|
【结 构 式】 
|
【分子编号】11102 【品名】(3S,4S)-3-Hexyl-4-[(2R)-2-(tetrahydro-2H-pyran-2-yloxy)tridecyl]-2-oxetanone 【CA登记号】 |
【 分 子 式 】C27H50O4 【 分 子 量 】438.6916 【元素组成】C 73.92% H 11.49% O 14.59% |
合成路线1
该中间体在本合成路线中的序号：(XLV)The oxetanone (XXIII) can also be obtained as follows: The condensation of 3(R)-benzyloxytetradecanal (XI) with octanoic acid (XXXIV) by means of lithium diisopropylamide gives 5(R)-benzyloxy-2-hexyl-3-hydroxyhexadecanoic acid (XXXV), which is deprotected by hydrogenation with H2 over Pd/C yielding the dihydroxy acid (XXXVI). The lactonization of (XXXVI) with p-toluenesulfonic acid affords the hydroxy lactone (XXXVII), which is oxidized with CrO3 H2SO4 to 3-hexyl-6(R)-undecyltetrahydropyran-2,4-dione (XXXVIII). Hydrogenation of (XXXVIII) with H2 over PtO2/C in ethylacetate gives (3S,4S,6R)-3-hexyl-4-hydroxy-6-undecyltetrahydropyran-2-one (XXXIX), which is benzylated with benzyl trichloroacetimidate to the 4-benzyloxy derivative (XL). Ring opening of (XL) with KOH in dioxane-water yields the hydroxy acid (XLI), which is esterified with benzyl bromide to the benzyl ester (XLII). The reaction of (XLII) with dihydropyran (DHP) by means of p-toluenesulfonic acid in dichloromethane affords (2S,3S,5R)-3-benzyloxy-2-hexyl-5-(tetrahydropyran-2-yloxy)hexadecanoic acid benzyl ester (XLIII), which is debenzylated by hydrogenation with H2 over Pd/C in THF to the hydroxy acid (XLIV). The cyclization of (XLIV) with p-toluenesulfonyl chloride in pyridine gives (3S,4S)-3-hexyl-4-[2(R)-(tetrahydropyran-2-yloxy)tridecyl]oxetan-2-one (XLV), which is finally deprotected with pyridinium p-toluenesulfonate in ethanol to afford the oxetanone (XXIII), already obtained in scheme 11082301a.
| 【1】 Barbier, P.; Schneider, F.; Synthesis of tetrahydrolipstatin and tetrahydroesterastin, compounds with beta-lactone moiety. Stereoselective hydrogenation of a beta-keto delta-lactone and conversion of the delta-lactone into a beta-lactone. J Org Chem 1988, 53, 6, 1218-21. |
| 【2】 Prous, J.; Mealy, N.; Castaner, J.; Orlistat. Drugs Fut 1994, 19, 11, 1003. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXIV) | 11091 | Octanoic acid | 124-07-2 | C8H16O2 | 详情 | 详情 |
| (XXXV) | 11092 | (5R)-5-(Benzyloxy)-2-hexyl-3-hydroxyhexadecanoic acid | C29H50O4 | 详情 | 详情 | |
| (XXXVI) | 11093 | (5R)-2-Hexyl-3,5-dihydroxyhexadecanoic acid | C22H44O4 | 详情 | 详情 | |
| (XXXVII) | 11094 | (6R)-3-Hexyl-4-hydroxy-6-undecyltetrahydro-2H-pyran-2-one | C22H42O3 | 详情 | 详情 | |
| (XXXVIII) | 11095 | (6R)-3-Hexyl-6-undecyldihydro-2H-pyran-2,4(3H)-dione | C22H40O3 | 详情 | 详情 | |
| (XXXIX) | 11096 | (3S,4S,6R)-3-Hexyl-4-hydroxy-6-undecyltetrahydro-2H-pyran-2-one | C22H42O3 | 详情 | 详情 | |
| (XL) | 11097 | (3S,4S,6R)-4-(Benzyloxy)-3-hexyl-6-undecyltetrahydro-2H-pyran-2-one | C29H48O3 | 详情 | 详情 | |
| (XLI) | 11098 | (2S,3S,5R)-3-(Benzyloxy)-2-hexyl-5-hydroxyhexadecanoic acid | C29H50O4 | 详情 | 详情 | |
| (XLII) | 11099 | benzyl (2S,3S,5R)-3-(benzyloxy)-2-hexyl-5-hydroxyhexadecanoate | C36H56O4 | 详情 | 详情 | |
