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【结 构 式】 
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【药物名称】AA-193 【化学名称】5-Chloro-3-phenyl-7,8-dihydrofuro[2,3-g]-1,2-benzisoxazole-7-carboxylic acid 【CA登记号】107804-48-8 【 分 子 式 】C16H10ClNO4 【 分 子 量 】315.7154 |
【开发单位】Chugai (Originator) 【药理作用】METABOLIC DRUGS, Treatment of Disorders of Purine and Pyrimidine Metabolism, Treatment of Gout, Uricosurics |
合成路线1
1) The Friedel-Crafts condensation of 4,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid ethyl ester (I) with benzoyl chloride (II) by means of AlCl3 in dichloroethane, followed by hydrolysis with ethanolic NaOH gives 5-benzoyl-4,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid (III), which by reaction with hydroxylamine in refluxing pyridine is converted into the corresponding oxime (IV). Finally, this compound is cyclized with NaH in DMF or with KOH in ethanol. 2) The Friedel-Crafts condensation of (V) with (II) as before gives 2-hydroxy-4-methoxybenzophenone (XVI), which by cyclocondensation with hydroxylamine as before is converted into 6-methoxy-3-phenyl-1,2-benzisoxazole (XVII). Demethylation of (XVII) as already indicated yields 6-hydroxy-3-phenyl-1,2-benzisoxazole (XVIII), which is converted into the allyloxy derivative (XIX). The rearrangement of (XIX) with N,N-dimethylamine as before affords the 7-allyl derivative (XX), which is cyclized with m-chloroperbenzoic acid (m-CPBA) to 3-phenyl-7,8-dihydrofuro[2,3-g]-1,2-benzisoxazole-7-methanol (XXI). Finally, this compound is chlorinated with SO2Cl2 in CH2Cl2 yielding compound (XV), which is oxidized with CrO3 / H2SO4 or KMnO4 in dichloromethane.
| 【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.); Method for the preparation of furobenzisoxazole derivs. JP 1989131180 . |
| 【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.); Industrial process for the preparation of furobenzisoxazole derivs. JP 1989143875 . |
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 11930 | ethyl 4,7-dichloro-2,3-dihydro-1-benzofuran-2-carboxylate | C11H10Cl2O3 | 详情 | 详情 | |
| (II) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (III) | 11932 | 5-Benzoyl-4,7-dichloro-2,3-dihydro-1-benzofuran-2-carboxylic acid | C16H10Cl2O4 | 详情 | 详情 | |
| (IV) | 11933 | 4,7-Dichloro-5-[(hydroxyimino)(phenyl)methyl]-2,3-dihydro-1-benzofuran-2-carboxylic acid | C16H11Cl2NO4 | 详情 | 详情 | |
| (V) | 11934 | m-Dimethoxybenzene; 1,3-Dimethoxybenzene; 3-Methoxyphenyl methyl ether | 151-10-0 | C8H10O2 | 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 | |
| (XVI) | 11935 | 2-Hydroxy-4-methoxybenzophenone; (2-Hydroxy-4-methoxyphenyl)(phenyl)methanone | 131-57-7 | C14H12O3 | 详情 | 详情 |
| (XVII) | 11936 | Methyl 3-phenyl-1,2-benzisoxazol-6-yl ether; 6-Methoxy-3-phenyl-1,2-benzisoxazole | C14H11NO2 | 详情 | 详情 | |
| (XVIII) | 11937 | 3-Phenyl-1,2-benzisoxazol-6-ol | C13H9NO2 | 详情 | 详情 | |
| (XIX) | 11938 | 6-(Allyloxy)-3-phenyl-1,2-benzisoxazole; Allyl 3-phenyl-1,2-benzisoxazol-6-yl ether | C16H13NO2 | 详情 | 详情 | |
| (XX) | 11939 | 7-Allyl-3-phenyl-1,2-benzisoxazol-6-ol | C16H13NO2 | 详情 | 详情 | |
| (XXI) | 11940 | (3-Phenyl-7,8-dihydrofuro[2,3-g][1,2]benzisoxazol-7-yl)methanol | C16H13NO3 | 详情 | 详情 |
合成路线2
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3
