CN103848813B - The preparation method of imatinib - Google Patents
The preparation method of imatinib Download PDFInfo
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- CN103848813B CN103848813B CN201210514803.XA CN201210514803A CN103848813B CN 103848813 B CN103848813 B CN 103848813B CN 201210514803 A CN201210514803 A CN 201210514803A CN 103848813 B CN103848813 B CN 103848813B
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- 239000005517 L01XE01 - Imatinib Substances 0.000 title claims abstract description 56
- 229960002411 imatinib Drugs 0.000 title claims abstract description 56
- 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 56
- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 84
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 53
- 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 48
- 239000007864 aqueous solution Substances 0.000 claims description 34
- 238000006243 chemical reaction Methods 0.000 claims description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 29
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 29
- 239000000376 reactant Substances 0.000 claims description 25
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 21
- 208000035126 Facies Diseases 0.000 claims description 16
- 239000002585 base Substances 0.000 claims description 15
- 125000001931 aliphatic group Chemical group 0.000 claims description 12
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims description 12
- 238000001953 recrystallisation Methods 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- 230000008859 change Effects 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 2
- 238000000746 purification Methods 0.000 claims 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 235000015598 salt intake Nutrition 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- -1 amino 2 aminomethyl phenyl Chemical group 0.000 abstract description 9
- 150000005006 2-aminopyrimidines Chemical class 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 22
- 238000003756 stirring Methods 0.000 description 17
- 238000000034 method Methods 0.000 description 15
- 229940086542 triethylamine Drugs 0.000 description 14
- 239000000047 product Substances 0.000 description 13
- 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
- 235000011121 sodium hydroxide Nutrition 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000012535 impurity Substances 0.000 description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
- 238000004809 thin layer chromatography Methods 0.000 description 8
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 229910017053 inorganic salt Inorganic materials 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- 150000003839 salts Chemical class 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
- 239000002994 raw material Substances 0.000 description 5
- 238000013517 stratification Methods 0.000 description 5
- 238000010792 warming Methods 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 229960000935 dehydrated alcohol Drugs 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 235000002639 sodium chloride Nutrition 0.000 description 3
- 239000012265 solid product Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 2
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 229910021529 ammonia Inorganic materials 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
- 229960004756 ethanol Drugs 0.000 description 2
- 150000002191 fatty alcohols Chemical class 0.000 description 2
- 238000001914 filtration Methods 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
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000004064 recycling Methods 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-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
- NRFGJRWYFWTGQM-UHFFFAOYSA-N C(C1=CC=CC=C1)Cl.C(=O)Cl Chemical compound C(C1=CC=CC=C1)Cl.C(=O)Cl NRFGJRWYFWTGQM-UHFFFAOYSA-N 0.000 description 1
- 241000254173 Coleoptera Species 0.000 description 1
- 208000008334 Dermatofibrosarcoma Diseases 0.000 description 1
- 206010057070 Dermatofibrosarcoma protuberans Diseases 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000014767 Myeloproliferative disease Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000005005 aminopyrimidines Chemical class 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000012769 display material Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000000222 eosinocyte Anatomy 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 208000008585 mastocytosis Diseases 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The application relates to the preparation method of imatinib, it comprises the steps: that with dichloromethane be anti-solvent-applied, triethylamine is alkali, makes N (5 amino 2 aminomethyl phenyl) 4 (3 pyridine radicals) 2 aminopyrimidines and 4 (4 methyl piperazine methyl) Benzenecarbonyl chloride. dihydrochloride react.
Description
Technical field
The application relates to the preparation method of imatinib.
Background technology
Imatinib mesylate is developed by Novartis, Switzerland, is used for treating various tumor, example
Such as acute transformation of chronic myelocytic leukemia phase, accelerated period, the chronic phase patient after alpha-interferon therapy failure,
And gastrointestinal stromal tumors.At present it is known that imatinib mesylate can be used for treating acute pouring
Bar chronic myeloid leukemia, high eosinophilic granulocyte syndrome, dermatofibrosarcoma, mastocytosis,
Melanoma, myeloproliferative disease, pulmonary fibrosis, renal cell carcinoma, pulmonary hypertension disease, rheumatism
The property multiple disease such as arthritis, carcinoma of prostate.Imatinib is the weight of synthesizing methanesulfonic acid imatinib
Want precursor.