| (XLIII) | 11100 | benzyl (2S,3S,5R)-3-(benzyloxy)-2-hexyl-5-(tetrahydro-2H-pyran-2-yloxy)hexadecanoate | C41H64O5 | 详情 | 详情 | |
| (XLIV) | 11101 | (2S,3S,5R)-2-Hexyl-3-hydroxy-5-(tetrahydro-2H-pyran-2-yloxy)hexadecanoic acid | C27H52O5 | 详情 | 详情 | |
| (XLV) | 11102 | (3S,4S)-3-Hexyl-4-[(2R)-2-(tetrahydro-2H-pyran-2-yloxy)tridecyl]-2-oxetanone | C27H50O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XLV)Oxetanone (XLV) can also be obtained as follows: The reaction of 3(R)-hydroxytetradecanoic acid tert-butyl ester (XLVI) with DHP and p-toluenesulfonic acid gives the corresponding tetrahydropyranyl ether (XLVII), which is reduced with dibutylaluminum hydride (DIBAL) in toluene to the aldehyde (XI), already obtained. Compound (XI) is condensed with 2-(p-toluenesulfinyl)acetic acid tert-butyl ester (XLVIII) by means of tert-butylmagnesium bromide in ether-THF affording the sulfinylhydroxy ester (II), which is treated with aluminum amalgam in THF-water to yield the hydroxy ester (L). The alkylation of (L) with hexyl bromide (LI) by means of butyllithium and diisopropylamine in THF-hexane affords 2-hexyl-3(S)-hydroxy-5(R)-(tetrahydropyranyloxy)hexadecanoic acid tert-butyl ester (LII), which is hydrolyzed with KOH in methanol to the corresponding free acid (LIII). The lactonization of (LIII) with pyridinium p-toluenesulfonate in hot ethanol affords oxetanone (LIV) as a diastereomeric mixture, which is separated by column chromatography, finally yielding oxetanone (XLV), previously obtained in scheme 11082301c.
| 【1】 Barbier, P.; Schneider, F.; Synthesis of tetrahydrolipstatin and tetrahydroesterastin, compounds with beta-lactone moiety. Stereoselective hydrogenation of a beta-keto delta-lactone and conversion of the delta-lactone into a beta-lactone. J Org Chem 1988, 53, 6, 1218-21. |
| 【2】 Prous, J.; Mealy, N.; Castaner, J.; Orlistat. Drugs Fut 1994, 19, 11, 1003. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IL) | 11106 | tert-butyl (3S,5R)-3-hydroxy-2-[(4-methylphenyl)sulfinyl]-5-(tetrahydro-2H-pyran-2-yloxy)hexadecanoate | C32H54O6S | 详情 | 详情 | |
| (XLV) | 11102 | (3S,4S)-3-Hexyl-4-[(2R)-2-(tetrahydro-2H-pyran-2-yloxy)tridecyl]-2-oxetanone | C27H50O4 | 详情 | 详情 | |
| (XLVI) | 11103 | tert-butyl (3R)-3-hydroxytetradecanoate | C18H36O3 | 详情 | 详情 | |
| (XLVII) | 11104 | tert-butyl (3R)-3-(tetrahydro-2H-pyran-2-yloxy)tetradecanoate | C23H44O4 | 详情 | 详情 | |
| (XLVIII) | 11105 | tert-butyl 2-[(4-methylphenyl)sulfinyl]acetate | C13H18O3S | 详情 | 详情 | |
| (L) | 11107 | tert-butyl (3S,5R)-3-hydroxy-5-(tetrahydro-2H-pyran-2-yloxy)hexadecanoate | C25H48O5 | 详情 | 详情 | |
| (LI) | 11108 | n-Hexyl bromide; 1-Bromohexane | 111-25-1 | C6H13Br | 详情 | 详情 |
| (LII) | 11109 | tert-butyl (3S,5R)-2-hexyl-3-hydroxy-5-(tetrahydro-2H-pyran-2-yloxy)hexadecanoate | C31H60O5 | 详情 | 详情 | |
| (LIII) | 11110 | (3S,5R)-2-Hexyl-3-hydroxy-5-(tetrahydro-2H-pyran-2-yloxy)hexadecanoic acid | C27H52O5 | 详情 | 详情 | |
| (LIV) | 63075 | (4S)-3-hexyl-4-[(2R)-2-(tetrahydro-2H-pyran-2-yloxy)tridecyl]-2-oxetanone | C27H50O4 | 详情 | 详情 |