MN-221, KUR-1246, -Drug Synthesis Database

【结构式】

【药物名称】MN-221, KUR-1246

【化学名称】(-)-2-[7(S)-[2(R)-Hydroxy-2-[4-hydroxy-3-(2-hydroxyethyl)phenyl]ethylamino]-5,6,7,8-tetrahydronaphthalen-2-yloxy]-N,N-dimethylacetamide sulfate (2:1)

【CA登记号】194785-31-4, 194785-19-8 (free base)

【分子式】C₄₈H₆₆N₄O₁₄S

【分子量】955.14362

【开发单位】Kissei (Originator), MediciNova (Licensee), Teikoku Hormone (Codevelopment)

【药理作用】ENDOCRINE DRUGS, Gynecological Disorders, Treatment of , Treatment of Preterm Labor, beta2-Adrenoceptor Agonists

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

The benzyl-protected 2-(2-hydroxyethyl)phenol (I) was brominated in HOAc to give (II). Lithiation of aryl bromide (II) followed by in situ condensation of the resulting organolithium derivative (III) with diethyl oxalate under -95 C furnished the keto ester (IV). Subsequent ketone reduction by NaBH4 afforded hydroxy ester (V), which was further hydrolyzed to the mandelic acid derivative (VI). The condensation of racemic acid (VI) with (S)-2-amino-7-hydroxytetraline (VII) gave rise to a diastereomeric mixture of hydroxy amides from which the desired (S,R)-diastereoisomer (VIII) was isolated by column chromatography. Reduction of the amide function of (VIII) using borane-dimethyl sulfide complex yielded the amino alcohol (IX). Alkylation of the phenolic hydroxyl group of (IX) with 2-bromo-N,N-dimethylacetamide (X) provided the corresponding (aryloxy)acetamide (XI). Then, hydrogenolysis of the benzyl protecting groups over Pd/C furnished the target compound, which was finally isolated as the corresponding sulfate salt.

参考文献中间体

【1】 Kitazawa, M.; Okazaki, K.; Tamai, T.; Saito, M.; Muranaka, H.; Tanaka, N.; Kobayahi, H.; Kikuchi, K. (Kissei Pharmaceutical Co., Ltd.); 3,4-Disubstd. phenylethanolaminotetralincarboxamide derivs.. EP 0882704; US 6133266; WO 9730023 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	50674	1-(benzyloxy)-2-[2-(benzyloxy)ethyl]benzene; benzyl 2-[2-(benzyloxy)ethyl]phenyl ether	C₂₂H₂₂O₂	详情	详情
(II)	50675	benzyl 2-(benzyloxy)-5-bromophenethyl ether; 1-(benzyloxy)-2-[2-(benzyloxy)ethyl]-4-bromobenzene	C₂₂H₂₁BrO₂	详情	详情
(III)	50676	[4-(benzyloxy)-3-[2-(benzyloxy)ethyl]phenyl]lithium	C₂₂H₂₁LiO₂	详情	详情
(IV)	50677	ethyl 2-[4-(benzyloxy)-3-[2-(benzyloxy)ethyl]phenyl]-2-oxoacetate	C₂₆H₂₆O₅	详情	详情
(V)	50678	ethyl 2-[4-(benzyloxy)-3-[2-(benzyloxy)ethyl]phenyl]-2-hydroxyacetate	C₂₆H₂₈O₅	详情	详情
(VI)	50679	2-[4-(benzyloxy)-3-[2-(benzyloxy)ethyl]phenyl]-2-hydroxyacetic acid	C₂₄H₂₄O₅	详情	详情
(VII)	32819	(7S)-7-amino-5,6,7,8-tetrahydro-2-naphthalenol	C₁₀H₁₃NO	详情	详情
(VIII)	50680	(2R)-2-[4-(benzyloxy)-3-[2-(benzyloxy)ethyl]phenyl]-2-hydroxy-N-[(2S)-7-hydroxy-1,2,3,4-tetrahydro-2-naphthalenyl]ethanamide	C₃₄H₃₅NO₅	详情	详情
(IX)	50681	(7S)-7-[((2R)-2-[4-(benzyloxy)-3-[2-(benzyloxy)ethyl]phenyl]-2-hydroxyethyl)amino]-5,6,7,8-tetrahydro-2-naphthalenol	C₃₄H₃₇NO₄	详情	详情
(X)	29753	2-bromo-N,N-dimethylacetamide	C₄H₈BrNO	详情	详情
(XI)	50682	2-([(7S)-7-[((2R)-2-[4-(benzyloxy)-3-[2-(benzyloxy)ethyl]phenyl]-2-hydroxyethyl)amino]-5,6,7,8-tetrahydro-2-naphthalenyl]oxy)-N,N-dimethylacetamide	C₃₈H₄₄N₂O₅	详情	详情