The chemical name of imatinib is:
4-[(4-methylpiperazine-1-yl) methyl]-N-[4-methyl-3-[[4-(pyridin-3-yl) pyrimidine-2-base] ammonia
Base] phenyl] Benzoylamide；Its structural formula is:
Open CN1077713A and CN101899035A of Chinese patent all discloses imatinib
Preparation method (scheme 1): by N-(5-amino-2-methyl phenyl)-4-(3-pyridine radicals)-2-aminopyrimidine
Carry out condensation reaction in the basic conditions with 4-(4-methyl piperazine methyl) Benzenecarbonyl chloride., prepare her horse and replace
Buddhist nun.
In CN1077713A, use pyridine is as reaction dissolvent, and the consumption of pyridine is very big,
Up to volume/mass=40/1.It is difficult to be recycled owing to pyridine boiling point is high, thus results in serious
Environmental pollution, production cost is high and product purity is low, the residual quantity of solvent is big in product.?
CN101899035A use acetonitrile as solvent and triethylamine as alkali.Due to aqueous acetonitrile
Good, and boiling point is close with triethylamine, the cost that thus be accordingly used in recovery refined is higher.
Scheme 1
Chinese patent CN1630648A discloses another preparation method (scheme 2) of imatinib:
It is to prepare imatinib for initiation material through multistep reaction with 4-methyl-3-nitro aniline.This preparation side
Method needs through multiple midbody compounds, and synthetic route is long, and total recovery is low, and production cost is high.
Scheme 2
Patent WO2004108699 discloses another preparation method (scheme 3) of imatinib:
Make N-(5-amino-2-methyl phenyl)-4-(3-pyridine radicals)-2-aminopyrimidine elder generation and to chloromethylbenzene formyl
Chlorine is condensed, then reacts generation imatinib with N-methyl piperazine.The method is opener than Chinese patent
The method of CN1077713A and CN101899035A adds single step reaction, reaction yield also phase
Should reduce on ground.
Scheme 3
Therefore, the method still needing new synthesis imatinib badly.
Summary of the invention
The application relates to imatinib (4-[(4-methylpiperazine-1-yl) methyl]-N-[4-methyl-3-[[4-(pyrrole
Pyridine-3-base) pyrimidine-2-base] amino] phenyl] Benzoylamide, formula I) preparation method, the method includes
Following steps: with dichloromethane as organic solvent, with triethylamine as alkali, make N-(5-amino-2-methyl
Phenyl)-4-(3-pyridine radicals)-2-aminopyrimidine and 4-(4-methyl piperazine methyl) Benzenecarbonyl chloride. dihydrochloride
React, form imatinib.
The method preparing imatinib of the application has following one or more advantages: produce into
This is the lowest, simple to operate, low for equipment requirements, react gentle, environmentally friendly, do not use and produce
Raw poisonous and harmful substance, yield are high and purity is high, can be suitable for the requirement of industrialization large-scale production.
Accompanying drawing explanation
Accompanying drawing 1: the high performance liquid chromatography (HPLC) of the refined imatinib that embodiment 1 obtains
Collection of illustrative plates
Accompanying drawing 2: the high performance liquid chromatography (HPLC) of the refined imatinib that embodiment 2 obtains
Collection of illustrative plates
Detailed description of the invention
Description below includes some detail thoroughly to understand various disclosed embodiment party
Case.But, various equivalent modifications should be appreciated that these can have without one or more
Body details, or the practice embodiments such as other method, composition, material can be used.
" embodiment ", " embodiment " mentioned in entire disclosure, " implement at another
In scheme ", " some embodiment " or " in certain embodiments " refer to and described embodiment
The relevant described feature being specifically related to, structure or characteristic is included at least one enforcement
In scheme.Therefore, the local phrase occurred of each in whole this specification is " an embodiment party
In case ", " in embodiments ", " in another embodiment " or " in some embodiment
In " it is not necessarily all referring to identical embodiment.Additionally, specific features, structure or characteristic can be
One or more embodiments combine in any suitable manner.
