N-(5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-N-methylamine; 5,6-dimethoxy-N-methyl-1,2,3,4-tetrahydro-2-naphthalenamine -Drug Synthesis Database

【结构式】

【分子编号】37381

【品名】N-(5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-N-methylamine; 5,6-dimethoxy-N-methyl-1,2,3,4-tetrahydro-2-naphthalenamine

【CA登记号】

【分子式】C₁₃H₁₉NO₂

【分子量】221.2994

【元素组成】C 70.56% H 8.65% N 6.33% O 14.46%

与该中间体有关的原料药合成路线共 6 条

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5 合成路线6

合成路线1

该中间体在本合成路线中的序号：(V)

Nolomirole is synthesized by acylation of (rac)-6-(methylamino)-5,6,7,8-tetrahydronaphthalene-1,2-diol, CHF-1024 (I) with isobutyryl chloride (II) in THF. Reductocondensation of 5,6-dimethoxy-2-tetralone (III) with methylamine (IV) by means of LiBH4 or NaBH4 gives N-(5,6-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methylamine (V), which is treated with 48% HBr at 110 C.

参考文献中间体

合成目标

【1】 Castaner, J.; Mealy, N.E.; Bayes, M.; Leeson, P.A.; Nolomirole Hydrochloride. Drugs Fut 2001, 26, 11, 1046.
【2】 Chiesi, P.; Villani, V. (Chiesi Farmaceutici SpA); 1,2,3,4-Tetrahydronaphthaline derivs., process for their preparation and pharmaceutical compsns. containing them. DE 3320936; GB 2123410 .

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)	49435	6-(methylamino)-5,6,7,8-tetrahydro-1,2-naphthalenediol		C₁₁H₁₅NO₂	详情	详情
(II)	14932	isobutyryl chloride; 2-methylpropanoyl chloride	79-30-1	C₄H₇ClO	详情	详情
(III)	37386	5,6-dimethoxy-3,4-dihydro-2(1H)-naphthalenone		C₁₂H₁₄O₃	详情	详情
(IV)	11021	Methanamine; Methylamine	74-89-5	CH₅N	详情	详情
(V)	37381	N-(5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-N-methylamine; 5,6-dimethoxy-N-methyl-1,2,3,4-tetrahydro-2-naphthalenamine		C₁₃H₁₉NO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

The condensation of 2,3-dimethoxybenzaldehyde (VI) with pyruvic acid (VII) by means of KOH in ethanol/water gives 4-(2,3-dimethoxyphenyl)-2-oxo-3-butenoic acid (VIII), which is reductocondensed with methylamine (IV) by means of H2 over Pd/C in ethanol/ acetic acid to yield 4-(2,3-dimethoxyphenyl)-2-methylamino)butyric acid (IX). Reaction of acid (IX) with benzyl chloroformate (X) and NaOH in water affords the carbamate (XI), which is treated with refluxing SOCl2 to provide 4-[2-(2,3-dimethoxyphenyl)ethyl]-3-methyloxazolidine-2,5-dione (XII). Reaction of oxazolidinone (XII) with AlCl3 in dichloromethane provides 5,6-dimethoxy-2-(methylamino)-1,2,3,4-tetrahydronaphthalen-1-one (XIII), which is reduced with H2 over Pd/C in ethanol containing some methanolic HCl in an autoclave at 80 C to yield N-(5,6-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methylamine (V). Finally, this compound is demethylated by treatment with AlCl3 in hot toluene. Alternatively, 5,6-dimethoxy-2-(methylamino)-1,2,3,4-tetrahydronaphthalen-1-one (XIII) can first be demethylated with 48% HBr to give 5,6-dihydroxy-2-(methylamino)-1,2,3,4-tetrahydronaphthalen-1-one (XIV), which is then reduced by means of H2 over Pd/C in an autoclave at 80 C.

参考文献中间体

合成目标

【1】 Castaner, J.; Mealy, N.E.; Bayes, M.; Leeson, P.A.; Nolomirole Hydrochloride. Drugs Fut 2001, 26, 11, 1046.
【2】 Servadio, V.; Ventura, P.; Amari, G.; Chiesi, P.; Del Canale, M.; De Fanti, R. (Chiesi Farmaceutici SpA); A process for the preparation of 5,6-dihydroxy-2-amino-1,2,3,4-tetrahydronaphthalene derivs.. WO 9529147 .

