4-(benzyloxy)butanal -Drug Synthesis Database

【结构式】

【分子编号】46170

【品名】4-(benzyloxy)butanal

【CA登记号】

【分子式】C₁₁H₁₄O₂

【分子量】178.23096

【元素组成】C 74.13% H 7.92% O 17.95%

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：(II)

The oxidation of 4-(benzyloxy)-1-butanol (I) with oxalyl chloride gives the corresponding aldehyde (II), which is condensed with the phosphonate (III) by means of DBU and LiCl in acetonitrile to yield the 2-hexenoate (IV). The asymmetric aminohydroxylation of (IV) by means of tert-butyl carbamate, K2[OsO2(OH)4] and a chiral catalyst ((DHQD)2PHAL) in propanol/water affords the desired regioisomer (V). The introduction of an azido group into the alpha-position with retention of the configuration was accomplished by two Mitsunobu reactions. The reaction of (V) with benzoic acid, PPh3 and DEAD in THF gives the benzoyloxy compound (VI) with inverted stereochemistry, which is hydrolyzed with K2CO3 in methanol to yield the corresponding alcohol (VII). Then the reaction of (VII) with HN3, DEAD and PPh3 in THF affords the azide (VIII) with the right stereochemistry. The hydrolysis of the ester group of (VIII) by means of K2CO3 in methanol/water, followed by cleavage of the protecting carbamate group with TFA, provides the carboxylic acid (IX). The cyclization of (IX) by means of 2-chloro-1-methylpyridinium iodide (CMPI) and TEA in acetonitrile gives the azetidinone (X), which is reduced with PPh3 in THF/water to yield the aminoazetidinone (XI). The acylation of the amino group of (XI) with 2-phenoxyacetyl chloride (A) and NaHCO3 in aqueous acetonitrile affords the amide (XII). The hydrogenation of (XII) with H2 over Pd/C in ethanol affords the primary alcohol (XIII), which is finally oxidized with the Jones reagent to provide the target carboxylic acid intermediate (XIV).

参考文献中间体

合成目标

【1】 Lee, J.C.; et al.; An asymmetric aminohydroxylation approach to the stereoselective synthesis of cis-substituted azetidinone of loracarbef. Tetrahedron Lett 2001, 42, 27, 4519.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	12180	Phenoxyacetyl chloride; 2-Phenoxyacetyl chloride	701-99-5	C₈H₇ClO₂	详情	详情
(I)	46169	4-(benzyloxy)-1-butanol		C₁₁H₁₆O₂	详情	详情
(II)	46170	4-(benzyloxy)butanal		C₁₁H₁₄O₂	详情	详情
(III)	10019	Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate	867-13-0	C₈H₁₇O₅P	详情	详情
(IV)	49625	ethyl (E)-6-(benzyloxy)-2-hexenoate		C₁₅H₂₀O₃	详情	详情
(V)	49626	ethyl (2S,3R)-6-(benzyloxy)-3-[(tert-butoxycarbonyl)amino]-2-hydroxyhexanoate		C₂₀H₃₁NO₆	详情	详情
(VI)	49627	(1R,2R)-5-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-1-(ethoxycarbonyl)pentyl benzoate		C₂₇H₃₅NO₇	详情	详情
(VII)	49628	ethyl (2R,3R)-6-(benzyloxy)-3-[(tert-butoxycarbonyl)amino]-2-hydroxyhexanoate		C₂₀H₃₁NO₆	详情	详情
(VIII)	49629	ethyl (2S,3R)-2-azido-6-(benzyloxy)-3-[(tert-butoxycarbonyl)amino]hexanoate		C₂₀H₃₀N₄O₅	详情	详情
(IX)	49630	(2S,3R)-3-amino-2-azido-6-(benzyloxy)hexanoic acid		C₁₃H₁₈N₄O₃	详情	详情
(X)	49631	(3S,4R)-3-azido-4-[3-(benzyloxy)propyl]-2-azetidinone		C₁₃H₁₆N₄O₂	详情	详情
(XI)	49632	(3S,4R)-3-amino-4-[3-(benzyloxy)propyl]-2-azetidinone		C₁₃H₁₈N₂O₂	详情	详情
(XII)	49633	N-[(2R,3S)-2-[3-(benzyloxy)propyl]-4-oxoazetidinyl]-2-phenoxyacetamide		C₂₁H₂₄N₂O₄	详情	详情
(XIII)	49634	N-[(2R,3S)-2-(3-hydroxypropyl)-4-oxoazetidinyl]-2-phenoxyacetamide		C₁₄H₁₈N₂O₄	详情	详情
(XIV)	12182	3-[(2R,3S)-4-Oxo-3-[(2-phenoxyacetyl)amino]azetanyl]propionic acid		C₁₄H₁₆N₂O₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IX)

Synthesis of intermediate aldehyde (XV): The oxidation of 4-(benzyloxy)butanol (VIII) with oxalyl chloride gives the aldehyde (IX), which is condensed with 2-(triphenylphosphoranylidene)propionic acid ethyl ester (X) in hot THF to yield the unsaturated ester (XI). The enantioselective dihydroxylation of (XI) by means of AD-mix beta and methanesulfonamide in butanol/water affords the chiral dihydroxyester (XII), which is protected with 2,2-dimethoxypropane and CSA to provide the acetonide (XIII). The reduction of the ester group of (XIII) with DIBAL in THF gives the alcohol (XIV), which is finally oxidized with DMP to yield the desired intermediate aldehyde (XV).

