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【结 构 式】 
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【药物名称】Amamistatin A 【化学名称】6-(N-Formyl-N-hydroxyamino)-2(R)-[2-(2-hydroxy-5-methoxyphenyl)-5-methyloxazol-4-ylcarboxamido]hexanoic acid 1(S)-[2-[1-hydroxy-2-oxoperhydroazepin-3(S)-ylamino]-1,1-dimethyl-2-oxoethyl]octyl ester 【CA登记号】225505-59-9 【 分 子 式 】C37H55N5O11 【 分 子 量 】745.8778 |
【开发单位】Sagami (Originator) 【药理作用】Oncolytic Drugs |
合成路线1
Synthesis of intermediate (V): The condensation of octanal (II) with the trimethylsilyl ether of the enol form of methyl isobutyrate (I) by means of the chiral oxazaborolidinone catalyst (III) in THF gives 3(S)-hydroxy-2,2-dimethyldecanoic acid methyl ester (IV), which is hydrolyzed with NaOH in methanol/water to yield the acid intermediate (V).
| 【1】 Yokokawa, F.; et al.; Total synthesis of amamistatin A, an antiproliferative linear peptide from an actinomycete. Tetrahedron 2000, 56, 19, 3027. |
| 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) | 42016 | 1-Methoxy-2-methyl-1-(trimethylsiloxy)propene;1-Methoxy-2,2-dimethyl-1-(trimethylsiloxy)ethene;1-Methoxy-1-(trimethylsilyloxy)-2-methylpropene;[(1-methoxy-2-methyl-1-propenyl)oxy](trimethyl)silane; 1-methoxy-2-methyl-1-propenyl trimethylsilyl ether ;dimethylketene methyl trimethylsilyl acetal | 31469-15-5 | C8H18O2Si | 详情 | 详情 |
| (II) | 25714 | octanal | 124-13-0 | C8H16O | 详情 | 详情 |
| (III) | 42017 | (5R)-5-isopropyl-1-[(4-methylphenyl)sulfonyl]-1,2-azaborolidin-4-one | C13H18BNO3S | 详情 | 详情 | |
| (IV) | 42018 | methyl (3S)-3-hydroxy-2,2-dimethyldecanoate | C13H26O3 | 详情 | 详情 | |
| (V) | 42019 | (3S)-3-hydroxy-2,2-dimethyldecanoic acid | C12H24O3 | 详情 | 详情 |
合成路线2
Synthesis of intermediate (XII): The protection of 2-hydroxy-5-methoxybenzoic acid (VI) with benzyl bromide and K2CO3 in DMF gives 2-(benzyloxy)-5-methoxybenzoic acid (VII), which is condensed with L-threonine methyl ester (VIII) by means of (OEt)2P(O)CN (DEPC) and TEA in DMF yielding the corresponding benzamide (IX). The oxidation of (IX) with DMP, followed by cyclization by means of PPh3 and TEA affords 2-[2-(benzyloxy)-5-methoxyphenyl]-5-methyloxazole-4-carboxylic acid methyl ester (X) which is debenzylated with H2 over Pd/C in methanol to the corresponding phenol (XI). Finally the ester group of (XI) is hydrolyzed with NaOH in THF/water to afford the acid intermediate (XII).
| 【1】 Yokokawa, F.; et al.; Total synthesis of amamistatin A, an antiproliferative linear peptide from an actinomycete. Tetrahedron 2000, 56, 19, 3027. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 42020 | 2-hydroxy-5-methoxybenzoic acid | 2612-02-4 | C8H8O4 | 详情 | 详情 |
| (VII) | 42021 | 2-(benzyloxy)-5-methoxybenzoic acid | C15H14O4 | 详情 | 详情 | |
| (VIII) | 42026 | methyl (2S,3R)-2-amino-3-hydroxybutanoate | C5H11NO3 | 详情 | 详情 | |
| (IX) | 42022 | methyl (2S,3R)-2-[[2-(benzyloxy)-5-methoxybenzoyl]amino]-3-hydroxybutanoate | C20H23NO6 | 详情 | 详情 | |
| (X) | 42023 | methyl 2-[2-(benzyloxy)-5-methoxyphenyl]-5-methyl-1,3-oxazole-4-carboxylate | C20H19NO5 | 详情 | 详情 | |
| (XI) | 42024 | methyl 2-(2-hydroxy-5-methoxyphenyl)-5-methyl-1,3-oxazole-4-carboxylate | C13H13NO5 | 详情 | 详情 | |
| (XII) | 42025 | 2-(2-hydroxy-5-methoxyphenyl)-5-methyl-1,3-oxazole-4-carboxylic acid | C12H11NO5 | 详情 | 详情 |
合成路线3
Synthesis of intermediate (XVI): The reaction of the nitrone (XIII) first with hydroxylamine and then with formic acid gives hydroxamate (XIV), which is protected with 2-(trimethylsilylethoxymethyl chloride (A), DIEA and DMAP in CH2Cl2 to affords the protected ester (XV). Finally the methyl ester group of (XV) is hydrolyzed with NaOH in THF/water to afford the acid intermediate (XVI).
