of practice, and the charging capacity of for example reactant is selected suitable ethyl acetate consumption.In some embodiment of the application, the mass ratio of described ethyl acetate consumption and N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-aminopyrimidine consumption is preferably 10-15:1, more preferably 10:1.
In some embodiment of the application, be preferably monohydroxy-alcohol straight chain, alkyl side chain or ring-type with 1-8 carbon atom for the saturated aliphatic monobasic alcohol of recrystallization; More preferably methyl alcohol, ethanol, Virahol and butanols; Even more preferably ethanol and Virahol; Most preferably dehydrated alcohol.
In recrystallization process, those skilled in the art can be according to the needs of practice, and the output of for example imatinib and imatinib alkali are selected the consumption of suitable saturated aliphatic monobasic alcohol in the solubleness of saturated aliphatic monobasic alcohol.In some embodiment of the application, the mass ratio of saturated aliphatic monobasic alcohol consumption and the amount of imatinib is 3-28:1, is preferably 15-28:1, more preferably 24:1.
Most preferably, the application's the method for preparing imatinib comprises the steps:
(1) in dichloromethane solvent, under the existence of triethylamine, in the time of 10 DEG C to 40 DEG C, make N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-aminopyrimidine react 3-10 hour with 4-(4-methylpiperazine methyl) Benzoyl chloride dihydrochloride;
(2) reaction solution is cooled to 0 DEG C, adds 2mol/L aqueous sodium hydroxide solution to the pH value of reaction solution to be greater than 14;
(3) after being separated, use dichloromethane extraction water, merge organic phase, with after saturated common salt aqueous solution washing organic phase, steam except methylene dichloride;
(4) in residuum, add ethyl acetate, stir after 3 hours, filter, dry cake, obtains solid;
(5) by saturated aliphatic monobasic alcohol recrystallization for gained solid.
The application's the method for preparing imatinib has following one or more advantages:
1, productive rate is high, and the yield of the imatinib highly finished product of purity >99.6% is greater than 70%;
2, reaction conditions gentleness, temperature of reaction is not more than 40 DEG C;
3, operation is simple, and low for equipment requirements, environmentally friendly, do not use and produce hazardous and noxious substances; Comparatively speaking, the reaction solvent pyridine environmental pollution using in the open CN1077713A of Chinese patent and CN101899035A is very large;
4, reaction solvent methylene dichloride is easy to reclaim and reuse, and has reduced production cost, is applicable to the requirement that large-scale industrialization is produced; Compare school, the reaction solvent pyridine using in the open CN101899035A of Chinese patent is difficult to recycling because boiling point is high, and reaction solvent acetonitrile is due to good water solubility, and boiling point and triethylamine approach, therefore, be difficult to contained water and triethylamine to be removed, be also difficult to recycling;
5, after recrystallization, can obtain the imatinib highly finished product that purity is greater than 99.6%, be applicable to medicinal requirements.
In fact the imatinib highly finished product that the preparation method of the imatinib by the application obtains have the higher purity of imatinib obtaining than in the open CN101899035A of Chinese patent.Not fettered by any theoretical institute, its reason may be as follows.
After the reaction of preparing imatinib finishes, the salt form, the salt form of unreacted raw material and the salt form of various impurity that conventionally in reaction solution, contain imatinib.First be greater than 14 to adding such as alkaline aqueous solution to the pH value of reaction solution of aqueous sodium hydroxide solution in reaction solution.Now, above-mentioned salt form is all converted into the form of free alkali.Then, utilize ethyl acetate to wash, because the free alkali of imatinib is dissolved in methylene dichloride, and be insoluble in ethyl acetate, therefore, it is retained in filter cake, and the free alkali form of various impurity and the free alkali form of unreacted raw material are all soluble in ethyl acetate, so washing effect is good, can obtain highly purified imatinib.Utilize, such as the saturated aliphatic monobasic alcohol of dehydrated alcohol, imatinib is carried out to recrystallization, because inorganic salt impurity is insoluble in the saturated aliphatic monobasic alcohol such as dehydrated alcohol, therefore in recrystallization process, can remove inorganic salt impurity by carrying out heat filtering after heat of solution, and then obtain more highly purified imatinib.
