CN1900073A - Process for preparing N-phenyl-2-pyrimidyl amine derivative - Google Patents
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Abstract
The present invention relates to new organic compound, and is especially the preparation process of N-(2-methyl-5-nitro) phenyl-4-(3-pyridyl) pyrimidiyl-2-amine as the key intermediate for imatinib, which is tyrosine protein kinase inhibitor for treating chronic myeloid leukemia and other diseases, and its analog N- phenyl-pyrimidiyl-2-amine derivative. The target product may be prepared through condensation of 4-aromatic heterocycle-2-halogenated pyrimidine and substituted aniline in the presence of catalyst. The preparation process has low material cost, scientific synthesis path, high product yield and other advantages.
Description
Technical field
The present invention relates to a kind of new organic chemistry synthetic method, especially for protein tyrosine kinase inhibitor imatinib key intermediate N-(2-methyl-5-nitro) phenyl-4-(3-pyridyl) pyrimidine-2-amine of diseases such as treatment chronic lymphocytic leukemia and the preparation method of analog N-n-phenyl-2-pyrimidine-amine derivatives thereof.
Background technology
Imatinib is to be the cancer therapy drug of theoretical direction appropriate design with the cancer cells mechanism of action by first of Switzerland Novartis invention.In May calendar year 2001, FDA (Food and Drug Adminstration) (FDA) ratifies it in two short first quarter moons goes on the market as oral PTS, is used for the treatment of chronic lymphocytic leukemia.In February, 2002, FDA ratifies its medicine as treatment gi tract mesenchymal neoplasm again.
Imatinib is a kind of novel tyrosine protein kinase inhibitor, can suppress the tyrosine kinase activity of abl/bcr, thereby can suppress granulocyte propagation, and induces abl/bcr positive cell collection bunch and newborn apoptosis of leukemia.It also can suppress the tyrosine kinase activity of platelet derived growth factor (PDGF), STEM CELL FACTOR (SCF) and c-Kit acceptor, and can suppress the cell response of PDGF-and SCF-mediation, thereby, a lot of purposes are arranged.
Its chemical name is: methyl 4-[(4-methyl isophthalic acid-piperazine)]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino]-phenyl] benzamide.
English name: Imatinib; 4-[(4-Methyl-1-piperazinyl) methyl]-N-] 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl] amino] phenyl] benzamide.
Outward appearance: white or off-white color crystal.
Structural formula:
United States Patent (USP) (US5521184), Chinese patent (CN1077713), Chinese patent (CN1043531), international monopoly (WO20040108699) and open source literature Journal of Medical Chemistry1993,36,2716-2725 etc. disclose a kind of processing method, be raw material with 5-nitro-o-toluidine and 3-acetylpyridine respectively, generate corresponding Guanidinium nitrate and β-ketene compound earlier, carry out the cyclic condensation reaction again and obtain key intermediate (I), the synthetic then imatinib that obtains.Its analog can obtain with identical method.
Above-mentioned preparation method exists that the reaction starting raw material is difficult to obtain, part material toxicity is big, costs an arm and a leg on Chinese market, reactions steps is long, reaction conditions shortcoming such as harshness relatively, is unsuitable for domestic production.
Summary of the invention
The purpose of this invention is to provide a kind of key intermediate N-(2-methyl-5-nitro) phenyl-4-(3-pyridyl) pyrimidine-2-amine (structural formula I) of simple and direct and economic tyrosine protein kinase inhibitor imatinib and the organic synthesis preparation method of analog N-phenyl-pyrimidine-2-sulfonamide derivatives (structural formula II) thereof, make preparation method's prices of raw and semifnished materials low, the synthetic route science, rationally, reaction times is short, and product yield height, and has an implementary value, bigger social benefit and economic benefit can be produced, and the prevention and the treatment of protein tyrosine kinase associated diseases can be used for.
