Nolomirole hydrochloride, CHF-1035, -Drug Synthesis Database

【结构式】

【药物名称】Nolomirole hydrochloride, CHF-1035

【化学名称】(±)-5,6-Diisobutyryloxy-2-(methylamino)-1,2,3,4-tetrahydronaphthalene hydrochloride

【CA登记号】138531-51-8, 90060-42-7 (free base)

【分子式】C₁₉H₂₈ClNO₄

【分子量】369.89231

【开发单位】Chiesi (Originator)

【药理作用】CARDIOVASCULAR DRUGS, Chemical Delivery Systems, DRUG DELIVERY, Drug Delivery Systems, Heart Failure Therapy, alpha2-Adrenoceptor Agonists, Dopamine D2 Agonists

合成路线1 合成路线2 合成路线3

合成路线1

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

【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

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

【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

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

【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

Extended Information