In the open CN101899035 of Chinese patent, although the salt form of imatinib is washed by ethyl acetate, but, due to the salt form of various impurity and the salt form of unreacted raw material solubleness in ethyl acetate little, therefore have residually significantly, and then affect the purity of finished product.
In the open CN101899035 of Chinese patent, although regulating pH with ammoniacal liquor is 9-10, in reaction solution, add saturated fatty alcohol, in the reaction solution that contains saturated fatty alcohol, separate out solid phase prod, but, this operation cannot be removed inorganic salt impurity, and the meeting of inorganic salt impurity and solid phase prod are together separated out and remained in solid phase prod.And inorganic salt impurity can't detect in high performance liquid chromatography, although therefore HPLC shows that the purity of gained imatinib is high, in fact exist the residual of inorganic salt.
In conjunction with the following example, the present invention is described in detail, instead of restriction the present invention.
Embodiment
Embodiment 1:4-[(4-methylpiperazine-1-yl) methyl]-N-[4-methyl-3-[[4-(pyridin-3-yl) pyrimidine-2-base] amino] phenyl] preparation of benzamide (I)
N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-aminopyrimidine (150.0g, 0.54mol) is added in methylene dichloride (3000.0g), then add triethylamine (164.0g, 1.62mol), stir and be warming up to 30 DEG C.Add 4-(4-methylpiperazine methyl) Benzoyl chloride dihydrochloride (193.6g, 0.60mol) solid in batches.After finishing, reaction solution insulation reaction 3h, shows that through TLC monitoring reaction is substantially complete.Reaction solution is cooled to room temperature, adds 2mol/L aqueous sodium hydroxide solution (1500g), be stirred to solid and all dissolve, now pH value is greater than 14.After stratification, isolate organic phase.Water is used dichloromethane extraction (1500.0g × 2) again, merges organic phase, uses saturated common salt solution washing once, then removes methylene dichloride under reduced pressure.In residuum, add ethyl acetate (1500g), stir 2h, filter, dry cake, obtains yellow solid 246.8g.Yellow solid is added in dehydrated alcohol (5930.0g), after heating for dissolving, filtered while hot, cooling, crystallization, refilter, in 45 DEG C of dry cake 4h, obtain product 198.8g, yield: 74.4%, purity: 99.692%.Accompanying drawing 1 is shown in by high performance liquid chromatography (HPLC) collection of illustrative plates of imatinib highly finished product.
Embodiment 2:4-[(4-methylpiperazine-1-yl) methyl]-N-[4-methyl-3-[[4-(pyridin-3-yl) pyrimidine-2-base] amino] phenyl] preparation of benzamide (I)
N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-aminopyrimidine (1.50kg, 5.4mol) is added in methylene dichloride (30.0kg), then add triethylamine (1.64kg, 16.2mol), stir and be warming up to 30 DEG C.Add 4-(4-methylpiperazine methyl) Benzoyl chloride dihydrochloride (1.94kg, 6.0mol) solid in batches.After finishing, reaction solution insulation reaction 8h, shows that through TLC monitoring reaction is substantially complete.Reaction solution is cooled to room temperature, adds 2mol/L sodium hydroxide solution (15.0kg), be stirred to solid and all dissolve, now pH value is greater than 14.After stratification, isolate organic phase.Water is used dichloromethane extraction (10.0kg × 2) again, merges organic phase, uses saturated common salt solution washing once, then removes methylene dichloride under reduced pressure.In residuum, add ethyl acetate (15.0kg), stir 3h, filter, dry cake, obtains yellow solid 2.55kg.Yellow solid is added in dehydrated alcohol (61.2kg), after heating for dissolving, filtered while hot, cooling, crystallization, refilter, in 45 DEG C of dry cake 4h, obtain product 1.96kg, yield: 73.5%, purity: 99.799%.Accompanying drawing 2 is shown in by high performance liquid chromatography (HPLC) collection of illustrative plates of imatinib highly finished product.