The preparation method of the key intermediate of tyrosine protein kinase inhibitor imatinib of the present invention (following molecular structure is graphic) N-(2-methyl-5-nitro) phenyl-4-(3-pyridyl) pyrimidine-2-amine (structural formula I) and analog N-phenyl-pyrimidine-2-sulfonamide derivatives (structural formula II) thereof, adopting 4-aromatic heterocyclic-2-halogenated pyrimidine (structural formula II I) and substituted aniline (structural formula IV) is raw material, condensation in the presence of an acidic catalyst and getting.
Preparation method's step of N-phenyl-pyrimidine of the present invention-2-sulfonamide derivatives is as follows:
Reaction scheme A:
In the above-mentioned reaction scheme, X represents halogen atom, is preferably chlorine, bromine, iodine.R1, R2 all can be the fatty alkyl of hydrogen or C1-C6, as methyl, ethyl, propyl group, butyl, sec.-propyl, the tertiary butyl; Be aryl perhaps, comprise benzyl, fragrant ethyl, substituted benzyl, trityl group, diphenyl methyl; Be halogen atom perhaps, comprise F, Cl, Br and I; Be acyl group perhaps, comprise ethanoyl, propionyl, trichlorine acetyl, benzoyl.The R3 definition is as R1, and R2 also can be nitro, amino, dialkyl group substituted-amino, hydroxyl, substituted hydroxy, carboxyl, carboxylicesters, acid amides, substituted amide, etc.
Among this reaction scheme A, reaction process comprises that with 4-aromatic heterocyclic-2-halogenated pyrimidine (structural formula II I) and substituted aniline (structural formula IV) be raw material, condensation in the presence of an acidic catalyst and obtain N-phenyl-pyrimidine-2-sulfonamide derivatives (II).In more detail, when R1 is that hydrogen atom, R2 are when the methyl while, R3 was nitro, be key intermediate N-(2-methyl-5-nitro) phenyl-4-(3-pyridyl) pyrimidine-2-amine (I) of imatinib, that is:
Among the reaction scheme A, reactant 4-aromatic heterocyclic-2-halogenated pyrimidine (structural formula II I) can cf. publication data Journal of Chemical Society, Perkin Trans 1,2002,1847 and Journal of Organic Chemistry, 1988,53,4137, obtain easily by the method shown in the following reaction scheme B;
Reaction scheme B:
Among the reaction scheme A, described substituted aniline (structural formula IV) then is generally commercially available chemicals.
Among the reaction scheme A, described an acidic catalyst can be a mineral acid, and example hydrochloric acid, sulfuric acid, phosphoric acid also can be organic acids, as trifluoracetic acid, Phenylsulfonic acid, tosic acid, methylsulfonic acid, and perhaps their mixture.Reaction medium changes according to the difference of catalyst system therefor, can be anhydrous organic solvent, as methylene dichloride, chloroform, tetrahydrofuran (THF), N, dinethylformamide, dioxane, benzene, toluene, acetone, acetonitrile, C1-C6 alcohol, can be inorganics also, as water, perhaps their mixture.
According to the difference of reaction medium, the temperature of reaction generally is controlled at-20 ℃～200 ℃, is generally 50～100 ℃.
Reaction product can obtain with the ordinary method separation, as obtaining product with organic solvent extraction.The purifying of product can be undertaken by ordinary method, as column chromatography, recrystallization etc., also can adopt other method according to the physico-chemical property of product, as acid fluid dissolves---and alkali lye precipitation method etc.
Resulting product is target product N-phenyl-pyrimidine-2-sulfonamide derivatives (II).When R1 is that hydrogen atom, R2 are when the methyl while, R3 was nitro, be the key intermediate (I) of imatinib.
These product preparation method prices of raw and semifnished materials are low, synthetic route science, reasonable, and product yield height, and have implementary value, bigger social benefit and economic benefit can be produced, and the prevention and the treatment of protein tyrosine kinase associated diseases can be used for.
