Alanosine, -Drug Synthesis Database

【结构式】

【药物名称】Alanosine

【化学名称】3-(N-Hydroxy-N-nitrosoamino)alanine
　　　　　　2-Amino-3-(N-hydroxy-N-nitrosoamino)propionic acid

【CA登记号】

【分子式】C₃H₇N₃O₄

【分子量】149.10694

【开发单位】Gilead (Originator)

【药理作用】Brain Cancer Therapy, Lung Cancer Therapy, Non-Small Cell Lung Cancer Therapy, Oncolytic Drugs

合成路线1 合成路线2

合成路线1

Ethyl 2,3-dibromopropionate (I) is condensed with N-tosyl-O-benzylhydroxylamine (A) by means of NaOEt in ethanol to give after a treatment with ammonia, propionic acid (II), which is detosylated by treatment with phenol and 36% HBr- yielding D,L-2-amino-3-(benzyloxyamino)propionic acid (III). The benzoylation of (III) with N-benzoyloxysuccinimide (B) by means of Triton B - in methanol affords D,L-2-benzoylamino-3-benzyloxyaminopropionic acid (IV), which is resolved into its optical isomers by treatment with aniline (C) and papain in 0.5M NaOH - 0.5M citric acid and L-cysteine hydrochloride; L-2-benzoylamino-3-benzyloxyaminopropionanilide (L)-(V) was isolated. The benzoylation of (L)-(V) with benzoyl chloride (D) in pyridine affords L-2-benzoylamino-3-(N-benzoyl-N-benzyloxyamino)propionanilide (L)-(VI), which is debenzylated by hydrogenation with H2 over Pd/C in methanol giving L-2-benzoylamino-3-(N-benzoyl-N-hydroxyamino)propionanilide (L)-(VII). The protecting groups of (L)-(VII) are eliminated by treatment with 6M HCl at 90-5 C yielding L-2-amino-3-hydroxyaminopropionic acid (L)-(VIII), which is finally nitrosated with NaNO2 and HCl.

参考文献中间体

【1】 Serradell, M.N.; Castañer, J.; Cabanillas, F.; Blancafort, P.; Alanosine. Drugs Fut 1979, 4, 7, 469.
【2】 Yoshikazu, I.; et al.; Synthesis of alanosine. Bull Chem Soc Jpn 1973, 46, 1847-50.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(D)	10463	Benzoyl chloride	98-88-4	C₇H₅ClO	详情	详情
(A)	39517	N-(benzyloxy)-4-methylbenzenesulfonamide		C₁₄H₁₅NO₃S	详情	详情
(B)	39520	1-(benzoyloxy)-2,5-pyrrolidinedione		C₁₁H₉NO₄	详情	详情
(L)-(V)	39522	N-((1S)-2-anilino-1-[[(benzyloxy)amino]methyl]-2-oxoethyl)benzamide		C₂₃H₂₃N₃O₃	详情	详情
(L)-(VI)	39523	N-[(2S)-3-anilino-3-oxo-2-(propionylamino)propyl]-N-(benzyloxy)benzamide		C₂₆H₂₇N₃O₄	详情	详情
(L)-(VII)	39524	N-((1S)-2-anilino-1-[[benzoyl(hydroxy)amino]methyl]-2-oxoethyl)benzamide		C₂₃H₂₁N₃O₄	详情	详情
(L)-(VIII)	39525	(2S)-2-amino-3-(hydroxyamino)propionic acid		C₃H₈N₂O₃	详情	详情
(I)	18341	ethyl 2,3-dibromopropanoate	3674-13-3	C₅H₈Br₂O₂	详情	详情
(II)	39518	3-[(benzyloxy)[(4-methylphenyl)sulfonyl]amino]alanine		C₁₇H₂₀N₂O₅S	详情	详情
(III)	39519	3-[(benzyloxy)amino]alanine		C₁₀H₁₄N₂O₃	详情	详情
(IV)	39521	N-benzoyl-3-[(benzyloxy)amino]alanine		C₁₇H₁₈N₂O₄	详情	详情
(C)	12294	Aniline; Phenylamine	62-53-3	C₆H₇N	详情	详情

合成路线2

The reaction of methyl 2-acetamido-3-chloropropionate (IX) with hydroxylamine followed by hydrolysis with concentrated HCl gives D,L-2-amino-3-hydroxyaminopropionic acid (VIII), which is benzoylated with benzoyl chloride in aqueous 10% NaOH yielding D,L-2-benzoylamino-3-(N-benzoyl-N-hydroxyamino)propionic acid (X). The resolution of (X) into optical isomers by treatment with cinchonine in ethanol, followed by treatment with 20% HCl at 100 C affords L-2-amino-3-hydroxyaminopropionic acid (L)-(VIII), which is nitrosated with NaNO2 and HCl. Racemic alanosine can be obtained by nitrosation of D,L-2-amino-3-hydroxyaminopropionic acid (VIII) obtained before.

参考文献中间体

【1】 Lancini, G.C.; et al.; Synthesis of homolog of the antibiotic alanosine. Farmaco 1969, 24, 2, 169-178.
【2】 US 3823186 .
【3】 Serradell, M.N.; Castañer, J.; Cabanillas, F.; Blancafort, P.; Alanosine. Drugs Fut 1979, 4, 7, 469.
【4】 Eaton, C.N.; et al.; Improved synthesis of D,L-alanosine. J Med Chem 1973, 16, 3, 289-290.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(L)-(VIII)	39525	(2S)-2-amino-3-(hydroxyamino)propionic acid		C₃H₈N₂O₃	详情	详情
(VIII)	39527	3-(hydroxyamino)alanine		C₃H₈N₂O₃	详情	详情
(IX)	39526	2-acetamido-3-chloromethyl propionate; methyl 2-(acetamido)-3-chloropropanoate	87333-22-0	C₆H₁₀ClNO₃	详情	详情
(X)	39528	N-benzoyl-3-[benzoyl(hydroxy)amino]alanine		C₁₇H₁₆N₂O₅	详情	详情

Extended Information

FDA Approved Drug Products(1)