CN102382100B - Preparation method of imatinib - Google Patents
Preparation method of imatinib Download PDFInfo
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- CN102382100B CN102382100B CN201110055144.3A CN201110055144A CN102382100B CN 102382100 B CN102382100 B CN 102382100B CN 201110055144 A CN201110055144 A CN 201110055144A CN 102382100 B CN102382100 B CN 102382100B
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- 239000005517 L01XE01 - Imatinib Substances 0.000 title claims abstract description 29
- 229960002411 imatinib Drugs 0.000 title claims abstract description 26
- 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 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims description 24
- 239000007787 solid Substances 0.000 claims description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 14
- 238000000967 suction filtration Methods 0.000 claims description 14
- 238000010992 reflux Methods 0.000 claims description 12
- 238000002425 crystallisation Methods 0.000 claims description 10
- 230000008025 crystallization Effects 0.000 claims description 10
- 239000000463 material Substances 0.000 claims description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-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
- 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 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-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
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 3
- TXZFBHYDQGYOIT-UHFFFAOYSA-N 2-(chloromethyl)benzoyl chloride Chemical class ClCC1=CC=CC=C1C(Cl)=O TXZFBHYDQGYOIT-UHFFFAOYSA-N 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 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
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 claims description 2
- 238000001035 drying Methods 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
- 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
- 238000004080 punching Methods 0.000 claims description 2
- 238000007670 refining Methods 0.000 claims description 2
- 238000010792 warming Methods 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims 1
- 238000010189 synthetic method Methods 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
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 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 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
- 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
- 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
- 229940080856 gleevec Drugs 0.000 description 2
- 230000008676 import Effects 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 2
- 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
- 239000003513 alkali Substances 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
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- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
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- 239000012467 final product Substances 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 229960003685 imatinib mesylate Drugs 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- DJYLHNATHGUBMB-UHFFFAOYSA-N n-bromo-4-methylaniline Chemical compound CC1=CC=C(NBr)C=C1 DJYLHNATHGUBMB-UHFFFAOYSA-N 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
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- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
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 the malignant disease that choriocarcinoma, malignant histocytosis, embryonal carcinoma, carcinoma of endometrium, brain mesoglia knurl etc. are serious.Mainly take import at present as main, and product and preparation method's patent great majority rest in overseas enterprise's hand.For example, the imatinib (imatinib) disclosing in the patent WO2006/042362A of Medvet Science Pty Ltd. application, gleevec (gleevec), imatinib mesylate (glivec) or and the purposes of pharmaceutical salts.For example, the imatinib disclosed in the WO2008/051597A1 of the 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, endure especially for a long time patient and the family thereof that cancer torments to the fullest extent and bring the economical load that is difficult to bear.
Domestic numerous pharmacy corporations are also very warm is loyal to the preparation production domesticization of this medicine, preparation method disclosed in " a kind of preparation method of imatinib " that the application number of applying for as Hangzhou Sheng Mei Medical Technology Development Co., Ltd is 200710067344.4, the method is that to take N-(4-methyl-3-aminophenyl)-4-(4-methyl-piperazinyl-1-methyl) benzamide be raw material, reaction makes imatinib with 2-halo-4-methyl-(3-pyridyl) pyrimidine, the halogenating agent using when synthetic 2-halo-4-methyl-(3-pyridyl) pyrimidine in this process belongs to highly toxic product as phosphorus oxychloride, environmental pollution is also larger, and working condition needs strict control, thereby the cost that causes safety in production increases and for the threat of environmental pollution etc.In addition, as Chinese patent CN1630648A is used the bromo-4-monomethylaniline of 3-, it is raw material, the ammonolysis reaction of realizing 4-(4-methyl-piperazinyl-1-methyl) methyl benzoate with trimethyl aluminium obtains N-(4-methyl-3-bromophenyl)-4-(4-methyl-piperazinyl-1-methyl) benzamide, finally with precious metal palladium catalysis and PYRIMITHAMINE reaction, obtain imatinib, in the method, having the trimethyl aluminium using is ignition control compound, with the violent shortcoming of water contact reacts, and final product obtained by this method has 10% isomer, be difficult to purifying.
It is starting raw material that the method for example disclosing in International Application No. WO 2004/108699 be take 2-methyl-5-nitro aniline, first be reacted into guanidine with cyanamide, then carry out ring-closure reaction with 3-dimethylamino-1-(3-pyridyl)-2-propylene-1-ketone, make imatinib, above-mentioned preparation method need to use the backflow of concentrated hydrochloric acid, sulfur oxychloride, so in factory, deposit inconvenience, be not easy to operation and environmental pollution also very large.Just there is above-mentioned shortcoming in the synthesis technique as shown in following synthesis path:
Goal of the invention
Aforesaid method is all deposited industrially the difficulty of utilizing, although all claim industrially can scale operation for above-mentioned patent, from its preparation process and risk and the difficulty of wherein using reagent that a large amount of operational conditions have relatively high expectations to exist its preparation process as seen.The present invention is to provide that a kind of preparation condition is safe and simple, cost significantly reduces, reactant is without the new preparation process that carries out the imatinib of cis-trans screening.
