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【结 构 式】 
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【分子编号】14673 【品名】N-[(1S,2S,3S,4R)-3-(2-oxoethyl)bicyclo[2.2.1]hept-2-yl]benzenesulfonamide 【CA登记号】 |
【 分 子 式 】C15H19NO3S 【 分 子 量 】293.3868 【元素组成】C 61.41% H 6.53% N 4.77% O 16.36% S 10.93% |
合成路线1
该中间体在本合成路线中的序号：(XIII)The condensation of bicyclo[2.2.1]hept-5-ene-2,3endo-dicarboxylic acid anhydride (I) with 2(R)-hydroxy-2-phenylacetic acid benzyl ester (II) by means of BuLi in THF gives the unsaturated hemiester (III), which is reduced with H2 over Pd/C in methanol yielding the saturated hemiester (IV). The trans-esterification of (IV) with NaOMe in refluxing methanol affords (1R,2S,3S,4S)-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-monomethyl ester (V), which by reaction first with ethyl chloroformate and triethylamine and then with ammonia is converted into the amide ester (VI). Hydrolysis of (VI) with KOH gives (1R,2S,3S,4S)-3-carbamoylbicyclo[2.2.1]heptane-2-carboxylic acid (VII), which by degradation with NaOCl and NaOH is converted to the corresponding amino acid (VIII). The acylation of (VIII) with benzenesulfonyl chloride yields (1R,2S,3S,4S)-3-(phenylsulfonamido)bicyclo[2.2.1]heptane-2-carboxylic acid (IX), which is reduced with NaBH4 in dimethoxyethane giving the corresponding methanol (X). The oxidation of (X) with oxalyl chloride in dichloromethane-DMSO affords the aldehyde (XI), which by a Wittig condensation with methoxymethyl triphenylphosphonium chloride and t-BuOK in THF is converted to the ether (XII). The hydrolysis of (XII) with formic acid gives the corresponding aldehyde (XIII), which by a new Wittig condensation with 4-carboxybutyl triphenylphosphonium bromide and t-BuOK in THF gives (+)-[1R,2S(5Z),3S,4S]-7-[3-(phenylsulfonamido)bicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (XIV). Finally, this compound is converted into the corresponding calcium salt with CaCl2 in water.
| 【1】 Castaner, J.; Prous, J.; Mealy, N.; S-1452. Drugs Fut 1994, 19, 11, 1011. |
| 【2】 Otani, M.; Thromboxane A2 receptor antagonist S-1452 and synthesis and biological activity of related compounds. 112th Annu Meet Pharmaceut Soc Jpn (March 29-31, Fukuoka) 1992, Abst 30ZF 3-1. |
| 【3】 Narisada, M.; Matsuura, T.; Ohtani, M.; Watanabe, F.; Enantioselective synthesis of S-1452, an orally active potent thromboxane A2 receptor antagonist. J Org Chem 1991, 56, 6, 2122-7. |
| 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) | 11184 | (1R,2S,6R,7S)-4-Oxatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione | C9H8O3 | 详情 | 详情 | |
| (II) | 14662 | 2(R)-hydroxy-2-phenylacetic acid benzyl ester lithium salt | C15H13LiO3 | 详情 | 详情 | |
| (III) | 14663 | (1R,2S,3R,4S)-3-([[(1R)-2-(benzyloxy)-2-oxo-1-phenylethyl]oxy]carbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid | C24H22O6 | 详情 | 详情 | |
| (IV) | 14664 | (1S,2S,3R,4R)-3-([[(R)-carboxy(phenyl)methyl]oxy]carbonyl)bicyclo[2.2.1]heptane-2-carboxylic acid | C17H18O6 | 详情 | 详情 | |
