CN102382100A - Preparation method of imatinib - Google Patents
Preparation method of imatinib Download PDFInfo
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- CN102382100A CN102382100A CN2011100551443A CN201110055144A CN102382100A CN 102382100 A CN102382100 A CN 102382100A CN 2011100551443 A CN2011100551443 A CN 2011100551443A CN 201110055144 A CN201110055144 A CN 201110055144A CN 102382100 A CN102382100 A CN 102382100A
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- 239000005517 L01XE01 - Imatinib Substances 0.000 title claims abstract description 30
- 229960002411 imatinib Drugs 0.000 title claims abstract description 28
- 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 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 26
- 239000007787 solid Substances 0.000 claims description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- 238000003756 stirring Methods 0.000 claims description 14
- 238000000967 suction filtration Methods 0.000 claims description 14
- 238000002425 crystallisation Methods 0.000 claims description 10
- 230000008025 crystallization Effects 0.000 claims description 10
- 238000010992 reflux Methods 0.000 claims description 9
- GDIIPKWHAQGCJF-UHFFFAOYSA-N 4-Amino-2-nitrotoluene Chemical compound CC1=CC=C(N)C=C1[N+]([O-])=O GDIIPKWHAQGCJF-UHFFFAOYSA-N 0.000 claims description 7
- 239000000463 material Substances 0.000 claims description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 230000006837 decompression Effects 0.000 claims description 6
- 239000005457 ice water Substances 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 6
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 claims description 4
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 4
- TXZFBHYDQGYOIT-UHFFFAOYSA-N 2-(chloromethyl)benzoyl chloride Chemical class ClCC1=CC=CC=C1C(Cl)=O TXZFBHYDQGYOIT-UHFFFAOYSA-N 0.000 claims description 4
- WEGYGNROSJDEIW-UHFFFAOYSA-N 3-Acetylpyridine Chemical compound CC(=O)C1=CC=CN=C1 WEGYGNROSJDEIW-UHFFFAOYSA-N 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 4
- 239000000047 product Substances 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- 239000012141 concentrate Substances 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 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 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 claims description 2
- 239000006260 foam Substances 0.000 claims description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 2
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 claims description 2
- 238000012423 maintenance Methods 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 238000007670 refining Methods 0.000 claims description 2
- 238000012546 transfer Methods 0.000 claims description 2
- 238000010792 warming Methods 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims 1
- 230000002194 synthesizing effect Effects 0.000 claims 1
- 239000000376 reactant Substances 0.000 abstract description 2
- 238000012216 screening Methods 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 229940125898 compound 5 Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000003912 environmental pollution Methods 0.000 description 3
- 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 3
- 238000004519 manufacturing process Methods 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000008676 import Effects 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 2
- GRXMMIBZRMKADT-UHFFFAOYSA-N 3-bromo-4-methylaniline Chemical compound CC1=CC=C(N)C=C1Br GRXMMIBZRMKADT-UHFFFAOYSA-N 0.000 description 1
- DSBIJCMXAIKKKI-UHFFFAOYSA-N 5-nitro-o-toluidine Chemical compound CC1=CC=C([N+]([O-])=O)C=C1N DSBIJCMXAIKKKI-UHFFFAOYSA-N 0.000 description 1
- 208000006332 Choriocarcinoma Diseases 0.000 description 1
- 201000009051 Embryonal Carcinoma Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 201000003914 endometrial carcinoma Diseases 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229940080856 gleevec Drugs 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 229960003685 imatinib mesylate Drugs 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
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Abstract
The invention provides a new preparation method of imatinib; the method comprises the steps of preparing imatinib by using N-(3-guanidyl-4-methylphenyl)-4-(4-methyl-piperazine-1-methyl)benzamide and 3-dimethylamino-1-(3-pyridyl)-2-propylene-1-one as intermediates; the method of the invention has the advantages of safe and simple preparation conditions, significantly low cost, no cis-trans screening of reactants.
Description
Technical field
The present invention relates to a kind of preparation method of imatinib.
Background technology
Imatinib is the common drug that can be used for treating serious malignant disease such as choriocarcinoma, malignant histocytosis, embryonal carcinoma, carcinoma of endometrium, brain mesoglia knurl.Be main with import mainly at present, product and preparing method's patent great majority are grasped abroad in enterprise's hand.For example, imatinib (imatinib), Ge Liweike (gleevec), imatinib mesylate (glivec) that discloses among the patent WO2006/042362A of Medvet Science Pty Ltd.'s application or the purposes that reaches pharmaceutical salts.For example, the imatinib disclosed in the WO2008/051597A1 of people such as MACDONALD Peter invention or the preparation method of its salt.And this import medicine high price in market at home gives domestic user, endures patient and the family thereof that cancer torments especially for a long time to the fullest extent and brings the economical load that is difficult to bear.
