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

【结构式】

【分子编号】23791

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

【CA登记号】2979-69-3

【分子式】C₁₂H₁₄O

【分子量】174.24256

【元素组成】C 82.72% H 8.1% O 9.18%

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)

Bromination of tetralone (I) in the presence of AlCl3 provided (II), which was coupled with (trimethylsilyl)acetylene (III) using PdCl2(PPh3)2 and CuI as the catalysts yielding (IV). Removal of the protecting trimethylsilyl group from (IV) with K2CO3 in MeOH gave the arylacetylene (V), which was subjected to a second Pd-catalyzed coupling reaction with ethyl 4-iodobenzoate (VI) to furnish diarylacetylene (VII). Ketone group of (VII) was then reduced with NaBH4 to provide racemic alcohol (VIII), which was separated into the enantiomers employing chiral HPLC. Alternatively, enantioselective reduction using several chiral reducing agents furnished the enantiomerically enriched alcohols. The desired (R)-alcohol was condensed with dihydropyran in the presence of a catalytic amount of p-toluenesulfonic acid to yield a diastereomeric mixture of tetrahydropyranyl ethers (IX). After isolation by means of normal phase-HPLC, the (R,R)-isomer was finally hydrolyzed with LiOH to the target carboxylic acid.

参考文献中间体

合成目标

【1】 Kochar, D.M.; Chandraratna, R.A.S.; Standeven, A.M.; Lin, Y.; Vuligonda, V.; Thacher, S.M.; A new class of RAR subtype selective retinoids: Co. Bioorg Med Chem 1999, 7, 2, 263.

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)	23791	4,4-dimethyl-3,4-dihydro-1(2H)-naphthalenone	2979-69-3	C₁₂H₁₄O	详情	详情
(II)	23792	7-bromo-4,4-dimethyl-3,4-dihydro-1(2H)-naphthalenone		C₁₂H₁₃BrO	详情	详情
(III)	23897	ethynyl(trimethyl)silane；trimethylsilyl acetylene	1066-54-2	C₅H₁₀Si	详情	详情
(IV)	23794	4,4-dimethyl-7-[2-(trimethylsilyl)ethynyl]-3,4-dihydro-1(2H)-naphthalenone		C₁₇H₂₂OSi	详情	详情
(V)	23795	7-ethynyl-4,4-dimethyl-3,4-dihydro-1(2H)-naphthalenone		C₁₄H₁₄O	详情	详情
(VI)	23796	ethyl 4-iodobenzoate	51934-41-9	C₉H₉IO₂	详情	详情
(VII)	23797	ethyl 4-[2-(5,5-dimethyl-8-oxo-5,6,7,8-tetrahydro-2-naphthalenyl)ethynyl]benzoate		C₂₃H₂₂O₃	详情	详情
(VIII)	23798	ethyl 4-[2-(8-hydroxy-5,5-dimethyl-5,6,7,8-tetrahydro-2-naphthalenyl)ethynyl]benzoate		C₂₃H₂₄O₃	详情	详情
(IX)	23799	ethyl 4-[2-[(8R)-5,5-dimethyl-8-(tetrahydro-2H-pyran-2-yloxy)-5,6,7,8-tetrahydro-2-naphthalenyl]ethynyl]benzoate		C₂₈H₃₂O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

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