N-Hydroxy-2-phenyl-4,5-dihydro-1,3-oxazole-4-carboxamide -Drug Synthesis Database

【结构式】

【分子编号】14227

【品名】N-Hydroxy-2-phenyl-4,5-dihydro-1,3-oxazole-4-carboxamide

【CA登记号】

【分子式】C₁₀H₁₀N₂O₃

【分子量】206.20108

【元素组成】C 58.25% H 4.89% N 13.59% O 23.28%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(V)

D-Cycloserine can be obtained by several different ways: 1) The esterification of DL-serine (I) with methanol gives the methyl ester (II), which is cyclized with ethyl imidobenzoate (III) yielding 2-phenyl-2-oxazoline-4-carboxylic acid methyl ester (IV). The reaction of (IV) with hydroxylamine and sodium ethoxide affords the hydroxamic acid (V), which is treated with HCl in dioxane to give 2-benzamido-3-chloropropionohydroxamic acid (VI). The cyclization of (VI) with base, followed by acidification yields 4-benzamidoisoxazolidin-3-one (VII), which by treatment with methanolic HCl is converted to 3-(aminooxy)-DL-alanine methyl ester (VIII). The cyclization of (VIII) with KOH affords DL-4-aminoisoxazolidin-3-one as a racemic mixture, which is resolved with D-tartaric acid.

参考文献中间体

合成目标

【1】 Folkers, K.; Stammer, C.H.; Holly, F.W.; Wilson, A.N.; Synthesis of D-4-amino-3-isoxazolidone. J Am Chem Soc 1955, 77, 2, 2346-7.
【2】 Schlapfer, R.; Majnoni, S.; Furst, A.; Von Plattner, P.A.; Frick, H.; Boller, A.; Kirchensteiner, H.; Hegedus, B.; Spiegelberg, H.; Synthesis of 4-amino-3-isoxazolidinone (cycloserine) and some analogs. Helv Chim Acta 1957, 40, 5, 1531-52.
【3】 Prous, J.; Mealy, N.; Castaner, J.; D-Cycloserine. Drugs Fut 1994, 19, 11, 988.

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)	14223	DL-2-Amino-3-hydroxypropionic acid; DL-Serine; (+/-)-2-Amino-3-hydroxypropionic acid; Serine	302-84-1	C₃H₇NO₃	详情	详情
(II)	14224	Serine, methyl ester; methyl 2-amino-3-hydroxypropanoate	2104-89-4	C₄H₉NO₃	详情	详情
(III)	14225	ethyl benzenecarboximidoate		C₉H₁₁NO	详情	详情
(IV)	14226	methyl 2-phenyl-4,5-dihydro-1,3-oxazole-4-carboxylate		C₁₁H₁₁NO₃	详情	详情
(V)	14227	N-Hydroxy-2-phenyl-4,5-dihydro-1,3-oxazole-4-carboxamide		C₁₀H₁₀N₂O₃	详情	详情
(VI)	14228	N-[1-(Chloromethyl)-2-(hydroxyamino)-2-oxoethyl]benzamide		C₁₀H₁₁ClN₂O₃	详情	详情
(VII)	14229	N-(3-Oxotetrahydro-4-isoxazolyl)benzamide		C₁₀H₁₀N₂O₃	详情	详情
(VIII)	14230	methyl 2-amino-3-(aminooxy)propanoate		C₄H₁₀N₂O₃	详情	详情
(IX)	63865	4-amino-3-isoxazolidinone		C₃H₆N₂O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Condensation of 2,6-diamino-4-hydroxypyrimidine (I) with chloroacetone (II) produced a mixture of pyrrolopyrimidine (III) and furopyrimidine (IV). After treatment of this mixture with pivalic anhydride, the insoluble pivaloyl amide of pyrrolopyrimidine (V) was separated from the soluble dipivaloyl furopyrimidine with boiling EtOAc. Subsequent Mannich reaction of (V) with dimethylamine and formaldehyde afforded the (dimethylamino)methyl derivative (VI). The dimethylamino group of (VI) was then displaced with 4-mercaptopyridine (VII) to give thioether (VIII). Finally, the pivaloyl amide group of (VIII) was hydrolyzed with NaOH to yield the target compound.

参考文献中间体

合成目标

【1】 Gangjee, A.; et al.; 2-Amino-4-oxo-5-substituted-pyrrolo[2,3-d.]pyrimidines as nonclassical antifolate inhibitors of thymidylate synthase. J Med Chem 1996, 39, 23, 4563-4568.
【2】 Gangjee, A.; et al.; Synthesis of classical and a nonclassical 2-amino-4-oxo-6-methyl-5-substituted Pyrrolo[2,3-d]pyrimidine antifolate inhibitors of thymidylate synthase1. J Med Chem 1999, 42, 12, 2272.

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)	14227	N-Hydroxy-2-phenyl-4,5-dihydro-1,3-oxazole-4-carboxamide		C₁₀H₁₀N₂O₃	详情	详情
(II)	15288	1-Chloroacetone; Chloroacetone	78-95-5	C₃H₅ClO	详情	详情
(III)	27932	2-amino-6-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one		C₇H₈N₄O	详情	详情
(IV)	27933	5-methylfuro[2,3-d]pyrimidine-2,4-diamine		C₇H₈N₄O	详情	详情
(V)	27934	2,2-dimethyl-N-(6-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)propanamide		C₁₂H₁₆N₄O₂	详情	详情
(VI)	27935	N-[5-[(dimethylamino)methyl]-6-methyl-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl]-2,2-dimethylpropanamide		C₁₅H₂₃N₅O₂	详情	详情
(VII)	27936	4-Mercaptopyridine; 4-pyridinethiol	4556-23-4	C₅H₅NS	详情	详情
(VIII)	27937	2,2-dimethyl-N-[6-methyl-4-oxo-5-[(4-pyridinylsulfanyl)methyl]-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl]propanamide		C₁₈H₂₁N₅O₂S	详情	详情

Extended Information