The application relates to the preparation method of imatinib (I), and described method comprises the steps: with two
Chloromethanes is organic solvent, with triethylamine as alkali, make N-(5-amino-2-methyl phenyl)-4-(3-pyridine
Base)-2-aminopyrimidine reacts with 4-(4-methyl piperazine methyl) Benzenecarbonyl chloride. dihydrochloride, formed
Imatinib.
Reaction scheme is:
Wherein TEA represents triethylamine.
In some embodiment of the application, N-(5-amino-2-methyl phenyl)-4-(3-pyridine
Base)-2-aminopyrimidine with the reaction mol ratio of 4-(4-methyl piperazine methyl) Benzenecarbonyl chloride. dihydrochloride is
0.9-2.0:1.0, preferably 0.9:1.0-1.0:1.0.
Those skilled in the art can select in suitably reaction organic according to the needs of practice
The consumption of methylene chloride, such as, its consumption can be that the routine in organic synthesis is used
Amount.In some embodiment of the application, organic solvent dichloromethane and N-(5-amino-2-first
Base phenyl) mass ratio of-4-(3-pyridine radicals)-2-aminopyrimidine is preferably 15-25:1, more preferably 20:1.
Those skilled in the art can also be according in the needs selection suitably reaction of practice three
The consumption of ethamine, such as, its consumption can be the conventional amount used in organic synthesis.At this
In some embodiment of application, triethylamine and N-(5-amino-2-methyl phenyl)-4-(3-pyridine
Base) mol ratio of-2-aminopyrimidine is preferably 2.5-4.0:1.0, more preferably 3:1.
In some embodiment of the application, the reaction temperature preparing imatinib is 10 DEG C-40
℃；Preferably 20 DEG C-40 DEG C；More preferably 30 DEG C.
Those skilled in the art it will be appreciated that the application the response time preparing imatinib with
Inventory (that is, the consumption of reactant) and change, inventory little then reaction required time few, inventory
Big then reaction required time long.Generally, the response time is for using thin layer chromatography (TLC) or high-efficient liquid
Till phase chromatograph (HPLC) detects that reaction raw materials no longer reduces or reacts completely, such as TLC
Detection display raw material is remaining few or HPLC detection display material content is less than 1%.With following enforcement
As a example by reaction scale described in example, the response time needed for preparing imatinib be 3 hours-8 little
Time.
The method preparing imatinib of the application also comprises the steps:
After reaction terminates, in reactant liquor, addition alkaline aqueous solution is more than 14 to the pH value of reactant liquor；
After Xiang Fenliing, the organic solvent being evaporated off in organic facies；In residue, add ethyl acetate, filter,
Obtain highly purified imatinib.
Preferably, the method preparing imatinib of the application also comprises the steps:
After reaction terminates, reactant liquor is cooled to 0 DEG C, is subsequently added alkaline aqueous solution to reactant liquor
PH value more than 14；After Xiang Fenliing, use dichloromethane aqueous phase extracted, merge organic facies, with full
After the common salt aqueous solution washing organic facies of sum, organic solvent dichloromethane is evaporated off；Add in residue
Enter ethyl acetate, after stirring 3 hours, filter, dry cake, obtain highly purified imatinib.
It is highly preferred that the method preparing imatinib of the application still further comprises following steps:
By the imatinib that is filtrated to get with saturated aliphatic monobasic alcohol recrystallization, obtain more high-purity
The imatinib of degree.
Even further preferably, the method preparing imatinib of the application still further comprises following step
Rapid:
Adding in saturated aliphatic monobasic alcohol by the imatinib being filtrated to get, heating for dissolving is to returning
Stream, is cooled to room temperature, crystallize, filters, be dried after heat filtering, her horse obtaining higher purity is replaced
Buddhist nun.
In some embodiment of the application, the limiting examples bag of described alkaline aqueous solution
Include, but be not limited to, the aqueous solution of sodium hydroxide, potassium hydroxide, Lithium hydrate and calcium hydroxide,
It is preferably sodium hydroxide and the aqueous solution of the aqueous solution of potassium hydroxide, more preferably sodium hydroxide.
