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【结 构 式】 
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【分子编号】14665 【品名】(1S,2S,3S,4R)-3-(methoxycarbonyl)bicyclo[2.2.1]heptane-2-carboxylic acid 【CA登记号】 |
【 分 子 式 】C10H14O4 【 分 子 量 】198.21876 【元素组成】C 60.59% H 7.12% O 32.29% |
合成路线1
该中间体在本合成路线中的序号：(V)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：(XLIII)The reaction of (1R,2S,3S,4S)-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-monomethyl ester (XLIII) with ethylchloroformate and NaN3 gives the corresponding azide (XLIV), which is submitted to degradation in the presence of benzyl alcohol to afford (1R,2S,3S,4S)-3-(benzyloxycarbonylamino)bicyclo[2.2.1]heptane-2-carboxylic acid methyl ester (XLV). The reduction of (XLV) with NaBH4 in THF gives the hydroxymethyl derivative (XLVI), which is oxidized with oxalyl chloride as before to the corresponding aldehyde (XLVII). The Wittig condensation of (XLVII) with methoxymethyl triphenylphosphonium chloride by means of t-BuOK in THF gives the vinyl ether (XLVIII), which is hydrolyzed to the corresponding aldehyde (XLIX) with formic acid. A new Wittig condensation of (XLIX) with 4-carboxybutyl triphenylphosphonium bromide as before, followed by methylation with diazomethane yields (1R,2S,3S,4S)-7-[3-(benzyloxycarbonylamino)bicyclo[2.2.1]heptan-2-yl]-5(Z)-heptenoic acid methyl ester (L). The deprotection of (L) with trifluoroacetic acid affords the 3-amino derivative (LI), which is then condensed with [14C]- or [3H]-radiolabeled benzenesulfonyl chloride (LII) to afford the radiolabeled sulfonamide ester (LIII). Finally, this compound is hydrolyzed with NaOH to the radiolabeled free acid (XIV), already obtained, which is converted to S-1452 by treatment of the Na salt with CaCl2 in methanol-water.
| 【1】 Narisada, M.; Katsuyama, Y.; Watanabe, F.; Hamada, Y.; Ohtani, M.; Nagasaki, T.; Synthesis of [14C]- and [3H]-labelled (+)-[1R-[1alpha,2alpha(Z),3beta,4alpha]]-7-[3-[(phenylsulfonyl)amino] bicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, ((+)-S-145) and its calcium salt (S-1452). J Label Compd Radiopharm 1992, 31, 1, 23-38. |
| 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) | 14681 | benzyl N-[(1S,2S,3S,4R)-3-(2-oxoethyl)bicyclo[2.2.1]hept-2-yl]carbamate | C17H21NO3 | 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 | |
| (XLIII) | 14665 | (1S,2S,3S,4R)-3-(methoxycarbonyl)bicyclo[2.2.1]heptane-2-carboxylic acid | C10H14O4 | 详情 | 详情 | |
| (XLIV) | 14704 | methyl (1R,2S,3S,4S)-3-(azidocarbonyl)bicyclo[2.2.1]heptane-2-carboxylate | C10H13N3O3 | 详情 | 详情 | |
| (XLV) | 14705 | methyl (1R,2S,3S,4S)-3-[[(benzyloxy)carbonyl]amino]bicyclo[2.2.1]heptane-2-carboxylate | C17H21NO4 | 详情 | 详情 | |
| (XLVI) | 14706 | benzyl N-[(1S,2S,3S,4R)-3-(hydroxymethyl)bicyclo[2.2.1]hept-2-yl]carbamate | C16H21NO3 | 详情 | 详情 | |
| (XLVII) | 14707 | benzyl N-[(1S,2S,3S,4R)-3-formylbicyclo[2.2.1]hept-2-yl]carbamate | C16H19NO3 | 详情 | 详情 | |
| (XLVIII) | 14708 | benzyl N-[(1S,2S,3R,4R)-3-[(E)-2-methoxyethenyl]bicyclo[2.2.1]hept-2-yl]carbamate | C18H23NO3 | 详情 | 详情 | |
| (L) | 14682 | methyl (Z)-7-((1R,2S,3S,4S)-3-[[(benzyloxy)carbonyl]amino]bicyclo[2.2.1]hept-2-yl)-5-heptenoate | C23H31NO4 | 详情 | 详情 | |
| (LI) | 14683 | methyl (Z)-7-[(1R,2S,3S,4S)-3-aminobicyclo[2.2.1]hept-2-yl]-5-heptenoate | C15H25NO2 | 详情 | 详情 | |
| (LII) | 14684 | methyl (Z)-7-[(1R,2S,3S,4S)-3-[(phenylsulfonyl)amino]bicyclo[2.2.1]hept-2-yl]-5-heptenoate | C21H29NO4S | 详情 | 详情 | |
| (LIII) | 14713 | benzenesulfonyl chloride | 98-09-9 | C6H5ClO2S | 详情 | 详情 |