| (V) | 14665 | (1S,2S,3S,4R)-3-(methoxycarbonyl)bicyclo[2.2.1]heptane-2-carboxylic acid | C10H14O4 | 详情 | 详情 | |
| (VI) | 14666 | methyl (1R,2S,3S,4S)-3-(aminocarbonyl)bicyclo[2.2.1]heptane-2-carboxylate | C10H15NO3 | 详情 | 详情 | |
| (VII) | 14667 | (1R,2S,3S,4S)-3-(aminocarbonyl)bicyclo[2.2.1]heptane-2-carboxylic acid | C9H13NO3 | 详情 | 详情 | |
| (VIII) | 14668 | (1R,2S,3S,4S)-3-aminobicyclo[2.2.1]heptane-2-carboxylic acid | 88330-32-9 | C8H13NO2 | 详情 | 详情 |
| (IX) | 14669 | (1R,2S,3S,4S)-3-[(phenylsulfonyl)amino]bicyclo[2.2.1]heptane-2-carboxylic acid | C14H17NO4S | 详情 | 详情 | |
| (X) | 14670 | N-[(1S,2S,3S,4R)-3-(hydroxymethyl)bicyclo[2.2.1]hept-2-yl]benzenesulfonamide | C14H19NO3S | 详情 | 详情 | |
| (XI) | 14671 | N-[(1S,2S,3S,4R)-3-formylbicyclo[2.2.1]hept-2-yl]benzenesulfonamide | C14H17NO3S | 详情 | 详情 | |
| (XII) | 14672 | N-[(1S,2S,3R,4R)-3-[(E)-2-methoxyethenyl]bicyclo[2.2.1]hept-2-yl]benzenesulfonamide | C16H21NO3S | 详情 | 详情 | |
| (XIII) | 14673 | N-[(1S,2S,3S,4R)-3-(2-oxoethyl)bicyclo[2.2.1]hept-2-yl]benzenesulfonamide | C15H19NO3S | 详情 | 详情 | |
| (XIV) | 14674 | (Z)-7-[(1R,2S,3S,4S)-3-[(phenylsulfonyl)amino]bicyclo[2.2.1]hept-2-yl]-5-heptenoic acid | C20H27NO4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XLII)The condensation of propane-1,3-diol (XXV) with benzaldehyde by means of p-toluenesulfonic acid gives the corresponding cyclic acetal (XXVI), which is reduced with diisobutylaluminum hydride in toluene yielding 3-benzoyloxy-1-propanol (XXVII). The oxidation of (XXVII) with oxalyl chloride as before affords the corresponding aldehyde (XXVIII), which is submitted to a Wittig condensation with 2-(triphenylphosphoranylidene)acetic acid methyl ester (XXIX) giving (E)-5-benzyloxy-2-pentenoic acid methyl ester (XXX). The hydrolysis of (XXX) with NaOH in THF-water yields the corresponding acid (XXXI), which is condensed with pivaloyl chloride (XXXII) to afford the mixed anhydride (XXXIII). The condensation of (XXXIII) with 4(S)-benzyloxazolidin-2-one (XXXIV) by means of BuLi in THF gives 4(S)-benzyl-3-[5-benzyloxy-2(E)-pentenoyl]oxazolidin-2-one (XXXV), which is submitted to a Diels-Alder cycloaddition with cyclopentadiene (XXXVI) to yield 4-benzyl-3-[(3R,4R,5S,6S)-5-(2-benzyloxyethyl)bicyclo[2.2.1]hept-2-en-4-ylcarbonyl]oxazolidin-2-one (XXXVII). Hydrogenation of (XXXVII) with H2 over Pt in ethylacetate, followed by hydrolysis with H2O2 and LiOH affords (1R,2R,3S,4S)-3-(2-benzyloxyethyl)bicyclo[2.2.1]heptane-2-carboxylic acid (XXXVIII). The formation of the corresponding azide with ethyl chloroformate and sodium azide followed by degradation in refluxing toluene gives the amine (XXXIX), which is acylated with benzenesulfonyl chloride as before yielding the sulfonamide (XL). The deprotection of (XL) by hydrogenolysis with H2 over Pd/C in ethanol affords the substituted ethanol (XLI). Oxidation of (XLI) with oxalyl chloride as before gives the aldehyde (XLII), which is finally submitted to a Wittig condensation with 4-carboxybutyl triphenylphosphonium bromide and t-BuOK to yield acid (XIV) enantiomerically pure, already obtained.