Embodiment 3:4-[(4-methylpiperazine-1-yl) methyl]-N-[4-methyl-3-[[4-(pyridin-3-yl) pyrimidine-2-base] amino] phenyl] preparation of benzamide (I)
N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-aminopyrimidine (150.0g, 0.54mol) is added in methylene dichloride (2250.0g), then add triethylamine (136.6g, 1.35mol), stir and be warming up to 20 DEG C.Add 4-(4-methylpiperazine methyl) Benzoyl chloride dihydrochloride (174.2g, 0.54mol) solid in batches.After finishing, reaction solution insulation reaction 3h, shows that through TLC monitoring reaction is substantially complete.Reaction solution is cooled to room temperature, adds 1mol/L potassium hydroxide aqueous solution (2250g), be stirred to solid and all dissolve, now pH value is greater than 14.After stratification, isolate organic phase.Water is used dichloromethane extraction (1500.0g × 2) again, merges organic phase, uses saturated common salt solution washing once, then removes methylene dichloride under reduced pressure.In residuum, add ethyl acetate (2250g), stir 3h, filter, dry cake, obtains yellow solid 235.6g.Yellow solid is added in anhydrous methanol (945.0g), after heating for dissolving, filtered while hot, cooling, crystallization, refilter, in 45 DEG C of dry cake 4h, obtain product 198.4g, yield: 74.3%, purity: 99.602%.
Embodiment 4:4-[(4-methylpiperazine-1-yl) methyl]-N-[4-methyl-3-[[4-(pyridin-3-yl) pyrimidine-2-base] amino] phenyl] preparation of benzamide (I)
N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-aminopyrimidine (333.3g, 1.2mol) is added in methylene dichloride (5000.0g), then add triethylamine (363.6g, 3.6mol), stir and be warming up to 40 DEG C.Add 4-(4-methylpiperazine methyl) Benzoyl chloride dihydrochloride (193.6g, 0.60mol) solid in batches.After finishing, reaction solution insulation reaction 5h, shows that through TLC monitoring reaction is substantially complete.Reaction solution is cooled to room temperature, adds 3mol/L sodium hydroxide solution (2500g), be stirred to solid and all dissolve, now pH value is greater than 14.After stratification, isolate organic phase.Water is used dichloromethane extraction (1500.0g × 2) again, merges organic phase, uses saturated common salt solution washing once, removes methylene dichloride under reduced pressure.In residuum, add ethyl acetate (3500g), stir 2h, filter, dry cake, obtains yellow solid 242.0g.Yellow solid is added in anhydrous isopropyl alcohol (6776.0g), after heating for dissolving, filtered while hot, cooling, crystallization, refilter, in 45 DEG C of dry 4h, obtain product 195.6g, yield: 73.2%, purity: 99.640%.
Embodiment 5:4-[(4-methylpiperazine-1-yl) methyl]-N-[4-methyl-3-[[4-(pyridin-3-yl) pyrimidine-2-base] amino] phenyl] preparation of benzamide (I)
N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-aminopyrimidine (150.0g, 0.54ml) is added in methylene dichloride (3000.0g), then add triethylamine (164.0g, 1.62mol), stir and be warming up to 10 DEG C.Add 4-(4-methylpiperazine methyl) Benzoyl chloride dihydrochloride (193.6g, 0.60mol) solid in batches.After finishing, reaction solution insulation reaction 4h, shows that through TLC monitoring reaction is substantially complete.Reaction solution is cooled to room temperature, adds 2mol/L sodium hydroxide solution (1500g), be stirred to solid and all dissolve, now pH value is greater than 14.After stratification, isolate organic phase.Water is used dichloromethane extraction (1500.0g × 2) again, merges organic phase, uses saturated common salt solution washing once, then removes methylene dichloride under reduced pressure.In residuum, add ethyl acetate (1500g), stir 3h, filter, dry cake, obtains yellow solid 250.9g.Yellow solid is added in anhydrous butanols (4200.0g), after heating for dissolving, filtered while hot, cooling, crystallization, refilter, in 45 DEG C of dry 4h, obtain product 200.4g, yield: 75.0%, purity: 99.622%.
