SR-58611, SR-58611A, -Drug Synthesis Database

【结构式】

【药物名称】SR-58611, SR-58611A

【化学名称】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

【CA登记号】107758-28-1 (oxalate salt;non-specified stereoch.), 107758-27-0 (undefined stereoch.)

【分子式】C₂₂H₂₇Cl₂NO₄

【分子量】440.37079

【开发单位】Sanofi-synthélabo (Originator)

【药理作用】Antidepressants, Antidiabetic Drugs, Antiobesity Drugs, ENDOCRINE DRUGS, METABOLIC DRUGS, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, Treatment of Diabetic Complications, Treatment of Nutritional Disorders, Type 2 Diabetes Mellitus, Agents for, beta3-Adrenoceptor Agonists

合成路线1 合成路线2 合成路线3

合成路线1

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.

参考文献中间体

【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

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).

参考文献中间体

【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.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(X)	15271	(R)-(+)-3-Chlorostyrene oxide; (2R)-2-(3-Chlorophenyl)oxirane	62600-71-9	C₈H₇ClO	详情	详情
(XI)	15268	m-chloroacetophenone; 1-(3-chlorophenyl)-1-ethanone	99-02-5	C₈H₇ClO	详情	详情
(XII)	32824	2-bromo-1-(3-chlorophenyl)-1-ethanone		C₈H₆BrClO	详情	详情
(XIII)	32825	1-(3-chlorophenyl)-2-(dimethylamino)-1-ethanone		C₁₀H₁₂ClNO	详情	详情
(XIV)	32826	(1R)-1-(3-chlorophenyl)-2-(dimethylamino)-1-ethanol		C₁₀H₁₄ClNO	详情	详情

合成路线3

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).

参考文献中间体

【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

Extended Information