【药物名称】Silodosin, KAD-3213, KMD-3213
化学结构式(Chemical Structure):
参考文献No.23977
标题:Indoline cpds. for the treatment of dysuria
作者:Kitazawa, M.; Ban, M.; Okazaki, K.; Ozawa, M.; Yazaki, T.; Yamagishi, R. (Kissei Pharmaceutical Co., Ltd.)
来源:EP 0600675; JP 1994220015; US 5387603
合成路线图解说明:

The bromination of 1-acetyl-5-propionylindoline (I) with pyrrolidone hydrotribromide (PTBr) and sulfuric acid in THF gives the alpha-bromo derivative (II), which is reduced with triethylsilane in TFA yielding the 2-bromopropyl compound (III). Nitration of (III) with HNO3 in HOAc affords the 7-nitroindoline (IV), which is reduced to the corresponding amine derivative (V) with H2 over PtO2 in ethanol. The reaction of amine (V) with NaNO2/HCl, followed by treatment with CuCN, provides 1-acetyl-5-(2-bromopropyl)indoline-7-carbonitrile (VI), which is treated with NaN3 in hot ethylene glycol monomethyl ether/water to yield the 2-azidopropyl derivative (VII). Reduction of (VII) with H2 over Pd/BaSO4 in ethanol affords the expected 2-aminopropyl compound (VIII), which is condensed with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl bromide (IX) by means of NaHCO3 in ethanol to provide the secondary amine (X). The intermediate 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl bromide (IX) has been obtained as follows: Alkylation of 2-methoxyphenol (XVIII) with 2,2,2-trifluoroethyl iodide (XIX) by means of K2CO3 in hot DMF gives 1-methoxy-2-(2,2,2-trifluoroethoxy)benzene (XX), which is demethylated by means of BBr3 in dichloromethane to yield the corresponding phenol (XXI). Finally, this compound is alkylated with 1,2-dibromoethane (XXII) and NaOH in water at 120 C (1,2).

合成路线图解说明:

The optical resolution of amine (X), performed by treatment with (+)-mandelic acid in ethanol, followed by crystallization of the resulting salt and then treatment with Na2CO3 affords the desired (R)-enantiomer (XI). Compound (XI) is protected with Boc2O to give the corresponding carbamate (XII), which is deacetylated with NaOH in ethanol to yield the intermediate (XIII). Hydrolysis of the cyano group of (XIII) with NaOH and H2O2 in DMSO furnishes the corresponding carboxamide (XIV), which is condensed with 3-(tert-butyldimethylsilyloxy)propyl 4-nitrobenzenesulfonate (XV) by means of K2CO3 and a crown ether in dioxane to provide the indoline adduct (XVI). Finally, desilylation of (XVI) with TBAF in THF yields the 3-hydroxypropyl derivative (XVII), which by removal of the Boc-protecting group by means of TFA in dichloromethane gives KMD-3213.

参考文献No.48686
标题:Indole derivs.
作者:Kitazawa, M.; Ozawa, M.; Okazaki, K.; Yamagishi, R.; Yazaki, T.; Saka, M. (Kissei Pharmaceutical Co., Ltd.)
来源:JP 1995330726
合成路线图解说明:

The bromination of 1-acetyl-5-propionylindoline (I) with pyrrolidone hydrotribromide (PTBr) and sulfuric acid in THF gives the alpha-bromo derivative (II), which is reduced with triethylsilane in TFA yielding the 2-bromopropyl compound (III). Nitration of (III) with HNO3 in HOAc affords the 7-nitroindoline (IV), which is reduced to the corresponding amine derivative (V) with H2 over PtO2 in ethanol. The reaction of amine (V) with NaNO2/HCl, followed by treatment with CuCN, provides 1-acetyl-5-(2-bromopropyl)indoline-7-carbonitrile (VI), which is treated with NaN3 in hot ethylene glycol monomethyl ether/water to yield the 2-azidopropyl derivative (VII). Reduction of (VII) with H2 over Pd/BaSO4 in ethanol affords the expected 2-aminopropyl compound (VIII), which is condensed with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl bromide (IX) by means of NaHCO3 in ethanol to provide the secondary amine (X). The intermediate 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl bromide (IX) has been obtained as follows: Alkylation of 2-methoxyphenol (XVIII) with 2,2,2-trifluoroethyl iodide (XIX) by means of K2CO3 in hot DMF gives 1-methoxy-2-(2,2,2-trifluoroethoxy)benzene (XX), which is demethylated by means of BBr3 in dichloromethane to yield the corresponding phenol (XXI). Finally, this compound is alkylated with 1,2-dibromoethane (XXII) and NaOH in water at 120 C (1,2).