Those skilled in the art can be in practice according to the reactant liquor after required regulation
PH value, selects other suitable alkaline aqueous solution and the concentration of alkaline aqueous solution and consumption.
In some embodiment of the application, the concentration of described alkaline aqueous solution is 1-4mol/L,
It is preferably 2mol/L；It is highly preferred that described sodium hydrate aqueous solution or potassium hydroxide aqueous solution is dense
Degree is 1-4mol/L, preferably 2mol/L.
In some embodiment of the application, alkaline aqueous solution consumption and N-(5-amino-2-methyl
Phenyl) mass ratio of-4-(3-pyridine radicals)-2-aminopyrimidine consumption is 3-15:1, preferably 10:1；Preferably
Ground, the alkaline aqueous solution consumption of 2mol/L and N-(5-amino-2-methyl phenyl)-4-(3-pyridine radicals)-2-
The mass ratio of aminopyrimidine consumption is 8-15:1.It is preferably 10:1；It is highly preferred that the hydrogen of 2mol/L
The consumption of aqueous solution of sodium oxide or potassium hydroxide aqueous solution and N-(5-amino-2-methyl phenyl)-4-(3-pyrrole
Piperidinyl) mass ratio of consumption of-2-aminopyrimidine is 8-15:1, more preferably 10:1.
Those skilled in the art can be according to the needs of practice, the such as inventory of reactant
Select suitable ethyl acetate consumption.In some embodiment of the application, described acetic acid
Ethyl ester consumption and the quality of N-(5-amino-2-methyl phenyl)-4-(3-pyridine radicals)-2-aminopyrimidine consumption
Ratio preferably 10-15:1, more preferably 10:1.
In some embodiment of the application, for the saturated aliphatic monobasic alcohol of recrystallization
Preferably there is the monohydric alcohol of straight chain, side chain or the ring-type alkyl of 1-8 carbon atom；
More preferably methanol, ethanol, isopropanol and butanol；Even more preferably ethanol and isopropanol；Optimum
Select dehydrated alcohol.
In recrystallization process, those skilled in the art can be according to the needs of practice, example
Yield and imatinib alkali such as imatinib come at the dissolubility of saturated aliphatic monobasic alcohol
Select the consumption of the most saturated aliphatic monobasic alcohol.In some embodiment of the application,
Saturated aliphatic monobasic alcohol consumption is 3-28:1 with the mass ratio of the amount of imatinib, is preferably
15-28:1, more preferably 24:1.
Most preferably, the method preparing imatinib of the application comprises the steps:
(1) in dichloromethane solvent, in the presence of triethyl amine, at 10 DEG C to 40 DEG C
Time, make N-(5-amino-2-methyl phenyl)-4-(3-pyridine radicals)-2-aminopyrimidine and 4-(4-methyl piperazine
Methyl) Benzenecarbonyl chloride. dihydrochloride react 3-10 hour；
(2) reactant liquor is cooled to 0 DEG C, adds 2mol/L sodium hydrate aqueous solution to reaction
The pH value of liquid is more than 14；
(3) after being separated, use dichloromethane aqueous phase extracted, merge organic facies, with saturated food
After aqueous salt solu-tion organic facies, dichloromethane is evaporated off；
(4) in residue, add ethyl acetate, after stirring 3 hours, filter, dry cake,
Obtain solid；
(5) by gained solid with saturated aliphatic monobasic alcohol recrystallization.
The method preparing imatinib of the application has following one or more advantages:
1, productivity is high, purity > yield of the imatinib highly finished product of 99.6% is more than 70%；
2, reaction condition is gentle, and reaction temperature is not more than 40 DEG C；
3, operation is simple, and low for equipment requirements, environmentally friendly, do not use and have
Poison harmful substance；Comparatively speaking, open CN1077713A and CN101899035A of Chinese patent
The reaction dissolvent pyridine environmental pollution of middle use is the biggest；
4, reaction dissolvent dichloromethane is easily recycled and reuses, and reduces production cost, is suitable for
The requirement of industrialization large-scale production；For comparing school, the open CN101899035A of Chinese patent
The reaction dissolvent pyridine of middle use is difficult to recycling owing to boiling point is high, reaction dissolvent acetonitrile by
In good water solubility, and boiling point is close with triethylamine, accordingly, it is difficult to contained water and triethylamine are removed
Go, it is also difficult to recycling；
5, after recrystallization, the available purity imatinib highly finished product more than 99.6%, it is suitable for medicine
With requiring.
