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【结 构 式】 
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【分子编号】49124 【品名】(Z)-5-dodecenoic acid 【CA登记号】 |
【 分 子 式 】C12H22O2 【 分 子 量 】198.30548 【元素组成】C 72.68% H 11.18% O 16.14% |
合成路线1
该中间体在本合成路线中的序号：(XXIX)The precursor cis-dodec-5-enoic acid (XXIX) was prepared as shown in Scheme 4. The lithium acetylide of 1-octyne (XXIV) was alkylated with 1,3-diiodopropane (XXV) to give the iodoalkyne (XXVI). Displacement of the iodide of (XXVI) with KCN in hot DMSO provided nitrile (XXVII), which was hydrolyzed to the corresponding carboxylic acid (XXVIII) employing KOH in ethylene glycol at 140 C. Partial hydrogenation of the triple bond in the presence of poisoned Lindlar catalyst furnished the (Z)-olefin (XXIX).
| 【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 |
|---|---|---|---|---|---|---|
| (XXIV) | 59091 | 1-octyne | C8H14 | 详情 | 详情 | |
| (XXV) | 42364 | 1,3-diiodopropane | 627-31-6 | C3H6I2 | 详情 | 详情 |
| (XXVI) | 59092 | 1-iodo-4-undecyne | C11H19I | 详情 | 详情 | |
| (XXVII) | 59093 | 5-dodecynenitrile | C12H19N | 详情 | 详情 | |
| (XXVIII) | 59094 | 5-dodecynoic acid | C12H20O2 | 详情 | 详情 | |
| (XXIX) | 49124 | (Z)-5-dodecenoic acid | C12H22O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXIX)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 |
合成路线3
该中间体在本合成路线中的序号：(VII)2-Amino-1,3-propanediol (I) was reacted with in situ generated trifluoromethanesulfonyl azide, and the resulting 2-azido compound was purified by chromatography after conversion to the diacetate ester (II). Deacetylation of (II) with sodium methoxide gave 2-azido-1,3-propanediol (III), which was condensed with tosylate (IV) in the presence of NaH to produce the dihydroxyether (V). The primary alcohol group of (V) was then protected as the mono-silyl derivative (VI) employing tert-butyldiphenylsilyl chloride. After acylation of the free hydroxyl group of (VI) with the unsaturated acid (VII), the resulting ester (VIII) was desilylated by using HF in acetonitrile to yield alcohol (IX). The phosphorylating reagent (XII) was prepared by treatment of allyl phosphorodiamidite (X) with N-Boc-ethanolamine (XI). Phosphitylation of alcohol (IX) with phosphoramidite (XII), followed by oxidation of the intermediate phosphite ester with oxone , furnished phosphate (XIII). The azido group of (XIII) was then reduced to the corresponding amine (XIV) by employing (PhS)2Sn.
| 【1】 Rossignol, D.P.; Ishizaka, S.T.; Nault, A.; Lewis, M.; Rose, J.; McGuiness, P.; Hawkins, L.D. (Eisai Co., Ltd.); Immunological adjuvant cpd.. EP 1147117; US 6290973; WO 0044758 . |
| 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) | 23333 | 2-amino-1,3-propanediol; serinol | 534-03-2 | C3H9NO2 | 详情 | 详情 |
| (II) | 49119 | 3-(acetoxy)-2-azidopropyl acetate | C7H11N3O4 | 详情 | 详情 | |
| (III) | 49120 | 2-azido-1,3-propanediol | C3H7N3O2 | 详情 | 详情 | |
| (IV) | 49121 | (3R)-3-hydroxydecyl 4-methylbenzenesulfonate | C17H28O4S | 详情 | 详情 | |
| (V) | 49122 | (3R)-1-(2-azido-3-hydroxypropoxy)-3-decanol | C13H27N3O3 | 详情 | 详情 | |
| (VI) | 49123 | (3R)-1-(2-azido-3-[[tert-butyl(diphenyl)silyl]oxy]propoxy)-3-decanol | C29H45N3O3Si | 详情 | 详情 | |
| (VII) | 49124 | (Z)-5-dodecenoic acid | C12H22O2 | 详情 | 详情 | |
| (VIII) | 49125 | (1R)-1-[2-(2-azido-3-[[tert-butyl(diphenyl)silyl]oxy]propoxy)ethyl]octyl (Z)-5-dodecenoate | C41H65N3O4Si | 详情 | 详情 | |
| (IX) | 49126 | (1R)-1-[2-(2-azido-3-hydroxypropoxy)ethyl]octyl (Z)-5-dodecenoate | C25H47N3O4 | 详情 | 详情 | |
| (X) | 49127 | C15H33N2OP | 详情 | 详情 | ||
| (XI) | 32500 | tert-butyl 2-hydroxyethylcarbamate | 26690-80-2 | C7H15NO3 | 详情 | 详情 |
| (XII) | 49128 | C16H33N2O4P | 详情 | 详情 | ||
| (XIII) | 49129 | (1R)-9-(allyloxy)-6-azido-1-heptyl-16,16-dimethyl-9,14-dioxo-4,8,10,15-tetraoxa-13-aza-9lambda(5)-phosphaheptadec-1-yl (Z)-5-dodecenoate | C35H65N4O9P | 详情 | 详情 | |
| (XIV) | 49130 | (1R)-9-(allyloxy)-6-amino-1-heptyl-16,16-dimethyl-9,14-dioxo-4,8,10,15-tetraoxa-13-aza-9lambda(5)-phosphaheptadec-1-yl (Z)-5-dodecenoate | C35H67N2O9P | 详情 | 详情 |