SR-58611, SR-58611A
Chemical Name: N-[7-(Ethoxycarbonylmethoxy)-1,2,3,4-tetrahydronaphth-2(S)-yl]-2(R)-(3-chlorophenyl)-2-hydroxyethanamine hydrochloride; [7-[2-(3-Chlorophenyl)-2(R)-hydroxyethylamino]-5,6,7,8-tetrahydro-2(S)-naphthalenyloxy]acetic acid ethyl ester hydrochloride
CAS No. 107758-28-1 (oxalate salt, non-specified stereoch.), 107758-27-0 (undefined stereoch.)
项目整合开发状态: Phase III
项目研究机构: Sanofi-Aventis (Originator)
合成路线:The reaction of 7-methoxy-2-tetralone (I) with benzamide in refluxing toluene gives N-(7-methoxy-3,4-dihydronpahthalen-2-yl)benzamide (II),which is enantioselectively hydrogenated with H2 over a chiral Ru or Rh catalyst yielding the chiral benzamide (III).The hydrolysis of (III) with methanesulfonic acid in acetic acid at 160 C affords the chiral 7-methoxy-1,2,3,4-tetrahydronaphthalen-2(S)-amine (IV) ,which is treated with 48% HBr affording 7-hydroxy-1,2,3,4-tetrahydronaphthalen-2(S)-ylamine (V).The protection of the amino group of (V) with Boc2O and triethylamine gives the carbamate (VI),which is condensed with ethyl 2-bromoacetate (VII) by means of K2CO3 yielding 2-[7(S)-(tert-butoxycarbonylamino)-5,6,7,8-tetrahydronaphthalen-2-yloxy]acetic acid ethyl ester (VIII).The deprotection of (VIII) with TFA affords 2-(7(S)-amino-5,6,7,8-tetrahydronaphthalen-2-yloxy]acetic acid ethyl ester (IX),which is finally condensed with the chiral 2(R)-(3-chlorophenyl)oxirane (X) in hot DMS.The chiral intermediate 7-methoxy-1,2,3,4-tetrahydronaphthalen-2(S)-amine (IV) can also by obtained by optical resolution of the racemic mixture (rac)-(IV) by means of (R)-(-)-mandelic acid.
合成路线:The chiral intermediate 7-methoxy-1,2,3,4-tetrahydronaphthalen-2(S)-amine (IV) has also been obtained as follows:The Friedel Crafts condensation of anisole (XV) with N-trifluoroacetyl-L-aspartic acid anhydride (XVI) by means of AlCl3 in dichloromethane gives 4-(4-methoxyphenyl)-4-oxo-2(S)-(trifluoro-acetamido)butyric acid (XVII),which is hydrogenated with H2 over Pd/C in ethanol/H2SO4 yielding 4-(4-methoxyphenyl)-2(S)-(trifluoroacetamido)butyric acid (XVIII).The cyclization of (XVIII) by its reaction with PCl5,followed by a treatment with SnCl4 provides the tetralone (XIX),which is hydrogenated as before to give N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-2(S)-yl)trifluoro-acetamide (XX).Finally,this compound is deacetylated with HCl in ethanol to provide the chiral intermediate the amine (IV).
📌 参考资料/链接：
参考文献标题:Synthesis and beta-adrenergic activity of atypical beta-adrenergic phenylethanolaminotetralin stereoisomers
文献作者:Cecchi,R.; et al.
参考来源:Eur J Med Chem 1994,29(4),259
📄 详细内容
合成路线:The reaction of 7-methoxy-2-tetralone (I) with benzamide in refluxing toluene gives N-(7-methoxy-3,4-dihydronpahthalen-2-yl)benzamide (II),which is enantioselectively hydrogenated with H2 over a chiral Ru or Rh catalyst yielding the chiral benzamide (III).The hydrolysis of (III) with methanesulfonic acid in acetic acid at 160 C affords the chiral 7-methoxy-1,2,3,4-tetrahydronaphthalen-2(S)-amine (IV) ,which is treated with 48% HBr affording 7-hydroxy-1,2,3,4-tetrahydronaphthalen-2(S)-ylamine (V).The protection of the amino group of (V) with Boc2O and triethylamine gives the carbamate (VI),which is condensed with ethyl 2-bromoacetate (VII) by means of K2CO3 yielding 2-[7(S)-(tert-butoxycarbonylamino)-5,6,7,8-tetrahydronaphthalen-2-yloxy]acetic acid ethyl ester (VIII).The deprotection of (VIII) with TFA affords 2-(7(S)-amino-5,6,7,8-tetrahydronaphthalen-2-yloxy]acetic acid ethyl ester (IX),which is finally condensed with the chiral 2(R)-(3-chlorophenyl)oxirane (X) in hot DMS.The chiral intermediate 7-methoxy-1,2,3,4-tetrahydronaphthalen-2(S)-amine (IV) can also by obtained by optical resolution of the racemic mixture (rac)-(IV) by means of (R)-(-)-mandelic acid.
合成路线:The chiral intermediate 2(R)-(3-chlorophenyl)oxirane (X) has been obtained as follows:The bromination of 3'-chloroacetophenone (XI) with Br2 in acetic acid gives the 3'-chlorophenacyl bromide (XII),which is treated with dimethylamine in toluene yielding 3'-chloro-2-(dimethylamino)acetophenone (XIII).The hydrogenation of (XIII) with H2 over a chiral Rh catalyst affords the (R)-alcohol (XIV),which is finally treated with NaOH in chloroform to provide the intermediate oxirane (X).
合成路线:The chiral intermediate 7-methoxy-1,2,3,4-tetrahydronaphthalen-2(S)-amine (IV) has also been obtained as follows:The Friedel Crafts condensation of anisole (XV) with N-trifluoroacetyl-L-aspartic acid anhydride (XVI) by means of AlCl3 in dichloromethane gives 4-(4-methoxyphenyl)-4-oxo-2(S)-(trifluoro-acetamido)butyric acid (XVII),which is hydrogenated with H2 over Pd/C in ethanol/H2SO4 yielding 4-(4-methoxyphenyl)-2(S)-(trifluoroacetamido)butyric acid (XVIII).The cyclization of (XVIII) by its reaction with PCl5,followed by a treatment with SnCl4 provides the tetralone (XIX),which is hydrogenated as before to give N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-2(S)-yl)trifluoro-acetamide (XX).Finally,this compound is deacetylated with HCl in ethanol to provide the chiral intermediate the amine (IV).
参考文献标题:Alternative synthesis of the chiral atypical beta-adrenergic phenylethanolaminotetraline agonist SR58611A using enantioselective hydrogenation
文献作者:Devocelle,M.; et al.
参考来源:Tetrahedron Lett 1999,40(24),4551