The imatinib highly finished product obtained by the preparation method of the imatinib of the application are actually
There is the higher purity of imatinib obtained in CN101899035A opener than Chinese patent.
Not fettered by any theory, its reason may be as follows.
After the reaction preparing imatinib terminates, usual reactant liquor contains the salt shape of imatinib
Formula, the salt form of unreacted raw material and the salt form of various impurity.First add in reactant liquor
The alkaline aqueous solution of such as sodium hydrate aqueous solution is more than 14 to the pH value of reactant liquor.Now, on
The salt form stated is converted to the form of free alkali.Then, utilize ethyl acetate to wash, by
Free alkali in imatinib is dissolved in dichloromethane, and insoluble in ethyl acetate, therefore, it is protected
Stay in filter cake, and the free alkali form of the free alkali form of various impurity and unreacted raw material is all
It is soluble in ethyl acetate, so, clean result is good, can obtain highly purified imatinib.
The saturated aliphatic monobasic alcohol utilizing such as dehydrated alcohol carries out recrystallization to imatinib, due to
In the inorganic salt impurities saturated aliphatic monobasic alcohol insoluble in such as dehydrated alcohol, therefore heavily tying
During crystalline substance, inorganic salt impurities can be removed by carrying out heat filtering after heat of solution, and then obtain
The imatinib of higher purity.
In the open CN101899035 of Chinese patent, although with the ethyl acetate salt to imatinib
Form is washed, but, due to salt form and the salt shape of unreacted raw material of various impurity
Formula dissolubility in ethyl acetate is little, therefore has and remains significantly, and then affects finished product
Purity.
In the open CN101899035 of Chinese patent, although regulating pH with ammonia is 9-10,
Reactant liquor adds saturated fatty alcohol, the reactant liquor containing saturated fatty alcohol separates out solid product,
But, this operation cannot remove inorganic salt impurities, and inorganic salt impurities together can be analysed with solid product
Go out and remain in solid product.And inorganic salt impurities can't detect in high performance liquid chromatography,
Thus while the purity of HPLC display gained imatinib is high, but there are in fact inorganic salt
Residual.
In conjunction with the following example, the present invention is described in detail rather than limits the present invention.
Embodiment
[[[4-(pyridin-3-yl) is phonetic for 4-methyl-3-for embodiment 1:4-[(4-methylpiperazine-1-yl) methyl]-N-
Pyridine-2-base] amino] phenyl] preparation of Benzoylamide (I)
By N-(5-amino-2-methyl phenyl)-4-(3-pyridine radicals)-2-aminopyrimidine (150.0g, 0.54mol)
Add in dichloromethane (3000.0g), be subsequently adding triethylamine (164.0g, 1.62mol), stirring
It is warming up to 30 DEG C.Be dividedly in some parts 4-(4-methyl piperazine methyl) Benzenecarbonyl chloride. dihydrochloride (193.6g,
0.60mol) solid.After finishing, reactant liquor insulation reaction 3h, through TLC monitoring display reactive group
This is completely.Reactant liquor is cooled to room temperature, adds 2mol/L sodium hydrate aqueous solution (1500g),
Stirring and all dissolve to solid, now pH value is more than 14.After stratification, isolate organic facies.
Aqueous phase extracts (1500.0g × 2) with dichloromethane again, merges organic facies, uses saturated common salt aqueous solution
Washed once, then remove dichloromethane under reduced pressure.Ethyl acetate (1500g) is added in residue,
Stirring 2h, filters, dry cake, obtains yellow solid 246.8g.Yellow solid is added anhydrous second
In alcohol (5930.0g), after heating for dissolving, filtered while hot, cooling, crystallize, refilter, in 45 DEG C
Dry cake 4h, obtains product 198.8g, yield: 74.4%, purity: 99.692%.Imatinib
Accompanying drawing 1 is shown in by high performance liquid chromatography (HPLC) collection of illustrative plates of highly finished product, and wherein sampling volume is 10 μ L
And peak is listed as follows.