合成路线2

An alternative method, suitable for large-scale synthesis, has been described: The chloromethylation of 4'-hydroxyacetophenone (XII) using formaldehyde and HCl gave (XIII). Displacement of the chloride group with NaCN provided nitrile (XIV), which was further hydrolyzed to the carboxylic acid (XV). Esterification of (XV) with methanol and sulfuric acid yields (XVI), whose phenolic hydroxyl group was protected as the benzyl ether (XVII) by alkylation with benzyl chloride. Subsequent bromination of ketone (XVII) yielded the phenacyl bromide (XVIII). The chiral amino alcohol (XX) was prepared from (-)-camphor (XIX) by ketone oxidation in position alpha with SeO2, followed by condensation with hydroxylamine and reduction with LiAlH4. Asymmetric reduction of the bromo ketone (XVIII) with borane in the presence of aluminum triethoxide and the chiral auxiliary (XX) provided the desired (R)-bromohydrin (XXI). The hydroxyl groups of (XXI) were then protected by silylation with tert-butyldimethylsilyl chloride, yielding (XXII). Condensation of the silyl-protected bromide (XXII) with (S)-2[(2-amino-1,2,3,4-tetrahydronaphthalen-7-yl)oxy]-N,N-dimethylacetamide (XXIII) furnished adduct (XXIV).

参考文献中间体

【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
(XII)	18123	1-(4-hydroxyphenyl)-1-ethanone; 4'-Hydroxyacetophenone	99-93-4	C₈H₈O₂	详情	详情
(XIII)	39615	1-[3-(chloromethyl)-4-hydroxyphenyl]-1-ethanone		C₉H₉ClO₂	详情	详情
(XIV)	50683	2-(5-acetyl-2-hydroxyphenyl)acetonitrile		C₁₀H₉NO₂	详情	详情
(XV)	50684	2-(5-acetyl-2-hydroxyphenyl)acetic acid		C₁₀H₁₀O₄	详情	详情
(XVI)	50685	methyl 2-(5-acetyl-2-hydroxyphenyl)acetate		C₁₁H₁₂O₄	详情	详情
(XVII)	50686	methyl 2-[5-acetyl-2-(benzyloxy)phenyl]acetate		C₁₈H₁₈O₄	详情	详情
(XVIII)	50687	methyl 2-[2-(benzyloxy)-5-(2-bromoacetyl)phenyl]acetate		C₁₈H₁₇BrO₄	详情	详情
(XIX)	17415	(1R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one	464-49-3	C₁₀H₁₆O	详情	详情
(XX)	50688	(1R,2S,3R,4S)-3-amino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol		C₁₀H₁₉NO	详情	详情
(XXI)	50689	(1R)-1-[4-(benzyloxy)-3-(2-hydroxyethyl)phenyl]-2-bromo-1-ethanol		C₁₇H₁₉BrO₃	详情	详情
(XXII)	50690	([(1R)-1-[4-(benzyloxy)-3-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)phenyl]-2-bromoethyl]oxy)(tert-butyl)dimethylsilane; benzyl 4-((1R)-2-bromo-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)phenyl ether		C₂₉H₄₇BrO₃Si₂	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
(XXIV)	50692	2-([(7S)-7-[((2R)-2-[4-(benzyloxy)-3-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)phenyl]-2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)amino]-5,6,7,8-tetrahydro-2-naphthalenyl]oxy)-N,N-dimethylacetamide		C₄₃H₆₆N₂O₅Si₂	详情	详情

合成路线3

The silyl protecting groups of (XXIV) were cleaved by acidic treatment yielding diol (XXV). Then, O-benzyl group hydrogenolysis in (XXV) using Pd/C, followed by salification with H2SO4, provided the title compound.

参考文献中间体

【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
(XXIV)	50692	2-([(7S)-7-[((2R)-2-[4-(benzyloxy)-3-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)phenyl]-2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)amino]-5,6,7,8-tetrahydro-2-naphthalenyl]oxy)-N,N-dimethylacetamide		C₄₃H₆₆N₂O₅Si₂	详情	详情
(XXV)	50693	2-[[(7S)-7-([(2R)-2-[4-(benzyloxy)-3-(2-hydroxyethyl)phenyl]-2-hydroxyethyl]amino)-5,6,7,8-tetrahydro-2-naphthalenyl]oxy]-N,N-dimethylacetamide		C₃₁H₃₈N₂O₅	详情	详情

合成路线4

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).

参考文献中间体

【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

Extended Information

Drug NewChemical Entity Original Patent(1)