参考文献中间体

合成目标

【1】 Mulzer, J.; et al.; A novel highly stereoselective total synthesis of epothilone B and of its (12R,13R) acetonide. Tetrahedron Lett 2000, 41, 40, 7635.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIII)	46169	4-(benzyloxy)-1-butanol		C₁₁H₁₆O₂	详情	详情
(IX)	46170	4-(benzyloxy)butanal		C₁₁H₁₄O₂	详情	详情
(X)	37071	ethyl 2-(triphenylphosphoranylidene)propanoate	5717-37-3	C₂₃H₂₃O₂P	详情	详情
(XI)	46171	ethyl (E)-6-(benzyloxy)-2-methyl-2-hexenoate		C₁₆H₂₂O₃	详情	详情
(XII)	46172	ethyl (2S,3R)-6-(benzyloxy)-2,3-dihydroxy-2-methylhexanoate		C₁₆H₂₄O₅	详情	详情
(XIII)	46173	ethyl (4S,5R)-5-[3-(benzyloxy)propyl]-2,2,4-trimethyl-1,3-dioxolane-4-carboxylate		C₁₉H₂₈O₅	详情	详情
(XIV)	46174	[(4R,5R)-5-[3-(benzyloxy)propyl]-2,2,4-trimethyl-1,3-dioxolan-4-yl]methanol		C₁₇H₂₆O₄	详情	详情
(XV)	46175	(4S,5R)-5-[3-(benzyloxy)propyl]-2,2,4-trimethyl-1,3-dioxolane-4-carbaldehyde		C₁₇H₂₄O₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

Aldehyde (II) was prepared by mono-benzylation of 1,4-butanediol (I) followed by Swern oxidation. Subsequent addition of ethynylmagnesium bromide (III) to the aldehyde function of (II) provided propargyl alcohol (IV). Kinetic resolution of the racemic alcohol (IV) by lipase-mediated acetylation in the presence of vinyl acetate produced a mixture of the (S)-acetate (V) and the unreacted (R)-alcohol (VI). The required (S)-propargyl acetate (V) was subjected to partial hydrogenation using Lindlar catalyst to furnish allyl acetate (VII), which was further hydrolyzed to the chiral alcohol (VIII). After protection of (VIII) as the silylated derivative (IX), reductive removal of the benzyl ether using lithium naphthalenide afforded the primary alcohol (X). This was then treated with methanesulfonyl chloride and triethylamine to give mesylate (XI). Ozonolysis of the double bond of (XI), followed by reductive work-up with dimethyl sulfide, yielded aldehyde (XII). This was reacted with hydroxylamine hydrochloride and Et3N in allyl alcohol (XIII) to produce the intermediate nitrone (XIV), which underwent simultaneous 1,3-dipolar cycloaddition to allyl alcohol to furnish the isoxazolopyridine (XV) as a mixture of three diastereoisomers. This mixture was then subjected to hydrogenolytic N-O bond fission, producing piperidine (XVI).

参考文献中间体

合成目标

【1】 Ooi, H.e; et al.; A concise enantioselective synthesis of antimalarial febrifugine alkaloids. Org Lett 2001, 3, 6, 953.

