|
【结 构 式】 
|
【药物名称】 【化学名称】(5Z,7E)-(3S,23S,25R)-1,3beta,25-Trihydroxy-9,10-seco-5,7,10(19)-cholestatrieno-26,23-lactone 【CA登记号】81203-50-1, 75519-08-3 (stereoisomer) 【 分 子 式 】C27H40O5 【 分 子 量 】444.61685 |
【开发单位】Okayama University (Originator), Roche (Originator) 【药理作用】Bone Diseases, Treatment of, METABOLIC DRUGS, Treatment of Osteoporosis, Vitamin D Analogs |
合成路线1
The 1alpha,3beta-diol (Ia) derived from ergosterol was used as the starting material. The alcohol (Ia) was converted to methoxymethyl derivative (Ib) by reaction with chloromethyl methyl ether (4 eq) in dichloromethane for 16 h, which was oxidized with 3 eq of N-methylmorpholine N-oxide in the presence of osmium tetroxide (0.5 eq) in tert-butanol:tetrahydrofuran:water (10:3:1) for 4 h at room temperature to afford the 22,23-diol. The resulting diol was then cleaved by sodium metaperiodate (2.5 eq) in aqueous tetrahydrofuran (5 h, room temperature) to give the 22-aldehyde (IIa) in 30% yield from (Ia). Reaction of (IIa) with 6 eq of vinyl magnesium bromide (tetrahydrofuran, 0 C to room temperature, 2 h) gave the allyl alcohol (IIb) as a mixture of C-22 diastereoisomers. The Claisen reaction of (IIb) with 10 eq of triethyl orthopropionate and a catalytic amount of propionic acid (benzene reflux, 16 h) gave gamma,delta-unsaturated ester (IIa) in 70% yield from (IIa). The lithium enolate of (IIIa) generated by lithium N-isopropylcyclohexylamide in tetrahydrofuran at -78 C was reacted with oxygen for 1 h and subsequent reduction with triethyl phosphine at -78 C gave the 25-hydroxy ester (IIIb) in 87% yield. (IIIb) was shown to be a 1:1 mixture of C-25 diastereoisomers by high-pressure liquid chromatographic (HPLC) analysis. Alkaline hydrolysis (KOH, methanol, 60 C, 2.5 h) of the ester gave the hydroxy acid (IIIc) in 87% yield. (IIIc) was treated with 6 eq of I2 in dichloromethane in the presence of pyridine (15 eq) to give the iodolactone (IVa) in 74% yield, which was separated into isomers by silica gel column chromatography in a 1.5:1 ratio.
| 【1】 Morris, D.S.; Norris, A.F.; Williams, D.H.; Structure and synthesis of 25-hydroxycholecalciferol-26,23-lactone, a metabolite of vitamin D3. J Org Chem 1981, 46, 3422-28. |
| 【2】 Seino, Y.; Ishizuka, S.; 23(S),25(R)-1alpha,25-(OH)2-D3-26,23-Lactone. Drugs Fut 1992, 17, 8, 655. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 16524 | bromo(vinyl)magnesium | 1826-67-1 | C2H3BrMg | 详情 | 详情 |
| (D) | 20178 | propionic acid | 79-09-4 | C3H6O2 | 详情 | 详情 |
| (Ia) | 31263 | (1S,8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-[(1R,2E,4R)-1,4,5-trimethyl-2-hexenyl]-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-1,3-diol | C28H46O2 | 详情 | 详情 | |
| (A) | 31264 | 4-methylmorpholin-4-ium-4-olate | C5H11NO2 | 详情 | 详情 | |
| (Ib) | 31265 | (1S,8S,9S,10R,13R,14S,17R)-1,3-bis(methoxymethoxy)-10,13-dimethyl-17-[(1R,2E,4R)-1,4,5-trimethyl-2-hexenyl]-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene; (1S,8S,9S,10R,13R,14S,17R)-1-(methoxymethoxy)-10,13-dimethyl-17-[(1R,2E,4R)-1,4,5-trimethyl-2-hexenyl]-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl methoxymethyl ether | C32H54O4 | 详情 | 详情 | |
| (IIa) | 31266 | (2S)-2-[(1S,8S,9S,10R,13S,14S,17R)-1,3-bis(methoxymethoxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]propanal | C26H42O5 | 详情 | 详情 | |
| (IIb) | 31267 | (4S)-4-[(1S,8S,9S,10R,13S,14S,17R)-1,3-bis(methoxymethoxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-penten-3-ol | C28H46O5 | 详情 | 详情 | |