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)	49435	6-(methylamino)-5,6,7,8-tetrahydro-1,2-naphthalenediol		C₁₁H₁₅NO₂	详情	详情
(IV)	11021	Methanamine; Methylamine	74-89-5	CH₅N	详情	详情
(V)	37381	N-(5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-N-methylamine; 5,6-dimethoxy-N-methyl-1,2,3,4-tetrahydro-2-naphthalenamine		C₁₃H₁₉NO₂	详情	详情
(VI)	17615	2,3-Dimethoxybenzaldehyde	86-51-1	C₉H₁₀O₃	详情	详情
(VII)	24066	2-oxopropionic acid	127-17-3	C₃H₄O₃	详情	详情
(VIII)	37376	(E)-4-(2,3-dimethoxyphenyl)-2-oxo-3-butenoic acid		C₁₂H₁₂O₅	详情	详情
(IX)	37377	4-(2,3-dimethoxyphenyl)-2-(methylamino)butyric acid		C₁₃H₁₉NO₄	详情	详情
(X)	10101	Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene	501-53-1	C₈H₇ClO₂	详情	详情
(XI)	37378	2-[[(benzyloxy)carbonyl](methyl)amino]-4-(2,3-dimethoxyphenyl)butyric acid		C₂₁H₂₅NO₆	详情	详情
(XII)	37379	4-(2,3-dimethoxyphenethyl)-3-methyl-1,3-oxazolidine-2,5-dione		C₁₄H₁₇NO₅	详情	详情
(XIII)	37380	5,6-dimethoxy-2-(methylamino)-3,4-dihydro-1(2H)-naphthalenone		C₁₃H₁₇NO₃	详情	详情
(XIV)	37387	5,6-dihydroxy-2-(methylamino)-3,4-dihydro-1(2H)-naphthalenone		C₁₁H₁₃NO₃	详情	详情

合成路线3

该中间体在本合成路线中的序号：(V)

Condensation of 4-(2,3-dimethoxyphenyl)-2-oxo-3-butenoic acid (VIII) with methyl carbamate (XV) by means of TsOH in refluxing toluene gives the substituted furanone (XVI), which is hydrogenated with H2 over Pd/C in hot ethanol to yield 4-(2,3-dimethoxyphenyl)-2-(methoxycarbonylamino)butyric acid (XVII). Cyclization of acid (XVII) by means of PPA at 60 C affords tetralone (XVIII), which is reduced with H2 over Pd/C in an autoclave at 80 C to provide N-(5,6-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)carbamic acid methyl ester (XIX). Finally, the carbamoyl group of (XIX) is reduced with LiAlH4 in hot THF to yield N-(5,6-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methylamine (V).

参考文献中间体

合成目标

【1】 Castaner, J.; Mealy, N.E.; Bayes, M.; Leeson, P.A.; Nolomirole Hydrochloride. Drugs Fut 2001, 26, 11, 1046.
【2】 Servadio, V.; Ventura, P.; Amari, G.; Chiesi, P.; Del Canale, M.; De Fanti, R. (Chiesi Farmaceutici SpA); A process for the preparation of 5,6-dihydroxy-2-amino-1,2,3,4-tetrahydronaphthalene derivs.. WO 9529147 .

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)	37381	N-(5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-N-methylamine; 5,6-dimethoxy-N-methyl-1,2,3,4-tetrahydro-2-naphthalenamine		C₁₃H₁₉NO₂	详情	详情
(VIII)	37376	(E)-4-(2,3-dimethoxyphenyl)-2-oxo-3-butenoic acid		C₁₂H₁₂O₅	详情	详情
(XV)	40724	methyl carbamate; carbamic acid methyl ester	598-55-0	C₂H₅NO₂	详情	详情
(XVI)	49436	methyl 5-(2,3-dimethoxyphenyl)-2-oxo-2,5-dihydro-3-furanylcarbamate		C₁₄H₁₅NO₆	详情	详情
(XVII)	49437	4-(2,3-dimethoxyphenyl)-2-[(methoxycarbonyl)amino]butyric acid		C₁₄H₁₉NO₆	详情	详情
(XVIII)	49438	methyl 5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthalenylcarbamate		C₁₄H₁₇NO₅	详情	详情
(XIX)	49439	methyl 5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphthalenylcarbamate		C₁₄H₁₉NO₄	详情	详情

合成路线4

该中间体在本合成路线中的序号：(VIII)

Condensation of 2,3-dimethoxybenzaldehyde (I) with pyruvic acid (II) in the presence of KOH produced oxobutenoic acid (III), which was hydrogenated in the presence of methylamine to give amino acid (IV). Reaction of (IV) with benzyl chloroformate afforded carbamate (V), which was subsequently cyclized to the N-carboxyanhydride (VI) upon treatment with SOCl2. Friedel-Crafts intramolecular acylation using AlCl3 yielded amino tetralone (VII). Reduction of the keto group of (VII) to give amino tetralin (VIII) was effected by catalytic hydrogenation over Pd/C. Finally, dealkylation of the methyl ether groups of (VIII) with AlCl3 in hot toluene afforded the title dihydroxy compound.

