(2S)-5-methoxy-N-propyl-1,2,3,4-tetrahydro-2-naphthalenamine; N-[(2S)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]-N-propylamine -Drug Synthesis Database

【结构式】

【分子编号】14649

【品名】(2S)-5-methoxy-N-propyl-1,2,3,4-tetrahydro-2-naphthalenamine; N-[(2S)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]-N-propylamine

【CA登记号】

【分子式】C₁₄H₂₁NO

【分子量】219.32688

【元素组成】C 76.67% H 9.65% N 6.39% O 7.29%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(V)

The overall synthetic approach to N-0923 is described: Methylation of 1,6-dihydroxynaphthalene (I) with dimethyl sulfate provides 1,6-dimethoxynaphthalene (II), which is converted to 5-methoxy-2-tetralone (III) by reduction with sodium in ethanol. Reductive amination of (III) with propylamine results in the racemic 5-methoxy-2-N-propylaminotetralin (IV), from which the (-)-enantiomer (V) is obtained by fractional crystallization of the dibenzoyl-L-tartaric acid (L-DBTA) salt. Demethylation with aqueous hydrobromic acid affords (-)-(S)-5-hydroxy-2-N-propylaminotetralin (VI), which is reductively alkylated with thienylacetic acid in the presence of trimethylaminoborane to (-)-(S)-5-hydroxy-2-[N-propyl-N-[2-(2-thienyl)ethyl]amino]tetralin (VII). Treatment with anhydrous hydrogen chloride in ether provides N-0923.

参考文献中间体

合成目标

【1】 Evans, D.; Grey, T.F.; Richards, K.E.; Ames, D.E.; Islip, P.J.; Synthesis of alkoxy-1,2,3,4-tetrahydronaphthalene derivatives. J Chem Soc 1965, 2636-41.
【2】 Wynberg, H.; Ten Hoeve, W.; Ten Hoeve, W., Wynberg, H. The design of resolving agents. Chiral phosphoric acids. J Org Chem 1985, 50, 4508-14.
【3】 Manimaran, T.; Impastato, F.J. (Ethyl Corporation); Resolution of racemic mixtures. US 4968837 .
【4】 Cusack, N.J.; Peck, J.V.; N-0923. Drugs Fut 1993, 18, 11, 1005.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	22959	2-(2-thienyl)acetic acid	1918-77-0	C₆H₆O₂S	详情	详情
(I)	14645	1,6-naphthalenediol; 1,6-Dihydroxynaphthalene	575-44-0	C₁₀H₈O₂	详情	详情
(II)	14646	5-methoxy-2-naphthyl methyl ether; 1,6-dimethoxynaphthalene	3900-49-0	C₁₂H₁₂O₂	详情	详情
(III)	14647	5-methoxy-3,4-dihydro-2(1H)-naphthalenone	32940-15-1	C₁₁H₁₂O₂	详情	详情
(IV)	14648	N-(5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-N-propylamine; 5-methoxy-N-propyl-1,2,3,4-tetrahydro-2-naphthalenamine		C₁₄H₂₁NO	详情	详情
(V)	14649	(2S)-5-methoxy-N-propyl-1,2,3,4-tetrahydro-2-naphthalenamine; N-[(2S)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]-N-propylamine		C₁₄H₂₁NO	详情	详情
(VI)	14650	(6S)-6-(propylamino)-5,6,7,8-tetrahydro-1-naphthalenol		C₁₃H₁₉NO	详情	详情
(VII)	14651	(6S)-6-[propyl[2-(2-thienyl)ethyl]amino]-5,6,7,8-tetrahydro-1-naphthalenol		C₁₉H₂₅NOS	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 acylation of 5-methoxy-1,2,3,4-tetrahydronaphthalene-2-(R)-amine (I) with propionyl chloride (II) and NaOH in dichloromethane/water gives the corresponding amide (III), which is reduced with LiAlH4 in refluxing THF yielding the corresponding secondary amine (IV). The alkylation of (IV) with bromoacetonitrile (V) by means of K2CO3 in refluxing acetone affords the expected tertiary amine (VI), which is reduced with LiAlH4 in refluxing THF providing the ethylenediamine (VII). Finally, this compound is benzoylated with benzoyl chloride and NaOH in dichloromethane/water.

参考文献中间体

合成目标

【1】 Homan, E.J.; Grol, C.J.; Unelius, L.; Wilkstrom, H.V.; Copinga, S.; Jackson, D.M.; Synthesis and pharmacology of the enantiomers of the potential atypical antipsychotic agents 5-OMe-BPAT and 5-OMe-(2,6-di-OMe)-BPAT. Bioorg Med Chem 1999, 7, 7, 1263.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	31886	(2R)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenamine; (2R)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenylamine		C₁₁H₁₅NO	详情	详情
(II)	15967	propanoyl chloride; propionyl chloride	79-03-8	C₃H₅ClO	详情	详情
(III)	31882	N-[(2R)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]propanamide; N-[(2R)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]propanamide		C₁₄H₁₉NO₂	详情	详情
(IV)	14649	(2S)-5-methoxy-N-propyl-1,2,3,4-tetrahydro-2-naphthalenamine; N-[(2S)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]-N-propylamine		C₁₄H₂₁NO	详情	详情
(V)	31883	2-bromoacetonitrile	590-17-0	C₂H₂BrN	详情	详情
(VI)	31884	2-[[(2R)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl](propyl)amino]acetonitrile		C₁₆H₂₂N₂O	详情	详情
(VII)	31885	N(1)-[(2R)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]-N(1)-propyl-1,2-ethanediamine; N-(2-aminoethyl)-N-[(2R)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]-N-propylamine		C₁₆H₂₆N₂O	详情	详情
(VIII)	10463	Benzoyl chloride	98-88-4	C₇H₅ClO	详情	详情

合成路线3

该中间体在本合成路线中的序号： (V)

参考文献中间体

合成目标

【1】 Hacksell U, Svensson U, Nilsson JLG.1979.N-Alkylated 2-aminotetralins: central dopamine-receptor stimulating activity.J Med Chem, 22: 1469～1475.
【2】 Marquillas Olondriz F, Pomares Marco M.2010.Process for the preparation of optically active (S)-(-)-2-(N-propylamino)-5-methoxytetraline and (S)-(-)-2-(N-propylamino)-5-hydroxytetraline compounds. WO 2010/043571 A1.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	14649	(2S)-5-methoxy-N-propyl-1,2,3,4-tetrahydro-2-naphthalenamine; N-[(2S)-5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]-N-propylamine		C₁₄H₂₁NO	详情	详情
(I)	14647	5-methoxy-3,4-dihydro-2(1H)-naphthalenone	32940-15-1	C₁₁H₁₂O₂	详情	详情
(II)	14648	N-(5-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-N-propylamine; 5-methoxy-N-propyl-1,2,3,4-tetrahydro-2-naphthalenamine		C₁₄H₂₁NO	详情	详情
(III)	67412	(R)-2-(3,5-dinitrobenzamido)-2-phenylacetic acid		C₁₅H₁₁N₃O₇	详情	详情
(IV)	67413			C₁₄H₂₁NO.C₁₅H₁₁N₃O₇	详情	详情
(VI)	67414	(R)-5-methoxy-N-propyl-N-(2-(thiophen-2-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-2-amine		C₂₀H₂₇NOS	详情	详情

Extended Information