合成路线:1) The reduction of 2-thiophenecarboxaldehyde cyanohydrin (I) with LiAlH4 gives 2-amino-1-(2-thienyl)ethanol (II),which is N-protected with di-tert-butyl pyrocarbonate yielding 2-(tert-butoxycarbonylamino)-1-(2-thienyl)ethanol (III).The reaction of (III) with PCl5 in dichloromethane affords 2-(tert-butoxycarbonylamino)-1-chloro-1-(2-thienyl)ethane (IV),which is condensed with benzhydryl N-phthaloylcysteinate (V) by means of Na2CO3 in hot DMF giving the S-substituted cysteinate (VI).The deprotection of (VI) with trifluoroacetic acid in anisole yields S-[2-amino-1-(2-thienyl)ethyl]-N-phthaloylcysteine (VII),which is cyclized by means of diphenylphosphoryl azide (DPA) in DMF giving 6-phthalimido-2-(2-thienyl)perhydro-1,4-thiazepin-5-one (VIII).The condensation of (VIII) with tert-butyl bromoacetate (IX) by means of NaH in DMF affords tert-butyl 2-[6-phthalimido-5-oxo-2-(2-thienyl)perhydro-1,4-thiazepin-4-yl]acetate (X),which is treated with methylhydrazine in methanol-dichloromethane yielding the 6-amino derivative (XI).The condensation of (XI) with ethyl 2-bromo-4-phenylbutyrate (XII) by means of Na2CO3 in hot DMF gives the tert-butyl ester of the desired product (XIII),which is finally deprotected with trifluoroacetic acid in anisole.
合成路线:2) The addition of tert-butoxycarbonyl)-L-cysteine (XIV) to 2-(2-nitroethenyl)thiophene (XV) by means of N-methylmorpholine in toluene gives S-[2-nitro-1-(2-thienyl)ethyl-N-(tert-butoxycarbonyl-L-cysteine (XVI),which is reduced with H2 over Pd/C in acetic acid yielding the corresponding amine (XVII).The cyclization of (XVII) by means of diphenyl phosphorazidate (DPN) and N-methylmorpholine in DMF affords (2RS,6R)-6-(tert-butoxycarbonylamino)-2-(2-thienyl)perhydro-1,4-thiazepine (XVIII),which by hydrolysis and fractional crystallization gives (2S,6R)-6-amino-2-(2-thienyl)perhydro-1,4-thiazepine (XIX).The condensation of (XIX) with ethyl 2(R)-(trifluoromethylsulfonyloxy)-4-phenylbutanoate (XX) by means of triethylamine in dichloromethane yields (2S,2R)-6-[1(S)-(ethoxycarbonyl)-3-phenylpropylamino]-2-(2-thienyl)- perhydro-1,4-thiazepin-5-one (XXI),which is condensed with tert-butyl bromoacetate (XXII) by means of NaH in DMF to give the precursor (XXIII).Finally,this compound is hydrolyzed with 4N-HCl-dioxane at room temperature.
参考文献标题:RS-5142
文献作者:Prous,J.; Castar,J.
参考来源:Drugs Fut 1989,14(4),336
合成路线:1) The reduction of 2-thiophenecarboxaldehyde cyanohydrin (I) with LiAlH4 gives 2-amino-1-(2-thienyl)ethanol (II),which is N-protected with di-tert-butyl pyrocarbonate yielding 2-(tert-butoxycarbonylamino)-1-(2-thienyl)ethanol (III).The reaction of (III) with PCl5 in dichloromethane affords 2-(tert-butoxycarbonylamino)-1-chloro-1-(2-thienyl)ethane (IV),which is condensed with benzhydryl N-phthaloylcysteinate (V) by means of Na2CO3 in hot DMF giving the S-substituted cysteinate (VI).The deprotection of (VI) with trifluoroacetic acid in anisole yields S-[2-amino-1-(2-thienyl)ethyl]-N-phthaloylcysteine (VII),which is cyclized by means of diphenylphosphoryl azide (DPA) in DMF giving 6-phthalimido-2-(2-thienyl)perhydro-1,4-thiazepin-5-one (VIII).The condensation of (VIII) with tert-butyl bromoacetate (IX) by means of NaH in DMF affords tert-butyl 2-[6-phthalimido-5-oxo-2-(2-thienyl)perhydro-1,4-thiazepin-4-yl]acetate (X),which is treated with methylhydrazine in methanol-dichloromethane yielding the 6-amino derivative (XI).The condensation of (XI) with ethyl 2-bromo-4-phenylbutyrate (XII) by means of Na2CO3 in hot DMF gives the tert-butyl ester of the desired product (XIII),which is finally deprotected with trifluoroacetic acid in anisole.
合成路线:2) The addition of tert-butoxycarbonyl)-L-cysteine (XIV) to 2-(2-nitroethenyl)thiophene (XV) by means of N-methylmorpholine in toluene gives S-[2-nitro-1-(2-thienyl)ethyl-N-(tert-butoxycarbonyl-L-cysteine (XVI),which is reduced with H2 over Pd/C in acetic acid yielding the corresponding amine (XVII).The cyclization of (XVII) by means of diphenyl phosphorazidate (DPN) and N-methylmorpholine in DMF affords (2RS,6R)-6-(tert-butoxycarbonylamino)-2-(2-thienyl)perhydro-1,4-thiazepine (XVIII),which by hydrolysis and fractional crystallization gives (2S,6R)-6-amino-2-(2-thienyl)perhydro-1,4-thiazepine (XIX).The condensation of (XIX) with ethyl 2(R)-(trifluoromethylsulfonyloxy)-4-phenylbutanoate (XX) by means of triethylamine in dichloromethane yields (2S,2R)-6-[1(S)-(ethoxycarbonyl)-3-phenylpropylamino]-2-(2-thienyl)- perhydro-1,4-thiazepin-5-one (XXI),which is condensed with tert-butyl bromoacetate (XXII) by means of NaH in DMF to give the precursor (XXIII).Finally,this compound is hydrolyzed with 4N-HCl-dioxane at room temperature.
参考文献标题:Angiotensin-converting enzyme inhibitors: Perhydro-1,4-thiazepin-5-one derivatives
文献作者:Ishihara,S.; Ando,A.; Miyamoto,S.; Kanazaki,T.; Hata,T.; Oizumi,K.; Matsushita,Y.; Koike,H.; Yanagisawa,H.; Iijima,Y.
参考来源:J Med Chem 1987,30(11),1984
产品链接: CAS No. 110221-44-8›› 产品链接: CAS No.111902-57-9››