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【结 构 式】

【分子编号】14282

【品名】N-(6-Ethynyl-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide

【CA登记号】

【 分 子 式 】C14H14N4O2

【 分 子 量 】270.29092

【元素组成】C 62.21% H 5.22% N 20.73% O 11.84%
与该中间体有关的原料药合成路线共 5 条
合成路线1合成路线2合成路线3合成路线4合成路线5

合成路线1

该中间体在本合成路线中的序号：(VI)

Racemic lometrexol has been prepared.

参考文献 中间体
合成目标
【1】 Harrington, P.M.; Shih, C.; Grindey, G.B.; Gossett, L.S.; Moran, R.G.; Taylor, S.C.; Synthesis and structure-activity relationship studies of 5,10-dideazatetrahydrofolic acid (DDATHF). Chemistry and Biology of Pteridines (1989): Pteridines and Folic Acid Derivatives. H.-C. Curtius, S. Ghisla and N. Blau (Eds.). de Gruyter, New York 1990, 1035.
【2】 Taylor, E.C.; Wong, G.S.K.; Convergent and efficient palladium-effected synthesis of 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF). J Org Chem 1989, 54, 15, 3618.
【3】 Castaner, J.; Prous, J.; Lometrexol. Drugs Fut 1993, 18, 2, 121.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
51602 1-Propyne C3H4 详情 详情
(I) 14277 2,6-Diamino-4(3H)-pyrimidinone C4H6N4O 详情 详情
(II) 14278 2-Bromomalonaldehyde C3H3BrO2 详情 详情
(III) 14279 2-Amino-6-bromopyrido[2,3-d]pyrimidin-4(3H)-one C7H5BrN4O 详情 详情
(IV) 14280 N-(6-Bromo-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide C12H13BrN4O2 详情 详情
(V) 14281 2,2-Dimethyl-N-[4-oxo-6-[2-(trimethylsilyl)ethynyl]-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl]propanamide C17H22N4O2Si 详情 详情
(VI) 14282 N-(6-Ethynyl-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide C14H14N4O2 详情 详情
(VII) 14283 diethyl (2S)-2-[(4-iodobenzoyl)amino]pentanedioate C16H20INO5 详情 详情
(VIII) 14284 diethyl (2S)-2-[[4-(2-[2-[(2,2-dimethylpropanoyl)amino]-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-6-yl]ethynyl)benzoyl]amino]pentanedioate C30H33N5O7 详情 详情
(IX) 14285 tert-butyl 4-ethynylbenzoate C13H14O2 详情 详情
(X) 14286 tert-butyl 4-bromobenzoate C11H13BrO2 详情 详情
(XI) 14287 diethyl (2S)-2-[(4-ethynylbenzoyl)amino]pentanedioate C18H21NO5 详情 详情
(XII) 14288 tert-butyl 4-(2-[2-[(2,2-dimethylpropanoyl)amino]-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-6-yl]ethynyl)benzoate C25H26N4O4 详情 详情
(XIII) 14289 4-(2-[2-[(2,2-Dimethylpropanoyl)amino]-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-6-yl]ethynyl)benzoic acid C21H18N4O4 详情 详情
(XIV) 11013 diethyl (2S)-2-aminopentanedioate C9H17NO4 详情 详情
(XV) 14291 diethyl (2S)-2-[[4-(2-[2-[(2,2-dimethylpropanoyl)amino]-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-6-yl]ethyl)benzoyl]amino]pentanedioate C30H41N5O7 详情 详情

合成路线2

该中间体在本合成路线中的序号：(IV)

Acylation of diethyl L-glutamate (I) with 5-bromo-4-methylthiophene-2-carboxylic acid (II) using EDC as the coupling reagent provided amide (III). Subsequent palladium-catalyzed coupling between bromothiophene (III) and ethynyl pyridopyrimidinone (IV) furnished the disubstituted acetylene (V), which was further hydrogenated to (VI) in the presence of Pd/C in trifluoroacetic acid. Finally, basic hydrolysis of the ethyl ester and pivaloyl groups of (VI) led to the title compound.

