【结 构 式】 |
【分子编号】14277 【品名】2,6-Diamino-4(3H)-pyrimidinone 【CA登记号】 |
【 分 子 式 】C4H6N4O 【 分 子 量 】126.118 【元素组成】C 38.09% H 4.8% N 44.42% O 12.69% |
合成路线1
该中间体在本合成路线中的序号:(I)Racemic lometrexol has been prepared.
【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:(VII)A concise and scalable synthesis of pemetrexed disodium has been presented: The alkylation of methyl 4-bromobenzoate (I) with 3-butyn-1-ol (II) by means of Pd(0) gives methyl 4-(4-hydroxy-1-butynyl)benzoate (III), which is reduced with H2 over Pd/C to the 4-hydroxybutyl derivative (IV). The oxidation of (IV) with NaOCl and 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO) yields the corresponding aldehyde (V), which is brominated with 5,5-dibromobarbituric acid (DBBA) and HBr in acetic acid/dichloromethane affording the alpha-bromoaldehyde (VI). The cyclization of (VI) with 2,6-diaminopyrimidin-4(3H)-one (VII) by means of NaOAc in acetonitrile/water gives the pyrrolopyrimidine (VIII), which is hydrolyzed with aqueous NaOH and acidified with aqueous HCl yielding the benzoic acid derivative (IX). The condensation of (IX) with L-glutamic acid diethyl ester (X) by means of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) and NMM in DMF affords the diethyl ester (XI) of pemetrexed, which is finally hydrolyzed with aqueous NaOH.
【1】 Kjell, D.P.; Slattery, B.J.; Improved route to multitargeted antifolate LY231514. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst ORG 130. |
【2】 Kobierski, M.E.; Wilson, T.M.; Barnett, C.J.; A practical synthesis of multitargeted antifolate LY231514. Org Process Res Dev 1999, 3, 3, 184. |
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) | 10168 | 4-Bromobenzoic acid methyl ester; methyl 4-bromobenzoate | 619-42-1 | C8H7BrO2 | 详情 | 详情 |
(II) | 32507 | 3-butyn-1-ol | 927-74-2 | C4H6O | 详情 | 详情 |
(III) | 35243 | methyl 4-(4-hydroxy-1-butynyl)benzoate | C12H12O3 | 详情 | 详情 | |
(IV) | 35241 | methyl 4-(4-hydroxybutyl)benzoate | C12H16O3 | 详情 | 详情 | |
(V) | 14808 | methyl 4-(4-oxobutyl)benzoate | C12H14O3 | 详情 | 详情 | |
(VI) | 35242 | methyl 4-(3-bromo-4-oxobutyl)benzoate | C12H13BrO3 | 详情 | 详情 | |
(VII) | 14277 | 2,6-Diamino-4(3H)-pyrimidinone | C4H6N4O | 详情 | 详情 | |
(VIII) | 14812 | methyl 4-[2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoate | C16H16N4O3 | 详情 | 详情 | |
(IX) | 14805 | 4-[2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoic acid | C15H14N4O3 | 详情 | 详情 | |
(X) | 11013 | diethyl (2S)-2-aminopentanedioate | C9H17NO4 | 详情 | 详情 | |
(XI) | 14807 | diethyl (2S)-2-([4-[2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino)pentanedioate | C24H29N5O6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(I)Condensation of 2,6-diaminopyrimidin-4-one (I) with 1,3-dichloroacetone (II) affords the furopyrimidine (III). Subsequent reaction of (III) with tributylphosphine provides the phosphonium salt (IV). Treatment of 4-hydroxypropiophenone (V) with trifluoromethanesulfonic anhydride leads to the aryl triflate (VI). This is then subjected to palladium-catalyzed carbonylation under modified Gerlach's conditions to furnish ethyl 4-propionylbenzoate (VII). Wittig condensation between the phosphorane derived from (IV) and keto ester (VII) produces olefin (VIIIa-b) as a mixture of Z/E isomers. Subsequent hydrogenation of (VIIIa-b) over Pd/C gives (IX). The methyl ester group of (IX) is hydrolyzed under alkaline conditions to afford acid (X), which is then activated as the mixed anhydride (XI) with isobutyl chloroformate and triethylamine.
【1】 Mcguire, J.J.; Zeng, Y.; Gangjee, A.; Kisliuk, R.L.; Synthesis of N-[4-[ethyl-2-(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid as an antifolate. J Med Chem 2002, 45, 9, 1942. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(VIIIa) | 58984 | methyl 4-[(Z)-2-(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)-1-ethylethenyl]benzoate | C18H18N4O3 | 详情 | 详情 | |
(VIIIb) | 58985 | methyl 4-[(E)-2-(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)-1-ethylethenyl]benzoate | C18H18N4O3 | 详情 | 详情 | |
(I) | 14277 | 2,6-Diamino-4(3H)-pyrimidinone | C4H6N4O | 详情 | 详情 | |
(II) | 63907 | 1,3-dichloroacetone | C3H4Cl2O | 详情 | 详情 | |
(III) | 18884 | 5-(chloromethyl)furo[2,3-d]pyrimidine-2,4-diamine; 2-amino-5-(chloromethyl)furo[2,3-d]pyrimidin-4-ylamine | C7H7ClN4O | 详情 | 详情 | |
(IV) | 58981 | tributyl[(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)methyl]phosphonium chloride | C19H34ClN4OP | 详情 | 详情 | |
(V) | 58982 | 4'-Hydroxypropiophenone; 4-Hydroxypropiophenone; Ethyl 4-Hydroxyphenyl ktone; p-Hydroxypropiophenone; Paroxypropione | 70-70-2 | C9H10O2 | 详情 | 详情 |
(VI) | 58983 | 4-propionylphenyl trifluoromethanesulfonate | C10H9F3O4S | 详情 | 详情 | |
(VII) | 11008 | methyl 4-propionylbenzoate | C11H12O3 | 详情 | 详情 | |
(IX) | 58988 | methyl 4-{1-[(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)methyl]propyl}benzoate | C18H20N4O3 | 详情 | 详情 | |
(X) | 58986 | 4-{1-[(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)methyl]propyl}benzoic acid | C17H18N4O3 | 详情 | 详情 | |
(XI) | 58987 | C22H26N4O5 | 详情 | 详情 |