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【结 构 式】 
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【分子编号】11947 【品名】(2-Ethoxy-2-oxoethyl)(dimethyl)sulfonium bromide 【CA登记号】5187-82-6 |
【 分 子 式 】C6H13BrO2S 【 分 子 量 】229.13802 【元素组成】C 31.45% H 5.72% Br 34.87% O 13.96% S 13.99% |
合成路线1
该中间体在本合成路线中的序号：(XI)3) The chlorination of 1,3-dimethoxybenzene (V) with SO2Cl2 in CHCl3 gives 1-chloro-2,4-dimethoxybenzene (VI), which is condensed with (II) by means of AlCl3 in dichloroethane yielding 5-chloro-2-hydroxy-4-methoxybenzophenone (VII). The cyclocondensation of (VII) with hydroxylamine - HCl and then with acetic anhydride - sodium acetate in refluxing DMF affords 5-chloro-6-methoxy-3-phenyl-1,2-benzoisoxazole (VIII), which is demethylated with pyridine hydrochloride at 180 C, giving 5-chloro-6-hydroxy-3-phenyl-1,2-benzoisoxazole (IX). The condensation of (IX) with dimethylamine and formaldehyde in water gives 5-chloro-7-(dimethylaminomethyl)-6-hydroxy-3-phenyl-1,2-benzoisoxazole (X), which is cyclized with (ethoxycarbonylmethyl)dimethylsulfonium bromide (XI) by means of K2CO3 in DMF, yielding 5-chloro-3-phenyl-7,8-dihydrofuro[2,3-g]-1,2-benzoisoxazole-7-carboxyli c acid ethyl ester (XII). Finally, this compound is hydrolyzed with NaOH in refluxing ethanol. 4) The condensation of isoxazole (IX) with allyl bromide by means of K2CO3 in DMF gives 6-allyloxy-5-chloro-3-phenyl-1,2-benzoisoxazole (XIII), which is rearranged with refluxing N,N-dimethylaniline yielding 7-allyl-5-chloro-6-hydroxy-3-phenyl-1,2-benzisoxazole (XIV). The cyclization of (XIV) with m-chloroperbenzoic acid (MCPBA) in refluxing CHCl3 or N-bromosuccinimide in DMSO affords 5-chloro-3-phenyl-7,8-dihydrofuro[2,3-g]-1,2-benzisoxazole-7-methanol (XV), which is finally oxidized with CrO3-H2SO4 in acetone or KMnO4 in dichloroethane. 5) The alkylation of phenol (IX) with ortho-acrylic acid trietyl ester (XXI) by means of pivalic acid in refluxing toluene gives the substituted chromane (XXIII), which is then treated with Br2 in pyridine-CHCl3 to afford ethyl ester (XII), already obtained.
| 【1】 Sato, H.; Koga, H.; Dan, T.; Onuma, E. (Chugai Pharmaceutical Co. Ltd.); Furobenzisoxazole derivs. EP 0205872; US 4791209 . |
| 【2】 Koga, H.; Sato, H. (Chugai Pharmaceutical Co. Ltd.); Industrial process for the preparation of furobenzisoxazole derivs. JP 1989143875 . |
| 【3】 Koga, H.; Sato, H. (Chugai Pharmaceutical Co. Ltd.); Method for the synthesis of furobenzisoxazole derivs. JP 1989143876 . |
| 【4】 Koga, H.; Sato, H. (Chugai Pharmaceutical Co. Ltd.); Method for the preparation of furobenzisoxazole derivs. JP 1989131180 . |
| 【5】 Prous, J.; Castaner, J.; AA-193. Drugs Fut 1991, 16, 11, 985. |
