CN101735196B - Method for synthesizing Imatinib - Google Patents
Method for synthesizing Imatinib Download PDFInfo
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- CN101735196B CN101735196B CN 200810202634 CN200810202634A CN101735196B CN 101735196 B CN101735196 B CN 101735196B CN 200810202634 CN200810202634 CN 200810202634 CN 200810202634 A CN200810202634 A CN 200810202634A CN 101735196 B CN101735196 B CN 101735196B
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- 0 *Cc(cc1)ccc1C#N Chemical compound *Cc(cc1)ccc1C#N 0.000 description 2
- IVSYNRMJMLDSIB-UHFFFAOYSA-N CN1CCN(Cc(cc2)ccc2C#N)CC1 Chemical compound CN1CCN(Cc(cc2)ccc2C#N)CC1 IVSYNRMJMLDSIB-UHFFFAOYSA-N 0.000 description 1
- ZJUXJQSYXBYFFO-UHFFFAOYSA-N CN1CCN(Cc(cc2)ccc2C(O)=O)CC1 Chemical compound CN1CCN(Cc(cc2)ccc2C(O)=O)CC1 ZJUXJQSYXBYFFO-UHFFFAOYSA-N 0.000 description 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N Cc(ccc(NC(c1ccc(CN2CCN(C)CC2)cc1)=O)c1)c1Nc1nc(-c2cccnc2)ccn1 Chemical compound Cc(ccc(NC(c1ccc(CN2CCN(C)CC2)cc1)=O)c1)c1Nc1nc(-c2cccnc2)ccn1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a method for synthesizing Imatinib, comprising the following steps: under the action of alkali, 4-methyl-N-3-(4-pyridine-3-radix-pyrimidine-2-radix)-1,3-phenylenediamine shown in the formula (I) reacts with 4-(4-methylpiperazine-1-methyl)-benzoate shown in the formula (II) in an aprotic inorganic solvent to form the Imatinib shown in the formula (III), namely 4-(4-methylpiperazine-1-methyl)-N-[4-methyl-3-[4-(3-pyridyl) pyrimidine-2-amino]-benzamide. In the above chemical structure general formula, R represents fatty alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl containing 1-10 carbon atoms. The invention provides the new method for synthesizing Imatinib, which has mild reaction conditions and high yield and is environment-friendly.
Description
Technical field
The invention belongs to the organic synthesis field, particularly a kind of synthetic method of imatinib.
Background technology
Imatinib mesylate is that a signal transduction inhibitor (being former STI571) is successfully studied in effort that Novartis Co.,Ltd was passed through 7 years, is first tumour generation coherent signal conduction depressant drug that gets the Green Light of the whole world.Imatinib mesylate obtains lonely rare medicine status in states such as the U.S., European Union and Japan, and obtain the approval of FDA Food and Drug Administration (FDA) May 10 calendar year 2001, be used for the treatment of alpha-interferon (the failed protoblast crisis stadium for the treatment of of interfer on-alfa), the chronic lymphocytic leukemia patient who accelerates stadium or chronic stadium.
The chemistry of imatinib (Imatinib) is by name: 4-(4-methylpiperazine base-1-methyl)-N-[4-methyl-3-[4-(3-pyridyl) pyrimidine-2-is amino]-benzamide, structural formula is as follows:
The synthetic route of imatinib is suitable for industrializedly being summarized as two.Route one is take 2-methyl-5-nitro aniline as starting raw material, generate guanidine with the cyanamide reaction first, then carry out ring-closure reaction with 3-dimethylamino-1-(3-pyridyl)-2-propylene-1-ketone, again nitroreduction is become amino, then carry out condensation reaction successively with to chloromethyl benzoic acid chlorides and N methyl piperazine, make imatinib (WO 2004/108699).