Peak list
Detector AChl268nm
| Peak # | Retention time | Area | Highly | Area % | Resolution |
| 1 | 2.008 | 789 | 148 | 0.005 | 0.000 |
| 2 | 3.657 | 939 | 72 | 0.006 | 6.702 |
| 3 | 7.241 | 19352 | 1034 | 0.114 | 8.690 |
| 4 | 14.383 | 2698 | 95 | 0.016 | 11.493 |
| 5 | 22.406 | 7788 | 168 | 0.046 | 7.967 |
| 6 | 30.899 | 16940051 | 692011 | 99.692 | 8.963 |
| 7 | 33.503 | 1279 | 94 | 0.008 | 5.185 |
| 8 | 33.949 | 2211 | 176 | 0.013 | 1.258 |
| 9 | 34.959 | 12820 | 1015 | 0.075 | 2.989 |
| 10 | 36.508 | 1208 | 47 | 0.007 | 4.715 |
| 11 | 37.441 | 3199 | 242 | 0.019 | 2.917 |
| Summation | 16992334 | 695102 | 100.000 |
[[[4-(pyridin-3-yl) is phonetic for 4-methyl-3-for embodiment 2:4-[(4-methylpiperazine-1-yl) methyl]-N-
Pyridine-2-base] amino] phenyl] preparation of Benzoylamide (I)
By N-(5-amino-2-methyl phenyl)-4-(3-pyridine radicals)-2-aminopyrimidine (1.50kg, 5.4mol)
Add in dichloromethane (30.0kg), be subsequently adding triethylamine (1.64kg, 16.2mol), stirring
It is warming up to 30 DEG C.Be dividedly in some parts 4-(4-methyl piperazine methyl) Benzenecarbonyl chloride. dihydrochloride (1.94kg,
6.0mol) solid.After finishing, reactant liquor insulation reaction 8h, basic through TLC monitoring display reaction
Completely.Reactant liquor is cooled to room temperature, adds 2mol/L sodium hydroxide solution (15.0kg), stirring
All dissolving to solid, now pH value is more than 14.After stratification, isolate organic facies.Water
Extract (10.0kg × 2) with dichloromethane the most again, merge organic facies, wash with saturated common salt aqueous solution
Once, dichloromethane is then removed under reduced pressure.In residue, add ethyl acetate (15.0kg), stir
Mix 3h, filter, dry cake, obtain yellow solid 2.55kg.Yellow solid is added dehydrated alcohol
(61.2kg), in, after heating for dissolving, filtered while hot, cooling, crystallize, refilter, in 45 DEG C
Dry cake 4h, obtains product 1.96kg, yield: 73.5%, purity: 99.799%.Imatinib
Accompanying drawing 2 is shown in by high performance liquid chromatography (HPLC) collection of illustrative plates of highly finished product, and wherein sampling volume is 10 μ L
And peak is listed as follows.
