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【结 构 式】 
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【分子编号】59085 【品名】(3R)-1-[((4aR,6S,7R,8R,8aS)-7-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-8-yl)oxy]-3-decanol 【CA登记号】 |
【 分 子 式 】C25H49N3O6Si 【 分 子 量 】515.76618 【元素组成】C 58.22% H 9.58% N 8.15% O 18.61% Si 5.45% |
合成路线1
该中间体在本合成路线中的序号：(XVIII)Reformatskii condensation of the organozinc reagent derived from methyl bromoacetate (XIII) with n-heptyl cyanide (XII) gave rise to the keto ester adduct (XIV). Catalytic hydrogenation of (XIV) in the presence of the chiral catalyst generated from dichloro(cycloocta-1,5-diene)ruthenium and (R)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl furnished the (R)-hydroxyester (XV) in high enantiomeric excess. Ester group reduction in (XV) by means of LiAlH4 afforded diol (XVI), which was further converted to the primary tosylate (XVII) with p-toluenesulfonyl chloride in pyridine. Then, alkylation of the intermediate alcohol (XI) with tosylate (XVII) under Williamson's ether synthesis conditions provided the common precursor (XVIII).
| 【1】 Christ, W.J.; Kawata, T.; Hawkins, L.D.; Kobayashi, S.; Asano, O.; Rossignol, D.P. (Eisai Co., Ltd.); Anti-endotoxin cpds.. EP 0536969; JP 1993194470; US 5530113 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 59080 | (4aR,6S,7R,8R,8aS)-7-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-8-ol | C15H29N3O5Si | 详情 | 详情 | |
| (XII) | 59081 | octanenitrile | 124-12-9 | C8H15N | 详情 | 详情 |
| (XIII) | 12309 | methyl 2-bromoacetate; methyl bromoacetate | 96-32-2 | C3H5BrO2 | 详情 | 详情 |
| (XIV) | 59082 | methyl 3-oxodecanoate | C11H20O3 | 详情 | 详情 | |
| (XV) | 59083 | methyl (3R)-3-hydroxydecanoate | C11H22O3 | 详情 | 详情 | |
| (XVI) | 59084 | (3R)-1,3-decanediol | C10H22O2 | 详情 | 详情 | |
| (XVII) | 49121 | (3R)-3-hydroxydecyl 4-methylbenzenesulfonate | C17H28O4S | 详情 | 详情 | |
| (XVIII) | 59085 | (3R)-1-[((4aR,6S,7R,8R,8aS)-7-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-8-yl)oxy]-3-decanol | C25H49N3O6Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVIII)Protection of the free hydroxyl of (XVIII) as the allyloxycarbonyl derivative (XIX) was achieved by sequential treatment with phosgene and then with allyl alcohol. Acetonide group hydrolysis in (XIX) under acidic conditions gave diol (XX), which was selectively silylated at the primary hydroxyl group with tert-butyldimethylsilyl chloride and imidazole to afford (XXI). The remaining hydroxyl group of (XXI) was subsequently protected as the allyl carbonate (XXII) with phosgene and allyl alcohol as above. Then, regioselective mono-desilylation of (XXII) with HF provided the desired building block (XXIII).
