|
【结 构 式】 
|
【分子编号】53799 【品名】(1R,4R)-4-[(5S,7R,8R,9S,10S,13R,14S,17R)-7-hydroxy-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-isopropylpentyl hydrogen sulfate 【CA登记号】n/a |
【 分 子 式 】C27H46O6S 【 分 子 量 】498.72464 【元素组成】C 65.03% H 9.3% O 19.25% S 6.43% |
合成路线1
该中间体在本合成路线中的序号：(CXXI)Treatment of the OH group of (CXIX) with SO3-pyridine provided sulfate (CXX). The benzoate ester of (CXX) was subsequently hydrolyzed under basic conditions to give (CXXI). Reductive amination of (CXXI) with the cyanodiamine (CXXII) afforded (CXXIII). The cyano group of (CXXIII) was finally reduced to the target amine by catalytic hydrogenation.
| 【1】 Zhang, X.; et al.; Synthesis of squalamine utilizing a readily accessible spermidine equivalent. J Org Chem 1998, 63, 23, 8599. |
| 【2】 Kinney, W.A.; Meckler, H.; Zhang, X.; Lee, N.; Jones, S.; Rao, M.N.; Bulliard, M. (Genaera Corp.); Stereoselective synthesis of 24-hydroxylated cpds. useful for the preparation of aminosterols, vitamin D analogs, and other cpds.. WO 9824800 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (CXIX) | 53797 | (5S,7R,8R,9S,10S,13R,14S,17R)-17-[(1R,4R)-4-hydroxy-1,5-dimethylhexyl]-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-7-yl benzoate | n/a | C34H50O4 | 详情 | 详情 |
| (CXX) | 53798 | (5S,7R,8R,9S,10S,13R,14S,17R)-17-[(1R,4R)-1,5-dimethyl-4-(sulfooxy)hexyl]-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-7-yl benzoate | n/a | C34H50O7S | 详情 | 详情 |
| (CXXI) | 53799 | (1R,4R)-4-[(5S,7R,8R,9S,10S,13R,14S,17R)-7-hydroxy-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-isopropylpentyl hydrogen sulfate | n/a | C27H46O6S | 详情 | 详情 |
| (CXXII) | 53800 | 4-[(3-aminopropyl)amino]butanenitrile | n/a | C7H15N3 | 详情 | 详情 |
| (CXXIII) | 53801 | (1R,4R)-4-[(3S,5R,7R,8R,9S,10S,13R,14S,17R)-3-({3-[(3-cyanopropyl)amino]propyl}amino)-7-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-isopropylpentyl hydrogen sulfate | n/a | C34H61N3O5S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(CXXI)In a further synthetic strategy, an azido precursor of spermidine (CXXX) was used in the reductive amination step. Condensation between 1,3-diaminopropane (CXXIV) and 4-chloro-1-butanol (CXXV) provided the diamino alcohol (CXXVI). Protection of the amino groups of (CXXVI) with di-tert-butyl dicarbonate yielded alcohol (CXXVII), which was converted to mesylate (CXXVIII) by treatment with methanesulfonyl chloride and triethylamine. Subsequent mesylate displacement in (CXXVIII) with NaN3 in DMF furnished the di-Boc-protected azide (CXXIX). The Boc protecting groups of (CXXIX) were then removed by treatment with HCl to give the desired diamino azide (CXXX). Reductive amination of the 3-keto steroid (CXXI) with amine (CXXX) yielded the 3-beta amino steroid (CXXXI). The azido group of (CXXXI) was finally reduced to the title triamino compound by catalytic hydrogenation over Raney-Ni.