Peak list
Detector AChl268nm
| Peak # | Retention time | Area | Highly | Area % | Resolution |
| 1 | 4.328 | 472 | 56 | 0.004 | 0.000 |
| 2 | 7.401 | 2199 | 185 | 0.019 | 10.983 |
| 3 | 8.112 | 1445 | 69 | 0.012 | 1.607 |
| 4 | 14.116 | 4591 | 195 | 0.039 | 9.976 |
| 5 | 20.094 | 6219 | 200 | 0.053 | 8.041 |
| 6 | 28.658 | 11717625 | 328452 | 99.799 | 9.543 |
| 7 | 32.942 | 1637 | -0 | 0.014 | 6.663 |
| 8 | 33.467 | 1902 | 1 | 0.016 | 1.724 |
| 9 | 36.084 | 443 | 60 | 0.004 | 10.767 |
| 10 | 37.015 | 2088 | 228 | 0.018 | 3.013 |
| 11 | 37.165 | 1520 | 182 | 0.013 | 0.247 |
| 12 | 37.529 | 594 | 70 | 0.005 | 0.693 |
| 13 | 38.361 | 476 | 46 | 0.004 | 3.212 |
| Summation | 11741212 | 329744 | 100.000 |
[[[4-(pyridin-3-yl) is phonetic for 4-methyl-3-for embodiment 3:4-[(4-methylpiperazine-1-yl) methyl]-N-
Pyridine-2-base] amino] phenyl] preparation of Benzoylamide (I)
By N-(5-amino-2-methyl phenyl)-4-(3-pyridine radicals)-2-aminopyrimidine (150.0g, 0.54mol)
Add in dichloromethane (2250.0g), be subsequently adding triethylamine (136.6g, 1.35mol), stirring
It is warming up to 20 DEG C.Be dividedly in some parts 4-(4-methyl piperazine methyl) Benzenecarbonyl chloride. dihydrochloride (174.2g,
0.54mol) solid.After finishing, reactant liquor insulation reaction 3h, through TLC monitoring display reactive group
This is completely.Reactant liquor is cooled to room temperature, adds 1mol/L potassium hydroxide aqueous solution (2250g),
Stirring and all dissolve to solid, now pH value is more than 14.After stratification, isolate organic facies.
Aqueous phase extracts (1500.0g × 2) with dichloromethane again, merges organic facies, uses saturated common salt aqueous solution
Washed once, then remove dichloromethane under reduced pressure.Ethyl acetate (2250g) is added in residue,
Stirring 3h, filters, dry cake, obtains yellow solid 235.6g.Yellow solid is added without water beetle
In alcohol (945.0g), after heating for dissolving, filtered while hot, cooling, crystallize, refilter, in 45 DEG C
Dry cake 4h, obtains product 198.4g, yield: 74.3%, purity: 99.602%.
[[[4-(pyridin-3-yl) is phonetic for 4-methyl-3-for embodiment 4:4-[(4-methylpiperazine-1-yl) methyl]-N-
Pyridine-2-base] amino] phenyl] preparation of Benzoylamide (I)
By N-(5-amino-2-methyl phenyl)-4-(3-pyridine radicals)-2-aminopyrimidine (333.3g, 1.2mol)
Add in dichloromethane (5000.0g), be subsequently adding triethylamine (363.6g, 3.6mol), stirring
It is warming up to 40 DEG C.Be dividedly in some parts 4-(4-methyl piperazine methyl) Benzenecarbonyl chloride. dihydrochloride (193.6g,
0.60mol) solid.After finishing, reactant liquor insulation reaction 5h, through TLC monitoring display reactive group
This is completely.Reactant liquor is cooled to room temperature, adds 3mol/L sodium hydroxide solution (2500g), stir
Mixing and all dissolve to solid, now pH value is more than 14.After stratification, isolate organic facies.
Aqueous phase extracts (1500.0g × 2) with dichloromethane again, merges organic facies, uses saturated common salt aqueous solution
Washed once, remove dichloromethane under reduced pressure.In residue, add ethyl acetate (3500g), stir
Mix 2h, filter, dry cake, obtain yellow solid 242.0g.Yellow solid is added anhydrous isopropyl
In alcohol (6776.0g), after heating for dissolving, filtered while hot, cooling, crystallize, refilter, in 45 DEG C
It is dried 4h, obtains product 195.6g, yield: 73.2%, purity: 99.640%.
[[[4-(pyridin-3-yl) is phonetic for 4-methyl-3-for embodiment 5:4-[(4-methylpiperazine-1-yl) methyl]-N-
Pyridine-2-base] amino] phenyl] preparation of Benzoylamide (I)
By N-(5-amino-2-methyl phenyl)-4-(3-pyridine radicals)-2-aminopyrimidine (150.0g, 0.54mol)
Add in dichloromethane (3000.0g), be subsequently adding triethylamine (164.0g, 1.62mol), stirring
It is warming up to 10 DEG C.Be dividedly in some parts 4-(4-methyl piperazine methyl) Benzenecarbonyl chloride. dihydrochloride (193.6g,
0.60mol) solid.After finishing, reactant liquor insulation reaction 4h, through TLC monitoring display reactive group
This is completely.Reactant liquor is cooled to room temperature, adds 2mol/L sodium hydroxide solution (1500g), stir
Mixing and all dissolve to solid, now pH value is more than 14.After stratification, isolate organic facies.
