methyl (3R)-5-hydroxy-3-methylpentanoate -Drug Synthesis Database

【结构式】

【分子编号】57410

【品名】methyl (3R)-5-hydroxy-3-methylpentanoate

【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：(I)

The reaction of methyl 5-hydroxy-3(R)-methylpentanoate (I) with 4-methoxybenzyalmine in refluxing toluene gives the corresponding amide (II), which is cyclized by means of SO3/pyridine in DMSO/TEA to yield the 6-hydroxypiperidinone (III). The dehydration of (III) in refluxing toluene, or by means of PPA in refluxing dimethyl carbonate affords the tetrahydropyridinone (IV). The reaction of (IV) with ethyl trichloroacetate (V) by means of Na-OEt in dimethyl carbonate gives the 2-azabicyclo[4,1,0]heptane derivative (VI), which is monodechlorinated by means of Zn and ethylenediamine in refluxing methanol/water to yield a diastereomeric mixture of monochloro compounds (VII). The treatment of (VII) with Ms-OH in refluxing toluene, followed by treatment with aq. NaOH affords the desired deprotected monochloro isomer (VIII). The reaction of the ketone group of (VIII) with trimethyloxonium tetrafluoroborate in dimethyl carbonate provides the enol ether (IX), which is finally treated with ammonium acetate in refluxing ethanol to give the target imine.

参考文献中间体

合成目标

【1】 Hashimoto, S.; Kusuda, S.; Kuwabe, S. (Ono Pharmaceutical Co., Ltd.); Process for the preparation of intermediate cpds. of drugs. EP 1188749; WO 0078722 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	57410	methyl (3R)-5-hydroxy-3-methylpentanoate	C₇H₁₄O₃	详情	详情
(II)	57411	(3R)-5-hydroxy-N-(4-methoxybenzyl)-3-methylpentanamide	C₁₄H₂₁NO₃	详情	详情
(III)	57412	(4R)-6-hydroxy-1-(4-methoxybenzyl)-4-methyl-2-piperidinone	C₁₄H₁₉NO₃	详情	详情
(IV)	57406	(4S)-1-(4-methoxybenzyl)-4-methyl-3,4-dihydro-2(1H)-pyridinone	C₁₄H₁₇NO₂	详情	详情
(V)	57413	ethyl 2,2,2-trichloroacetate	C₄H₅Cl₃O₂	详情	详情
(VI)	57047	5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile	C₁₆H₁₂N₄O	详情	详情
(VII)	57414	(1S,5S,6R)-7-chloro-2-(4-methoxybenzyl)-5-methyl-2-azabicyclo[4.1.0]heptan-3-one	C₁₅H₁₈ClNO₂	详情	详情
(VIII)	57408	(1S,5S,6R,7R)-7-chloro-5-methyl-2-azabicyclo[4.1.0]heptan-3-one	C₇H₁₀ClNO	详情	详情
(IX)	57415	(1S,5S,6R,7R)-7-chloro-3-methoxy-5-methyl-2-azabicyclo[4.1.0]hept-2-ene; (1S,5S,6R,7R)-7-chloro-5-methyl-2-azabicyclo[4.1.0]hept-2-en-3-yl methyl ether	C₈H₁₂ClNO	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 condensation between methyl (R)-5-hydroxy-3-methylpentanoate (I) and 4-methoxybenzylamine (II) afforded amide (III). Swern oxidation of the alcohol function led to the corresponding aldehyde, which spontaneously evolved to the cyclic hemiaminal form (IV). Dehydration of (IV) to the tetrahydropyridinone (V) was accomplished by either heating in toluene, or by treatment with phosphoric acid in refluxing dimethyl carbonate. The bicyclic derivative (VI) was then obtained by addition of dichlorocarbene, generated from either ethyl trichloroacetate or chloroform and a base, to tetrahydropyridinone (V). Mono-dehalogenation of dichloro compound (VI) employing zinc dust and ethylenediamine provided a mixture of diastereomeric mono-chloro derivatives (VIIa-b) . After acid-promoted cleavage of the p-methoxybenzyl group, the major isomer (VIII) was isolated by selective crystallization from the reaction mixture. Alternatively, dichloro compound (VI) was first subjected to acidic p-methoxybenzyl group cleavage yielding (IX). Then, radical dehalogenation with triphenyltin hydride and AIBN produced a mixture of mono-chloro compounds, which were separated by column chromatography. Lactam (VIII) was converted to imidate (X) upon treatment with trimethyloxonium tetrafluoroborate. Optionally, the analogous ethyl imidate (XI) was prepared by a similar procedure. Treatment of imidates (X) or (XI) with either ammonia or ammonium acetate furnished the target amidine, which was finally isolated as the corresponding hydrochloride salt.

