A-177430, -Drug Synthesis Database

【结构式】

【药物名称】A-177430

【化学名称】(7S,8R,11S)-8-Isobutyl-N7-hydroxy-N11-methyl-9-oxo-2-oxa-10-azabicyclo[11.2.2]heptadeca-1(15),13,16-triene-7,11-dicarboxamide

【CA登记号】210483-49-1

【分子式】C₂₂H₃₃N₃O₅

【分子量】419.52541

【开发单位】Abbott (Originator)

【药理作用】ONCOLYTIC DRUGS, Angiogenesis Inhibitors, Matrix Metalloproteinase Inhibitors

合成路线1 合成路线2

合成路线1

4-Methylvaleric acid (I) was converted to acid chloride (II) and then condensed with (S)-4-benzyl-2-oxazolidinone (III) to give (IV). Subsequent alkylation of (IV) with tert-butyl bromoacetate (V) in the presence of sodium bis(trimethylsilyl)amide produced the chiral intermediate (VI), which was hydrolyzed with lithium peroxide to yield (R)-2-isobutylsuccinic acid 4-tert-butyl ester (VII). Further alkylation of (VII) with 4-bromo-1-butene (VIII) afforded a 6:1 mixture of syn/anti isobutenyl compounds (IX), which upon isomerization with LDA in THF at -20 C, followed by quenching with MeOH, provided a 1:1.5 mixture of isomers. Condensation of N-Boc-L-tyrosine (X) with methylamine in the presence of EDC and HOBt gave amide (XI). Then, removal of the Boc protecting group with HCl in dioxan yielded tyrosinamide (XII). This was coupled to succinic acid derivative (IX) using EDC and HOBt to afford the corresponding amide (XIII) as an epimeric mixture. Hydroboration of the butenyl double bond, followed by oxidative treatment with H2O2 produced alcohol (XIV).

参考文献中间体

【1】 Sheppard, G.S.; Guo, Y.; Siummers, J.B.; Holms, J.H.; Steinman, D.H.; Michaelides, M.R.; Florjancic, A.S.; Xu, L.; Davidsen, S.K. (Abbott Laboratories Inc.); Macrocyclic inhibitors of matrix metalloproteinases and TNFalpha secretion. EP 1021423; WO 9830551 .

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)	25389	4-methylpentanoic acid	646-07-1	C₆H₁₂O₂	详情	详情
(II)	25390	4-methylpentanoyl chloride	38136-29-7	C₆H₁₁ClO	详情	详情
(III)	25351	(4R)-4-benzyl-1,3-oxazolidin-2-one; (R)-(+)-4-benzyl-2-oxazolidinone	102029-44-7	C₁₀H₁₁NO₂	详情	详情
(IV)	25391	(4S)-4-benzyl-3-(4-methylpentanoyl)-1,3-oxazolidin-2-one		C₁₆H₂₁NO₃	详情	详情
(V)	17430	2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate	5292-43-3	C₆H₁₁BrO₂	详情	详情
(VI)	25392	tert-butyl (3R)-3-[[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-5-methylhexanoate		C₂₂H₃₁NO₅	详情	详情
(VII)	25393	(2R)-2-[2-(tert-butoxy)-2-oxoethyl]-4-methylpentanoic acid		C₁₂H₂₂O₄	详情	详情
(VIII)	11720	4-Bromo-1-butene	5162-44-7	C₄H₇Br	详情	详情
(IX)	25394	(2R)-3-(tert-butoxycarbonyl)-2-isobutyl-6-heptenoic acid		C₁₆H₂₈O₄	详情	详情
(X)	25395	(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propionic acid	3978-80-1	C₁₄H₁₉NO₅	详情	详情
(XI)	25396	tert-butyl (1S)-1-(4-hydroxybenzyl)-2-(methylamino)-2-oxoethylcarbamate		C₁₅H₂₂N₂O₄	详情	详情
(XII)	25397	(2S)-2-amino-3-(4-hydroxyphenyl)-N-methylpropanamide		C₁₀H₁₄N₂O₂	详情	详情
(XIII)	25398	tert-butyl 2-[(1R)-1-([[(1S)-1-(4-hydroxybenzyl)-2-(methylamino)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]-5-hexenoate		C₂₆H₄₀N₂O₅	详情	详情
(XIV)	25399	tert-butyl (3R)-3-([[(1S)-1-(4-hydroxybenzyl)-2-(methylamino)-2-oxoethyl]amino]carbonyl)-2-(4-hydroxybutyl)-5-methylhexanoate		C₂₆H₄₂N₂O₆	详情	详情

合成路线2

Then, cyclization of (XIV) under Mitsunobu conditions furnished macrocyclic ether (XV). The deprotection of (XV) with trifluoroacetic acid yielded carboxylic acid (XVI), which was treated with silyl protected hydroxylamine to afford hydroxamic acid (XVII). The required isomer of (XVII) was isolated using reverse-phase HPLC.

参考文献中间体

【1】 Sheppard, G.S.; Guo, Y.; Siummers, J.B.; Holms, J.H.; Steinman, D.H.; Michaelides, M.R.; Florjancic, A.S.; Xu, L.; Davidsen, S.K. (Abbott Laboratories Inc.); Macrocyclic inhibitors of matrix metalloproteinases and TNFalpha secretion. EP 1021423; WO 9830551 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XIV)	25399	tert-butyl (3R)-3-([[(1S)-1-(4-hydroxybenzyl)-2-(methylamino)-2-oxoethyl]amino]carbonyl)-2-(4-hydroxybutyl)-5-methylhexanoate	C₂₆H₄₂N₂O₆	详情	详情
(XV)	25400	tert-butyl (8R,11S)-8-isobutyl-11-[(methylamino)carbonyl]-9-oxo-2-oxa-10-azabicyclo[11.2.2]heptadeca-1(15),13,16-triene-7-carboxylate	C₂₆H₄₀N₂O₅	详情	详情
(XVI)	25401	(8R,11S)-8-isobutyl-11-[(methylamino)carbonyl]-9-oxo-2-oxa-10-azabicyclo[11.2.2]heptadeca-1(15),13,16-triene-7-carboxylic acid	C₂₂H₃₂N₂O₅	详情	详情
(XVII)	25402	(8R,11S)-N(7)-hydroxy-8-isobutyl-N(11)-methyl-9-oxo-2-oxa-10-azabicyclo[11.2.2]heptadeca-1(15),13,16-triene-7,11-dicarboxamide	C₂₂H₃₃N₃O₅	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)