(2R,4S,5R,6S,8R)-5,9-bis[[tert-butyl(dimethyl)silyl]oxy]-4,6-dimethoxy-2,8-dimethylnonyl pivalate -Drug Synthesis Database

【结构式】

【分子编号】11517

【品名】(2R,4S,5R,6S,8R)-5,9-bis[[tert-butyl(dimethyl)silyl]oxy]-4,6-dimethoxy-2,8-dimethylnonyl pivalate

【CA登记号】

【分子式】C₃₀H₆₄O₆Si₂

【分子量】577.00556

【元素组成】C 62.45% H 11.18% O 16.64% Si 9.73%

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：(XVIII)

A new total synthesis of FK-506 is described: This synthesis has been performed by previous construction of two building fragments (XXIV) and (LI), which later were coupled and cyclized. (Schemes 1-3): 1) (1R*S*,3R,5S,6R,7S,9R)-6-(tert-butyldimethylsilyloxy)-9-(1,3-dithian-2-yl)-5,7-dimethoxy-1-methyldecyl diphenyl phosphine oxide (XXIV). The Sharpless asymetric epoxidation of 1,4-pentadien-3-ol (I) with (-)-diisopropyltartrate and tert-butylhydroperoxide gives the epoxy alcohol (II) with high optical purity, which is benzylated in the usual way to (III). The reaction of (III) with lithioacetonitrile and then HCl yields lactone (IV), which is methylated with lithium diisopropylamide and methyl iodide to lactone (V) as major isomer (separated by chromatography on SiO2). The reduction of (V) with LiAlH4 affords the diol (VI), which is converted into the bis(tert-butyl carbonate) (VII) with 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (BOC-N). The reaction of (VII) with Br2 and K2CO3 in dichloromethane gives the bromocarbonate (VIII), which by selective saponification of the cyclic carbonate with NaOCH3 in methanol yields the epoxy alcohol (IX). Methylation of (IX) with NaH and methyl iodide affords the methyl ether (X), which is converted into the butyrolactone (XI) with lithioacetonitrile as before. The protection of the OH group of (XI) with TBS-Cl gives the silyl ether (XII), which by trans-selective methylation with lithium diisopropylamide and methyl iodide yields lactone (XIII). The reduction of (XIII) with LiAlH4 affords diol (XIV) as major isomer (separated by column chromatography). The selective esterification of the primary OH group of (XIV) with pivaloyl chloride gives the hydroxy ester (XV), which is methylated with NaH and methyl iodide as usual to the methoxy derivative (XVI). Debenzylation of (XVI) by hydrogenolysis with H2 over Pd/C yields the hydroxy ester (XVII), which is silylated with TBS-SO3CF3 to the fully protected compound (XVIII).

参考文献中间体

合成目标

【1】 Jones, T.K.; Askin, D.; Mills, S.G.; Reamer, R.A.; Desmond, R.; Volante, R.P.; Tschaen, D.M.; Shinkai, I. (Merck & Co., Inc.); Process for synthesis of FK-506 and tricarbonyl intermediates. EP 0378318; JP 1990233643 .

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)	11471	1,4-Pentadien-3-ol	922-65-6	C₅H₈O	详情	详情
(II)	11501	(1R)-1-[(2S)Oxiranyl]-2-propen-1-ol		C₅H₈O₂	详情	详情
(III)	11502	(2S)-2-[(1R)-1-(Benzyloxy)-2-propenyl]oxirane; benzyl (1R)-1-[(2S)Oxiranyl]-2-propenyl ether		C₁₂H₁₄O₂	详情	详情
(IV)	11503	(5S)-5-[(1R)-1-(Benzyloxy)-2-propenyl]dihydro-2(3H)-furanone		C₁₄H₁₆O₃	详情	详情
(V)	11504	(3R,5S)-5-[(1R)-1-(Benzyloxy)-2-propenyl]-3-methyldihydro-2(3H)-furanone		C₁₅H₁₈O₃	详情	详情
(VI)	11505	(2R,4S,5R)-5-(Benzyloxy)-2-methyl-6-heptene-1,4-diol		C₁₅H₂₂O₃	详情	详情
(VII)	11506	(2R,4S,5R)-5-(benzyloxy)-4-[(tert-butoxycarbonyl)oxy]-2-methyl-6-heptenyl tert-butyl carbonate		C₂₅H₃₈O₇	详情	详情
(VIII)	11507	(2R)-3-[(4S,5S)-5-(benzyloxy)-6-(bromomethyl)-2-oxo-1,3-dioxan-4-yl]-2-methylpropyl tert-butyl carbonate		C₂₁H₂₉BrO₇	详情	详情
(IX)	11508	(2R,4S,5S)-5-(benzyloxy)-4-hydroxy-2-methyl-5-[(2S)oxiranyl]pentyl tert-butyl carbonate		C₂₀H₃₀O₆	详情	详情
(X)	11509	(2R,4S,5S)-5-(benzyloxy)-4-methoxy-2-methyl-5-[(2S)oxiranyl]pentyl tert-butyl carbonate		C₂₁H₃₂O₆	详情	详情
(XI)	11510	(5S)-5-[(1S,2S,4R)-1-(Benzyloxy)-5-hydroxy-2-methoxy-4-methylpentyl]dihydro-2(3H)-furanone		C₁₈H₂₆O₅	详情	详情
(XII)	11511	(5S)-5-((1S,2S,4R)-1,5-Bis[[tert-butyl(dimethyl)silyl]oxy]-2-methoxy-4-methylpentyl)dihydro-2(3H)-furanone		C₂₃H₄₈O₅Si₂	详情	详情
(XIII)	11512	(3R,5S)-5-((1S,2S,4R)-1-(Benzyloxy)-5-[[tert-butyl(dimethyl)silyl]oxy]-2-methoxy-4-methylpentyl)-3-methyldihydro-2(3H)-furanone		C₂₅H₄₂O₅Si	详情	详情
(XIV)	11513	(2R,4S,5R,6S,8R)-5-(Benzyloxy)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-methoxy-2,8-dimethyl-1,4-nonanediol		C₂₅H₄₆O₅Si	详情	详情
(XV)	11514	(2R,4S,5R,6S,8R)-5-(benzyloxy)-9-[[tert-butyl(dimethyl)silyl]oxy]-4-hydroxy-6-methoxy-2,8-dimethylnonyl pivalate		C₃₀H₅₄O₆Si	详情	详情
(XVI)	11515	(2R,4S,5R,6S,8R)-5-(benzyloxy)-9-[[tert-butyl(dimethyl)silyl]oxy]-4,6-dimethoxy-2,8-dimethylnonyl pivalate		C₃₁H₅₆O₆Si	详情	详情
(XVII)	11516	(2R,4S,5R,6S,8R)-9-[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-4,6-dimethoxy-2,8-dimethylnonyl pivalate		C₂₄H₅₀O₆Si	详情	详情
(XVIII)	11517	(2R,4S,5R,6S,8R)-5,9-bis[[tert-butyl(dimethyl)silyl]oxy]-4,6-dimethoxy-2,8-dimethylnonyl pivalate		C₃₀H₆₄O₆Si₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XVIII)