Summary of the invention
The invention provides a kind of preparation method of imatinib, it take 4-methyl-3-nitro aniline is starting raw material, first carry out condensation reaction successively with to chloromethyl benzoic acid chlorides and N methyl piperazine, then nitroreduction is become to amino, be reacted into guanidine with cyanamide again, and then carry out ring-closure reaction with 3-dimethylamino-1-(3-pyridyl)-2-propylene-1-ketone and make imatinib.The synthesis path of imatinib of the present invention (all indicates numeral as shown in Figure 3 under each compound in this path, to facilitate below, be described, N-(3-amino-4-aminomethyl phenyl)-4-(4-methyl-piperazine-1-methyl) benzamide for example, under it, indicating numeral is 5, is hereinafter 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 tetrahydrofuran (THF), ethanol, Virahol, methyl alcohol, these organic solvents are all there is no particular requirement for preserving environment and operational condition, 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 original as comparing that the disclosed synthesis path of a certain document (CN101735197A) of for example take becomes, and cost is listed as follows:
The cost of the imatinib of synthesis path (CN101735197A) 1kg that produces disclosed in certain prior art
And the required cost of 1kg imatinib that the present invention produces
Meanwhile, reaction process of the present invention need not high pressure-temperature etc. special conditions, temperature of reaction is between 0-100 degree, the concentration of alkali is 0.1-10M.
Accompanying drawing explanation
Accompanying drawing 1 is the structural formula of midbody compound 6
Accompanying drawing 2 is the structural formula of another midbody compound 7
The synthesis path that accompanying drawing 3 is imatinib of the present invention
Embodiment
Concrete syntheti c route of the present invention and process thereof
Step 1
By dioxane (3000ml) and 4-methyl-3-nitro aniline (1Kg, 6.65mol) after dissolving completely in input reaction flask, add anhydrous K 2CO3 (3500g), under stirring at 0 ℃, drip chloromethyl benzoic acid chlorides (2000g, 10.5mol is dissolved in 1500ml dioxane), drip off rear stirring reaction 1 hour, then add N methyl piperazine (3735g, 37.35mol), easily heat up, now should be noted that temperature control, stir under the same conditions and be incubated to the complete (TLCEA: MeOH=10: 1) of 4-methyl-3-nitro aniline reaction, suction filtration falls the solid in system, filtrate decompression is concentrated into dry, under vigorous stirring, add water 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), yield reaches 85.5%, purity HPLC: be greater than 95%.
Step 2:
By the solid of above-mentioned preparation (1000g) and ethanol (15000ml), drop in reaction flask, under stirring, in system, drip hydrazine hydrate (4000g is dissolved in 4000ml ethanol), in process, a large amount of foams produce.Reflux keeps being back to above-mentioned solid reaction (TLC CH2Cl2: MeOH=8: 1) completely, suction filtration falls catalyzer, filtrate decompression is concentrated into dry (can not concentrate directly and use), obtain thick enriched material 1100g, for N-(3-amino-4-aminomethyl phenyl)-4-(4-methyl-piperazine-1-methyl) benzamide (compound 5), only contain a small amount 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 reaction flask, reflux, with dense HCl, system pH is adjusted to 1.5-2, there is thick product to produce, then add the 50% cyanamide aqueous solution (660g, 15.7mol), holder ties up to pH and between 3-4, refluxes 30 hours, TLCEA: MeOH=5: 1, after demonstration reaction finishes, be evaporated to dry, add water (6000ml) to dissolve enriched material, then cooling lower to sodium hydroxide (20%) aqueous solution tune pH to 13 at ice-water bath, process has oily matter and continues under ice-water bath stirred crystallization more than 4 hours, suction filtration, decompression drying, obtain off-white color solid 600g, for N-(3-guanidine radicals-4-aminomethyl phenyl)-4-(4-methyl-piperazine-1-methyl) benzamide (compound 6), yield: 60.2% left and right, HPLC: be greater than 95%.
Step 4:
N; dinethylformamide dimethylacetal (1600g; 13.6mol) be dissolved in ethanol (10000ml); be warming up to 60 degree; in system, drip 3-acetylpyridine (1000g, 8.6mol), prevent punching material; reflux 12 hours, (TLCCH2Cl2: MeOH=8: 1) show that raw material reaction is complete.The concentrated ethanol that removes, after slightly cooling, add toluene and normal hexane mixed solution (3: 2) 4000ml, then stirred crystallization more than 4 hours under ice-water bath, suction filtration is dried and is obtained orange solid 800g, for 3-dimethylamino-1-(3-pyridyl)-2-propylene-1-ketone (compound 7), yield 62%, HPLC:98%.
Step 5:
By in compound 6 (1600g) and compound 7 (1000g) and primary isoamyl alcohol (15L) input reaction flask; under nitrogen protection, add backflow; more than carrying out reflux water-dividing 12h, slightly cold after finishing to react, then under refluxing, add ethyl acetate; stirring at room crystallization 4 hours; suction filtration is dried and is obtained beige solid 1650g, is imatinib (compound 8), yield 90%; HPLC:98.3% is white solid (purification step is as follows) after refining.
