ethyl (6S)-6,8-dihydroxyoctanoate -Drug Synthesis Database

【结构式】

【分子编号】57958

【品名】ethyl (6S)-6,8-dihydroxyoctanoate

【CA登记号】

【分子式】C₁₀H₂₀O₄

【分子量】204.2664

【元素组成】C 58.8% H 9.87% O 31.33%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(XXIX)

An alternative route to (+)-lipoic acid used ethyl 4,6-di-O-acetyl-2,3-dideoxy-alpha-D-erythro-hexopyranoside (XX), prepared from triacetyl-D-glucal, as the chiral starting point. Deacetylation of (XX) with sodium methoxide under Zemplen conditions gave diol (XXI) which, after conventional benzylation, led to the 4,6-di-O-benzyl derivative (XXII). Ring opening of the cyclic acetal (XXII) with propanediol in the presence of boron trifluoride afforded the dithiane derivative (XXIII). The free hydroxyl group of (XXIII) was converted into xanthate (XXIV) by reaction with NaH and CS2, followed by methyl iodide. Reductive cleavage of the xanthate group by means of Bu3SnH and AIBN provided (XXV). Hydrolysis of the thioacetal function with HgO and BF3 provided aldehyde (XXVI). Chain homologation was performed by Wittig reaction of aldehyde (XXVI) with phosphorane (XXVII) to afford the unsaturated ester (XXVIII). Simultaneous double bond hydrogenation and benzyl ether cleavage in the presence of Raney nickel led to dihydroxy ester (XXIX). This was converted to the corresponding dimesylate (XXX), which was further cyclized to disulfide (XXXI) using the in situ generated sodium disulfide as in the precedent Schemes. Finally, basic hydrolysis of the ethyl ester (XXXI) yielded the title carboxylic acid.

参考文献中间体

合成目标

【1】 Rao, A.V.R.; et al.; Enantiospecific synthesis of (R)-(+)-alpha-lipoic acid from D-glucose. Carbohydr Res 1986, 148, 1, 51.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XVI)	57956	(4S)-4,6-bis(benzyloxy)hexanal		C₂₀H₂₄O₃	详情	详情
(XX)	57950	[(2R,3S,6S)-3-(acetyloxy)-6-ethoxytetrahydro-2H-pyran-2-yl]methyl acetate		C₁₂H₂₀O₆	详情	详情
(XXI)	57951	(2R,3S,6S)-6-ethoxy-2-(hydroxymethyl)tetrahydro-2H-pyran-3-ol		C₈H₁₆O₄	详情	详情
(XXII)	57952	(2R,3S,6S)-3-(benzyloxy)-2-[(benzyloxy)methyl]-6-ethoxytetrahydro-2H-pyran; benzyl [(2R,3S,6S)-3-(benzyloxy)-6-ethoxytetrahydro-2H-pyran-2-yl]methyl ether		C₂₂H₂₈O₄	详情	详情
(XXIII)	57953	(2R,3S)-1,3-bis(benzyloxy)-5-(1,3-dithian-2-yl)-2-pentanol		C₂₃H₃₀O₃S₂	详情	详情
(XXIV)	57954	O-[(1R,2S)-2-(benzyloxy)-1-[(benzyloxy)methyl]-4-(1,3-dithian-2-yl)butyl] S-methyl carbonodithioate		C₂₅H₃₂O₃S₄	详情	详情
(XXV)	57955	benzyl (1S)-3-(benzyloxy)-1-[2-(1,3-dithian-2-yl)ethyl]propyl ether; 2-[(3S)-3,5-bis(benzyloxy)pentyl]-1,3-dithiane		C₂₃H₃₀O₂S₂	详情	详情
(XXVII)	14182	ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane	1099-45-2	C₂₂H₂₁O₂P	详情	详情
(XXVIII)	57957	ethyl (E,6S)-6,8-bis(benzyloxy)-2-octenoate		C₂₄H₃₀O₄	详情	详情
(XXIX)	57958	ethyl (6S)-6,8-dihydroxyoctanoate		C₁₀H₂₀O₄	详情	详情
(XXX)	57959	ethyl (6S)-6,8-bis[(methylsulfonyl)oxy]octanoate		C₁₂H₂₄O₈S₂	详情	详情
(XXXI)	57960	ethyl 5-[(3R)-1,2-dithiolan-3-yl]pentanoate		C₁₀H₁₈O₂S₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XII)