Several related syntheses for AA-193 have been reported: 1) The Friedel-Crafts' condensation of 2,5-dichlorophenol (I) with benzoyl chloride (II) by means of AlCl3 gives 2,5-dichloro-4-hydroxybenzophenone (III), which by reaction with hydroxylamine and KOH is converted to 5-chloro-6-hydroxy-3-phenylbenzisoxazole (IV). The condensation of (IV) with allyl bromide (V) by means of K2CO3 affords the 7-allyl derivative (VI), which is cyclized by means of N-bromosuccinimide and NaOH to 5-chloro-7-(hydroxymethyl)-3-phenyl-7,8-dihydrofuro[2,3-g]-1,2-benzisox azole (VII). Finally, this compound is oxidized to the final product with KMnO4 in refluxing dichloromethane. 2) The chlorination of 1,3-dimethoxybenzene (VIII) with SO2Cl2 gives 1-chloro-2,4-dimethoxybenzene (IX), which is condensed with benzoyl chloride (II) as before, yielding 5-chloro-2,4-dihydroxybenzophenone (X). Tosylation of (X) with tosyl chloride gives the corresponding ditosyl derivative (XI), which by reaction with hydroxylamine is converted to the oxime (XII). Finally, this compound is treated with KOH in order to cyclize to the benzisoxazole (IV). 3) The reaction of the benzisoxazole (IV) with formaldehyde and dimethylamine gives 5-chloro-7-(dimethylaminomethyl)-6-hydroxy-3-phenylbenzisoxazole (XIII), which is condensed and cyclized with the ylide (XIV) to yield the ethyl ester of the desired product (XV). Finally, this compound is hydrolyzed with NaOH.
| 【1】 Koga, H.; Kuromaru, K.; Ishizawa, T.; Aoki, B.; Sato, H.; Studies on uricosuric diuretics. V. Convenient and efficient synthesis of 2,3-dihydrobenzofuran derivatives. Chem Pharm Bull 1992, 40, 10, 2597. |
| 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) | 11953 | 2,5-Dichlorophenol | 583-78-8 | C6H4Cl2O | 详情 | 详情 |
| (II) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (III) | 11955 | (2,5-Dichloro-4-hydroxyphenyl)(phenyl)methanone | C13H8Cl2O2 | 详情 | 详情 | |
| (IV) | 11945 | 5-Chloro-3-phenyl-1,2-benzisoxazol-6-ol | C13H8ClNO2 | 详情 | 详情 | |
| (V) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (VI) | 11950 | 7-Allyl-5-chloro-3-phenyl-1,2-benzisoxazol-6-ol | C16H12ClNO2 | 详情 | 详情 | |
| (VII) | 11941 | (5-Chloro-3-phenyl-7,8-dihydrofuro[2,3-g][1,2]benzisoxazol-7-yl)methanol | C16H12ClNO3 | 详情 | 详情 | |
| (VIII) | 11934 | m-Dimethoxybenzene; 1,3-Dimethoxybenzene; 3-Methoxyphenyl methyl ether | 151-10-0 | C8H10O2 | 详情 | 详情 |
| (IX) | 11942 | 1-Chloro-2,4-dimethoxybenzene; 2-Chloro-5-methoxyphenyl methyl ether | 7051-13-0 | C8H9ClO2 | 详情 | 详情 |
| (X) | 11962 | (5-Chloro-2,4-dihydroxyphenyl)(phenyl)methanone | C13H9ClO3 | 详情 | 详情 | |
| (XI) | 11963 | 2-benzoyl-4-chloro-5-[[(4-methylphenyl)sulfonyl]oxy]phenyl 4-methylbenzenesulfonate | C27H21ClO7S2 | 详情 | 详情 | |
| (XII) | 11964 | 4-chloro-2-[(hydroxyimino)(phenyl)methyl]-5-[[(4-methylphenyl)sulfonyl]oxy]phenyl 4-methylbenzenesulfonate | C27H22ClNO7S2 | 详情 | 详情 | |
| (XIII) | 11946 | 5-Chloro-7-[(dimethylamino)methyl]-3-phenyl-1,2-benzisoxazol-6-ol | C16H15ClN2O2 | 详情 | 详情 | |
| (XIV) | 11966 | 2-(Dimethylsulfonium)acetic acid ethyl ester inner salt | C6H12O2S | 详情 | 详情 | |
| (XV) | 11948 | ethyl 5-chloro-3-phenyl-7,8-dihydrofuro[2,3-g][1,2]benzisoxazole-7-carboxylate | C18H14ClNO4 | 详情 | 详情 |