7-amino-4,4-dimethyl-3,4-dihydro-1(2H)-naphthalenone -Drug Synthesis Database

【结构式】

【分子编号】27269

【品名】7-amino-4,4-dimethyl-3,4-dihydro-1(2H)-naphthalenone

【CA登记号】

【分子式】C₁₂H₁₅NO

【分子量】189.25724

【元素组成】C 76.16% H 7.99% N 7.4% O 8.45%

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：(I)

The reaction of 7-amino-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-one (I) with NaNO2 and BF4H in water gives the corresponding diazo compound (II), which is treated with H2SO4 in refluxing water yielding 7-hydroxy-4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-one (III). The reaction of (III) with trifluoromethanesulfonic anhydride in pyridine affords the expected sulfonate (IV), which is carboxylated with CO, PdAc2 and 1,3-bis(diphenylphosphino)propane in methanol/DMSO yielding 5,5-dimethyl-8-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid methyl ester (V). The Grignard condensation of (V) with phenylmagnesium bromide (VI) in THF affords the corresponding addition product (VII), which is dehydrated with p-toluenesulfonic acid in hot toluene affording the dihydronaphtoic ester (VIII). The hydrolysis of (VIII) with NaOH in ethanol gives the corresponding free acid (IX), which is treated with SOCl2 and DMF yielding the expected acyl chloride (X). The condensation of (X) with methyl 4-aminobenzoate (XI) in pyridine affords the expected amide (XII), which is finally hydrolyzed to the target compound with NaOH in ethanol/water.

参考文献中间体

合成目标

【1】 Starrett, J.E. Jr.; Yu, K.-L.; Mansuri, M.M.; Tortolani, D.R. (Bristol-Myers Squibb Co.); Substd. (5,6)-dihydronaphthalenyl cpds. having retinoid-like activity. CA 2138000; EP 0661259; JP 1995242591; US 5648385 .

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)	27269	7-amino-4,4-dimethyl-3,4-dihydro-1(2H)-naphthalenone		C₁₂H₁₅NO	详情	详情
(II)	27793	5,5-Dimethyl-8-oxo-5,6,7,8-tetrahydronaphthalen-2-yldiazonium tetrafluoroborate		C₁₂H₁₃BF₄N₂O	详情	详情
(III)	27794	7-hydroxy-4,4-dimethyl-3,4-dihydro-1(2H)-naphthalenone		C₁₂H₁₄O₂	详情	详情
(IV)	27795	5,5-dimethyl-8-oxo-5,6,7,8-tetrahydro-2-naphthalenyl trifluoromethanesulfonate		C₁₃H₁₃F₃O₄S	详情	详情
(V)	27796	methyl 5,5-dimethyl-8-oxo-5,6,7,8-tetrahydro-2-naphthalenecarboxylate		C₁₄H₁₆O₃	详情	详情
(VI)	17616	bromo(phenyl)magnesium; Phenyl Magnesium Bromide	100-58-3	C₆H₅BrMg	详情	详情
(VII)	27797	methyl 8-hydroxy-5,5-dimethyl-8-phenyl-5,6,7,8-tetrahydro-2-naphthalenecarboxylate		C₂₀H₂₂O₃	详情	详情
(VIII)	27798	methyl 5,5-dimethyl-8-phenyl-5,6-dihydro-2-naphthalenecarboxylate		C₂₀H₂₀O₂	详情	详情
(IX)	27799	5,5-dimethyl-8-phenyl-5,6-dihydro-2-naphthalenecarboxylic acid		C₁₉H₁₈O₂	详情	详情
(X)	27800	5,5-dimethyl-8-phenyl-5,6-dihydro-2-naphthalenecarbonyl chloride		C₁₉H₁₇ClO	详情	详情
(XI)	20537	methyl 4-aminobenzoate	619-45-4	C₈H₉NO₂	详情	详情
(XII)	27801	methyl 4-[[(5,5-dimethyl-8-phenyl-5,6-dihydro-2-naphthalenyl)carbonyl]amino]benzoate		C₂₇H₂₅NO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

Ethyl levulinate (I) was reacted with one equivalent of methylmagnesium bromide to produce 5,5-dimethyldihydrofuran-2-one (II). Friedel-Crafts condensation of (III) with benzene in the presence of AlCl3 afforded 4,4-dimethyl-1-tetralone (III) which, after nitration and reduction furnished the aminotetralone (V). This was converted to iodide (VI) upon diazotization, followed by treatment with KI. Methyl 4-vinylbenzoate (VIII) was obtained by alkylation of the corresponding carboxylic acid (VII) with MeI in the presence of DBU. Coupling of this olefin (VIII) with iodide (VI) was carried out using palladium diacetate and tetrabutylammonium chloride at 70 C to yield the diaryl ethylene derivative (IX). Subsequent addition of phenylmagnesium bromide to (IX) produced the tertiary alcohol (X). Finally, dehydration of (X) using p-toluenesulfonic acid, followed by basic hydrolysis, provided the title compound.

参考文献中间体

合成目标

【1】 Starrett, J.E. Jr.; Yu, K.-L.; Mansuri, M.M.; Tortolani, D.R. (Bristol-Myers Squibb Co.); Substd. (5,6)-dihydronaphthalenyl cpds. having retinoid-like activity. CA 2138000; EP 0661259; JP 1995242591; US 5648385 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	17616	bromo(phenyl)magnesium; Phenyl Magnesium Bromide	100-58-3	C₆H₅BrMg	详情	详情
(I)	27267	ethyl 4-oxopentanoate	539-88-8	C₇H₁₂O₃	详情	详情
(II)	23768	5,5-dimethyldihydro-2(3H)-furanone		C₆H₁₀O₂	详情	详情
(III)	23791	4,4-dimethyl-3,4-dihydro-1(2H)-naphthalenone	2979-69-3	C₁₂H₁₄O	详情	详情
(IV)	27268	4,4-dimethyl-7-nitro-3,4-dihydro-1(2H)-naphthalenone		C₁₂H₁₃NO₃	详情	详情
(V)	27269	7-amino-4,4-dimethyl-3,4-dihydro-1(2H)-naphthalenone		C₁₂H₁₅NO	详情	详情
(VI)	27270	7-iodo-4,4-dimethyl-3,4-dihydro-1(2H)-naphthalenone		C₁₂H₁₃IO	详情	详情
(VII)	27271	4-vinylbenzoic acid	1075-49-6	C₉H₈O₂	详情	详情
(VIII)	27272	methyl 4-vinylbenzoate		C₁₀H₁₀O₂	详情	详情
(IX)	27273	methyl 4-[(E)-2-(5,5-dimethyl-8-oxo-5,6,7,8-tetrahydro-2-naphthalenyl)ethenyl]benzoate		C₂₂H₂₂O₃	详情	详情
(X)	27274	methyl 4-[(E)-2-(8-hydroxy-5,5-dimethyl-8-phenyl-5,6,7,8-tetrahydro-2-naphthalenyl)ethenyl]benzoate		C₂₈H₂₈O₃	详情	详情

Extended Information