Route two is take 4-methyl-3-nitro aniline as starting raw material, first carry out condensation reaction successively with to chloromethyl benzoic acid chlorides and N methyl piperazine, then nitroreduction is become amino, generate guanidine with the cyanamide reaction again, then carry out ring-closure reaction with 3-dimethylamino-1-(3-pyridyl)-2-propylene-1-ketone, make imatinib (WO 03/066613).
The response hierarchy that is the cyclization pyrimidine ring of the difference maximum of two lines is different.But all there is following shortcoming in these two lines: 1) because the use cyanamide synthesizes guanidine radicals, and cyanamide is lower boiling, highly volatile, thereby the yield of guanidine radicals is low and unstable; 2) synthesis yield of pyrimidine ring is low, long reaction time, and raw material reaction is incomplete.
Chinese patent CN1630648A also discloses a kind of synthetic method of imatinib.The method uses 3-bromo-4-monomethylaniline to be raw material, aminolysis reaction with trimethyl aluminium realization and 4-(4-methyl-piperazinyl-methyl) methyl benzoate obtains N-(4-methyl-3-bromophenyl)-4-(4-methyl-piperazinyl-1-methyl)-benzamide, obtains imatinib with precious metal palladium catalysis and PYRIMITHAMINE reaction at last.Its maximum shortcoming is 1) trimethyl aluminium that uses is ignition control compound, and the water contact reacts is violent; 2) final product has 10% isomer, is difficult to purifying.
Chinese patent CN101016293A discloses the synthetic method of another kind of imatinib.The method is also take N-(4-methyl-3-3 aminophenyl)-4-(4-methyl-piperazinyl-1-methyl)-benzamide as raw material, and 2-halo-4-methyl-(3-pyridyl)-pyrimidine reaction obtains imatinib.Halogenating agent such as phosphorus oxychloride that the method is used when synthetic 2-halo-4-methyl-(3-pyridyl)-pyrimidine belong to highly toxic product, and be very large on the impact of environment.
Summary of the invention
Therefore, the technical problem to be solved in the present invention is exactly the defective that exists in the synthetic method for existing imatinib, and a kind of synthetic method of new imatinib is provided, and this synthesising method reacting condition is gentle, and is environmentally friendly, and yield is high.
The present invention solves the problems of the technologies described above the technical scheme that adopts: a kind of synthetic method of imatinib, it is characterized in that, may further comprise the steps: in organic solvent, under the effect of alkali, 4-methyl-N-3-shown in the formula (I) (4-pyridin-3-yl-pyrimidine-2-base)-1,4-shown in 3-phenylenediamine and the formula (II) (4-methylpiperazine-1-methyl)-benzoic ether reacts, form the imatinib shown in the formula (III), be that 4-(4-methylpiperazine-1-methyl)-N-[4-methyl-3-[4-(3-pyridyl) pyrimidine-2-is amino]-benzamide
In the above-mentioned chemical structure of general formula, R represents the fatty alkyl of 1～10 carbon, phenyl, substituted-phenyl, benzyl or substituted benzyl.
Among the present invention, the fatty alkyl of described 1-10 carbon is methyl, ethyl or propyl group preferably, and described substituted-phenyl is p-methylphenyl preferably, and described substituted benzyl is preferably to methoxy-benzyl.
Among the present invention, described alkali can be selected from organic bases and mineral alkali.Described organic bases preferably is selected from one or more in sodium alkoxide, potassium alcoholate, butyllithium, isobutyl-lithium, tert-butyl lithium, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide and the salt of wormwood.Wherein, described sodium alkoxide preferably is selected from sodium methylate, sodium ethylate, sodium propylate, sodium butylate, sodium tert-butoxide and benzylalcohol sodium, and described potassium alcoholate preferably is selected from potassium methylate, potassium ethylate, potassium propylate, butanols potassium, potassium tert.-butoxide and potassium benzyl alcoholate.That the concentration of described alkali is better is 0.1～10M, and that better is 1～2M.
Among the present invention, described organic solvent is better is selected from tetrahydrofuran (THF), ether, methylene dichloride, 1, one or more in alcohol, toluene, ethyl acetate, dimethyl formamide, methyl-sulphoxide and the dimethylbenzene of 2-ethylene dichloride, acetonitrile, 1～4 carbon.