合成路线图解说明:

The optical resolution of amine (X), performed by treatment with (+)-mandelic acid in ethanol, followed by crystallization of the resulting salt and then treatment with Na2CO3 affords the desired (R)-enantiomer (XI). Compound (XI) is protected with Boc2O to give the corresponding carbamate (XII), which is deacetylated with NaOH in ethanol to yield the intermediate (XIII). Hydrolysis of the cyano group of (XIII) with NaOH and H2O2 in DMSO furnishes the corresponding carboxamide (XIV), which is condensed with 3-(tert-butyldimethylsilyloxy)propyl 4-nitrobenzenesulfonate (XV) by means of K2CO3 and a crown ether in dioxane to provide the indoline adduct (XVI). Finally, desilylation of (XVI) with TBAF in THF yields the 3-hydroxypropyl derivative (XVII), which by removal of the Boc-protecting group by means of TFA in dichloromethane gives KMD-3213.

参考文献No.626807
标题:KMD-3213
作者:Sorbera, L.A.; Casta馿r, J.; Silvestre, J.S.
来源:Drugs Fut 2001,26(6),553
合成路线图解说明:

The bromination of 1-acetyl-5-propionylindoline (I) with pyrrolidone hydrotribromide (PTBr) and sulfuric acid in THF gives the alpha-bromo derivative (II), which is reduced with triethylsilane in TFA yielding the 2-bromopropyl compound (III). Nitration of (III) with HNO3 in HOAc affords the 7-nitroindoline (IV), which is reduced to the corresponding amine derivative (V) with H2 over PtO2 in ethanol. The reaction of amine (V) with NaNO2/HCl, followed by treatment with CuCN, provides 1-acetyl-5-(2-bromopropyl)indoline-7-carbonitrile (VI), which is treated with NaN3 in hot ethylene glycol monomethyl ether/water to yield the 2-azidopropyl derivative (VII). Reduction of (VII) with H2 over Pd/BaSO4 in ethanol affords the expected 2-aminopropyl compound (VIII), which is condensed with 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl bromide (IX) by means of NaHCO3 in ethanol to provide the secondary amine (X). The intermediate 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl bromide (IX) has been obtained as follows: Alkylation of 2-methoxyphenol (XVIII) with 2,2,2-trifluoroethyl iodide (XIX) by means of K2CO3 in hot DMF gives 1-methoxy-2-(2,2,2-trifluoroethoxy)benzene (XX), which is demethylated by means of BBr3 in dichloromethane to yield the corresponding phenol (XXI). Finally, this compound is alkylated with 1,2-dibromoethane (XXII) and NaOH in water at 120 C (1,2).

合成路线图解说明:

The optical resolution of amine (X), performed by treatment with (+)-mandelic acid in ethanol, followed by crystallization of the resulting salt and then treatment with Na2CO3 affords the desired (R)-enantiomer (XI). Compound (XI) is protected with Boc2O to give the corresponding carbamate (XII), which is deacetylated with NaOH in ethanol to yield the intermediate (XIII). Hydrolysis of the cyano group of (XIII) with NaOH and H2O2 in DMSO furnishes the corresponding carboxamide (XIV), which is condensed with 3-(tert-butyldimethylsilyloxy)propyl 4-nitrobenzenesulfonate (XV) by means of K2CO3 and a crown ether in dioxane to provide the indoline adduct (XVI). Finally, desilylation of (XVI) with TBAF in THF yields the 3-hydroxypropyl derivative (XVII), which by removal of the Boc-protecting group by means of TFA in dichloromethane gives KMD-3213.

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