The also very hot preparation production domesticization of being loyal to of domestic numerous pharmacy corporations with this medicine; Like the application number of Hangzhou Sheng Mei Medical Technology Development Co., Ltd application the preparation method disclosed in 200710067344.4 " a kind of preparation method of imatinib "; This method is to be raw material with N-(4-methyl-3-aminophenyl)-4-(4-methyl-piperazinyl-1-methyl) BM; Make imatinib with 2-halo-4-methyl-(3-pyridyl) pyrimidine reaction; The halogenating agent such as the POCl3 that when Synthetic 2-halo-4-methyl-(3-pyridyl) pyrimidine, use in this process belong to highly toxic product; Environmental pollution is also bigger, and working condition needs strict control, thereby causes the cost of safety in production to increase and for the threat of environmental pollution etc.In addition; Use 3-bromo-4-monomethylaniline to be raw material like Chinese patent CN1630648A; The ammonolysis reaction of realizing 4-(4-methyl-piperazinyl-1-methyl) oil of Niobe with trimethylaluminium obtains N-(4-methyl-3-bromophenyl)-4-(4-methyl-piperazinyl-1-methyl) BM; Obtain imatinib with precious metal palladium catalysis and PYRIMITHAMINE reaction at last, having the trimethylaluminium that uses in this method is ignition control compound and the violent shortcoming of water contact reacts; And final product obtained by this method has 10% isomer, is difficult to purifying.
The method that for example discloses in the International Application No. WO 2004/108699 is a starting raw material with 2-methyl-5-nitro aniline; Be reacted into guanidine with cyanamide earlier; Carry out ring-closure reaction with 3-dimethylamino-1-(3-pyridyl)-2-propylene-1-ketone then, make imatinib, above-mentioned preparation method need use the backflow of concentrated hydrochloric acid, sulfur oxychloride; So deposit inconvenience in the factory, be not easy to the operation and environmental pollution also very big.Just there is above-mentioned shortcoming in synthesis technique shown in following synthesis path:
Goal of the invention
It is thus clear that all there is the difficulty of utilizing on the industry in aforesaid method, though all claim on industry can scale operation for above-mentioned patent, from its preparation process and wherein use reagent that a large amount of operational conditions have relatively high expectations risk and the difficulty that exists its preparation process.The new preparation process of the imatinib that the present invention provides that a kind of preparation condition is safe and simple, cost significantly reduces, reactant need not to carry out the cis-trans screening.
Summary of the invention
The present invention provides a kind of preparation method of imatinib; It is a starting raw material with 4-methyl-3-nitro aniline; Earlier carry out condensation reaction successively with to chloromethyl benzoic acid chlorides and N methyl piperazine; Then nitroreduction is become amino, be reacted into guanidine with cyanamide again, and then carry out ring-closure reaction and make imatinib with 3-dimethylamino-1-(3-pyridyl)-2-propylene-1-ketone.The synthesis path of imatinib of the present invention is as follows (all to indicate numeral under each compound in this path; Describe to make things convenient for hereinafter; N-(3-amino-4-aminomethyl phenyl) 4-(4-methyl-piperazine-1-methyl) benzamide for example, indicating numeral under it is hereinafter to be referred to as compound 5.In addition, concrete reaction conditions and operation steps have description in specification sheets thereafter):
Solvent is the common kind that is easy to deposit; For example THF, ethanol, Virahol, methyl alcohol, these organic solvents all are not have particular requirement for preserving environment and operational condition, and is easy to operate; And use the yield of the imatinib that preparation method of the present invention obtains also higher; And compare with prior art and save cost, it is comparison that the synthesis path that is for example disclosed with a certain document (CN101735197A) becomes originally, and cost is tabulated as follows:
Synthesis path (CN101735197A) disclosed in certain prior art the cost of imatinib of production 1kg
And the required cost of 1kg imatinib that the present invention produces
Simultaneously, reaction process of the present invention need not high pressure-temperature etc. special conditions, temperature of reaction is between the 0-100 degree, the concentration of alkali is 0.1-10M.
Description of drawings
Accompanying drawing 1 is the structural formula of midbody compound 6
Accompanying drawing 2 is the structural formula of another midbody compound 7
Accompanying drawing 3 is the synthesis path of imatinib of the present invention
Embodiment
Concrete preparation route of the present invention and process thereof
Step 1
With dioxane (3000ml) and 4-methyl-3-nitro aniline (1Kg, 6.65mol) drop in the reaction flask dissolving fully after, add anhydrous K 2CO3 (3500g); Drip chloromethyl benzoic acid chlorides (2000g, 10.5mol are dissolved in the 1500ml dioxane) under the stirring down at 0 ℃, drip off back stirring reaction 1 hour; (3735g 37.35mol), is prone to heat up to add N methyl piperazine then; Should be noted that temperature control this moment, stirs under the same conditions to be incubated that (TLCEA: MeOH=10: 1), suction filtration falls the solid in the system fully to 4-methyl-3-nitro aniline reaction; Filtrate decompression is concentrated into dried, under vigorous stirring, adds entry 12L, stirring at room 2 hours; Crystallization, suction filtration, oven dry obtains beige solid 1900g; This solid is N-(4-methyl-3-nitro phenyl)-4-(4-methyl-piperazine-1-methyl) benzamide (compound 4), and yield reaches 85.5%, purity HPLC: greater than 95%.