Aqueous phase with dichloromethane extraction (1500.0g × 2), merges organic facies, uses saturated common salt aqueous solution again
Washed once, then remove dichloromethane under reduced pressure.Ethyl acetate (1500g) is added in residue,
Stirring 3h, filters, dry cake, obtains yellow solid 250.9g.Yellow solid is added anhydrous fourth
In alcohol (4200.0g), after heating for dissolving, filtered while hot, cooling, crystallize, refilter, in 45 DEG C
It is dried 4h, obtains product 200.4g, yield: 75.0%, purity: 99.622%.
Claims (14)
1. the preparation method of imatinib (I), it comprises the steps: with dichloromethane is organic molten
Agent, with triethylamine as alkali, make N-(5-amino-2-methyl phenyl)-4-(3-pyridine radicals)-2-aminopyrimidine with
4-(4-methyl piperazine methyl) Benzenecarbonyl chloride. dihydrochloride reacts；And
After reaction terminates, in reactant liquor, addition alkaline aqueous solution is more than 14 to the pH value of reactant liquor；
After Xiang Fenliing, the organic solvent being evaporated off in organic facies；In residue, add ethyl acetate, filter,
Obtain the imatinib of purification.
Preparation method the most according to claim 1, wherein N-(5-amino-2-methyl benzene
Base)-4-(3-pyridine radicals)-2-aminopyrimidine consumption and 4-(4-methyl piperazine methyl) Benzenecarbonyl chloride. two hydrochloric acid
The mol ratio of salt consumption is 0.9-2.0:1.0.
Preparation method the most according to claim 1, wherein methylene chloride and N-(5-amino
-2-aminomethyl phenyl) mass ratio of-4-(3-pyridine radicals)-2-aminopyrimidine consumption is 15-25:1.
Preparation method the most according to claim 1, wherein triethylamine consumption and N-(5-amino-2-
Aminomethyl phenyl) mol ratio of-4-(3-pyridine radicals)-2-aminopyrimidine consumption is 2.5-4.0:1.0.
Preparation method the most according to claim 1, wherein reaction temperature is 20 DEG C-40 DEG C.
Preparation method the most according to claim 1, wherein said alkaline aqueous solution is selected from hydrogen-oxygen
Change aqueous solution and the aqueous solution of potassium hydroxide of sodium.
Preparation method the most according to claim 6, the concentration of wherein said alkaline aqueous solution
For 1-4mol/L.
Preparation method the most according to claim 6, the concentration of wherein said alkaline aqueous solution
For 2mol/L.
Preparation method the most according to claim 1, wherein said alkaline aqueous solution consumption with
The mass ratio of N-(5-amino-2-methyl phenyl)-4-(3-pyridine radicals)-2-aminopyrimidine consumption is 3-15:1.
Preparation method the most according to claim 8, the wherein water of the sodium hydroxide of 2mol/L
The consumption of the aqueous solution of solution or potassium hydroxide and N-(5-amino-2-methyl phenyl)-4-(3-pyridine
Base) mass ratio of consumption of-2-aminopyrimidine is 8-15:1.
11. preparation methoies according to claim 1, wherein said ethyl acetate consumption and N-(5-
Amino-2-methyl phenyl) mass ratio of-4-(3-pyridine radicals)-2-aminopyrimidine consumption is 10-15:1.
12. according to the preparation method described in any claim in claim 1-11, and it also enters one
Walk and include following purification step:
The saturated aliphatic monobasic alcohol recrystallization of imatinib that will be filtrated to get.
13. preparation methoies according to claim 12, wherein said saturated aliphatic unitary
Alcohol is methanol, ethanol, isopropanol and butanol.
14. preparation methoies according to claim 12, wherein said saturated aliphatic unitary
Alcohol consumption is 15-28:1 with the mass ratio of imatinib consumption.
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