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【结 构 式】 
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【分子编号】47516 【品名】(E)-3-(dimethylamino)-1-(3-pyridinyl)-2-propen-1-one 【CA登记号】123367-26-0 |
【 分 子 式 】C10H12N2O 【 分 子 量 】176.21816 【元素组成】C 68.16% H 6.86% N 15.9% O 9.08% |
与该中间体有关的原料药合成路线共 6 条
合成路线1
该中间体在本合成路线中的序号：(V)MGCD-0103 can be prepared as follows. Reaction of 4-(aminomethyl)benzoic acid methyl ester hydrochloride (I) with pyrazole-1-carboxamidine hydrochloride (II) affords guanidine (III). 3-Acetylpyridine (IV) is then heated with dimethylformamide dimethyl acetal to furnish the enaminone (V), which is cyclized with guanidine (III), giving the pyridyl pyrimidine (VI). After saponification of the methyl ester (VI) by means of LiOH, the resulting carboxylic acid (VII) is coupled with o-phenylenediamine (VIII) to provide the title compound (1). Scheme 1.
| 【1】 Delorme, D., Zhou, Z. (MethylGene, Inc.). Inhibitors of histone deacetylase. EP 1590340, JP 2006514998, US 2004142953, US 6897220, WO 2004069823. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 65629 | Methyl 4-(aminomethyl)benzoate hydrochloride | 6232-11-7 | C9H11NO2.HCl | 详情 | 详情 |
| (II) | 65630 | 1H-Pyrazole-1-carboxamidine hydrochloride; 1-Amidinopyrazole hydrochloride; Praxadine | 4023-02-3 | C4H6N4.HCl | 详情 | 详情 |
| (III) | 65631 | 4-Guanidinomethylbenzoic acid methyl ester; 4-[[(Aminoiminomethyl)amino]methyl]benzoic acid methyl ester | 736080-30-1 | C10H13N3O2 | 详情 | 详情 |
| (IV) | 12027 | 1-(3-Pyridinyl)-1-ethanone; 1-(3-Pyridinyl)ethanone | 350-03-8 | C7H7NO | 详情 | 详情 |
| (V) | 47516 | (E)-3-(dimethylamino)-1-(3-pyridinyl)-2-propen-1-one | 123367-26-0 | C10H12N2O | 详情 | 详情 |
| (VI) | 65632 | 4-[[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]methyl]benzoic acid methyl ester | 849235-67-2 | C18H16N4O2 | 详情 | 详情 |
| (VII) | 65633 | 4-[[[4-(3-Pyridinyl)-2-pyrimidinyl]amino]methyl]benzoic acid | C17H14N4O2 | 详情 | 详情 | |
| (VIII) | 12824 | 2-Aminophenylamine; o-Phenylenediamine; 1,2-Benzenediamine | 95-54-5 | C6H8N2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)The condensation of 1-(3-pyridyl)ethanone (I) with dimethylformamide dimethylacetal (II) gives 3-(dimethylamino)-1-(3-pyridyl)-2-propen-1-one (III), which is cyclized with 1-(2-methyl-5-nitrophenyl)guanidine (IV) [obtained by reaction of 2-methyl-5-nitroaniline (V) with cyanamide (VI)] in refluxing isopropanol to yield the pyrimidine derivative (VII). Reduction of the nitro group of (VII) with H2 over Pd/C in THF affords the corresponding amino compound (VIII), which is finally condensed with 4-(4-methylpiperazin-1-ylmethyl)benzoyl chloride (IV) in pyridine.