Step 2:
With the solid (1000g) and the ethanol (15000ml) of above-mentioned preparation, drop in the reaction flask, stir down and in system, drip Hydrazine Hydrate 80 (4000g is dissolved in the 4000ml ethanol), significant foam produces in the process.Reflux keeps being back to above-mentioned solid reaction (TLC CH2Cl2: MeOH=8: 1) fully; Suction filtration falls catalyzer; Filtrate decompression is concentrated into dried (can not concentrate directly and use), gets thick enriched material 1100g, is N-(3-amino-4-aminomethyl phenyl) 4-(4-methyl-piperazine-1-methyl) benzamide (compound 5); Only contain a spot of solvent, so yield is greater than 100%.HPLC:94.6% does not need purifying can directly use yet
Step 3:
Compound 5 (1000g, 3mol), Virahol (10000ml) drops in the reaction flask, reflux; With dense HCl system pH is transferred to 1.5-2, has thick product to produce, add then the 50% cyanamide aqueous solution (660g, 15.7mol); The maintenance system refluxed between 3-4 30 hours at pH, TLCEA: MeOH=5: 1, be evaporated to dried after the demonstration reaction finishes; Add entry (6000ml) dissolving enriched material, transfer pH to 13 with sodium hydroxide (20%) aqueous solution down in the ice-water bath cooling then, process has also continuation stirred crystallization more than 4 hours under ice-water bath of oily matter; Suction filtration, the decompression oven dry gets off-white color solid 600g; Be N-(3-guanidine radicals one 4 monomethyl phenyl)-4-(4-methyl-piperazine-1-methyl) benzamide (compound 6), yield: about 60.2%, HPLC: greater than 95%.
Step 4:
N, (1600g 13.6mol) is dissolved in the ethanol (10000ml) the dinethylformamide dimethylacetal; Be warming up to 60 degree, and dropping 3-acetylpyridine in system (1000g, 8.6mol); Prevent to dash material, refluxed 12 hours, (TLCCH2Cl2: MeOH=8: 1) show that raw material reaction is complete.Concentrate and remove ethanol; The cooling back adds toluene and normal hexane mixed solution (3: 2) 4000ml slightly; Stirred crystallization is more than 4 hours under ice-water bath then, and the suction filtration oven dry obtains orange solid 800g, is 3-dimethylamino-1-(3-pyridyl)-2-propylene-1-ketone (compound 7); Yield 62%, HPLC:98%.
Step 5:
In compound 6 (1600g) and compound 7 (1000g) and primary isoamyl alcohol (15L) input reaction flask, nitrogen protection adds backflow down, carries out more than the reflux water-dividing 12h; Cold slightly after finishing to react, under refluxing, add ETHYLE ACETATE, stirring at room crystallization 4 hours then; The suction filtration oven dry obtains beige solid 1650g, is imatinib (compound 8), yield 90%; HPLC:98.3%, refining back is white solid (purification step is as follows).
Step 6 (purification step):
In bottle, add compound 8 (1000g), MeOH (10000ml) and methanesulfonic (218g), be added to solid complete be concentrated into after molten dried; Add 1000ml ethanol stirred crystallization, the suction filtration oven dry obtains white solid 1150g, yield 90%; HPLC:99.8%, fusing point: 216-219 degree.