Claims (13)
1. the preparation method of imatinib (I), it comprises the steps: taking methylene dichloride as organic solvent, taking triethylamine as alkali, and N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-aminopyrimidine is reacted with 4-(4-methylpiperazine methyl) Benzoyl chloride dihydrochloride:
In reaction formula, TEA represents triethylamine.
2. preparation method according to claim 1, wherein the mol ratio of N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-aminopyrimidine consumption and 4-(4-methylpiperazine methyl) Benzoyl chloride dihydrochloride consumption is 0.9-2.0:1.0, preferably 0.9:1.0-1.0:1.0.
3. preparation method according to claim 1 and 2, wherein the mass ratio of methylene dichloride consumption and N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-aminopyrimidine consumption is 15-25:1, preferably 20:1.
4. according to the preparation method described in arbitrary claim in claim 1-3, it is characterized in that, the mol ratio of triethylamine consumption and N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-aminopyrimidine consumption is 2.5-4.0:1.0, preferably 3:1.
5. according to the preparation method described in arbitrary claim in claim 1-4, it is characterized in that, temperature of reaction is 10 DEG C-40 DEG C, preferably 20 DEG C-40 DEG C, and more preferably 30 DEG C.
6. the preparation method described in arbitrary claim in claim 1-5, it also comprises the steps:
After reaction finishes, in reaction solution, add alkaline aqueous solution to the pH value of reaction solution to be greater than 14; After being separated, steam except the organic solvent in organic phase; In residuum, add ethyl acetate, filter, obtain highly purified imatinib.
7. preparation method according to claim 6, wherein said alkaline aqueous solution is selected from the aqueous solution of sodium hydroxide, potassium hydroxide, lithium hydroxide and calcium hydroxide, is preferably the aqueous solution of sodium hydroxide and potassium hydroxide, more preferably the aqueous solution of sodium hydroxide.
8. according to the preparation method described in arbitrary claim in claim 6 or 7, the concentration of wherein said alkaline aqueous solution is 1-4mol/L, preferably 2mol/L; Preferred, the concentration of aqueous sodium hydroxide solution or potassium hydroxide aqueous solution is 1-4mol/L, preferably 2mol/L.
9. according to the preparation method described in arbitrary claim in claim 6-8, the mass ratio of wherein said alkaline aqueous solution consumption and N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-aminopyrimidine consumption is 3-15:1, preferably 10:1; More preferably, the mass ratio of 2mol/L alkaline aqueous solution consumption and N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-aminopyrimidine consumption is 8-15:1, preferably 10:1; Even preferred, the mass ratio of the consumption of the aqueous sodium hydroxide solution of 2mol/L or the consumption of potassium hydroxide aqueous solution and N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-aminopyrimidine is 8-15:1, preferably 10:1.
10. according to the preparation method described in arbitrary claim in claim 6-9, the mass ratio of wherein said ethyl acetate consumption and N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-aminopyrimidine consumption is 10-15:1, preferably 10:1.
11. according to the preparation method described in arbitrary claim in claim 6-10, and it also further comprises the steps:
Saturated aliphatic monobasic alcohol recrystallization for the imatinib that filtration is obtained, obtains more highly purified imatinib.
12. preparation methods according to claim 11, wherein said saturated aliphatic monobasic alcohol is monohydroxy-alcohol straight chain, alkyl side chain or ring-type with 1-8 carbon atom; Be preferably methyl alcohol, ethanol, Virahol and butanols; More preferably ethanol and Virahol; Most preferably dehydrated alcohol.
13. according to the preparation method described in claim 11 or 12, and the mass ratio of wherein said saturated aliphatic monobasic alcohol consumption and imatinib consumption is 3-28:1, preferably 15-28:1, more preferably 24:1.
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