Embodiment
Embodiment 1:2-chloro-4-(3-pyridyl) pyrimidine
3-bromopyridine 2.25g is dissolved among the anhydrous diethyl ether 5mL, under the nitrogen protection, dropwise adds the n-Butyl Lithium 3mL of 1.6M under-40 ℃ of low temperature, drips Bi Jixu and stirs 0.5h.Behind the solution of property adding 3.3g zinc bromide in the 10mL anhydrous diethyl ether, insulated and stirred is reacted 1h again.Rise to room temperature, add 2,4-dichloro pyrimidine 1.49g closes palladium, back flow reaction 18h in the solution and the catalytic amount four (triphenyl phosphorus) of 5mL anhydrous tetrahydro furan.Reaction is finished, and uses ethyl acetate extraction earlier, adds dilute hydrochloric acid extraction in the extracting solution again, is adjusted to pH 10 with sodium hydroxide then, separates out cotton-shaped solid.Collect, get 2-chloro-4-(3-pyridyl) pyrimidine 1.65g behind the purifying, mp142-143 ℃,
1H-NMR (CDCl
3): 748 (1H, m, 5 '-H), 7.71 (1H, d, 5-H), 8.45 (1H, m, 4 '-H), 8.72 (1H, d, 6-H), 8.78 (1H, dd, 6 '-H), 9.26 (1H, dd, 2 '-H).
13C-NMR (CDCl
3): 115.3,123.9,131.0,135.0,148.7,152.6,160.4,162.2,164.9.
Embodiment 2:N-(2-methyl-4-oil of mirbane) base-4-(3-pyridyl)-pyrimidine-2-amine
Above-mentioned 2-chloro-4-(3-pyridyl) pyrimidine 1.91g, to nitro o-toluidine 1.6g, methylsulfonic acid 0.6g back flow reaction 6h in the anhydrous dioxane of 10mL.Reaction is finished, and reclaims solvent, adds a large amount of cold water in the resistates, and alkalizes with sodium bicarbonate.The solid that collection is separated out, drying gets 2.5g, mp 195-196 ℃.
13C-NMR:164.1,156.2,155.5,149.4,148.8,148.6,139.7,135.4,132.3,132.1,130.2,121.9,121.8,118.5,108.9,18.2.
Embodiment 3:N-phenyl-4-(3-pyridyl)-pyrimidine-2-amine
With embodiment 2 similar methods, 2-chloro-4-(3-pyridyl) pyrimidine 1.91g and aniline 1.0g, tosic acid 0.6g back flow reaction 6h in the anhydrous dioxane of 10mL gets target product, mp.147-148 ℃.
13C-NMR:164.1,155.5,154.4,151.2,149.3,148.8,135.5,132.3,130.2,129.3,129.3,122.1,113.5,113.5,108.9.
Embodiment 4:N-(2-chloro-phenyl)-4-(3-pyridyl)-pyrimidine-2-amine
With embodiment 2 similar methods, 2-chloro-4-(3-pyridyl) pyrimidine 1.91g and 2-chloroaniline 1.3g, concentrated hydrochloric acid 1ml react in 80% ethanol, get target product, mp.103-104 ℃.
13C-NMR:163.9,159.4,155.3,149.3,148.9,145.9,135.5,132.3,130.2,130.1,129.2,119.3,114.6,109.9,108.9.
Embodiment 5:N-(2,4-dimethyl-phenyl)-4-(3-pyridyl)-pyrimidine-2-amine
With embodiment 2 similar methods, 2-chloro-4-(3-pyridyl) pyrimidine 1.91g and 2,4-xylidine 1.1g, methylsulfonic acid 0.6g react in dehydrated alcohol, get target product, mp.113-114 ℃.
13C-NMR:164.1,158.3,155.5,148.0,148.0,135.5,132.9,132.3,123.7,123.4,120.1,108.9,105.0,20.7,17.8.
Claims (5)
1. the preparation method of the key intermediate of a tyrosine protein kinase inhibitor imatinib (following molecular structure is graphic) N-(2-methyl-5-nitro) phenyl-4-(3-pyridyl) pyrimidine-2-amine (structural formula I) and analog N-phenyl-pyrimidine-2-sulfonamide derivatives (structural formula II) thereof is characterized in that: the condensation and getting in the presence of catalyzer of 4-aromatic heterocyclic-2-halogenated pyrimidine (structural formula II I) and substituted aniline (structural formula IV).