| 【6】 Onuma, E.; Dan, T.; Koga, H.; Sato, H.; Aoki, B.; Tanaka, H.; Studies on uricosuric diuretics. II. Substituted 7,8-dihydrofuro[2,3-g]-1,2-benzisoxazole-7-carboxylic acids and 7,8-dihydrofuro[2,3-g]benzoxazole-7-carboxylic acids. Chem Pharm Bull 1991, 39, 7, 1760-72. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (V) | 11934 | m-Dimethoxybenzene; 1,3-Dimethoxybenzene; 3-Methoxyphenyl methyl ether | 151-10-0 | C8H10O2 | 详情 | 详情 |
| (VI) | 11942 | 1-Chloro-2,4-dimethoxybenzene; 2-Chloro-5-methoxyphenyl methyl ether | 7051-13-0 | C8H9ClO2 | 详情 | 详情 |
| (VII) | 11943 | (5-Chloro-2-hydroxy-4-methoxyphenyl)(phenyl)methanone | C14H11ClO3 | 详情 | 详情 | |
| (VIII) | 11944 | 5-Chloro-3-phenyl-1,2-benzisoxazol-6-yl methyl ether; 5-Chloro-6-methoxy-3-phenyl-1,2-benzisoxazole | C14H10ClNO2 | 详情 | 详情 | |
| (IX) | 11945 | 5-Chloro-3-phenyl-1,2-benzisoxazol-6-ol | C13H8ClNO2 | 详情 | 详情 | |
| (X) | 11946 | 5-Chloro-7-[(dimethylamino)methyl]-3-phenyl-1,2-benzisoxazol-6-ol | C16H15ClN2O2 | 详情 | 详情 | |
| (XI) | 11947 | (2-Ethoxy-2-oxoethyl)(dimethyl)sulfonium bromide | 5187-82-6 | C6H13BrO2S | 详情 | 详情 |
| (XII) | 11948 | ethyl 5-chloro-3-phenyl-7,8-dihydrofuro[2,3-g][1,2]benzisoxazole-7-carboxylate | C18H14ClNO4 | 详情 | 详情 | |
| (XIII) | 11949 | Allyl 5-chloro-3-phenyl-1,2-benzisoxazol-6-yl ether; 6-(Allyloxy)-5-chloro-3-phenyl-1,2-benzisoxazole | C16H12ClNO2 | 详情 | 详情 | |
| (XIV) | 11950 | 7-Allyl-5-chloro-3-phenyl-1,2-benzisoxazol-6-ol | C16H12ClNO2 | 详情 | 详情 | |
| (XV) | 11941 | (5-Chloro-3-phenyl-7,8-dihydrofuro[2,3-g][1,2]benzisoxazol-7-yl)methanol | C16H12ClNO3 | 详情 | 详情 | |
| (XXII) | 11951 | 3,3,3-Triethoxy-1-propene; 1,1-Diethoxy-2-propenyl ethyl ether | C9H18O3 | 详情 | 详情 | |
| (XXIII) | 11952 | 5-Chloro-7-ethoxy-3-phenyl-8,9-dihydro-7H-chromeno[6,5-d]isoxazol-7-yl ethyl ether; 5-Chloro-7,7-diethoxy-3-phenyl-8,9-dihydro-7H-chromeno[6,5-d]isoxazole | C20H20ClNO4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The cyclopropanation of (-)-2,3-(cyclohexylidenedioxy)-4-cyclopentenone (I) with (ethoxycarbonylmethyl)dimethylsulfonium bromide (II) by means of DBU in chloroform gives the bicyclo[3.1.0]hexane derivative (II), which is treated with chloroform and LiHMDS in THF yielding the trichloromethyl derivative (IV). The reaction of (IV) with sodium azide, DBU and 18-crown-6 in methanol affords the azido-dicarboxylate derivative (V), which is hydrogenated with H2 over Pd/C in ethyl acetate to give the amino-dicarboxylic ester (VI). The acylation of (VI) with acetyl chloride and TEA in dichloromethane yields the corresponding acetamide (VII), which is treated with TFA to afford the bicyclic diol (VIII). The esterification of (VIII) with triethyl orthoformate provides the cyclic orthoester (IX), which is decomposed thermically at 170-90 C giving the unsaturated bicyclic compound (X). The hydrogenation of (X) with H2 over Pd/C in ethyl acetate affords the saturated compound (XI), which is finally deacetylated and hydrolyzed by a treatment with refluxing 1H aqueous HCl.