| 【1】 Yokokawa, F.; et al.; Total synthesis of amamistatin A, an antiproliferative linear peptide from an actinomycete. Tetrahedron 2000, 56, 19, 3027. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 42027 | ((4R)-4-[[(benzyloxy)carbonyl]amino]-5-methoxy-5-oxopentyl)(1-methylethylidene)ammoniumolate | C17H24N2O5 | 详情 | 详情 | |
| (XIV) | 42028 | methyl (2R)-2-[[(benzyloxy)carbonyl]amino]-5-[formyl(hydroxy)amino]pentanoate | C15H20N2O6 | 详情 | 详情 | |
| (XV) | 27243 | [2-(chloromethoxy)ethyl](trimethyl)silane | 76513-69-4 | C6H15ClOSi | 详情 | 详情 |
| (XVI) | 42029 | methyl (12R)-12-[[(benzyloxy)carbonyl]amino]-8-formyl-2,2-dimethyl-5,7-dioxa-8-aza-2-silatridecan-13-oate | C21H34N2O7Si | 详情 | 详情 | |
| (XVII) | 42030 | (12R)-12-[[(benzyloxy)carbonyl]amino]-8-formyl-2,2-dimethyl-5,7-dioxa-8-aza-2-silatridecan-13-oic acid | C20H32N2O7Si | 详情 | 详情 |
合成路线4
Synthesis of the final product: The cyclization of L-lysine (XVII) according to Miller et al. gives cyclic hydroxamate (XVIII), which is deprotected by hydrogenation with H2 over Pd/C in MeOH yielding 3-amino-1-(tert-butyldiphenylsilyloxy)perhydroazepin-2-one (XIX). The condensation of (XIX) with acid intermediate (V) by means of DEPC and TEA in DMF affords the corresponding amide (XX), which is esterified at its free OH group with acid intermediate (XVI) by means of DCC and DMAP in toluene to provide the ester (XXI). The deprotection of (XXI) with H2 over Pd/C in MeOH gives the amine (XXII), which is acylated with acid intermediate (XII) by means of EDC in CH2Cl2 to furnish the corresponding amide (XXIII). Finally this compound is deprotected with trifluoroacetic acid in CH2Cl2 to give the title product.
| 【1】 Miller, M.J.; Hu, J.; Total synthesis of a mycobactin S, a siderophore and growth promoter of Mycobacterium smegmatis, and determination of its growth inhibitory activity against Mycobacterium tuberculosis. J Am Chem Soc 1997, 119, 15, 3462. |
| 【2】 Yokokawa, F.; et al.; Total synthesis of amamistatin A, an antiproliferative linear peptide from an actinomycete. Tetrahedron 2000, 56, 19, 3027. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 42019 | (3S)-3-hydroxy-2,2-dimethyldecanoic acid | C12H24O3 | 详情 | 详情 | |
| (XII) | 42025 | 2-(2-hydroxy-5-methoxyphenyl)-5-methyl-1,3-oxazole-4-carboxylic acid | C12H11NO5 | 详情 | 详情 | |
| (XVI) | 42030 | (12R)-12-[[(benzyloxy)carbonyl]amino]-8-formyl-2,2-dimethyl-5,7-dioxa-8-aza-2-silatridecan-13-oic acid | C20H32N2O7Si | 详情 | 详情 | |
| (XVII) | 17525 | (2S)-6-amino-2-[[(benzyloxy)carbonyl]amino]hexanoic acid | C14H20N2O4 | 详情 | 详情 | |
| (XVIII) | 42031 | benzyl (3S)-1-[[tert-butyl(diphenyl)silyl]oxy]-2-oxoazepanylcarbamate | C30H36N2O4Si | 详情 | 详情 | |
| (XIX) | 42032 | (3S)-3-amino-1-[[tert-butyl(diphenyl)silyl]oxy]-2-azepanone | C22H30N2O2Si | 详情 | 详情 | |
| (XX) | 42033 | (3S)-N-((3S)-1-[[tert-butyl(diphenyl)silyl]oxy]-2-oxoazepanyl)-3-hydroxy-2,2-dimethyldecanamide | C34H52N2O4Si | 详情 | 详情 | |
| (XXI) | 42034 | (1S)-1-[2-[((3S)-1-[[tert-butyl(diphenyl)silyl]oxy]-2-oxoazepanyl)amino]-1,1-dimethyl-2-oxoethyl]octyl (12R)-12-[[(benzyloxy)carbonyl]amino]-8-formyl-2,2-dimethyl-5,7-dioxa-8-aza-2-silatridecan-13-oate | C54H82N4O10Si2 | 详情 | 详情 | |
| (XXII) | 42035 | (1S)-1-[2-[((3S)-1-[[tert-butyl(diphenyl)silyl]oxy]-2-oxoazepanyl)amino]-1,1-dimethyl-2-oxoethyl]octyl (12R)-12-amino-8-formyl-2,2-dimethyl-5,7-dioxa-8-aza-2-silatridecan-13-oate | C46H76N4O8Si2 | 详情 | 详情 | |
| (XXIII) | 42036 | (1S)-1-[2-[((3S)-1-[[tert-butyl(diphenyl)silyl]oxy]-2-oxoazepanyl)amino]-1,1-dimethyl-2-oxoethyl]octyl (12R)-8-formyl-12-([[2-(2-hydroxy-5-methoxyphenyl)-5-methyl-1,3-oxazol-4-yl]carbonyl]amino)-2,2-dimethyl-5,7-dioxa-8-aza-2-silatridecan-13-oate | C58H85N5O12Si2 | 详情 | 详情 |