合成路线:1) The reaction of dimethyl sulfate (I) with dimethyl sulfide (II) by means of sodium methoxide in acetonitrile gives dimethyl (methylene)-lambda4-sulfane (III),which,without isolation,is condensed with benzo[b]thiophene-5-carbaldehyde (IV) in the same solvent to yield 2-(benzo[b]thiophen-5-yl)oxirane (V) (1).The reaction of (V) with 2-(dimethylamino)ethanol (VI) by means of potassium tert-butoxide in hot DMSO (1,2),or hot DMF (3) affords (?-1-(benzo[b]thiophen-5-yl)-2-[2-(diethylamino)ethoxy]ethanol (racemic T-588) (VII),which is submitted to optical resolution first by treatment with acetic anhydride in refluxing toluene to give the corresponding acetate (VIII),and then by reaction of (VIII) with D-dibenzoyltartaric acid (IX) in ethyl acetate/acetone/water followed by fractionated crystallization of the resulting salt to yield the D-dibenzoyltartrate salt of the (R)-isomer (X).Finally,(X) is deacetylated with sodium methoxide in methanol and salified with ethanolic hydrochloric acid.
参考文献标题:1,2-Ethanediol derivs.and their salts
文献作者:Ono,T.; Yamafuji,T.; Chaki,H.; Maekawa,M.; Fujido,Y.; Narita,H.(Toyama Chemical Co.,Ltd.)
参考来源:JP 1992095070
合成路线:2) The condensation of aldehyde (IV) with bromoform by means of LiOH in hot dioxane/water gives (?-2-(benzo[b]thiophen-5-yl)-2-hydroxyacetic acid (XI),which is submitted to optical resolution by fractional crystallization of its 2(R)-aminobutanol salt in isopropanol and acidification with HCl to yield (R)-(-)-2-(benzo[b]thiophen-5-yl)-2-hydroxyacetic acid (XII).The cyclization of (XII) with acetone and concentrated H2SO4 affords (R)-(-)-5-(benzo[b]thiophen-5-yl)-2,2-dimethyl-1,3-dioxolan-4-one (XIII),which,by treatment with methanol and H2SO4,is converted into (R)-(-)-2-(benzo[b]thiophen-5-yl)-2-hydroxyacetic acid methyl ester (XIV).The protection of the OH group of (XIV) with dihydropyran (DHP) and pyridinium p-toluenesulfonate (Pyr稵sOH) affords the corresponding tetrahydropyranyl ether (XV),which is reduced with NaBH4 in ethanol,giving (R)-(-)-2-(benzo[b]thiophen-5-yl)-2-(tetrahydropyranyloxy)ethanol (XVI).Finally,this compound is condensed with 2-(diethylamino)ethyl chloride (XVII) by means of NaOH and tetrabutylammonium hydrogensulfate in toluene/water,followed by acidification with HCl.3) The (R)-dioxolane (XIII) can also be obtained as follows: The racemic hydroxyacetic acid (XI) is cyclized with acetone and H2SO4 as before,giving the racemic dioxolane (XVIII).This compound is dissolved in hot (50 C) tert-amyl alcohol along with 1,8-diazabicyclo[5.4.0]-7-undecene (DCU); this solution is then seeded with a suspension of the (R)-(-)-isomer (XIII) in the same solvent and is slowly cooled at 25 C; a 81% yield of pure crystals of (R)-(-)-isomer (XIII) is obtained.This procedure allows for improving the yields by recovering the unused (S)-(+)-isomer.
参考文献标题:Benzo b thiophen-5-yl deriv.and process for producing the same
文献作者:Nakano,J.; Taya,N.; Chaki,H.; Yamafuji,T.; Momonoi,K.(Toyama Chemical Co.,Ltd.)
参考来源:EP 0565965
合成路线:1) The reaction of dimethyl sulfate (I) with dimethyl sulfide (II) by means of sodium methoxide in acetonitrile gives dimethyl (methylene)-lambda4-sulfane (III),which,without isolation,is condensed with benzo[b]thiophene-5-carbaldehyde (IV) in the same solvent to yield 2-(benzo[b]thiophen-5-yl)oxirane (V) (1).The reaction of (V) with 2-(dimethylamino)ethanol (VI) by means of potassium tert-butoxide in hot DMSO (1,2),or hot DMF (3) affords (?-1-(benzo[b]thiophen-5-yl)-2-[2-(diethylamino)ethoxy]ethanol (racemic T-588) (VII),which is submitted to optical resolution first by treatment with acetic anhydride in refluxing toluene to give the corresponding acetate (VIII),and then by reaction of (VIII) with D-dibenzoyltartaric acid (IX) in ethyl acetate/acetone/water followed by fractionated crystallization of the resulting salt to yield the D-dibenzoyltartrate salt of the (R)-isomer (X).Finally,(X) is deacetylated with sodium methoxide in methanol and salified with ethanolic hydrochloric acid.
参考文献标题:A new cognition-enhancing agent,(R)-(-)-1-(benzo[b]thiophen-5-yl)-2-[2-(N,N-diethylamino)ethoxy]ethanol hydrochloride.Effects on memory impairment in rats generated by cerebral embolization and basal forebrain lesions
文献作者:Ono,S.; Yamafuji,T.; Chaki,H.; Todo,Y.; Maekawa,M.; Kitamura,K.; Kimura,T.; Nakada,Y.; Mozumi,K.; Narita,H.