| (E) | 31268 | N-Cyclohexyl-N-methylamide lithium salt | C9H18LiN | 详情 | 详情 | |
| (IIIa) | 31269 | ethyl (E,6R)-6-[(1S,8S,9S,10R,13R,14S,17R)-1,3-bis(methoxymethoxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-methyl-4-heptenoate | C33H54O6 | 详情 | 详情 | |
| (IIIb) | 31270 | ethyl (E,6R)-6-[(1S,8S,9S,10R,13R,14S,17R)-1,3-bis(methoxymethoxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-hydroxy-2-methyl-4-heptenoate | C33H54O7 | 详情 | 详情 | |
| (IIIc) | 31271 | (E,6R)-6-[(1S,8S,9S,10R,13R,14S,17R)-1,3-bis(methoxymethoxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-hydroxy-2-methyl-4-heptenoic acid | C31H50O7 | 详情 | 详情 | |
| (IVa) | 31272 | 5-[(2S)-2-[(1S,8S,9S,10R,13S,14S,17R)-1,3-bis(methoxymethoxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-iodopropyl]-3-hydroxy-3-methyldihydro-2(3H)-furanone | C31H49IO7 | 详情 | 详情 | |
| (C) | 10395 | 1,1,1-Triethoxypropane; 1,1-Diethoxypropyl ethyl ether; Triethyl orthopropionate | 115-80-0 | C9H20O3 | 详情 | 详情 |
合成路线2
The less polar major isomer (IVa) was reduced to lactone (IVb) with 10 eq of tri-n-butyltin hydride (tetrahydrofuran, room temperature, 4 h) in 88% yield. Treatment of the lactone (IVb) with a catalytic amount of HCl in methanol at 50 C for 5 h gave the diol (IVc) in 88% yield. Reaction of (IVc) with ethyl chloroformate (16 eq) in the presence of 4-dimethylaminopyridine (17 eq) at room temperature for 15 h afforded ethyl carbonate (IVd) in 82% yield. Allylic bromination of (IVd) with 0.6 eq of 1,3-dibromo-5,5-dimethylhydantoin in n-hexane under reflux followed by dehydrobromination with collidine in refluxing xylene gave the 5,7-diene (V) as the major product. Alkaline hydrolysis (KOH, methanol, room temperature, 15 h) and purification by preparative thin-layer chromatography (TLC) gave the 5,7-diene in 53% yield from (IVd).
| 【1】 Morris, D.S.; Norris, A.F.; Williams, D.H.; Structure and synthesis of 25-hydroxycholecalciferol-26,23-lactone, a metabolite of vitamin D3. J Org Chem 1981, 46, 3422-28. |
| 【2】 Seino, Y.; Ishizuka, S.; 23(S),25(R)-1alpha,25-(OH)2-D3-26,23-Lactone. Drugs Fut 1992, 17, 8, 655. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IVa) | 31272 | 5-[(2S)-2-[(1S,8S,9S,10R,13S,14S,17R)-1,3-bis(methoxymethoxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-iodopropyl]-3-hydroxy-3-methyldihydro-2(3H)-furanone | C31H49IO7 | 详情 | 详情 | |
| (IVb) | 31273 | 5-[(2R)-2-[(1S,8S,9S,10R,13R,14S,17R)-1,3-bis(methoxymethoxy)-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]propyl]-3-hydroxy-3-methyldihydro-2(3H)-furanone | C31H50O7 | 详情 | 详情 | |
| (IVc) | 31274 | 5-[(2R)-2-[(1S,8S,9S,10R,13R,14S,17R)-1,3-dihydroxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]propyl]-3-hydroxy-3-methyldihydro-2(3H)-furanone | C27H42O5 | 详情 | 详情 | |
| (F) | 31275 | N,N-dimethyl-N-(4-pyridinyl)amine; N,N-dimethyl-4-pyridinamine | 1122-58-3 | C7H10N2 | 详情 | 详情 |
| (IVd) | 31276 | (1S,8S,9S,10R,13R,14S,17R)-1-[(ethoxycarbonyl)oxy]-17-[(1R)-2-(4-hydroxy-4-methyl-5-oxotetrahydro-2-furanyl)-1-methylethyl]-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl ethyl carbonate | C33H50O9 | 详情 | 详情 | |
| (G) | 31277 | 1,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione | 77-48-5 | C5H6Br2N2O2 | 详情 | 详情 |
| (V) | 31278 | ethyl (1S,9S,10S,13R,14R,17R)-3-[(ethoxycarbonyl)oxy]-17-[(1R)-2-(4-hydroxy-4-methyl-5-oxotetrahydro-2-furanyl)-1-methylethyl]-10,13-dimethyl-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthrene-1-carboxylate | C33H48O8 | 详情 | 详情 |