参考文献中间体

合成目标

【1】 Kobayashi, K.; Taniguchi, N.; Naka, M. (Ono Pharmaceutical Co., Ltd.); Condensed piperidine derivs. used as a nitrogen monoxide synthase inhibitors. EP 0870763; JP 1999171866; US 6110930; US 6228866 .
【2】 Hashimoto, S.; Kusuda, S.; Kuwabe, S. (Ono Pharmaceutical Co., Ltd.); Process for the preparation of intermediate cpds. of drugs. EP 1188749; WO 0078722 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIIa)	58739	(1S,5S,6R,7S)-7-chloro-2-(4-methoxybenzyl)-5-methyl-2-azabicyclo[4.1.0]heptan-3-one		C₁₅H₁₈ClNO₂	详情	详情
(VIIa)	58740	(1S,5S,6R,7R)-7-chloro-2-(4-methoxybenzyl)-5-methyl-2-azabicyclo[4.1.0]heptan-3-one		C₁₅H₁₈ClNO₂	详情	详情
(I)	57410	methyl (3R)-5-hydroxy-3-methylpentanoate		C₇H₁₄O₃	详情	详情
(II)	15098	4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine	2393-23-9	C₈H₁₁NO	详情	详情
(III)	57411	(3R)-5-hydroxy-N-(4-methoxybenzyl)-3-methylpentanamide		C₁₄H₂₁NO₃	详情	详情
(IV)	58412	N-[(E)-(4-{[tert-butyl(dimethyl)silyl]oxy}-3-methoxy-5-methylphenyl)methylidene]-N-(3-pyridinyl)amine; N-[(E)-(4-{[tert-butyl(dimethyl)silyl]oxy}-3-methoxy-5-methylphenyl)methylidene]-3-pyridinamine		C₂₀H₂₈N₂O₂Si	详情	详情
(V)	57406	(4S)-1-(4-methoxybenzyl)-4-methyl-3,4-dihydro-2(1H)-pyridinone		C₁₄H₁₇NO₂	详情	详情
(VI)	57407	(1S,5S,6R)-7,7-dichloro-2-(4-methoxybenzyl)-5-methyl-2-azabicyclo[4.1.0]heptan-3-one		C₁₅H₁₇Cl₂NO₂	详情	详情
(VIII)	57408	(1S,5S,6R,7R)-7-chloro-5-methyl-2-azabicyclo[4.1.0]heptan-3-one		C₇H₁₀ClNO	详情	详情
(IX)	58738	(1S,5S,6R)-7,7-dichloro-5-methyl-2-azabicyclo[4.1.0]heptan-3-one		C₇H₉Cl₂NO	详情	详情
(X)	57415	(1S,5S,6R,7R)-7-chloro-3-methoxy-5-methyl-2-azabicyclo[4.1.0]hept-2-ene; (1S,5S,6R,7R)-7-chloro-5-methyl-2-azabicyclo[4.1.0]hept-2-en-3-yl methyl ether		C₈H₁₂ClNO	详情	详情
(XI)	58741	(1S,5S,6R,7R)-7-chloro-3-ethoxy-5-methyl-2-azabicyclo[4.1.0]hept-2-ene; (1S,5S,6R,7R)-7-chloro-5-methyl-2-azabicyclo[4.1.0]hept-2-en-3-yl ethyl ether		C₉H₁₄ClNO	详情	详情

Extended Information