benzyl (2S)-2-hydroxy-3-methylbutanoate -Drug Synthesis Database

【结构式】

【分子编号】25720

【品名】benzyl (2S)-2-hydroxy-3-methylbutanoate

【CA登记号】

【分子式】C₁₂H₁₆O₃

【分子量】208.25724

【元素组成】C 69.21% H 7.74% O 23.05%

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：(VIII)

Boron enolate obtained from chiral propionyloxazolidinone (I) and dibutylboron triflate (Bu2BOTf) was condensed with n-octanal (II) to produce the syn aldol compound (III), which was protected as the silyl ether (IV) with tert-butyldimethylsilyl triflate. Then, removal of the chiral auxiliary by hydrolysis with lithium peroxide afforded the (2S,3R)-beta-(silyloxy)acid (V). After activation as the mixed anhydride (VII) with 2,4,6-trichlorobenzoyl chloride (VI), esterification with benzyl (S)-2-hydroxy-3-methylbutyrate (VIII) gave diester (IX). Subsequent removal of the silyl group using HF in acetonitrile provided intermediate (X).

参考文献中间体

合成目标

【1】 Wagner, B.; et al.; Total synthesis and conformational studies of hapalosin, N-desmethylhapalosin and 8-deoxyhapalosin. Bioorg Med Chem 1999, 7, 5, 737.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	40666	tert-butyl(dimethyl)silyl trifluoromethanesulfonoperoxoate		C₇H₁₅F₃O₄SSi	详情	详情
(I)	25713	(4S)-4-benzyl-3-propionyl-1,3-oxazolidin-2-one		C₁₃H₁₅NO₃	详情	详情
(II)	25714	octanal	124-13-0	C₈H₁₆O	详情	详情
(III)	25715	(4S)-4-benzyl-3-[(2S,3R)-3-hydroxy-2-methyldecanoyl]-1,3-oxazolidin-2-one		C₂₁H₃₁NO₄	详情	详情
(IV)	25716	(4S)-4-benzyl-3-((2S,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyldecanoyl)-1,3-oxazolidin-2-one		C₂₇H₄₅NO₄Si	详情	详情
(V)	25717	(2S,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyldecanoic acid		C₁₇H₃₆O₃Si	详情	详情
(VI)	25718	2,4,6-trichlorobenzoyl chloride	4136-95-2	C₇H₂Cl₄O	详情	详情
(VII)	25719	(2S,3R)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-methyldecanoic 2,4,6-trichloro-1-benzenecarboxylic anhydride		C₂₄H₃₇Cl₃O₄Si	详情	详情
(VIII)	25720	benzyl (2S)-2-hydroxy-3-methylbutanoate		C₁₂H₁₆O₃	详情	详情
(IX)	25721	(1S)-1-[(benzyloxy)carbonyl]-2-methylpropyl (2S,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methyldecanoate		C₂₉H₅₀O₅Si	详情	详情
(X)	25722	(1S)-1-[(benzyloxy)carbonyl]-2-methylpropyl (2S,3R)-3-hydroxy-2-methyldecanoate		C₂₃H₃₆O₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

The condensation of the choral oxazolidinone (I) with octanal (II) by means of Bu2B-OTf and TEA in dichloromethane gives the chiral alcohol (III), which is protected with DHP and PPTS, yielding the tetrahydropyranyl ether (IV). The cleavage of the chiral adjuvant of (IV) by means of LiOH and H2O2 affords the carboxylic acid (V), which is esterified with (2S)-hydroxy-3-methylbutyric acid benzyl ester (VI) by means of trichlorobenzoyl chloride and TEA to provide the adduct (VII). Elimination of the tetrahydropyranyl protecting group of (VII) by means of Ts-OH gives the hydroxyester (VIII), which is condensed with the chiral amino acid (IX) by means of trichlorobenzoyl chloride as before to yield the triester compound (X). Elimination of the Mom protecting group of (X) by means of Tms-Cl and tetrabutylammonium bromide affords the hydroxy compound (XI), which is hydrogenated with H2 over Pd(OH)2 to provide the carboxylic acid (XII). Elimination of the Boc protecting group of (XII) by means of TFA gives the amino acid (XII), which is finally submitted to a macrocyclization by means of DPPA and DIEA in DMF to yield the target hapalosin.

参考文献中间体

合成目标

【1】 Hermann, C.; et al.; Total synthesis of hapalosin and two ring expanded analogs. Tetrahedron 2000, 56, 43, 8461.

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)	25713	(4S)-4-benzyl-3-propionyl-1,3-oxazolidin-2-one		C₁₃H₁₅NO₃	详情	详情
(II)	25714	octanal	124-13-0	C₈H₁₆O	详情	详情
(III)	25715	(4S)-4-benzyl-3-[(2S,3R)-3-hydroxy-2-methyldecanoyl]-1,3-oxazolidin-2-one		C₂₁H₃₁NO₄	详情	详情
(IV)	50327	Cyanoethane; Ethyl cyanide; Propionitrile	107-12-0	C₂₆H₃₉NO₅	详情	详情
(V)	50328	(2S,3R)-2-methyl-3-(tetrahydro-2H-pyran-2-yloxy)decanoic acid		C₁₆H₃₀O₄	详情	详情
(VI)	25720	benzyl (2S)-2-hydroxy-3-methylbutanoate		C₁₂H₁₆O₃	详情	详情
(VII)	50329	(1S)-1-[(benzyloxy)carbonyl]-2-methylpropyl (2S,3R)-2-methyl-3-(tetrahydro-2H-pyran-2-yloxy)decanoate		C₂₈H₄₄O₆	详情	详情
(VIII)	25722	(1S)-1-[(benzyloxy)carbonyl]-2-methylpropyl (2S,3R)-3-hydroxy-2-methyldecanoate		C₂₃H₃₆O₅	详情	详情
(IX)	50330	(3R,4S)-4-[(tert-butoxycarbonyl)(methyl)amino]-3-(methoxymethoxy)-5-phenylpentanoic acid		C₁₉H₂₉NO₆	详情	详情
(X)	50331	benzyl (6S,7R,11R,12S,15S)-6-benzyl-11-heptyl-15-isopropyl-7-(methoxymethoxy)-2,2,5,12-tetramethyl-4,9,13-trioxo-3,10,14-trioxa-5-azahexadecan-16-oate		C₄₂H₆₃NO₁₀	详情	详情
(XI)	50332	benzyl (6S,7R,11S,12S,15S)-6-benzyl-11-heptyl-7-hydroxy-15-isopropyl-2,2,5,12-tetramethyl-4,9,13-trioxo-3,10,14-trioxa-5-azahexadecan-16-oate		C₄₀H₅₉NO₉	详情	详情
(XII)	50333	(6S,7R,11R,12S,15S)-6-benzyl-11-heptyl-7-hydroxy-15-isopropyl-2,2,5,12-tetramethyl-4,9,13-trioxo-3,10,14-trioxa-5-azahexadecan-16-oic acid		C₃₃H₅₃NO₉	详情	详情
(XIII)	50334	(2S)-2-[((2S,3R)-3-[[(3R,4S)-3-hydroxy-4-(methylamino)-5-phenylpentanoyl]oxy]-2-methyldecanoyl)oxy]-3-methylbutyric acid		C₂₈H₄₅NO₇	详情	详情

Extended Information