2-(7-methoxy-1-naphthyl)acetonitrile -Drug Synthesis Database

【结构式】

【分子编号】36604

【品名】2-(7-methoxy-1-naphthyl)acetonitrile

【CA登记号】

【分子式】C₁₃H₁₁NO

【分子量】197.23648

【元素组成】C 79.17% H 5.62% N 7.1% O 8.11%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VII)

Reformatskii reaction between 7-methoxy-1-tetralone (I) and the organozinc reagent generated from ethyl bromoacetate, followed by dehydration of the intermediate carbinol in the presence of P2O5 gives 2-(7-methoxy-1,2,3,4-tetrahydro-1-naphthylidene)acetic acid ethyl ester (II). Aromatization of compound (II) by heating with sulfur at 215 C results in the corresponding naphthalene derivative (III), which is submited to basic hydrolysis of the ethyl ester group (III) to provide 2-(7-methoxy-1-naphthyl)acetic acid (IV). After activation of (IV) with SOCl2, the crude acid chloride is treated with ammonium hydroxide to produce amide (V), which by direct reduction with LiAlH4 furnishes amine (VI) in low yields. An alternative procedure consists of the dehydration of amide (V) with trifluoroacetic anhydride to afford nitrile (VII), which is then reduced to the desired amine (VI) by catalytic hydrogenation. Finally, agomelatine is obtained by reaction of amine (VI) with acetyl chloride in pyridine or in a biphasic medium (H2OCHCl3) under Schotten-Baumann conditions.

参考文献中间体

合成目标

【1】 Silvestre, J.S.; Bayes, M.; Chilman-Blair, K.; Castaner, J.; Agomelatine. Drugs Fut 2003, 28, 1, 7.
【2】 Andrieux, J.; Houssin, R.; Said, Y.; Guardiola-Lemaitre, B.; Lesieur, D. (ADIR et Cie.); Novel derivs. with a naphthalenic structure, their process of preparation and pharmaceutical compsns. containing them. EP 0447285; FR 2658819; JP 1995048331; US 5318994 .
【3】 Guardiola-Lemaitre, B.; Renard, P.; Pfeiffer, B.; Caignard, D.-H.; Andrieux, J.; Howell, H.-E.; Morgan, P.; Yous, S.; Lesieur, D.; Adam, G.; Novel naphthalenic ligands for the melatonin receptor. J Pharm Belg 1992, 47, 4, 374.
【4】 Morgan, P.J.; Howell, H.E.; Lesieur, D.; Guardiola-Lemaitre, B.; Pfeiffer, B.; Andrieux, J.; Renard, P.; Yous, S.; Novel naphthalenic ligands with high affinity for the melatonin receptor. J Med Chem 1992, 35, 8, 1484.
【5】 Depreux, P.; Lesieur, D.; Mansour, H.A.; et al.; Synthesis and structure-activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligands. J Med Chem 1994, 37, 20, 3231.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	16640	Ethyl 2-bromoacetate; Ethyl bromoacetate	105-36-2	C₄H₇BrO₂	详情	详情
	19273	acetyl chloride	75-36-5	C₂H₃ClO	详情	详情
(I)	21385	7-methoxy-3,4-dihydro-1(2H)-naphthalenone	6836-19-7	C₁₁H₁₂O₂	详情	详情
(II)	58079	ethyl 2-[7-methoxy-3,4-dihydro-1(2H)-naphthalenylidene]acetate		C₁₅H₁₈O₃	详情	详情
(III)	58080	ethyl 2-(7-methoxy-1-naphthyl)acetate		C₁₅H₁₆O₃	详情	详情
(IV)	58081	2-(7-methoxy-1-naphthyl)acetic acid		C₁₃H₁₂O₃	详情	详情
(V)	58082	2-(7-methoxy-1-naphthyl)acetamide		C₁₃H₁₃NO₂	详情	详情
(VI)	58083	2-(7-methoxy-1-naphthyl)-1-ethanamine; 2-(7-methoxy-1-naphthyl)ethylamine		C₁₃H₁₅NO	详情	详情
(VII)	36604	2-(7-methoxy-1-naphthyl)acetonitrile		C₁₃H₁₁NO	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Alkylation of (7-methoxy-1-naphthyl)acetonitrile (I) with iodomethane in the presence of NaH gave the corresponding naphthylpropionitrile (II), which was reduced to amine (III) by catalytic hydrogenation over Raney-Ni. Finally, condensation of (III) with butyryl chloride in the presence of triethylamine provided the title butyramide.

参考文献中间体

合成目标

【1】 Andrieux, J.; Jellimann, C.; Langlois, M.; Mathé-Allainmat, M.; le Gall, M.; Synthesis of beta-substituted naphth-1-yl ethylamido derivatives as new melatoninergic agonists. Bioorg Med Chem 1999, 7, 12, 2945.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	15967	propanoyl chloride; propionyl chloride	79-03-8	C₃H₅ClO	详情	详情
(I)	36604	2-(7-methoxy-1-naphthyl)acetonitrile		C₁₃H₁₁NO	详情	详情
(II)	36605	2-(7-methoxy-1-naphthyl)propanenitrile		C₁₄H₁₃NO	详情	详情
(III)	36606	2-(7-methoxy-1-naphthyl)-1-propanamine; 2-(7-methoxy-1-naphthyl)propylamine		C₁₄H₁₇NO	详情	详情

Extended Information