| 【1】 Weis, A.L.; et al.; Synthesis of an azido spermidine equivalent. Tetrahedron Lett 1999, 40, 26, 4863. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (CXXIV) | 19331 | 3-aminopropylamine; 1,3-propanediamine | 109-76-2 | C3H10N2 | 详情 | 详情 |
| (CXXV) | 19490 | 3-chloro-1-propanol | 627-30-5 | C3H7ClO | 详情 | 详情 |
| (CXXI) | 53799 | (1R,4R)-4-[(5S,7R,8R,9S,10S,13R,14S,17R)-7-hydroxy-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-isopropylpentyl hydrogen sulfate | n/a | C27H46O6S | 详情 | 详情 |
| (CXXVI) | 53802 | 3-[(3-aminopropyl)amino]-1-propanol | n/a | C6H16N2O | 详情 | 详情 |
| (CXXVII) | 53803 | tert-butyl 3-[(tert-butoxycarbonyl)amino]propyl(3-hydroxypropyl)carbamate | n/a | C16H32N2O5 | 详情 | 详情 |
| (CXXVIII) | 53804 | 3-((tert-butoxycarbonyl){3-[(tert-butoxycarbonyl)amino]propyl}amino)propyl methanesulfonate | n/a | C17H34N2O7S | 详情 | 详情 |
| (CXXIX) | 53805 | tert-butyl 3-azidopropyl{3-[(tert-butoxycarbonyl)amino]propyl}carbamate | n/a | C16H31N5O4 | 详情 | 详情 |
| (CXXX) | 53806 | N-(3-aminopropyl)-N-(3-azidopropyl)amine; N1-(3-azidopropyl)-1,3-propanediamine | n/a | C6H15N5 | 详情 | 详情 |
| (CXXXII) | 53807 | (1R,4R)-4-[(3S,5R,7R,8R,9S,10S,13R,14S,17R)-3-({3-[(3-azidopropyl)amino]propyl}amino)-7-hydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-isopropylpentyl hydrogen sulfate | n/a | C33H61N5O5S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(CXXI)Steroid (CV) was treated with the fungal species Diplodia gossipina to yield the 7-hydroxylated compound (CXXXII) as a fermentation metabolite. Reduction of enone (CXXXII) by lithium in liquid ammonia afforded the saturated ketone (CXXXIII), which was subsequently protected as the ethylene ketal (CXXXIV) by treatment with ethylene glycol and chlorotrimethylsilane. Selective oxidation of the C-22 alcohol group of (CXXXIV) with NaOCl in the presence of TEMPO provided aldehyde (CXXXV). Wadsworth-Emmons condensation of (CXXXV) with phosphonate (CXV) gave enone (CXXXVI). Stereoselective reduction of (CXXXVI) to the 24-(S)-alcohol (CXXXVII) was achieved by treatment with borane-tetrahydrofuran complex in the presence of the chiral catalyst (R)-MeCBS. After catalytic hydrogenation of the double bond of (CXXXVII), the resultant ketal (CXXXVIII) was hydrolyzed to ketone (CXXXIX) under acidic conditions. Sulfation of (CXXXIX) by means of sulfur trioxide-pyridine furnished the key precursor (CXXI), which was then reductively aminated as in the precedent Scheme
| 【1】 Kinney, W.A.; et al.; A short formal synthesis of squalamine from a microbial metabolite. Org Lett 2000, 2, 19, 2921. |
| 【2】 Kinney, W.A.; Zhang, X.; Michalak, R. (Genaera Corp.); A process for the preparation of 7alpha-hydroxy 3-aminosubstd. sterols using intermediates with an unprotected 7alpha-hydroxy group. WO 0179255 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (CV) | 53783 | (8S,9S,10R,13S,14S,17R)-17-[(1S)-2-hydroxy-1-methylethyl]-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one | n/a | C22H34O2 | 详情 | 详情 |
| (CXV) | 53793 | diethyl 3-methyl-2-oxobutylphosphonate | n/a | C9H19O4P | 详情 | 详情 |
| (CXXI) | 53799 | (1R,4R)-4-[(5S,7R,8R,9S,10S,13R,14S,17R)-7-hydroxy-10,13-dimethyl-3-oxohexadecahydro-1H-cyclopenta[a]phenanthren-17-yl]-1-isopropylpentyl hydrogen sulfate | n/a | C27H46O6S | 详情 | 详情 |
| (CXXXII) | 53808 | (7R,8S,9S,10R,13R,14S,17R)-7-hydroxy-17-[(1S)-2-hydroxy-1-methylethyl]-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-3H-cyclopenta[a]phenanthren-3-one | n/a | C22H34O3 | 详情 | 详情 |
| (CXXXIII) | 53809 | (5S,7R,8R,9S,10S,13R,14S,17R)-7-hydroxy-17-[(1S)-2-hydroxy-1-methylethyl]-10,13-dimethylhexadecahydro-3H-cyclopenta[a]phenanthren-3-one | n/a | C22H36O3 | 详情 | 详情 |
| (CXXXIV) | 53810 | n/a | C24H40O4 | 详情 | 详情 | |
| (CXXXV) | 53811 | n/a | C24H38O4 | 详情 | 详情 | |
| (CXXXVI) | 53812 | n/a | C29H46O4 | 详情 | 详情 | |
| (CXXXVII) | 53813 | n/a | C29H48O4 | 详情 | 详情 | |
| (CXXXVIII) | 53814 | n/a | C29H50O4 | 详情 | 详情 | |
| (CXXXIX) | 53815 | (5S,7R,8R,9S,10S,13R,14S,17R)-7-hydroxy-17-[(1R,4R)-4-hydroxy-1,5-dimethylhexyl]-10,13-dimethylhexadecahydro-3H-cyclopenta[a]phenanthren-3-one | n/a | C27H46O3 | 详情 | 详情 |