参考文献 中间体
合成目标
【1】 Varney, M.D.; Romines, W.H. (Agouron Pharmaceuticals, Inc.); Cpds. useful as antiproliferative agents and GARFT inhibitors. WO 9603406 .
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) 11013 diethyl (2S)-2-aminopentanedioate C9H17NO4 详情 详情
(II) 55966 5-bromo-4-methyl-2-thiophenecarboxylic acid C6H5BrO2S 详情 详情
(III) 55967 diethyl (2S)-2-{[(5-bromo-4-methyl-2-thienyl)carbonyl]amino}pentanedioate C15H20BrNO5S 详情 详情
(IV) 14282 N-(6-Ethynyl-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide C14H14N4O2 详情 详情
(V) 55968 diethyl (2S)-2-({[5-(2-{2-[(2,2-dimethylpropanoyl)amino]-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-6-yl}ethynyl)-4-methyl-2-thienyl]carbonyl}amino)pentanedioate C29H33N5O7S 详情 详情
(VI) 55969 diethyl (2S)-2-({[5-(2-{2-[(2,2-dimethylpropanoyl)amino]-4-oxo-3,4,5,6,7,8-hexahydropyrido[2,3-d]pyrimidin-6-yl}ethyl)-4-methyl-2-thienyl]carbonyl}amino)pentanedioate C29H41N5O7S 详情 详情

合成路线3

该中间体在本合成路线中的序号：(I)

Pyridopyrimidinone (I) was condensed with triazole (II) in the presence of 4-chlorophenyl dichlorophosphate and pyridine to afford (III). Further reaction of (III) with ammonia in dioxan gave amino compound (IV), which was submitted to a Heck reaction with 4-iodobenzoyl-L-glutamic acid diethyl ester (V) in the presence of palladium catalyst and CuI to provide the disubstituted acetylene (VI). Hydrogenation of both acetylene group and pyridine ring of (VI) over Pd/C gave intermediate (VII). The amide and ester groups of (VII) were finally hydrolyzed with 1 N NaOH to furnish the title compound.

参考文献 中间体
合成目标
【1】 Gossett, L.S.; Habeck, L.L.; Shackelford, K.A.; Mendelsohn, L.G.; Gates, S.B.; Worzalla, J.F.; Self, T.D.; Theobald, K.S.; Andis, S.L.; Schultz, R.M.; Shih, C.; The synthesis and biological activity of a series of 2,4-diaminopyrido[2,3-d]pyrimidine based antifolates as antineoplastic and antiarthritic agents. Bioorg Med Chem Lett 1999, 9, 1, 75.
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) 14282 N-(6-Ethynyl-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide C14H14N4O2 详情 详情
(II) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(III) 23132 N-[6-ethynyl-4-(1H-1,2,4-triazol-1-yl)pyrido[2,3-d]pyrimidin-2-yl]-2,2-dimethylpropanamide C16H15N7O 详情 详情
(IV) 23133 N-(4-amino-6-ethynylpyrido[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide C14H15N5O 详情 详情
(V) 14283 diethyl (2S)-2-[(4-iodobenzoyl)amino]pentanedioate C16H20INO5 详情 详情
(VI) 23135 diethyl (2S)-2-[[4-(2-[4-amino-2-[(2,2-dimethylpropanoyl)amino]pyrido[2,3-d]pyrimidin-6-yl]ethynyl)benzoyl]amino]pentanedioate C30H34N6O6 详情 详情
(VII) 23136 diethyl (2S)-2-[[4-(2-[4-amino-2-[(2,2-dimethylpropanoyl)amino]-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl]ethyl)benzoyl]amino]pentanedioate C30H42N6O6 详情 详情

合成路线4

该中间体在本合成路线中的序号：(I)

Pyridopyrimidinone (I) was condensed with triazole (II) in the presence of 4-chlorophenyl dichlorophosphate and pyridine to afford (III). Further reaction of (III) with ammonia in dioxan gave amino compound (IV), which was submitted to a Heck reaction with N-(2-bromothien-5-yl)-L-glutamic acid diethyl ester (V) in the presence of palladium catalyst and CuI to provide the disubstituted acetylene (VI). Hydrogenation of both acetylene group and pyridine ring of (VI) over Pd/C gave intermediate (VII). The amide and ester groups of (VII) were finally hydrolyzed with 1 N NaOH to furnish the title compound.