| 【1】 Dominguez Fernandez, C.; Ezquerra Carrera, J.; Baker, S.R.; Monn, J.A. (Eli Lilly and Company; Lilly SA); Bicyclohexane derivs.. WO 0004010 . |
| 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) | 35479 | C11H14O3 | 详情 | 详情 | ||
| (II) | 11947 | (2-Ethoxy-2-oxoethyl)(dimethyl)sulfonium bromide | 5187-82-6 | C6H13BrO2S | 详情 | 详情 |
| (III) | 35480 | C15H20O5 | 详情 | 详情 | ||
| (IV) | 35481 | C16H21Cl3O5 | 详情 | 详情 | ||
| (V) | 35482 | C16H21N3O6 | 详情 | 详情 | ||
| (VI) | 35483 | C16H23NO6 | 详情 | 详情 | ||
| (VII) | 35484 | C18H25NO7 | 详情 | 详情 | ||
| (VIII) | 35485 | dimethyl (1S,2R,3S,4R,5R,6R)-2-(acetamido)-3,4-dihydroxybicyclo[3.1.0]hexane-2,6-dicarboxylate | C12H17NO7 | 详情 | 详情 | |
| (IX) | 35486 | dimethyl (3aR,3bR,4R,4aS,5R,5aS)-5-(acetamido)-2-ethoxyhexahydrocyclopropa[3,4]cyclopenta[1,2-d][1,3]dioxole-4,5-dicarboxylate | C15H21NO8 | 详情 | 详情 | |
| (X) | 35487 | dimethyl (1S,2S,5R,6S)-2-(acetamido)bicyclo[3.1.0]hex-3-ene-2,6-dicarboxylate | C12H15NO5 | 详情 | 详情 | |
| (XI) | 35488 | dimethyl (1S,2S,5R,6S)-2-(acetamido)bicyclo[3.1.0]hexane-2,6-dicarboxylate | C12H17NO5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Condensation of ethyl bromoacetate (I) with dimethyl sulfide gave the sulfonium salt (II). Addition of the sulfur ylide resulting from (II) and DBU to cyclopentenone (III) produced the bicyclic compound (IV). This was converted into the silyl enolate (V), which was subsequently oxidized to the unsaturated ketone (VI) by means of palladium diacetate. Alternatively, (IV) was directly oxidized to (VI) using allyl methyl carbonate and palladium diacetate. Treatment of enone (VI) with tert-butyl hydroperoxide and DBU produced epoxide (VII), which was further converted into hydroxy ketone (VIII) by reaction with diphenyl diselenide in the presence of N-acetyl-cysteine and sodium borate. Bucherer-Bergs reaction of ketone (VIII) with potassium cyanide and ammonium carbamate produced a mixture of diastereomeric hydantoins (IX). After N-alkylation of the hydantoin ring of (IX) with benzyl bromide, the desired isomer (X) was isolated by preparative HPLC. Finally, alcohol oxidation, with concomitant hydantoin hydrolysis, by treatment with Jones reagent furnished the title compound.
| 【1】 Massey, S.M.; Monn, J.A.; Valli, M.J. (Eli Lilly and Company); Excitatory amino acid receptor modulators. EP 0878463; US 5958960 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IXa) | 44097 | C11H14N2O5 | 详情 | 详情 | ||
| (IXb) | 44098 | C11H14N2O5 | 详情 | 详情 | ||
| (I) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (II) | 11947 | (2-Ethoxy-2-oxoethyl)(dimethyl)sulfonium bromide | 5187-82-6 | C6H13BrO2S | 详情 | 详情 |
| (III) | 25950 | 2-cyclopenten-1-one | 930-30-3 | C5H6O | 详情 | 详情 |
| (IV) | 44092 | ethyl (1S,5R,6S)-2-oxobicyclo[3.1.0]hexane-6-carboxylate | C9H12O3 | 详情 | 详情 | |
| (V) | 44093 | ethyl (1S,5R,6S)-2-[(trimethylsilyl)oxy]bicyclo[3.1.0]hex-2-ene-6-carboxylate | C12H20O3Si | 详情 | 详情 | |
| (VI) | 44094 | ethyl (1R,5S,6S)-4-oxobicyclo[3.1.0]hex-2-ene-6-carboxylate | C9H10O3 | 详情 | 详情 | |
| (VII) | 44095 | ethyl (1R,2R,4R,6S,7S)-5-oxo-3-oxatricyclo[4.1.0.0(2,4)]heptane-7-carboxylate | C9H10O4 | 详情 | 详情 | |
| (VIII) | 44096 | ethyl (1R,2S,5S,6S)-2-hydroxy-4-oxobicyclo[3.1.0]hexane-6-carboxylate | C9H12O4 | 详情 | 详情 | |
| (X) | 44099 | C18H20N2O5 | 详情 | 详情 |