(1R,2S,6R,7S)-4-Oxatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione -Drug Synthesis Database

【结构式】

【分子编号】11184

【品名】(1R,2S,6R,7S)-4-Oxatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione

【CA登记号】

【分子式】C₉H₈O₃

【分子量】164.16072

【元素组成】C 65.85% H 4.91% O 29.24%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(III)

The synthesis of SM-3997 labeled in the carbonyl groups or the pyrimidine ring has been reported: The Diels-Alder condensation of cyclopentadiene (II) with [14C]-labeled maleic anhydride (I) gives bicyclo[2.2.1]hept-5-ene-2,3-endo-di[14C]-carboxylic anhydride (III), which by treatment with ammonia in THF is converted to the corresponding imide (IV endo). Heating of (IV endo) at 190 C in diphenylether affords the corresponding exo isomer (IV exo), which is hydrogenated with H2 over Pd/C in ethanol - THF to give the saturated exo-imide (V). The condensation of (V) with 1,4-dibromobutane (VI) by means of K2CO3 in refluxing acetone yields the N-(4-bromobutyl)imide (VII), which is finally condensed with 1-(2-pyrimidinyl)piperazine (VIII) by means of K2CO3 and KI in hot DMF to afford SM-399 [14C]-labeled at the carbonyl groups.

参考文献中间体

合成目标

【1】 Kanamaru, H.; Nishioka, K.; 14C-labeling of a novel anxiolytic agent tandospirone. J Label Compd Radiopharm 1992, 31, 6, 427.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV endo)	11185	(1R,2S,6R,7S)-4-Azatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione		C₉H₉NO₂	详情	详情
(IV exo)	11186	(1R,2R,6S,7S)-4-Azatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione		C₉H₉NO₂	详情	详情
(IV endo)	45052	(1R,2R,6S,7S)-4-azatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione		C₉H₉NO₂	详情	详情
(IV exo)	45053	(1R,2S,6R,7S)-4-azatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione		C₉H₉NO₂	详情	详情
(I)	11182	2,5-Furandione; Maleic anhydride	108-31-6	C₄H₂O₃	详情	详情
(I)	45050	2,5-furandione		C₄H₂O₃	详情	详情
(II)	11183	1,3-Cyclopentadiene		C₅H₆	详情	详情
(III)	11184	(1R,2S,6R,7S)-4-Oxatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione		C₉H₈O₃	详情	详情
(III)	45051	(1R,2R,6S,7S)-4-oxatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione		C₉H₈O₃	详情	详情
(V)	11173	(1R,2S,6R,7S)-4-Azatricyclo[5.2.1.0(2,6)]decane-3,5-dione		C₉H₁₁NO₂	详情	详情
(V)	45054	(1R,2R,6S,7S)-4-azatricyclo[5.2.1.0(2,6)]decane-3,5-dione		C₉H₁₁NO₂	详情	详情
(VII)	11174	(1R,2S,6R,7S)-4-(4-Bromobutyl)-4-azatricyclo[5.2.1.0(2,6)]decane-3,5-dione		C₁₃H₁₈BrNO₂	详情	详情
(VII)	45055	(1R,2R,6S,7S)-4-(4-bromobutyl)-4-azatricyclo[5.2.1.0(2,6)]decane-3,5-dione		C₁₃H₁₈BrNO₂	详情	详情
(VIII)	11175	2-(1-Piperazinyl)pyrimidine; 2-Piperazinopyrimidine; N-(Pyrimidinyl)piperazine	20980-22-7	C₈H₁₂N₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

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.

参考文献中间体

合成目标

【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