Selective deprotection of (XVIII) with trifluoroacetic acid in THF - water affords the primary alcohol (XIX), which is oxidized with oxalyl chloride and DMSO in dichloromethane to the aldehyde (XX). The protection of the aldehyde group of (XX) with propane-1,3-dithiol and BF3 gives the dithiane derivative (XXI), which is resilylated with TBS-SO3CF3 as before to the dithiane (XXII). The pivaloyl group of (XXII) is eliminated with LiAlH4 in THF yielding the alcohol (XXIII), which is finally treated with benzenesulfonyl chloride and then with ethyl diphenylphosphine oxide and butyllithium in THF to obtain the first building group, the phosphine derivative (XXIV).

参考文献中间体

合成目标

【1】 Jones, T.K.; Askin, D.; Mills, S.G.; Reamer, R.A.; Desmond, R.; Volante, R.P.; Tschaen, D.M.; Shinkai, I. (Merck & Co., Inc.); Process for synthesis of FK-506 and tricarbonyl intermediates. EP 0378318; JP 1990233643 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XVIII)	11517	(2R,4S,5R,6S,8R)-5,9-bis[[tert-butyl(dimethyl)silyl]oxy]-4,6-dimethoxy-2,8-dimethylnonyl pivalate	C₃₀H₆₄O₆Si₂	详情	详情
(XIX)	11518	(2R,4S,5S,6S,8R)-5-[[tert-butyl(dimethyl)silyl]oxy]-9-hydroxy-4,6-dimethoxy-2,8-dimethylnonyl pivalate	C₂₄H₅₀O₆Si	详情	详情
(XX)	11519	(2R,4S,5R,6S,8R)-5-[[tert-butyl(dimethyl)silyl]oxy]-4,6-dimethoxy-2,8-dimethyl-9-oxononyl pivalate	C₂₄H₄₈O₆Si	详情	详情
(XXI)	11520	(2R,4S,5R,6S,8R)-8-(1,3-dithian-2-yl)-5-hydroxy-4,6-dimethoxy-2-methylnonyl pivalate	C₂₁H₄₀O₅S₂	详情	详情
(XXII)	11521	(2R,4S,5R,6S,8R)-5-[[tert-butyl(dimethyl)silyl]oxy]-8-(1,3-dithian-2-yl)-4,6-dimethoxy-2-methylnonyl pivalate	C₂₇H₅₄O₅S₂Si	详情	详情
(XXIII)	11522	(2R,4S,5R,6S,8R)-5-[[tert-Butyl(dimethyl)silyl]oxy]-8-(1,3-dithian-2-yl)-4,6-dimethoxy-2-methyl-1-nonanol	C₂₂H₄₆O₄S₂Si	详情	详情
(XXIV)	11523	(3R,5S,6R,7S,9R)-6-[[tert-Butyl(dimethyl)silyl]oxy]-9-(1,3-dithian-2-yl)-5,7-dimethoxy-1,3-dimethyldecyl(diphenyl)phosphine oxide; [(3R,5S,6R,7S,9R)-6-[[tert-Butyl(dimethyl)silyl]oxy]-9-(1,3-dithian-2-yl)-5,7-dimethoxy-1,3-dimethyldecyl](oxo)diphenylphosphorane	C₃₆H₅₉O₄PS₂Si	详情	详情

Extended Information