| 【1】 Castaner, J.; Fernandez, R.; de Bree, F.; Sorbera, L.A.; Imatinib Mesilate. Drugs Fut 2001, 26, 6, 545. |
| 【2】 Buchdunger, E.; Mett, H.; Meyer, T.; Lydon, N.B.; Zimmermann, J.; Potent and selective inhibitors of the Abl-kinase: Phenylaminopyrimidine (PAP) derivatives. Bioorg Med Chem Lett 1997, 7, 2, 187. |
| 【3】 Zimmermann, J. (Novartis AG); Pyrimidine derivs. and process for their preparation. EP 0564409; JP 1994087834; US 5521184 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 12027 | 1-(3-Pyridinyl)-1-ethanone; 1-(3-Pyridinyl)ethanone | 350-03-8 | C7H7NO | 详情 | 详情 |
| (II) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
| (III) | 47516 | (E)-3-(dimethylamino)-1-(3-pyridinyl)-2-propen-1-one | 123367-26-0 | C10H12N2O | 详情 | 详情 |
| (IV) | 47517 | N-(2-methyl-5-nitrophenyl)guanidine | 152460-07-6 | C8H10N4O2 | 详情 | 详情 |
| (V) | 47518 | 2-Amino-4-nitrotoluene; 5-Nitro-o-toluidine; 4-Nitro-2-aminotoluene; 2-methyl-5-nitrophenylamine; 2-methyl-5-nitroaniline | 99-55-8 | C7H8N2O2 | 详情 | 详情 |
| (VI) | 19648 | Cyanamide | 420-04-2 | CH2N2 | 详情 | 详情 |
| (VII) | 47519 | N-(2-methyl-5-nitrophenyl)-N-[4-(3-pyridinyl)-2-pyrimidinyl]amine; N-(2-methyl-5-nitrophenyl)-4-(3-pyridinyl)-2-pyrimidinamine | 152460-09-8 | C16H13N5O2 | 详情 | 详情 |
| (VIII) | 47520 | 4-methyl-N(3)-[4-(3-pyridinyl)-2-pyrimidinyl]-1,3-benzenediamine; N-(5-amino-2-methylphenyl)-N-[4-(3-pyridinyl)-2-pyrimidinyl]amine | 152460-10-1 | C16H15N5 | 详情 | 详情 |
| (IX) | 47521 | 4-[(4-methyl-1-piperazinyl)methyl]benzoyl chloride | 148077-69-4 | C13H17ClN2O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)
| 【1】 Kompella A, Bhujanga Rao AKS, Venkaiah Chowdary N, et aL 2004. Process for the preparation of the anti-cancer drug imatinib and its analogs via aminolysis of a (chloromethyl benzamide intermediate. WO 2004108699(本专利申请人为: Natco Pharma Limited, India) |
| 【2】 Szczepek W, Luniewski W, Kaczmarek L, et aL 2006.A process for preparation of imatinib base. W0 2006071130(本专利申请人为: Instytut Farmaceutyczny, Pol) |
| 【3】 Szakacs Z,Beni S,VargaZ,et aL 2005. Acid-base profiling of imatinib(gleevec) and its fragments. J Med Chem,8(1): 249一255 |
| 【4】 Zimmermann J.Buchdunger E, Mett H, et aL 1997. Potent and selective inhibitors of the abl-kinase: phenylaminopyrimidine (PAP) derivatives. Bioorg Med Chem Lett,7(2): 187～191 |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 47518 | 2-Amino-4-nitrotoluene; 5-Nitro-o-toluidine; 4-Nitro-2-aminotoluene; 2-methyl-5-nitrophenylamine; 2-methyl-5-nitroaniline | 99-55-8 | C7H8N2O2 | 详情 | 详情 |
| (II) | 47517 | N-(2-methyl-5-nitrophenyl)guanidine | 152460-07-6 | C8H10N4O2 | 详情 | 详情 |
| (III) | 47516 | (E)-3-(dimethylamino)-1-(3-pyridinyl)-2-propen-1-one | 123367-26-0 | C10H12N2O | 详情 | 详情 |
| (IV) | 47519 | N-(2-methyl-5-nitrophenyl)-N-[4-(3-pyridinyl)-2-pyrimidinyl]amine; N-(2-methyl-5-nitrophenyl)-4-(3-pyridinyl)-2-pyrimidinamine | 152460-09-8 | C16H13N5O2 | 详情 | 详情 |
| (V) | 47520 | 4-methyl-N(3)-[4-(3-pyridinyl)-2-pyrimidinyl]-1,3-benzenediamine; N-(5-amino-2-methylphenyl)-N-[4-(3-pyridinyl)-2-pyrimidinyl]amine | 152460-10-1 | C16H15N5 | 详情 | 详情 |
| (VI) | 49112 | 4-(Chloromethyl)benzoyl chloride; p-(Chloromethyl)benzoyl chloride | 876-08-4 | C8H6Cl2O | 详情 | 详情 |