参考来源:Biol Pharm Bull 1995,18(12),1779-83
合成路线:1) The reaction of dimethyl sulfate (I) with dimethyl sulfide (II) by means of sodium methoxide in acetonitrile gives dimethyl (methylene)-lambda4-sulfane (III),which,without isolation,is condensed with benzo[b]thiophene-5-carbaldehyde (IV) in the same solvent to yield 2-(benzo[b]thiophen-5-yl)oxirane (V) (1).The reaction of (V) with 2-(dimethylamino)ethanol (VI) by means of potassium tert-butoxide in hot DMSO (1,2),or hot DMF (3) affords (?-1-(benzo[b]thiophen-5-yl)-2-[2-(diethylamino)ethoxy]ethanol (racemic T-588) (VII),which is submitted to optical resolution first by treatment with acetic anhydride in refluxing toluene to give the corresponding acetate (VIII),and then by reaction of (VIII) with D-dibenzoyltartaric acid (IX) in ethyl acetate/acetone/water followed by fractionated crystallization of the resulting salt to yield the D-dibenzoyltartrate salt of the (R)-isomer (X).Finally,(X) is deacetylated with sodium methoxide in methanol and salified with ethanolic hydrochloric acid.
参考文献标题:Studies on cognitive enhancing agents.III.Antiamnestic and antihypoxic activities of a series of 1-bicycloaryl-2-(omega-aminoalkoxy)ethanols
文献作者:Ono,S.; Yamafuji,T.; Chaki,H.; Morita,H.; Todo,Y.; Okada,N.; Maekawa,M.; Kitamura,K.; Tai,M.; Narita,H.
参考来源:Chem Pharm Bull 1995,43(9),1492-6
合成路线:1) The reaction of dimethyl sulfate (I) with dimethyl sulfide (II) by means of sodium methoxide in acetonitrile gives dimethyl (methylene)-lambda4-sulfane (III),which,without isolation,is condensed with benzo[b]thiophene-5-carbaldehyde (IV) in the same solvent to yield 2-(benzo[b]thiophen-5-yl)oxirane (V) (1).The reaction of (V) with 2-(dimethylamino)ethanol (VI) by means of potassium tert-butoxide in hot DMSO (1,2),or hot DMF (3) affords (?-1-(benzo[b]thiophen-5-yl)-2-[2-(diethylamino)ethoxy]ethanol (racemic T-588) (VII),which is submitted to optical resolution first by treatment with acetic anhydride in refluxing toluene to give the corresponding acetate (VIII),and then by reaction of (VIII) with D-dibenzoyltartaric acid (IX) in ethyl acetate/acetone/water followed by fractionated crystallization of the resulting salt to yield the D-dibenzoyltartrate salt of the (R)-isomer (X).Finally,(X) is deacetylated with sodium methoxide in methanol and salified with ethanolic hydrochloric acid.
合成路线:2) The condensation of aldehyde (IV) with bromoform by means of LiOH in hot dioxane/water gives (?-2-(benzo[b]thiophen-5-yl)-2-hydroxyacetic acid (XI),which is submitted to optical resolution by fractional crystallization of its 2(R)-aminobutanol salt in isopropanol and acidification with HCl to yield (R)-(-)-2-(benzo[b]thiophen-5-yl)-2-hydroxyacetic acid (XII).The cyclization of (XII) with acetone and concentrated H2SO4 affords (R)-(-)-5-(benzo[b]thiophen-5-yl)-2,2-dimethyl-1,3-dioxolan-4-one (XIII),which,by treatment with methanol and H2SO4,is converted into (R)-(-)-2-(benzo[b]thiophen-5-yl)-2-hydroxyacetic acid methyl ester (XIV).The protection of the OH group of (XIV) with dihydropyran (DHP) and pyridinium p-toluenesulfonate (Pyr稵sOH) affords the corresponding tetrahydropyranyl ether (XV),which is reduced with NaBH4 in ethanol,giving (R)-(-)-2-(benzo[b]thiophen-5-yl)-2-(tetrahydropyranyloxy)ethanol (XVI).Finally,this compound is condensed with 2-(diethylamino)ethyl chloride (XVII) by means of NaOH and tetrabutylammonium hydrogensulfate in toluene/water,followed by acidification with HCl.3) The (R)-dioxolane (XIII) can also be obtained as follows: The racemic hydroxyacetic acid (XI) is cyclized with acetone and H2SO4 as before,giving the racemic dioxolane (XVIII).This compound is dissolved in hot (50 C) tert-amyl alcohol along with 1,8-diazabicyclo[5.4.0]-7-undecene (DCU); this solution is then seeded with a suspension of the (R)-(-)-isomer (XIII) in the same solvent and is slowly cooled at 25 C; a 81% yield of pure crystals of (R)-(-)-isomer (XIII) is obtained.This procedure allows for improving the yields by recovering the unused (S)-(+)-isomer.
参考文献标题:T-588
文献作者:Martel,A.M.; Prous,J.; Castar,J.
参考来源:Drugs Fut 1997,22(4),386
产品链接: CAS No. 142935-03-3››