2. preparation method according to claim 1 is characterized in that X represents halogen atom, is F, Cl, Br and I; R1, R2 are hydrogen or the fatty alkyl that is less than six carbon, as methyl, ethyl, propyl group, butyl, sec.-propyl, the tertiary butyl; Be aryl perhaps, comprise benzyl, fragrant ethyl, substituted benzyl, trityl group, diphenyl methyl; Be halogen atom perhaps, comprise F, Cl, Br and I; Be acyl group perhaps, comprise ethanoyl, propionyl, trichlorine acetyl, benzoyl; The R3 definition is as R1, and R2 also can be nitro, amino, dialkyl group substituted-amino, hydroxyl, substituted hydroxy, carboxyl, carboxylicesters, acid amides, substituted amide.
3. preparation method according to claim 1, it is characterized in that carrying out under the catalysis that is reflected at acidic medium of described 4-aromatic heterocyclic-2-halogenated pyrimidine (structural formula II I) and substituted aniline (structural formula IV), catalytic media is mineral acid (example hydrochloric acid, sulfuric acid, phosphoric acid) or organic acid (as trifluoracetic acid, Phenylsulfonic acid, tosic acid, methylsulfonic acid) or is their mixture.
4. preparation method according to claim 3, it is characterized in that reaction medium can be anhydrous organic solvent (as methylene dichloride, chloroform, tetrahydrofuran (THF), N, dinethylformamide, dioxane, benzene, toluene, acetone, acetonitrile, C1-C6 alcohol) or inorganics (as water) and their mixture.
5. preparation method according to claim 3, it is characterized in that described reaction temperature be controlled at-20 ℃～200 ℃, be generally 50～100 ℃.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101503402A (en) * | 2009-03-10 | 2009-08-12 | 沈阳药科大学 | 2-aniline pyrimidine derivative, as well as preparation and uses thereof |
| CN102212057A (en) * | 2011-04-13 | 2011-10-12 | 合肥工业大学 | Carboxylic acid non-steroidal anti-inflammatory agent derivative and preparation method and application thereof |
| CN102225925A (en) * | 2011-04-13 | 2011-10-26 | 合肥工业大学 | Compound with activity for resisting chronic cell leukemia and preparation method thereof |
| CN114585615A (en) * | 2019-10-14 | 2022-06-03 | 新加坡艺思高艾斯特生物科技有限公司 | Synthesis of 6-methyl-N1- (4- (pyridin-3-yl) pyrimidin-2-yl) benzene-1, 3-diamine |
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2006
- 2006-07-12 CN CNB2006100524182A patent/CN100537563C/en not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101503402A (en) * | 2009-03-10 | 2009-08-12 | 沈阳药科大学 | 2-aniline pyrimidine derivative, as well as preparation and uses thereof |
| CN101503402B (en) * | 2009-03-10 | 2014-06-25 | 沈阳药科大学 | 2-aniline pyrimidine derivative, as well as preparation and uses thereof |
| CN102212057A (en) * | 2011-04-13 | 2011-10-12 | 合肥工业大学 | Carboxylic acid non-steroidal anti-inflammatory agent derivative and preparation method and application thereof |
| CN102225925A (en) * | 2011-04-13 | 2011-10-26 | 合肥工业大学 | Compound with activity for resisting chronic cell leukemia and preparation method thereof |
| CN102212057B (en) * | 2011-04-13 | 2013-11-27 | 合肥工业大学 | Carboxylic acid non-steroidal anti-inflammatory agent derivative and preparation method and application thereof |
| CN114585615A (en) * | 2019-10-14 | 2022-06-03 | 新加坡艺思高艾斯特生物科技有限公司 | Synthesis of 6-methyl-N1- (4- (pyridin-3-yl) pyrimidin-2-yl) benzene-1, 3-diamine |
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Granted publication date: 20090909 Termination date: 20120712 |