Among the present invention, that the reaction mol ratio of the compound shown in the compound shown in the formula (I) and the formula (II) is better is 1:1～1:10, and that best is 1:1.5～1:4.The consumption of organic solvent is the conventional amount used in the organic synthesis.
Among the present invention, what the temperature of reaction of described reaction was better is 0～100 ℃, and better is 25～50 ℃.The reaction times of described reaction better for till detecting reaction raw materials and no longer reducing.
The synthetic method of the compound shown in the formula (I) can be referring to patent WO 2004/108699:
2-methyl-5-nitro aniline and cyanamide reaction obtain 2-methyl-5-nitrophenyl guanidine, and itself and 3-dimethylin-1-pyridin-3-yl acetone reaction obtain the pyrimidine ring compound, and the nitro that then reduces obtains the compound shown in the formula (I).
The synthetic method of the compound shown in the formula (II) can be referring to document syn.comm.2003,3597, comprise the steps: to cyano group halogen benzyl or to the sulphonate of cyano-benzyl alcohol and methylpiperazine reaction, then be hydrolyzed cyano group and be acid, last and corresponding alcohol reaction obtains corresponding ester, i.e. compound shown in the formula (II);
In the said structure, R represents the fatty alkyl of 1～10 carbon, phenyl, substituted-phenyl, benzyl or substituted benzyl; X represents Cl, Br, I, OMS or OTS.
The raw material that the present invention is used or reagent except specifying, equal commercially available getting.
Than prior art, beneficial effect of the present invention is as follows:
1, in the inventive method, the aminolysis reaction of ester is totally complete, and yield improves greatly,
2, in the inventive method, the by product of aminolysis reaction is corresponding alcohol, and is environmentally friendly,
3, in the inventive method, reaction conditions is gentle, and easy handling is beneficial to suitability for industrialized production.
Embodiment
The below further specifies the present invention with embodiment, but the present invention is not limited.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, or the condition of advising according to manufacturer.
Embodiment 1 imatinib,
In the four-hole bottle of 500ml drying, add tetrahydrofuran (THF) 250ml, 4-methyl-N-3-(4-pyridin-3-yl-pyrimidine-2-base)-1,3-phenylenediamine 27.7g and 4-(4-methylpiperazine-1-methyl)-methyl benzoate 25g is after the stirring and dissolving, add sodium methylate 10g, heat 70 ℃ of back flow reaction and spend the night, concentrate tetrahydrofuran (THF) after detection reaction is complete, the solid washing that obtains, dry imatinib 45g, the yield 91.0% of getting.
Spectroscopic data is as follows:
1H?NMR(500M，DMSO)δ：10.2(s，1H)，9.30(s，1H)，8.99(s，1H)，8.72(d，J＝4.0Hz，1H)，8.57(s，1H)，8.53(s，1H)，8.11(s，1H)，8.00(s，1H)，7.98(s，1H)，7.58-7.51(m，4H)，7.44(d，J＝4.3Hz，1H)，7.22(d，J＝8.1Hz，1H)，3.70(s，2H)，3.50-3.25(m，2H)，3.20-2.90(m，4H)，2.81(s，3H)，2.40(s，3H)，2.24(s，3H).
13C?NMR(125M，DMSO)δ：164.9，161.3，161.1，159.4，150.8，147.7，137.7，137.1，134.9，134.3，132.3，129.9，129.1，127.7，127.6，123.9，117.2，116.8，107.5，59.9，52.1，48.9，42.2，17.5.
MS(M
++1)：494.3
Embodiment 2
In the four-hole bottle of 5000ml drying, add methylene dichloride 3000ml, 4-methyl-N-3-(4-pyridin-3-yl-pyrimidine-2-base)-1,3-phenylenediamine 277g and 4-(4-methylpiperazine-1-methyl)-ethyl benzoate 270g is after the stirring and dissolving, add sodium methylate 100g, heat 40 ℃ of back flow reaction and spend the night, concentrate toluene after detection reaction is complete, the solid washing that obtains, dry imatinib 455g, the yield 92.0% of getting.Spectroscopic data is the same.
