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【结 构 式】

【分子编号】14664

【品名】(1S,2S,3R,4R)-3-([[(R)-carboxy(phenyl)methyl]oxy]carbonyl)bicyclo[2.2.1]heptane-2-carboxylic acid

【CA登记号】

【 分 子 式 】C17H18O6

【 分 子 量 】318.32632

【元素组成】C 64.14% H 5.7% O 30.16%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(IV)

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
Extended Information