【结 构 式】 |
【分子编号】32820 【品名】(2S)-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenylamine; (2S)-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenamine 【CA登记号】 |
【 分 子 式 】C11H15NO 【 分 子 量 】177.24624 【元素组成】C 74.54% H 8.53% N 7.9% O 9.03% |
合成路线1
该中间体在本合成路线中的序号:(IV)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.
【1】 Devocelle, M.; et al.; Alternative synthesis of the chiral atypical beta-adrenergic phenylethanolaminotetraline agonist SR58611A using enantioselective hydrogenation. Tetrahedron Lett 1999, 40, 24, 4551. |
【2】 Cecchi, R.; et al.; Synthesis and beta-adrenergic activity of atypical beta-adrenergic phenylethanolaminotetralin stereoisomers. Eur J Med Chem 1994, 29, 4, 259. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
40592 | Benzamide | 55-21-0 | C7H7NO | 详情 | 详情 | |
(rac)-(IV) | 32818 | 7-methoxy-1,2,3,4-tetrahydro-2-naphthalenylamine; 7-methoxy-1,2,3,4-tetrahydro-2-naphthalenamine | C11H15NO | 详情 | 详情 | |
(I) | 24999 | 7-methoxy-3,4-dihydro-2(1H)-naphthalenone | 4133-34-0 | C11H12O2 | 详情 | 详情 |
(II) | 32816 | N-(7-methoxy-3,4-dihydro-2-naphthalenyl)benzamide | C18H17NO2 | 详情 | 详情 | |
(III) | 32817 | N-[(2S)-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]benzamide | C18H19NO2 | 详情 | 详情 | |
(IV) | 32820 | (2S)-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenylamine; (2S)-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenamine | C11H15NO | 详情 | 详情 | |
(V) | 32819 | (7S)-7-amino-5,6,7,8-tetrahydro-2-naphthalenol | C10H13NO | 详情 | 详情 | |
(VI) | 32821 | tert-butyl (2S)-7-hydroxy-1,2,3,4-tetrahydro-2-naphthalenylcarbamate | C15H21NO3 | 详情 | 详情 | |
(VII) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
(VIII) | 32822 | ethyl 2-([(7S)-7-[(tert-butoxycarbonyl)amino]-5,6,7,8-tetrahydro-2-naphthalenyl]oxy)acetate | C19H27NO5 | 详情 | 详情 | |
(IX) | 32823 | ethyl 2-[[(7S)-7-amino-5,6,7,8-tetrahydro-2-naphthalenyl]oxy]acetate | C14H19NO3 | 详情 | 详情 | |
(X) | 15271 | (R)-(+)-3-Chlorostyrene oxide; (2R)-2-(3-Chlorophenyl)oxirane | 62600-71-9 | C8H7ClO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(IV)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).
【1】 Devocelle, M.; et al.; Alternative synthesis of the chiral atypical beta-adrenergic phenylethanolaminotetraline agonist SR58611A using enantioselective hydrogenation. Tetrahedron Lett 1999, 40, 24, 4551. |
【2】 Cecchi, R.; et al.; Synthesis and beta-adrenergic activity of atypical beta-adrenergic phenylethanolaminotetralin stereoisomers. Eur J Med Chem 1994, 29, 4, 259. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(IV) | 32820 | (2S)-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenylamine; (2S)-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenamine | C11H15NO | 详情 | 详情 | |
(XV) | 18410 | N-[(3S)-2,5-dioxotetrahydro-3-furanyl]-2,2,2-trifluoroacetamide | 777-33-3 | C6H4F3NO4 | 详情 | 详情 |
(XVI) | 23767 | Methoxybenzene; Methyl phenyl ether; Anisole | 100-66-3 | C7H8O | 详情 | 详情 |
(XVII) | 32827 | (2S)-4-(4-methoxyphenyl)-4-oxo-2-[(2,2,2-trifluoroacetyl)amino]butyric acid | C13H12F3NO5 | 详情 | 详情 | |
(XVIII) | 32828 | (2S)-4-(4-methoxyphenyl)-2-[(2,2,2-trifluoroacetyl)amino]butyric acid | C13H14F3NO4 | 详情 | 详情 | |
(XIX) | 32829 | 2,2,2-trifluoro-N-[(2S)-7-methoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthalenyl]acetamide | C13H12F3NO3 | 详情 | 详情 | |
(XX) | 32830 | 2,2,2-trifluoro-N-[(2S)-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]acetamide | C13H14F3NO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(XXVI)The optically pure (S)-amine (XXIII) was prepared as follows: Demethylation of the previously described (S)-7-methoxy-1,2,3,4-tetrahydronaphth-2-ylamine (XXVI) in concentrated HBr under reflux gave the amino naphthol (VII). After protection of the amino group of (VII) as the N-Boc derivative (XXVII), the phenolic hydroxyl was alkylated with 2-chloro-N,N-dimethylacetamide (XXVIII) to give (XXIX). Then, Boc group cleavage in (XXIX) by means of HCl in isopropanol furnished the intermediate amine (XXIII).
【1】 Yanagi, T.; et al.; The practical synthesis of a uterine relaxant, bis (2-{[2S)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(2-hydroxyethyl)-phenyl]ethyl}amino)-1,2,3,4-tetrahydronaphthalen-7-yl]oxy}-N,N-dimethylacetamide)sulfate (KUR-1246). Chem Pharm Bull 2001, 49, 8, 1018. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(VII) | 32819 | (7S)-7-amino-5,6,7,8-tetrahydro-2-naphthalenol | C10H13NO | 详情 | 详情 | |
(XXIII) | 50691 | 2-[[(7S)-7-amino-5,6,7,8-tetrahydro-2-naphthalenyl]oxy]-N,N-dimethylacetamide | C14H20N2O2 | 详情 | 详情 | |
(XXVI) | 32820 | (2S)-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenylamine; (2S)-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenamine | C11H15NO | 详情 | 详情 | |
(XXVII) | 32821 | tert-butyl (2S)-7-hydroxy-1,2,3,4-tetrahydro-2-naphthalenylcarbamate | C15H21NO3 | 详情 | 详情 | |
(XXVIII) | 12998 | 2-Chloro-N,N-dimethylacetamide | 2675-89-0 | C4H8ClNO | 详情 | 详情 |
(XXIX) | 50694 | tert-butyl (2S)-7-[2-(dimethylamino)-2-oxoethoxy]-1,2,3,4-tetrahydro-2-naphthalenylcarbamate | C19H28N2O4 | 详情 | 详情 |