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【结 构 式】 
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【分子编号】10027 【品名】Benzyl (1S)-1-[[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl]-3-butenyl(benzyl)carbamate 【CA登记号】 |
【 分 子 式 】C28H35NO6 【 分 子 量 】481.58904 【元素组成】C 69.83% H 7.33% N 2.91% O 19.93% |
合成路线1
该中间体在本合成路线中的序号：(XII)A total synthesis of (+)-sinefungin has been reported: The reaction of D-ribose (I) with acetone and methanol by means of CuSO4 and a catalytic amount of H2SO4 gives methyl 2,3-O-isopropylidene-beta-D-ribofuranoside (II), which is oxidized to the aldehyde (III) with oxalyl chloride in DMSO/dichloromethane. The Wittig condensation of (III) with triethyl phosphonoacetate (IV) by means of NaH in THF affords the unsaturated ester (V), which is hydrogenated with H2 over Pd/C in ethyl acetate and saponified with LiOH in methanol/water to give the propionic acid (VI). The condensation of (VI) with the chiral oxazolidone (VII) by means of pivaloyl chloride and triethylamine in THF yields the oxalidone (VIII). The stereoselective alkylation of (VIII) with allyl bromide by means of lithium hexamethyldisylazide in THF affords the 2(S)-allyl derivative (IX), which is hydrolyzed with LiOH in THF/water to the corresponding free acid (X). The Curtius degradation of the acid (X) by means of diphenyl phosphorazidate and benzyl alcohol gives the corresponding benzyloxycarbonylamino derivative (XI), which is benzylated with benzyl bromide to the fully protected compound (XII). The ozonolysis of the allyl double bond of (XII) with O3 in methanol/dichloromethane yields the aldehyde (XIII).
| 【1】 Ghosh, A.K.; Liu, W.M.; Total synthesis of (+)-sinefungin. J Org Chem 1996, 61, 18, 6175. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 32112 | 3-iodo-1-propene;3-iodo-propen;allyl iodide | 556-56-9 | C3H5I | 详情 | 详情 | |
| (I) | 10016 | D-Ribose; (3R,4S,5R)-5-(Hydroxymethyl)tetrahydro-2,3,4-furantriol; (2R,3R,4R)-2,3,4,5-Tetrahydroxypentanal | 50-69-1 | C5H10O5 | 详情 | 详情 |
| (II) | 10017 | [(3aR,4R,6R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methanol | 4099-85-8 | C9H16O5 | 详情 | 详情 |
| (III) | 10018 | (3aR,4S,6R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbaldehyde | C9H14O5 | 详情 | 详情 | |
| (IV) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (V) | 10020 | Ethyl (E)-3-[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-2-propenoate | C13H20O6 | 详情 | 详情 | |
| (VI) | 10021 | 3-[(3aR,4R,6R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]propionic acid | C11H18O6 | 详情 | 详情 | |
| (VII) | 10022 | [(3aS,8aR)-2-Oxo-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]lithium | C10H8LiNO2 | 详情 | 详情 | |
| (VIII) | 10023 | (3aS,8aR)-3-[3-[(3aR,4R,6R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]propanoyl]-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d][1,3]oxazol-2-one | C21H25NO7 | 详情 | 详情 | |
| (IX) | 10024 | (3aS,8aR)-3-((2S)-2-[[(3aR,4R,6R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl]-4-pentenoyl)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d][1,3]oxazol-2-one | C24H29NO7 | 详情 | 详情 | |
| (X) | 10025 | (2S)-2-[[(3aR,4R,6R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl]-4-pentenoic acid | C14H22O6 | 详情 | 详情 | |
| (XI) | 10026 | Benzyl N-((1S)-1-[[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl]-3-butenyl)carbamate | 180776-29-8 | C21H29NO6 | 详情 | 详情 |
| (XII) | 10027 | Benzyl (1S)-1-[[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl]-3-butenyl(benzyl)carbamate | C28H35NO6 | 详情 | 详情 | |
| (XIII) | 10028 | Benzyl (1R)-1-[[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl]-3-oxopropyl(benzyl)carbamate | C27H33NO7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The chlorination of 3-acetylpyridine (I) with N-chlorosuccinimide (NCS) in acetic acid gives 3-(2-chloroacetyl)pyridine (II), which is reduced with (-)-B-chlorodiisopinocampheylborane [(-)-DIP-Cl] yielding the chiral chloroethanol (III). The epoxidation of (III) with K2CO3 in refluxing acetone affords the chiral epoxide (IV), which is opened with 4-(2-aminoethyl)aniline (V) in refluxing methanol giving the chiral aminoethanol (VI). The protection of the aliphatic amino group of (VI) with di-tert-butyl dicarbonate yields the carbamate (VII), which is finally condensed with the sulfonyl chloride (VIII) by means of pyridine in dichloromethane and deprotected with TFA in the same solvent.
| 【1】 Colandrea, V.J.; Naylor, E.M.; Parmee, E.R.; et al.; Human beta3 adrenergic receptor agonists containing imidazolidinone and imidazolone benzenesulfonamides. Bioorg Med Chem Lett 1999, 9, 5, 755. |
| 【2】 Fisher, M.H.; Naylor, E.M.; Ok, D.; Weber, A.E.; Shih, T.; Ok, H. (Merck & Co., Inc.); Substd. sulfonamides as selective beta3 agonists for the treatment of diabetes and obesity. EP 0757674; JP 1997512275; US 5541197; US 5561142; WO 9529159 . |
| 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) | 10027 | Benzyl (1S)-1-[[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl]-3-butenyl(benzyl)carbamate | C28H35NO6 | 详情 | 详情 | |
| (II) | 26549 | 2-chloro-1-(3-pyridinyl)-1-ethanone | C7H6ClNO | 详情 | 详情 | |
| (III) | 26550 | (1R)-2-chloro-1-(3-pyridinyl)-1-ethanol | C7H8ClNO | 详情 | 详情 | |
| (IV) | 26551 | 3-[(2R)oxiranyl]pyridine | C7H7NO | 详情 | 详情 | |
| (V) | 18961 | 4-(2-aminoethyl)aniline; 4-(2-aminoethyl)phenylamine | 13472-00-9 | C8H12N2 | 详情 | 详情 |
| (VI) | 26552 | (1R)-2-[(4-aminophenethyl)amino]-1-(3-pyridinyl)-1-ethanol | C15H19N3O | 详情 | 详情 | |
| (VII) | 30449 | (1R)-2-[(4-aminophenethyl)[1-(tert-butoxy)vinyl]amino]-1-(3-pyridinyl)-1-ethanol | C21H29N3O2 | 详情 | 详情 | |
| (VIII) | 30450 | 4-[3-(3-cyclopentylpropyl)-2-oxo-1-imidazolidinyl]benzenesulfonyl chloride | C17H23ClN2O3S | 详情 | 详情 |