| (VII) | 66476 | 4-(chloromethyl)-N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)benzamide | 404844-11-7 | C24H20ClN5O | 详情 | 详情 |
| (VIII) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)
| 【1】 Kompella A, Bhujanga Rao AKS, Venkaiah Chowdary N, et aL 2004. Process for the preparation of the anti-cancer drug imatinib and its analogs via aminolysis of a (chloromethyl benzamide intermediate. WO 2004108699(本专利申请人为: Natco Pharma Limited, India) |
| 【2】 Szczepek W, Luniewski W, Kaczmarek L, et aL 2006.A process for preparation of imatinib base. W0 2006071130(本专利申请人为: Instytut Farmaceutyczny, Pol) |
| 【3】 Szakacs Z,Beni S,VargaZ,et aL 2005. Acid-base profiling of imatinib(gleevec) and its fragments. J Med Chem,8(1): 249一255 |
| 【4】 Zimmermann J.Buchdunger E, Mett H, et aL 1997. Potent and selective inhibitors of the abl-kinase: phenylaminopyrimidine (PAP) derivatives. Bioorg Med Chem Lett,7(2): 187～191 |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 12027 | 1-(3-Pyridinyl)-1-ethanone; 1-(3-Pyridinyl)ethanone | 350-03-8 | C7H7NO | 详情 | 详情 |
| (II) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
| (III) | 47516 | (E)-3-(dimethylamino)-1-(3-pyridinyl)-2-propen-1-one | 123367-26-0 | C10H12N2O | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(III)
| 【1】 Kompella A, Bhujanga Rao AKS, Venkaiah Chowdary N, et aL 2004. Process for the preparation of the anti-cancer drug imatinib and its analogs via aminolysis of a (chloromethyl benzamide intermediate. WO 2004108699(本专利申请人为: Natco Pharma Limited, India) |
| 【2】 Szczepek W, Luniewski W, Kaczmarek L, et aL 2006.A process for preparation of imatinib base. W0 2006071130(本专利申请人为: Instytut Farmaceutyczny, Pol) |
| 【3】 Szakacs Z,Beni S,VargaZ,et aL 2005. Acid-base profiling of imatinib(gleevec) and its fragments. J Med Chem,8(1): 249一255 |
| 【4】 Zimmermann J.Buchdunger E, Mett H, et aL 1997. Potent and selective inhibitors of the abl-kinase: phenylaminopyrimidine (PAP) derivatives. Bioorg Med Chem Lett,7(2): 187～191 |
合成路线6
该中间体在本合成路线中的序号：(III)
| 【1】 Huang WS, Shakespeare WC. 2007. An efficient synthesis of nilotinib (AMN107). Synthesis, 14: 2121～2124. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| （XI） | 67344 | 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline | 641571-11-1 | C11H10F3N3 | 详情 | 详情 |
| (I) | 67350 | ethyl 4-amino-3-methylbenzoate | C10H13NO2 | 详情 | 详情 | |
| (II) | 67345 | ethyl 3-guanidino-4-methylbenzoate | C11H15N3O2 | 详情 | 详情 | |
| (III) | 47516 | (E)-3-(dimethylamino)-1-(3-pyridinyl)-2-propen-1-one | 123367-26-0 | C10H12N2O | 详情 | 详情 |
| (IV) | 67347 | ethyl 4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)benzoate | 641569-97-3 | C19H18N4O2 | 详情 | 详情 |
| (V) | 67340 | 3-fluoro-5-(trifluoromethyl)benzonitrile | 149793-69-1 | C8H3F4N | 详情 | 详情 |
| (VI) | 34070 | 5-methyl-1H-imidazole | 822-36-6 | C4H6N2 | 详情 | 详情 |
| (VII) | 67341 | 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzonitrile | C12H8F3N3 | 详情 | 详情 | |
| (VIII) | 67342 | 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid | C12H9F3N2O2 | 详情 | 详情 | |
| (IX) | 67343 | tert-butyl (3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)carbamate | C16H18F3N3O2 | 详情 | 详情 | |
| (X) | 67348 | 4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)benzoic acid | 641569-94-0 | C17H14N4O2 | 详情 | 详情 |
Extended Information