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 dry, add 1000ml ethanol stirred crystallization, suction filtration is dried and is obtained white solid 1150g, yield 90%, HPLC:99.8%, fusing point: 216-219 degree.
Claims (2)
1. a preparation method for imatinib, the synthetic method of described imatinib comprises the following steps of carrying out in order:
1) by after dissolving completely in dioxane and 4-methyl-3-nitro aniline input reaction flask, add anhydrous K
2cO
3under stirring at 0 ℃, drip chloromethyl benzoic acid chlorides, it is dissolved in dioxane by a certain percentage, drip off rear stirring reaction 1 hour, then add N methyl piperazine, this reaction easily heats up, and is noticing that, under the condition of temperature control, stirring is incubated to 4-methyl-3-nitro aniline reaction complete, suction filtration falls the solid in system, filtrate decompression is concentrated into dry, adds water 12L under vigorous stirring, stirring at room 2 hours, crystallization, suction filtration, dries and obtains beige solid, and this solid is N-(4-methyl-3-nitro phenyl)-4-(4-methyl-piperazine-1-methyl) benzamide;
2) by beige solid and the ethanol of above-mentioned preparation, drop in reaction flask, under stirring to dripping and be dissolved in the hydrazine hydrate in ethanol in system, in process, a large amount of foams produce, and reflux keeps being back to above-mentioned solid reaction complete, suction filtration falls catalyzer, filtrate decompression is concentrated into dry, obtains 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 reaction flask, reflux, with dense HCl, system pH is adjusted to 1.5-2, there is thick product to produce, then add the 50% cyanamide aqueous solution, holder ties up to pH and between 3-4, refluxes 30 hours, after demonstration reaction finishes, be evaporated to dry, add water dissolution enriched material, then at the aqueous solution of cooling lower use 20% sodium hydroxide of ice-water bath, adjust pH to 13, process has oily matter and continues under ice-water bath stirred crystallization more than 4 hours, suction filtration, decompression drying, obtaining off-white color solid is N-(3-guanidine radicals-4-aminomethyl phenyl)-4-(4-methyl-piperazine-1-methyl) benzamide,
4) N, dinethylformamide dimethylacetal is dissolved in ethanol, is warming up to 60 degree, in system, drips 3-acetylpyridine, prevent punching material, reflux 12 hours, show that raw material reaction is complete, the concentrated ethanol that removes, after slightly cooling, adding volume ratio is 3: 2 toluene and normal hexane mixed solution, then under ice-water bath, stirred crystallization is more than 4 hours, and suction filtration is dried and obtained orange solid, is 3-dimethylamino-1-(3-pyridyl)-2-propylene-1-ketone;
5) by intermediate N (3-guanidine radicals-4-aminomethyl phenyl)-4-(4-methyl-piperazine-1-methyl) benzamide; with another intermediate 3-dimethylamino-1-(3-pyridyl)-2-propylene-1-ketone; and primary isoamyl alcohol drops in reaction flask; under nitrogen protection, add backflow; carry out reflux water-dividing more than 12 hours; slightly cold after finishing to react; then under refluxing, add ethyl acetate; stirring at room crystallization 4 hours; suction filtration is dried and is obtained beige solid; for imatinib, after refining, be white solid.
2. the preparation method of imatinib according to claim 1, it is characterized in that, described step 5) purification step after is as follows: in bottle, add above-mentioned beige solid, MeOH and methanesulfonic, be added to solid complete be concentrated into after molten dry, add ethanol stirred crystallization, suction filtration is dried and is obtained white solid.
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| CN104072477B (en) * | 2013-07-26 | 2016-01-27 | 江苏豪森药业股份有限公司 | The process for purification of imatinib |
| 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 |
| CN111518088B (en) * | 2020-06-10 | 2021-09-03 | 山东创新药物研发有限公司 | Preparation method and application of aniline quinazoline intermediate |
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| CN101016293A (en) * | 2007-02-14 | 2007-08-15 | 杭州盛美医药科技开发有限公司 | Preparing method of imatinib |
| US7507821B2 (en) * | 2004-12-30 | 2009-03-24 | Chemagis Ltd. | Process for preparing Imatinib |
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| CN101735197A (en) * | 2009-12-18 | 2010-06-16 | 天津市炜杰科技有限公司 | Method for synthesizing Imatinib |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| GB2398565A (en) * | 2003-02-18 | 2004-08-25 | Cipla Ltd | Imatinib preparation and salts |
| WO2004099186A1 (en) * | 2003-05-06 | 2004-11-18 | Il Yang Pharm Co., Ltd. | N-phenyl-2-pyrimidine-amine derivatives and process for the preparation thereof |
| AU2003242988A1 (en) * | 2003-06-06 | 2005-01-04 | Adibhatla Kali Sathya Bhujanga Rao | Process for the preparation of the anti-cancer drug imatinib and its analogues |
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