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)	43160	1,4-butanediol;1,4-Dihydroxybutane;1,4-Butylene glycol;Tetramethylene glycol	110-63-4	C₄H₁₀O₂	详情	详情
(II)	46170	4-(benzyloxy)butanal		C₁₁H₁₄O₂	详情	详情
(III)	17778	ETHYNYLMAGNESIUM BROMIDE; bromo(ethynyl)magnesium	4301-14-8	C₂HBrMg	详情	详情
(IV)	47833	6-(benzyloxy)-1-hexyn-3-ol		C₁₃H₁₆O₂	详情	详情
(V)	47834	(1S)-1-[3-(benzyloxy)propyl]-2-propynyl acetate		C₁₅H₁₈O₃	详情	详情
(VI)	47835	(3R)-6-(benzyloxy)-1-hexyn-3-ol		C₁₃H₁₆O₂	详情	详情
(VII)	47836	(1S)-1-[3-(benzyloxy)propyl]-2-propenyl acetate		C₁₅H₂₀O₃	详情	详情
(VIII)	47837	(3S)-6-(benzyloxy)-1-hexen-3-ol		C₁₃H₁₈O₂	详情	详情
(IX)	47838	([(1S)-1-[3-(benzyloxy)propyl]-2-propenyl]oxy)(tert-butyl)diphenylsilane; benzyl (4S)-4-[[tert-butyl(diphenyl)silyl]oxy]-5-hexenyl ether		C₂₉H₃₆O₂Si	详情	详情
(X)	47839	(4S)-4-[[tert-butyl(diphenyl)silyl]oxy]-5-hexen-1-ol		C₂₂H₃₀O₂Si	详情	详情
(XI)	47840	(4S)-4-[[tert-butyl(diphenyl)silyl]oxy]-5-hexenyl methanesulfonate		C₂₃H₃₂O₄SSi	详情	详情
(XII)	47841	(4S)-4-[[tert-butyl(diphenyl)silyl]oxy]-5-oxopentyl methanesulfonate		C₂₂H₃₀O₅SSi	详情	详情
(XIII)	12234	2-Propen-1-ol; Allyl alcohol	107-18-6	C₃H₆O	详情	详情
(XIV)	47842	(5S)-5-[[tert-butyl(diphenyl)silyl]oxy]-2,3,4,5-tetrahydro-1-pyridiniumolate		C₂₁H₂₇NO₂Si	详情	详情
(XV)	47843	((4S)-4-[[tert-butyl(diphenyl)silyl]oxy]hexahydro-2H-isoxazolo[2,3-a]pyridin-2-yl)methanol		C₂₄H₃₃NO₃Si	详情	详情
(XVI)	47844	3-((3S)-3-[[tert-butyl(diphenyl)silyl]oxy]piperidinyl)-1,2-propanediol		C₂₄H₃₅NO₃Si	详情	详情

合成路线4

该中间体在本合成路线中的序号：(II)

参考文献中间体

合成目标

【1】 Ooi, H.e; et al.; A concise enantioselective synthesis of antimalarial febrifugine alkaloids. Org Lett 2001, 3, 6, 953.

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)	43160	1,4-butanediol;1,4-Dihydroxybutane;1,4-Butylene glycol;Tetramethylene glycol	110-63-4	C₄H₁₀O₂	详情	详情
(II)	46170	4-(benzyloxy)butanal		C₁₁H₁₄O₂	详情	详情
(III)	17778	ETHYNYLMAGNESIUM BROMIDE; bromo(ethynyl)magnesium	4301-14-8	C₂HBrMg	详情	详情
(IV)	47833	6-(benzyloxy)-1-hexyn-3-ol		C₁₃H₁₆O₂	详情	详情
(V)	47834	(1S)-1-[3-(benzyloxy)propyl]-2-propynyl acetate		C₁₅H₁₈O₃	详情	详情
(VI)	47835	(3R)-6-(benzyloxy)-1-hexyn-3-ol		C₁₃H₁₆O₂	详情	详情
(VII)	47836	(1S)-1-[3-(benzyloxy)propyl]-2-propenyl acetate		C₁₅H₂₀O₃	详情	详情
(VIII)	47837	(3S)-6-(benzyloxy)-1-hexen-3-ol		C₁₃H₁₈O₂	详情	详情
(IX)	47838	([(1S)-1-[3-(benzyloxy)propyl]-2-propenyl]oxy)(tert-butyl)diphenylsilane; benzyl (4S)-4-[[tert-butyl(diphenyl)silyl]oxy]-5-hexenyl ether		C₂₉H₃₆O₂Si	详情	详情
(X)	47839	(4S)-4-[[tert-butyl(diphenyl)silyl]oxy]-5-hexen-1-ol		C₂₂H₃₀O₂Si	详情	详情
(XI)	47840	(4S)-4-[[tert-butyl(diphenyl)silyl]oxy]-5-hexenyl methanesulfonate		C₂₃H₃₂O₄SSi	详情	详情
(XII)	47841	(4S)-4-[[tert-butyl(diphenyl)silyl]oxy]-5-oxopentyl methanesulfonate		C₂₂H₃₀O₅SSi	详情	详情
(XIII)	12234	2-Propen-1-ol; Allyl alcohol	107-18-6	C₃H₆O	详情	详情
(XIV)	47842	(5S)-5-[[tert-butyl(diphenyl)silyl]oxy]-2,3,4,5-tetrahydro-1-pyridiniumolate		C₂₁H₂₇NO₂Si	详情	详情
(XV)	47843	((4S)-4-[[tert-butyl(diphenyl)silyl]oxy]hexahydro-2H-isoxazolo[2,3-a]pyridin-2-yl)methanol		C₂₄H₃₃NO₃Si	详情	详情
(XVI)	47844	3-((3S)-3-[[tert-butyl(diphenyl)silyl]oxy]piperidinyl)-1,2-propanediol		C₂₄H₃₅NO₃Si	详情	详情

Extended Information