Diisopropylidene mannitol (I) was first converted into the dibutyltin derivative (II), which was subsequently mono-benzylated to (III). Acetylation of (III) with acetic anhydride in pyridine gave (IV). After acidic hydrolysis of the isopropylidene ketals of (IV), the resultant tetraol (V) was converted into tetramesylate (VI). Reductive elimination in (VI) with Zn and NaI produced diene (VII). The acetate group of (VII) was then hydrolyzed to (VIII) using NaOMe. Intermediate (VIII) was reacted with triethyl orthoacetate in the presence of propionic acid to generate the allyl vinyl ether (IX), which underwent a Claisen rearrangement to the diene-ester (X). Selective hydroboration-oxidation of the terminal double bond of (X) yielded the primary alcohol (XI). Subsequent benzyl group hydrogenolysis in (XI) furnished the target intermediate diol (XII).

参考文献中间体

合成目标

【1】 Rao, A.V.R.; et al.; Synthesis of (3R,4R)-1,5-hexadien-3,4-diol and its unsymmetrical derivatives: Application to (R)-(+)-alpha-lipoic acid. Tetrahedron Lett 1987, 28, 19, 2183.
【2】 Yadav, J.S.; et al.; Synthesis of (3R,4R)-1,2-divinylglycol and its unsymmetrical derivatives: An application to the synthesis of R-(+)-alpha lipoic acid. J Carbohydr Chem 1990, 9, 2-3, 307.

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)	45944	(1S,2S)-1,2-bis[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-1,2-ethanediol	1707-77-3	C₁₂H₂₂O₆	详情	详情
(II)	57998	(4R,5R)-2,2-dibutoxy-4,5-bis[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-1,3,2-dioxastannolane		C₂₀H₃₈O₈Sn	详情	详情
(III)	57999	(1S,2S)-2-(benzyloxy)-1,2-bis[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-1-ethanol		C₁₉H₂₈O₆	详情	详情
(IV)	58000	(1S,2R)-2-(benzyloxy)-1,2-bis[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl acetate		C₂₁H₃₀O₇	详情	详情
(V)	58001	(1R,2R,3R)-2-(benzyloxy)-1-[(1R)-1,2-dihydroxyethyl]-3,4-dihydroxybutyl acetate		C₁₅H₂₂O₇	详情	详情
(VI)	58002	(1S,2S,3R)-2-(benzyloxy)-1-{(1R)-1,2-bis[(methylsulfonyl)oxy]ethyl}-3,4-bis[(methylsulfonyl)oxy]butyl acetate		C₁₉H₃₀O₁₅S₄	详情	详情
(VII)	58003	(1R,2R)-2-(benzyloxy)-1-vinyl-3-butenyl acetate		C₁₅H₁₈O₃	详情	详情
(VIII)	58004	(3R,4R)-4-(benzyloxy)-1,5-hexadien-3-ol		C₁₃H₁₆O₂	详情	详情
(IX)	58005	1-[({(1R,2R)-2-[(1-ethoxyvinyl)oxy]-1-vinyl-3-butenyl}oxy)methyl]benzene; benzyl (1R,2R)-2-[(1-ethoxyvinyl)oxy]-1-vinyl-3-butenyl ether		C₁₇H₂₂O₃	详情	详情
(X)	58006	ethyl (4E,6R)-6-(benzyloxy)-4,7-octadienoate		C₁₇H₂₂O₃	详情	详情
(XI)	58007	ethyl (E,6R)-6-(benzyloxy)-8-hydroxy-4-octenoate		C₁₇H₂₄O₄	详情	详情
(XII)	57958	ethyl (6S)-6,8-dihydroxyoctanoate		C₁₀H₂₀O₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XII)