Embodiment 3
In the four-hole bottle of 5000ml drying, add toluene 3000ml, 4-methyl-N-3-(4-pyridin-3-yl-pyrimidine-2-base)-1,3-phenylenediamine 277g and 4-(4-methylpiperazine-1-methyl)-peruscabin 450g is after the stirring and dissolving, add sodium ethylate 200g, be heated to 50 ℃ of reactions and spend the night, concentrate toluene after detection reaction is complete, the solid washing that obtains, dry imatinib 445g, the yield 90.0% of getting.Spectroscopic data is the same.
Embodiment 4
Add 25 liters of dimethyl formamides in 50 liters of reactors, 4-methyl-N-3-(4-pyridin-3-yl-pyrimidine-2-base)-1,3-phenylenediamine 2.77kg and 4-(4-methylpiperazine-1-methyl)-propyl benzoate 3.50kg is after the stirring and dissolving, add butanols potassium 3kg, be heated to 50 ℃ of reactions and spend the night, detection reaction is separated out solid in falling back fully, centrifugal, the solid washing that obtains, dry imatinib 4.45kg, the yield 90.0% of getting.Spectroscopic data is the same.
Embodiment 5
In the four-hole bottle of 5000ml drying, add acetonitrile 3000ml, 4-methyl-N-3-(4-pyridin-3-yl-pyrimidine-2-base)-1,3-phenylenediamine 277g and 4-(4-methylpiperazine-1-methyl)-phenylformic acid is to methoxy benzyl ester 450g, after the stirring and dissolving, add butyllithium 400ml (2.5M), be heated to 20 ℃ of reactions and spend the night, concentrate acetonitrile after detection reaction is complete, the solid washing that obtains, dry imatinib 445g, the yield 90.0% of getting.Spectroscopic data is the same.
Embodiment 6
In the four-hole bottle of 5000ml drying, add propyl alcohol 3000ml, 4-methyl-N-3-(4-pyridin-3-yl-pyrimidine-2-base)-1,3-phenylenediamine 277g and 4-(4-methylpiperazine-1-methyl)-phenylformic acid phenyl ester 2250g is after the stirring and dissolving, add cesium hydroxide 1500g, be heated to 80 ℃ of reactions and spend the night, concentrate propyl alcohol after detection reaction is complete, the solid washing that obtains, dry imatinib 450g, the yield 90.5% of getting.Spectroscopic data is the same.
Embodiment 7
In the four-hole bottle of 5000ml drying, add ethyl acetate 3000ml, 4-methyl-N-3-(4-pyridin-3-yl-pyrimidine-2-base)-1,3-phenylenediamine 277g and 4-(4-methylpiperazine-1-methyl)-phenylformic acid p-methylphenyl ester 450g is after the stirring and dissolving, add salt of wormwood 138g, be heated to 50 ℃ of reactions and spend the night, concentrate ethyl acetate after detection reaction is complete, the solid washing that obtains, dry imatinib 445g, the yield 90.0% of getting.Spectroscopic data is the same
Embodiment 8
In the four-hole bottle of 5000ml drying, add methyl-sulphoxide 3000ml, 4-methyl-N-3-(4-pyridin-3-yl-pyrimidine-2-base)-1,3-phenylenediamine 277g and 4-(4-methylpiperazine-1-methyl)-phenylformic acid p-methylphenyl ester 450g is after the stirring and dissolving, add sodium hydroxide 800g, be heated to 70 ℃ of reactions and spend the night, concentrate methyl-sulphoxide after detection reaction is complete, the solid washing that obtains, dry imatinib 445g, the yield 90.0% of getting.Spectroscopic data is the same.
