methyl (3R)-3-hydroxyhexanoate -Drug Synthesis Database

【结构式】

【分子编号】44116

【品名】methyl (3R)-3-hydroxyhexanoate

【CA登记号】

【分子式】C₇H₁₄O₃

【分子量】146.18636

【元素组成】C 57.51% H 9.65% O 32.83%

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：(II)

Hydrogenation of methyl butyrylacetate (I) in the presence of the chiral catalyst [RuCl2(BINAP)]2.Et3N furnished the (R)-hydroxyester (II). Alkylation of (II) with 3-bromo-2-methyl-1-propene (III) in the presence of lithium diisopropylamide gave the isobutenyl derivative (IV), which was further hydrogenated to (V) in the presence of Pd/C. After basic hydrolysis of the methyl ester of (V), the resulting carboxylic acid (VI) was coupled with 2-tetrahydropyranyloxyamine by means of EDC to provide the tetrahydropyranyl-protected hydroxamic acid (VII). Mesylation of the free hydroxyl group of (VII) to give (VIII), followed by its cyclization in the presence of potassium carbonate, gave rise to the azetidinone (IX). Opening of the lactam ring of (IX) with NaOH afforded the protected hydroxyamino acid (X). Then, formylation of the amino group with formic acetic anhydride in pyridine provided intermediate (XI).

参考文献中间体

合成目标

【1】 Wiethe, R.W.; Andrews, R.C.; Rabinowitz, M.H.; Musso, D.L.; Chan, J.H.; McDougald, D.L.; Gaul, M.D.; Cowan, D.J.; Stanford, J.B.; Babacz, D.G.; Andersen, M.W. (Glaxo Group Ltd.); Formamide cpds. as therapeutic agents. US 6191150; WO 0012466 .

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)	44115	methyl 3-oxohexanoate	30414-54-1	C₇H₁₂O₃	详情	详情
(II)	44116	methyl (3R)-3-hydroxyhexanoate		C₇H₁₄O₃	详情	详情
(III)	40015	3-bromo-2-methyl-1-propene	1458-98-6	C₄H₇Br	详情	详情
(IV)	44117	methyl (2R)-2-[(1R)-1-hydroxybutyl]-4-methyl-4-pentenoate		C₁₁H₂₀O₃	详情	详情
(V)	44118	methyl (2R,3R)-3-hydroxy-2-isobutylhexanoate		C₁₁H₂₂O₃	详情	详情
(VI)	44119	(2R,3R)-3-hydroxy-2-isobutylhexanoic acid		C₁₀H₂₀O₃	详情	详情
(VII)	44120	(2R,3R)-3-hydroxy-2-isobutyl-N-(tetrahydro-2H-pyran-2-yloxy)hexanamide		C₁₅H₂₉NO₄	详情	详情
(VIII)	44121	(1R,2R)-4-methyl-1-propyl-2-[[(tetrahydro-2H-pyran-2-yloxy)amino]carbonyl]pentyl methanesulfonate		C₁₆H₃₁NO₆S	详情	详情
(IX)	44122	(3R,4S)-3-isobutyl-4-propyl-1-(tetrahydro-2H-pyran-2-yloxy)-2-azetidinone		C₁₅H₂₇NO₃	详情	详情
(X)	44123	(2R,3S)-2-isobutyl-3-[(tetrahydro-2H-pyran-2-yloxy)amino]hexanoic acid		C₁₅H₂₉NO₄	详情	详情
(XI)	44124	(2R,3S)-3-[formyl(tetrahydro-2H-pyran-2-yloxy)amino]-2-isobutylhexanoic acid		C₁₆H₂₉NO₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

The alkylation of 3(R)-hydroxyhexanoic acid methyl ester (I) with isobutyl bromide (II) and LDA in THF gives 3(R)-hydroxy-2(R)-isobutylhexanoic acid methyl ester (III), which is hydrolyzed with LiOH in THF/MeOH/water to yield the corresponding lithium salt (IV). The condensation of (IV) with O-tetrahydropyranyl-hydroxylamine (V) by means of DCC in ethyl acetate affords the protected hydroxamic acid (VI), which is treated with Ms-Cl and pyridine to provide the mesylate (VII). The cyclization of (VII) by means of K2CO3 in refluxing acetone gives the chiral azetidinone (VIII), which is opened by means of NaOH in dioxane/water, yielding the carboxylic acid (IX). The formylation of the NH group of (IX) with acetic formic anhydride and pyridine in dichloromethane affords the intermediate (X). The condensation of the N-protected nitro arginine (XI) with 2-aminothiazole (XII) by means of EDC in DMF gives the argininamide (XIII), which is deprotected by means of HCl in dioxane to yield the intermediate (XIV). Condensation of (XIV) with (X) by means of diethyl phosphorylcyanide (DEPC) and NMM in DMF gives the protected dipeptide (XV), which is treated with AcOH in warm water to yield the target dipeptide.

参考文献中间体

合成目标

【1】 Rabinowitz, M.H.; Andrews, R.C.; Becherer, J.D.; et al.; Design of selective and soluble inhibitors of tumor necrosis factor-alpha converting enzyme (TACE). J Med Chem 2001, 44, 24, 4252.

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)	44116	methyl (3R)-3-hydroxyhexanoate		C₇H₁₄O₃	详情	详情
(II)	24599	1-bromo-2-methylpropane	78-77-3	C₄H₉Br	详情	详情
(III)	44118	methyl (2R,3R)-3-hydroxy-2-isobutylhexanoate		C₁₁H₂₂O₃	详情	详情
(IV)	62871			C₁₀H₁₉LiO₃	详情	详情
(V)	52106	2-(aminooxy)tetrahydro-2H-pyran; O-tetrahydro-2H-pyran-2-ylhydroxylamine		C₅H₁₁NO₂	详情	详情
(VI)	44120	(2R,3R)-3-hydroxy-2-isobutyl-N-(tetrahydro-2H-pyran-2-yloxy)hexanamide		C₁₅H₂₉NO₄	详情	详情
(VII)	44121	(1R,2R)-4-methyl-1-propyl-2-[[(tetrahydro-2H-pyran-2-yloxy)amino]carbonyl]pentyl methanesulfonate		C₁₆H₃₁NO₆S	详情	详情
(VIII)	44122	(3R,4S)-3-isobutyl-4-propyl-1-(tetrahydro-2H-pyran-2-yloxy)-2-azetidinone		C₁₅H₂₇NO₃	详情	详情
(IX)	44123	(2R,3S)-2-isobutyl-3-[(tetrahydro-2H-pyran-2-yloxy)amino]hexanoic acid		C₁₅H₂₉NO₄	详情	详情
(X)	44124	(2R,3S)-3-[formyl(tetrahydro-2H-pyran-2-yloxy)amino]-2-isobutylhexanoic acid		C₁₆H₂₉NO₅	详情	详情
(XI)	29372	N-alpha-(tert-butoxycarbonyl)-N-omega'-nitro-L-arginine		C₁₁H₂₁N₅O₆	详情	详情
(XII)	19795	2-Thiazolamine; 1,3-thiazol-2-amine; 1,3-thiazol-2-ylamine	96-50-4	C₃H₄N₂S	详情	详情
(XIII)	44125			C₁₄H₂₃N₇O₅S	详情	详情
(XIV)	44126			C₉H₁₅N₇O₃S	详情	详情
(XV)	44127			C₂₅H₄₂N₈O₇S	详情	详情

Extended Information