参考文献 中间体
合成目标
【1】 Gossett, L.S.; Habeck, L.L.; Shackelford, K.A.; Mendelsohn, L.G.; Gates, S.B.; Worzalla, J.F.; Self, T.D.; Theobald, K.S.; Andis, S.L.; Schultz, R.M.; Shih, C.; The synthesis and biological activity of a series of 2,4-diaminopyrido[2,3-d]pyrimidine based antifolates as antineoplastic and antiarthritic agents. Bioorg Med Chem Lett 1999, 9, 1, 75.
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) 14282 N-(6-Ethynyl-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide C14H14N4O2 详情 详情
(II) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(III) 23132 N-[6-ethynyl-4-(1H-1,2,4-triazol-1-yl)pyrido[2,3-d]pyrimidin-2-yl]-2,2-dimethylpropanamide C16H15N7O 详情 详情
(IV) 23133 N-(4-amino-6-ethynylpyrido[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide C14H15N5O 详情 详情
(V) 23137 diethyl (2S)-2-[[(5-bromo-2-thienyl)carbonyl]amino]pentanedioate C14H18BrNO5S 详情 详情
(VI) 23138 diethyl (2S)-2-([[5-(2-[4-amino-2-[(2,2-dimethylpropanoyl)amino]pyrido[2,3-d]pyrimidin-6-yl]ethynyl)-2-thienyl]carbonyl]amino)pentanedioate C28H32N6O6S 详情 详情
(VII) 23139 diethyl (2S)-2-([[5-(2-[4-amino-2-[(2,2-dimethylpropanoyl)amino]-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl]ethyl)-2-thienyl]carbonyl]amino)pentanedioate C28H40N6O6S 详情 详情

合成路线5

该中间体在本合成路线中的序号：(I)

Pyridopyrimidinone (I) was condensed with triazole (II) in the presence of 4-chlorophenyl dichlorophosphate and pyridine to afford (III). Further reaction of (III) with ammonia in dioxan gave amino compound (IV), which was submitted to a Heck reaction with N-(2-bromofuran-5-yl)-L-glutamic acid diethyl ester (V) in the presence of palladium catalyst and CuI to provide the disubstituted acetylene (VI). Hydrogenation of both acetylene group and pyridine ring of (VI) over Pd/C gave intermediate (VII). The amide and ester groups of (VII) were finally hydrolyzed with 1 N NaOH to furnish the title compound.

参考文献 中间体
合成目标
【1】 Gossett, L.S.; Habeck, L.L.; Shackelford, K.A.; Mendelsohn, L.G.; Gates, S.B.; Worzalla, J.F.; Self, T.D.; Theobald, K.S.; Andis, S.L.; Schultz, R.M.; Shih, C.; The synthesis and biological activity of a series of 2,4-diaminopyrido[2,3-d]pyrimidine based antifolates as antineoplastic and antiarthritic agents. Bioorg Med Chem Lett 1999, 9, 1, 75.
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) 14282 N-(6-Ethynyl-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide C14H14N4O2 详情 详情
(II) 13135 1H-1,2,4-Triazole; 1,2,4-Triazole 288-88-0 C2H3N3 详情 详情
(III) 23132 N-[6-ethynyl-4-(1H-1,2,4-triazol-1-yl)pyrido[2,3-d]pyrimidin-2-yl]-2,2-dimethylpropanamide C16H15N7O 详情 详情
(IV) 23133 N-(4-amino-6-ethynylpyrido[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide C14H15N5O 详情 详情
(V) 23140 diethyl (2S)-2-[(5-bromo-2-furoyl)amino]pentanedioate C14H18BrNO6 详情 详情
(VI) 23141 diethyl (2S)-2-[[5-(2-[4-amino-2-[(2,2-dimethylpropanoyl)amino]pyrido[2,3-d]pyrimidin-6-yl]ethynyl)-2-furoyl]amino]pentanedioate C28H32N6O7 详情 详情
(VII) 23142 diethyl (2S)-2-[[5-(2-[4-amino-2-[(2,2-dimethylpropanoyl)amino]-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl]ethyl)-2-furoyl]amino]pentanedioate C28H40N6O7 详情 详情
Extended Information