Embodiment 9
In the four-hole bottle of 5000ml drying, add ether 3000ml, 4-methyl-N-3-(4-pyridin-3-yl-pyrimidine-2-base)-1,3-phenylenediamine 277g and 4-(4-methylpiperazine-1-methyl)-peruscabin 1500g is after the stirring and dissolving, add benzylalcohol sodium 1000g (1mol), 0 ℃ of reaction is spent the night, and concentrates ether after detection reaction is complete, the solid washing that obtains, dry imatinib 445g, the yield 90.0% of getting.Spectroscopic data is the same.
Claims (6)
1. the synthetic method of an imatinib, it is characterized in that, may further comprise the steps: in organic solvent, under the effect of alkali, formula, (I) the 4-methyl-N-3-shown in, (4-pyridin-3-yl-pyrimidine-2-base)-1,3-phenylenediamine and formula, (II) 4-shown in, (4-methylpiperazine-1-methyl)-benzoic ether reacts, form formula, (III) imatinib shown in, be 4-, (4-methylpiperazine-1-methyl)-N-[4-methyl-3-[4-, (3-pyridyl) pyrimidine-2-is amino]-benzamide
In the above-mentioned chemical structure of general formula, R represents the fatty alkyl of 1～10 carbon, phenyl, substituted-phenyl, benzyl or substituted benzyl; Wherein, described organic solvent is selected from tetrahydrofuran (THF), ether, methylene dichloride, 1, one or more in alcohol, toluene, ethyl acetate, dimethyl formamide, methyl-sulphoxide and the dimethylbenzene of 2-ethylene dichloride, acetonitrile, 1～4 carbon; Described alkali is selected from one or more in sodium alkoxide, potassium alcoholate, butyllithium, isobutyl-lithium, tert-butyl lithium, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide and the salt of wormwood; Described substituted-phenyl is p-methylphenyl, and described substituted benzyl is to methoxy-benzyl.
2. synthetic method according to claim 1 is characterized in that, the fatty alkyl of described 1～10 carbon is methyl, ethyl or propyl group.
3. synthetic method according to claim 1 is characterized in that, the reaction mol ratio of the compound shown in the compound shown in the described formula (I) and the formula (II) is 1: 1～1: 5.
4. synthetic method according to claim 1 is characterized in that, the concentration of described alkali is 0.1～10M.
5. synthetic method according to claim 1 is characterized in that, temperature of reaction is 0～80 ℃.
6. synthetic method according to claim 1 is characterized in that, the reaction times is for till detecting reaction raw materials and no longer reducing.
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| CN101735196B true CN101735196B (en) | 2013-03-20 |
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| US8609842B2 (en) * | 2010-04-23 | 2013-12-17 | Fujian South Pharmaceutical Co., Ltd. | Method for synthesizing Imatinib |
| JP2014509642A (en) * | 2011-03-31 | 2014-04-21 | アイエヌディー−スイフト ラボラトリーズ リミテッド | An improved method for the formation of imatinib and its mesylate |
| CN105859682A (en) * | 2015-01-18 | 2016-08-17 | 杨俊� | Synthetic method of imatinib mesylate |
| CN112920163B (en) * | 2021-01-26 | 2023-09-26 | 华中科技大学同济医学院附属协和医院 | Hapten, antigen and antibody of imatinib and N-demethyl imatinib and application thereof |
| CN112946282B (en) * | 2021-01-26 | 2022-08-09 | 北京丹大生物技术有限公司 | Detection reagent and detection kit for detecting imatinib and/or N-demethylimatinib |
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Effective date of registration: 20160707 Address after: Mingxi County of Sanming City province Fujian 365200 Xuefeng New Town Road No. 98 Patentee after: Fujian South Pharmaceutical Co., Ltd. Address before: 200444, No. 868, Chen Cheng Road, No. 2, Shanghai, Baoshan District Patentee before: Parling Shanghai Pharm-technology Co., Ltd. Patentee before: Fujian South Pharmaceutical Co., Ltd. |