Claims (4)
1. the preparation method of an imatinib, described synthesizing imatinib comprises the following steps of carrying out in order:
1) with after dissolving fully in dioxane and the 4-methyl-3-nitro aniline input reaction flask, adds anhydrous K
2CO
3, dripping chloromethyl benzoic acid chlorides under the stirring down at 0 ℃, it is dissolved in the dioxane by a certain percentage, drips off back stirring reaction 1 hour; Add N methyl piperazine then, this reaction is prone to heat up, under the condition of noting temperature control; Stirring is incubated to 4-methyl-3-nitro aniline reaction complete, and suction filtration falls the solid in the system, and filtrate decompression is concentrated into dried; Under vigorous stirring, add entry 12L, stirring at room 2 hours, crystallization; Suction filtration, oven dry obtains the beige solid, and this solid is N-(4-methyl-3-nitro phenyl)-4-(4-methyl-piperazine-1-methyl) benzamide;
2) with the beige solid and the ethanol of above-mentioned preparation, drop in the reaction flask, stirring drips in system down and is dissolved in the Hydrazine Hydrate 80 in the ethanol; Significant foam produces in the process, reflux, and it is complete to keep being back to above-mentioned solid reaction; Suction filtration falls catalyzer; Filtrate decompression is concentrated into dried, gets thick enriched material, is N-(3-amino-4-aminomethyl phenyl) 4-(4-methyl-piperazine-1-methyl) benzamide;
3) above-mentioned thick enriched material and Virahol are dropped in the reaction flask, reflux transfers to 1.5-2 with dense HCl with system pH; Have thick product to produce, add the 50% cyanamide aqueous solution then, the maintenance system refluxed between 3-4 30 hours at pH; Show to be evaporated to driedly after reaction finishes, add the water dissolution enriched material, then in the ice-water bath cooling down with the aqueous solution accent pH to 13 of 20% sodium hydroxide; Process has oily matter and continues under ice-water bath stirred crystallization more than 4 hours; Suction filtration, the decompression oven dry, getting the off-white color solid is N-(3-guanidine radicals one 4 monomethyl phenyl)-4-(4-methyl-piperazine-1-methyl) benzamide;
4) N, the dinethylformamide dimethylacetal is dissolved in the ethanol, is warming up to 60 degree, in system, drips the 3-acetylpyridine, prevents to dash material, refluxes 12 hours, shows that raw material reaction is complete.Concentrate and to remove ethanol, to add volume ratio be 3: 2 toluene and normal hexane mixed solution in the cooling back slightly, and stirred crystallization is more than 4 hours under ice-water bath then, and suction filtration is dried and obtained the orange solid, is 3-dimethylamino-1-(3-pyridyl)-2-propylene-1-ketone;
5) with intermediate N (3-guanidine radicals one 4 monomethyl phenyl)-4-(4-methyl-piperazine-1-methyl) benzamide and another midbody 3-dimethylamino-1-(3-pyridyl)-2-propylene-1-ketone, and primary isoamyl alcohol drops in the reaction flask; Nitrogen protection adds backflow down, carries out reflux water-dividing more than 12 hours, and is cold slightly after finishing to react; Under refluxing, add ETHYLE ACETATE then, stirring at room crystallization 4 hours, the suction filtration oven dry obtains the beige solid; Be imatinib, refining back is a white solid.
2. the preparation method of imatinib according to claim 1; It is characterized in that; Purification step after the described step 5) is following: in bottle, add above-mentioned beige solid, MeOH and methanesulfonic, be added to be concentrated into after solid dissolves entirely dried; Add the ethanol stirred crystallization, the suction filtration oven dry obtains white solid.
3. the preparation method of imatinib according to claim 1 and 2 is characterized in that, when the dioxane in the described step 1) was 3000ml, 4-methyl-3-nitro aniline was 1Kg, and 6.65mol after dissolving fully in the input reaction flask, adds the 3500g anhydrous K
2CO
3, dripping chloromethyl benzoic acid chlorides is 2000g, and 10.5mol is dissolved in the 1500ml dioxane, adds 3735g, and the 37.35mol N methyl piperazine is incubated to 4-methyl-3-nitro aniline reaction when complete TLCEA: MeOH=10: 1.
4. the preparation method of imatinib according to claim 1 is characterized in that, back TLCEA: MeOH=5 reacts completely in the described step 3): 1.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201110055144.3A CN102382100B (en) | 2011-03-09 | 2011-03-09 | Preparation method of imatinib |
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| CN102382100A true CN102382100A (en) | 2012-03-21 |
| CN102382100B CN102382100B (en) | 2014-04-16 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104072477A (en) * | 2013-07-26 | 2014-10-01 | 江苏豪森药业股份有限公司 | Refining method for imatinib |
| CN110872279A (en) * | 2019-12-13 | 2020-03-10 | 安徽峆一药业股份有限公司 | High-yield synthesis method of nilotinib |
| CN111518088A (en) * | 2020-06-10 | 2020-08-11 | 山东创新药物研发有限公司 | Preparation method and application of aniline quinazoline intermediate |
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| CN104072477A (en) * | 2013-07-26 | 2014-10-01 | 江苏豪森药业股份有限公司 | Refining method for imatinib |
| CN110872279A (en) * | 2019-12-13 | 2020-03-10 | 安徽峆一药业股份有限公司 | High-yield synthesis method of nilotinib |
| CN110872279B (en) * | 2019-12-13 | 2023-09-08 | 安徽峆一药业股份有限公司 | High-yield synthesis method of nilotinib |
| CN111518088A (en) * | 2020-06-10 | 2020-08-11 | 山东创新药物研发有限公司 | Preparation method and application of aniline quinazoline intermediate |
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| CN102382100B (en) | 2014-04-16 |
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