参考文献中间体

合成目标

【1】 Servadio, V.; Ventura, P.; Amari, G.; Chiesi, P.; Del Canale, M.; De Fanti, R. (Chiesi Farmaceutici SpA); A process for the preparation of 5,6-dihydroxy-2-amino-1,2,3,4-tetrahydronaphthalene derivs.. WO 9529147 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	10101	Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene	501-53-1	C₈H₇ClO₂	详情	详情
(I)	17615	2,3-Dimethoxybenzaldehyde	86-51-1	C₉H₁₀O₃	详情	详情
(II)	24066	2-oxopropionic acid	127-17-3	C₃H₄O₃	详情	详情
(III)	37376	(E)-4-(2,3-dimethoxyphenyl)-2-oxo-3-butenoic acid		C₁₂H₁₂O₅	详情	详情
(IV)	37377	4-(2,3-dimethoxyphenyl)-2-(methylamino)butyric acid		C₁₃H₁₉NO₄	详情	详情
(V)	37378	2-[[(benzyloxy)carbonyl](methyl)amino]-4-(2,3-dimethoxyphenyl)butyric acid		C₂₁H₂₅NO₆	详情	详情
(VI)	37379	4-(2,3-dimethoxyphenethyl)-3-methyl-1,3-oxazolidine-2,5-dione		C₁₄H₁₇NO₅	详情	详情
(VII)	37380	5,6-dimethoxy-2-(methylamino)-3,4-dihydro-1(2H)-naphthalenone		C₁₃H₁₇NO₃	详情	详情
(VIII)	37381	N-(5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-N-methylamine; 5,6-dimethoxy-N-methyl-1,2,3,4-tetrahydro-2-naphthalenamine		C₁₃H₁₉NO₂	详情	详情

合成路线5

该中间体在本合成路线中的序号：(VIII)

Condensation of oxobutenoic acid (III) with methyl carbamate produced dihydrofuranone (X). Catalytic hydrogenation of this compound gave (ethoxycarbonylamino)butyric acid derivative (XI). Intramolecular cyclization of (XI) to the tetralone (XII) was carried out in hot polyphosphoric acid. After hydrogenolysis of the keto group of (XII), the resulting carbamate (XIII) was reduced with LiAlH4 to the methylamino derivative (VIII), which was finally demethylated.

参考文献中间体

合成目标

【1】 Servadio, V.; Ventura, P.; Amari, G.; Chiesi, P.; Del Canale, M.; De Fanti, R. (Chiesi Farmaceutici SpA); A process for the preparation of 5,6-dihydroxy-2-amino-1,2,3,4-tetrahydronaphthalene derivs.. WO 9529147 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	40724	methyl carbamate; carbamic acid methyl ester	598-55-0	C₂H₅NO₂	详情	详情
(III)	37376	(E)-4-(2,3-dimethoxyphenyl)-2-oxo-3-butenoic acid		C₁₂H₁₂O₅	详情	详情
(VIII)	37381	N-(5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-N-methylamine; 5,6-dimethoxy-N-methyl-1,2,3,4-tetrahydro-2-naphthalenamine		C₁₃H₁₉NO₂	详情	详情
(X)	37382	ethyl 5-(2,3-dimethoxyphenyl)-2-oxo-2,5-dihydro-3-furanylcarbamate		C₁₅H₁₇NO₆	详情	详情
(XI)	37383	4-(2,3-dimethoxyphenyl)-2-[(ethoxycarbonyl)amino]butyric acid		C₁₅H₂₁NO₆	详情	详情
(XII)	37384	ethyl 5,6-dimethoxy-1-oxo-1,2,3,4-tetrahydro-2-naphthalenylcarbamate		C₁₅H₁₉NO₅	详情	详情
(XIII)	37385	ethyl 5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphthalenylcarbamate		C₁₅H₂₁NO₄	详情	详情

合成路线6

该中间体在本合成路线中的序号：(VIII)

Aminotetralin (VIII) was obtained by reductive amination of the 2-tetralone (XIV) in the presence of NaBH3CN.

参考文献中间体

合成目标

【1】 Chiesi, P.; Villani, V. (Chiesi Farmaceutici SpA); 1,2,3,4-Tetrahydronaphthaline derivs., process for their preparation and pharmaceutical compsns. containing them. DE 3320936; GB 2123410 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	11021	Methanamine; Methylamine	74-89-5	CH₅N	详情	详情
(VIII)	37381	N-(5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-N-methylamine; 5,6-dimethoxy-N-methyl-1,2,3,4-tetrahydro-2-naphthalenamine		C₁₃H₁₉NO₂	详情	详情
(XIV)	37386	5,6-dimethoxy-3,4-dihydro-2(1H)-naphthalenone		C₁₂H₁₄O₃	详情	详情

Extended Information