| 【1】 Wong and F.F. Sun (Eds.), Raven Press, Ltd., New York 1989, 19, 659-62. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIV) | 14674 | (Z)-7-[(1R,2S,3S,4S)-3-[(phenylsulfonyl)amino]bicyclo[2.2.1]hept-2-yl]-5-heptenoic acid | C20H27NO4S | 详情 | 详情 | |
| (XXV) | 14685 | 1,3-propanediol; Trimethylene Glycol | 504-63-2 | C3H8O2 | 详情 | 详情 |
| (XXVI) | 14686 | 2-phenyl-1,3-dioxane | C10H12O2 | 详情 | 详情 | |
| (XXVII) | 14687 | 3-(benzyloxy)-1-propanol; 3-(Benzyloxy)propanol | 4799-68-2 | C10H14O2 | 详情 | 详情 |
| (XXVIII) | 14688 | 3-(benzyloxy)propanal | C10H12O2 | 详情 | 详情 | |
| (XXIX) | 14689 | Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate | 2605-67-6 | C21H19O2P | 详情 | 详情 |
| (XXX) | 14690 | Methyl (E)-5-(benzyloxy)-2-pentenoate | C13H16O3 | 详情 | 详情 | |
| (XXXI) | 14691 | (E)-5-(Benzyloxy)-2-pentenoic acid | C12H14O3 | 详情 | 详情 | |
| (XXXII) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (XXXIII) | 14693 | (E)-4-(Benzyloxy)-2-pentenoic 1,1-Dimethylpropionic anhydride | C17H22O4 | 详情 | 详情 | |
| (XXXIV) | 14694 | (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone | 90719-32-7 | C10H11NO2 | 详情 | 详情 |
| (XXXV) | 14695 | (4S)-4-benzyl-3-[(E)-5-(benzyloxy)-2-pentenoyl]-1,3-oxazolan-2-one | C22H23NO4 | 详情 | 详情 | |
| (XXXVI) | 11183 | 1,3-Cyclopentadiene | C5H6 | 详情 | 详情 | |
| (XXXVII) | 14697 | (4S)-4-benzyl-3-([(1R,2S,3S,4S)-3-[2-(benzyloxy)ethyl]bicyclo[2.2.1]hept-5-en-2-yl]carbonyl)-1,3-oxazolan-2-one | C27H29NO4 | 详情 | 详情 | |
| (XXXVIII) | 14698 | (1S,2S,3S,4R)-3-[2-(benzyloxy)ethyl]bicyclo[2.2.1]heptane-2-carboxylic acid | C17H22O3 | 详情 | 详情 | |
| (XXXIX) | 14699 | (1S,2S,3S,4R)-3-[2-(benzyloxy)ethyl]bicyclo[2.2.1]heptan-2-amine; (1S,2S,3S,4R)-3-[2-(benzyloxy)ethyl]bicyclo[2.2.1]hept-2-ylamine | C16H23NO | 详情 | 详情 | |
| (XL) | 14700 | N-[(1S,2S,3S,4R)-3-[2-(benzyloxy)ethyl]bicyclo[2.2.1]hept-2-yl]benzenesulfonamide | C22H27NO3S | 详情 | 详情 | |
| (XLI) | 14701 | N-[(1S,2S,3S,4R)-3-(2-hydroxyethyl)bicyclo[2.2.1]hept-2-yl]benzenesulfonamide | C15H21NO3S | 详情 | 详情 | |
| (XLII) | 14673 | N-[(1S,2S,3S,4R)-3-(2-oxoethyl)bicyclo[2.2.1]hept-2-yl]benzenesulfonamide | C15H19NO3S | 详情 | 详情 |