| 【1】 Christ, W.J.; Kawata, T.; Hawkins, L.D.; Kobayashi, S.; Asano, O.; Rossignol, D.P. (Eisai Co., Ltd.); Anti-endotoxin cpds.. EP 0536969; JP 1993194470; US 5530113 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVIII) | 59085 | (3R)-1-[((4aR,6S,7R,8R,8aS)-7-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-8-yl)oxy]-3-decanol | C25H49N3O6Si | 详情 | 详情 | |
| (XIX) | 59086 | (1R)-1-{2-[((4aR,6S,7R,8R,8aS)-7-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-8-yl)oxy]ethyl}octyl allyl carbonate | C29H53N3O8Si | 详情 | 详情 | |
| (XX) | 59087 | allyl (1R)-1-(2-{[(2S,3R,4R,5S,6R)-3-azido-2-{[tert-butyl(dimethyl)silyl]oxy}-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]oxy}ethyl)octyl carbonate | C26H49N3O8Si | 详情 | 详情 | |
| (XXI) | 59088 | allyl (1R)-1-(2-{[(2S,3R,4R,5S,6R)-3-azido-2-{[tert-butyl(dimethyl)silyl]oxy}-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-hydroxytetrahydro-2H-pyran-4-yl]oxy}ethyl)octyl carbonate | C32H63N3O8Si2 | 详情 | 详情 | |
| (XXII) | 59089 | allyl (1R)-1-(2-{[(2R,3S,4R,5R,6S)-3-{[(allyloxy)carbonyl]oxy}-5-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)tetrahydro-2H-pyran-4-yl]oxy}ethyl)octyl carbonate | C36H67N3O10Si2 | 详情 | 详情 | |
| (XXIII) | 59009 | N-(1-adamantyl)-N-methylamine; N-methyl-1-adamantanamine | C11H19N | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XVIII)The common precursor (XVIII) was converted into building block (XXXV) as follows. Esterification of (XVIII) with the unsaturated fatty acid (XXIX) by means of DCC and DMAP gave ester (XXX). The acetonide group of (XXX) was then hydrolyzed to diol (XXXI) under acidic conditions. Methylation of (XXXI) with iodomethane in the presence of silver oxide produced a mixture of two regioisomeric methyl ethers. In this mixture, the undesired 4-methoxy compound (XXXIII) was then selectively silylated at the free primary 6-hydroxyl group, which allowed chromatographic separation from the target 6-methoxy compound (XXXII). Phosphitylation of (XXXII), followed by oxidation of the intermediate phosphite with m-chloroperbenzoic acid, furnished phosphate (XXXIV). Desilylation of (XXXIV) to the required intermediate (XXXV) was accomplished by treatment with HF in acetonitrile.
| 【1】 Christ, W.J.; Kawata, T.; Hawkins, L.D.; Kobayashi, S.; Asano, O.; Rossignol, D.P. (Eisai Co., Ltd.); Anti-endotoxin cpds.. EP 0536969; JP 1993194470; US 5530113 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVIII) | 59085 | (3R)-1-[((4aR,6S,7R,8R,8aS)-7-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-8-yl)oxy]-3-decanol | C25H49N3O6Si | 详情 | 详情 | |
| (XXIX) | 49124 | (Z)-5-dodecenoic acid | C12H22O2 | 详情 | 详情 | |
| (XXX) | 59095 | (1R)-1-{2-[((4aR,6S,7R,8R,8aS)-7-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-8-yl)oxy]ethyl}octyl (Z)-5-dodecenoate | C37H69N3O7Si | 详情 | 详情 | |
| (XXXI) | 59096 | (1R)-1-(2-{[(2S,3R,4R,5S,6R)-3-azido-2-{[tert-butyl(dimethyl)silyl]oxy}-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]oxy}ethyl)octyl (Z)-5-dodecenoate | C34H65N3O7Si | 详情 | 详情 | |
| (XXXII) | 59097 | (1R)-1-(2-{[(2S,3R,4R,5S,6R)-3-azido-2-{[tert-butyl(dimethyl)silyl]oxy}-5-hydroxy-6-(methoxymethyl)tetrahydro-2H-pyran-4-yl]oxy}ethyl)octyl (Z)-5-dodecenoate | C35H67N3O7Si | 详情 | 详情 | |
| (XXXIII) | 59098 | (1R)-1-(2-{[(2S,3R,4R,5S,6R)-3-azido-2-{[tert-butyl(dimethyl)silyl]oxy}-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-methoxytetrahydro-2H-pyran-4-yl]oxy}ethyl)octyl (Z)-5-dodecenoate | C51H85N3O7Si2 | 详情 | 详情 | |
| (XXXIV) | 59099 | (1R)-1-(2-{[(2S,3R,4R,5S,6R)-3-azido-5-{[bis(allyloxy)phosphoryl]oxy}-2-{[tert-butyl(dimethyl)silyl]oxy}-6-(methoxymethyl)tetrahydro-2H-pyran-4-yl]oxy}ethyl)octyl (Z)-5-dodecenoate | C41H76N3O10PSi | 详情 | 详情 | |
| (XXXV) | 59100 | (1R)-1-(2-{[(3R,4R,5S,6R)-3-azido-5-{[bis(allyloxy)phosphoryl]oxy}-2-hydroxy-6-(methoxymethyl)tetrahydro-2H-pyran-4-yl]oxy}ethyl)octyl (Z)-5-dodecenoate | C35H62N3O10P | 详情 | 详情 |