Alkylation of the dianion of octyl acetoacetate (XIII) with 4-iodobutyronitrile (XIV) provided the cyano keto ester (XV). Enantiospecific reduction of (XV) utilizing baker's yeast gave rise to the desired (S)-hydroxy ester (XVI) in high enantiomeric excess. Subsequent ester group reduction in (XVI) by means of LiBH4 provided diol (XVII). The target dihydroxy ester (XII) was then obtained by alcoholysis of nitrile (XVII) under acidic conditions.

参考文献中间体

合成目标

【1】 Jacobs, H.K.; Gopalan, A.S.; Stereochemical control of yeast reductions: Synthesis of R-(+)-alpha-lipoic acid. Tetrahedron Lett 1989, 30, 42, 5705.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XII)	57958	ethyl (6S)-6,8-dihydroxyoctanoate	C₁₀H₂₀O₄	详情	详情
(XIII)	58008	octyl 3-oxobutanoate	C₁₂H₂₂O₃	详情	详情
(XIV)	58009	4-iodobutanenitrile	C₄H₆IN	详情	详情
(XV)	58010	octyl 7-cyano-3-oxoheptanoate	C₁₆H₂₇NO₃	详情	详情
(XVI)	58011	octyl (3S)-7-cyano-3-hydroxyheptanoate	C₁₆H₂₉NO₃	详情	详情
(XVII)	58012	(6S)-6,8-dihydroxyoctanenitrile	C₈H₁₅NO₂	详情	详情

合成路线4

该中间体在本合成路线中的序号：(XII)

In a related method, keto ester (XX) was prepared by Claisen condensation of the lithium enolate of octyl acetate (XVIII) with 4-chlorobutanoyl chloride (XIX). Reduction of the beta-keto ester (XX) with baker's yeast gave rise to the (S)-alcohol (XXI). Subsequent ester group reduction in (XXI) with LiBH4 furnished diol (XXII), which was protected as the acetonide (XXIII) upon treatment with 2,2-dimethoxypropane under acidic conditions. Displacement of the chloride of (XXIII) with the sodium salt of diethyl malonate afforded the substituted malonate (XXIV). Decarbethoxylation of malonate (XXIV) to mono-ester (XXV) was accomplished employing NaCN in hot DMSO. The target dihydroxy ester (XII) was then obtained by acidic acetonide (XXV) hydrolysis.

参考文献中间体

合成目标

【1】 Jacobs, H.K.; Gopalan, A.S.; Bakers' yeast reduction of alkyl 6-chloro-3-oxohexanoates: Synthesis of (R)-(+)-alpha-lipoic acid. J Chem Soc - Perkins Trans I 1990, 7, 1897.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XII)	57958	ethyl (6S)-6,8-dihydroxyoctanoate		C₁₀H₂₀O₄	详情	详情
(XVIII)	58013	octyl acetate		C₁₀H₂₀O₂	详情	详情
(XIX)	11265	4-Chlorobutanoyl chloride; 4-Chlorobutyric acid chloride	4635-59-0	C₄H₆Cl₂O	详情	详情
(XX)	58014	octyl 6-chloro-3-oxohexanoate		C₁₄H₂₅ClO₃	详情	详情
(XXI)	58015	octyl (3S)-6-chloro-3-hydroxyhexanoate		C₁₄H₂₇ClO₃	详情	详情
(XXII)	58016	(3S)-6-chloro-1,3-hexanediol		C₆H₁₃ClO₂	详情	详情
(XXIII)	58017	(4S)-4-(3-chloropropyl)-2,2-dimethyl-1,3-dioxolane		C₈H₁₅ClO₂	详情	详情
(XXIV)	58018	diethyl 2-{3-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]propyl}malonate		C₁₅H₂₆O₆	详情	详情
(XXV)	58019	ethyl 5-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]pentanoate		C₁₂H₂₂O₄	详情	详情

Extended Information