6-methoxy-1-indanone -Drug Synthesis Database

【结构式】

【分子编号】34514

【品名】6-methoxy-1-indanone

【CA登记号】13623-25-1

【分子式】C₁₀H₁₀O₂

【分子量】162.1882

【元素组成】C 74.06% H 6.21% O 19.73%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(I)

Reductive coupling of 6-methoxy-1-indanone (I) with 1-benzylimidazole-5-carbaldehyde (II) using TiCl4 and Zn in boiling THF afforded the indanylidenemethyl imidazole (III). Hydrogenation of the double bond of (III) and simultaneous debenzylation in the presence of Pd/C provided the indanylmethyl derivative (IV). The methyl ether group of (IV) was finally cleaved by refluxing in concentrated HBr, and the title compound was isolated after conversion to the hydrochloride salt.

参考文献中间体

合成目标

【1】 Karjalainen, A.; Huhtala, P.; Savola, J.-M.; Wurster, S.; Eloranta, M.; Savola, M.; Saxlund, R.; Cockcroft, V. (Orion Corporation); Imidazole derivs. having affinity for alpha2 receptors activity. EP 0888309; JP 2000507914; WO 9712874 .

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)	34514	6-methoxy-1-indanone	13623-25-1	C₁₀H₁₀O₂	详情	详情
(II)	36347	1-benzyl-1H-imidazole-5-carbaldehyde		C₁₁H₁₀N₂O	详情	详情
(III)	36348	1-benzyl-5-[(6-methoxy-2,3-dihydro-1H-inden-1-ylidene)methyl]-1H-imidazole; 1-[(E)-(1-benzyl-1H-imidazol-5-yl)methylidene]-2,3-dihydro-1H-inden-6-yl methyl ether		C₂₁H₂₀N₂O	详情	详情
(IV)	36349	4-[(6-methoxy-2,3-dihydro-1H-inden-1-yl)methyl]-1H-imidazole; 3-(1H-imidazol-4-ylmethyl)-2,3-dihydro-1H-inden-5-yl methyl ether		C₁₄H₁₆N₂O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Addition of phenylmagnesium bromide to 6-methoxy-1-indanone (I) gave carbinol (II), which was dehydrated to phenylindene (III) upon treatment with p-toluenesulfonic acid in refluxing toluene. Oxidative cleavage of (III) with Jones reagent in the presence of OsO4 provided 2-benzoyl-4-methoxyphenylacetic acid (IV), which was further reduced to the 2-benzyl analogue (V) by hydrogenation over Pd/C. After conversion of (V) to the corresponding acid chloride (VI) using oxalyl chloride and a trace of DMF, Friedel-Crafts cyclization with AlCl3 furnished the dibenzocycloheptenone (VII). Addition of the lithium enolate of ethyl acetate to the carbonyl group of (VII) in the presence of tetramethylethylenediamine at -78 C generated the hydroxyester (VIII). Then, hydrogenolysis of the benzylic alcohol of (VIII) in the presence of Pd/C gave (IX). Subsequent cleavage of the methyl ether of (IX) by means of ethane thiol and AlCl3 provided the corresponding racemic phenol. Isolation of the required (S)-enantiomer (X) was carried out by chiral HPLC.

参考文献中间体

合成目标

【1】 Drake, F.H. (SmithKline Beecham plc); Method for stimulating bone formation. EP 0946180; WO 9815278 .
【2】 Miller, W.H.; Samanen, J.M.; Heerding, D.; Bondinell, W.E. (SmithKline Beecham Corp.); Vitronectin receptor antagonists. EP 1025090; WO 9915508 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	17491	ethyl acetate	141-78-6	C₄H₈O₂	详情	详情
	17616	bromo(phenyl)magnesium; Phenyl Magnesium Bromide	100-58-3	C₆H₅BrMg	详情	详情
(I)	34514	6-methoxy-1-indanone	13623-25-1	C₁₀H₁₀O₂	详情	详情
(II)	34515	6-methoxy-1-phenyl-1-indanol		C₁₆H₁₆O₂	详情	详情
(III)	34516	5-methoxy-3-phenyl-1H-indene; methyl 3-phenyl-1H-inden-5-yl ether		C₁₆H₁₄O	详情	详情
(IV)	34517	2-(2-benzoyl-4-methoxyphenyl)acetic acid		C₁₆H₁₄O₄	详情	详情
(V)	34518	2-(2-benzyl-4-methoxyphenyl)acetic acid		C₁₆H₁₆O₃	详情	详情
(VI)	34519	2-(2-benzyl-4-methoxyphenyl)acetyl chloride		C₁₆H₁₅ClO₂	详情	详情
(VII)	34520	3-methoxy-5,11-dihydro-10H-dibenzo[a,d]cyclohepten-10-one		C₁₆H₁₄O₂	详情	详情
(VIII)	34521	ethyl 2-(10-hydroxy-3-methoxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl)acetate		C₂₀H₂₂O₄	详情	详情
(IX)	34522	ethyl 2-(3-methoxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl)acetate		C₂₀H₂₂O₃	详情	详情
(X)	34523	ethyl 2-[(10S)-3-hydroxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl]acetate		C₁₉H₂₀O₃	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

Reductive amination of 6-methoxy-1-indanone (I) with piperazine (II) in the presence of titanium isopropoxide and NaBH4 furnishes the indanyl piperazine (III). Racemic amine (III) is then resolved employing (S)-10-camphorsulfonic acid to provide the (R)-enantiomer (IV). Condensation of the optically active piperazine (IV) with ethyl isocyanate then affords the target urea (1-3).

参考文献中间体

合成目标

【1】 Mattson, R.J.; Catt, J.D.; Keavy, D.; Sloan, C.P.; Epperson, J.; Gao, Q.; Hodges, D.B.; Iben, L.; Mahle, C.D.; Ryan, E.; Yocca, F.D.; Indanyl piperazines as melatonergic MT2 selective agents. Bioorg Med Chem Lett 2003, 13, 6, 1199.
【2】 Mattson, R.J.; Sloan, C.P.; Catt, J.D. (Bristol-Myers Squibb Co.); Novel melatonergic indanyl piperazines or homopiperazines. CA 2175395; EP 0745597 .
【3】 Mattson, R.J.; Catt, J.D. (Bristol-Myers Squibb Co.); Melatonergic indanyl piperazines. US 5780470 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	64586	1-nitrosoethane		C₂H₅NO	详情	详情
(I)	34514	6-methoxy-1-indanone	13623-25-1	C₁₀H₁₀O₂	详情	详情
(II)	10355	Diethylenediamine; Piperazine	110-85-0	C₄H₁₀N₂	详情	详情
(III)	64353	1-(6-methoxy-2,3-dihydro-1H-inden-1-yl)piperazine; methyl 3-(1-piperazinyl)-2,3-dihydro-1H-inden-5-yl ether		C₁₄H₂₀N₂O	详情	详情
(IV)	64354	1-[(1R)-6-methoxy-2,3-dihydro-1H-inden-1-yl]piperazine; methyl (3R)-3-(1-piperazinyl)-2,3-dihydro-1H-inden-5-yl ether		C₁₄H₂₀N₂O	详情	详情

Extended Information