6-methoxy-1-phenyl-1-indanol -Drug Synthesis Database

【结构式】

【分子编号】34515

【品名】6-methoxy-1-phenyl-1-indanol

【CA登记号】

【分子式】C₁₆H₁₆O₂

【分子量】240.30184

【元素组成】C 79.97% H 6.71% O 13.32%

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 condensation of 6-methoxyindan-1-one (I) with phosphonate (II) by means of NaH in THF gives 2-(6-methoxyindan-1-ylidene)acetonitrile (III), which is hydrogenated with h2 over Raney Co in ethanol/NH3 to yield 2-(6-methoxyindan-1-ylidene)ethylamine (IV). The acylation of (IV) with propionyl chloride (V) and TEA in THF affords the corresponding amide (VI), which is submitted to an asymmetric reduction with H2 and a chiral Ru catalyst to provide N-[2-(6-methoxyindan-1(S)-yl)ethyl]propionamide (VII). The bromination of (VII) with Br2 and NaOAc in methanol gives the 5-bromo derivative (VIII), which is demethylated by means of BBr3 in dichloromethane to yield the hydroxy compound (IX). The reaction of (IX) with allyl bromide (X) by means of NaH in DMF affords the allyl ether (XI), which is submitted to a Claisen rearrangement in N,N-diethylaniline at 200 C to provide the 7-allyl derivative (XII).The reaction of (XII) with ozone in methanol gives the acetaldehyde derivative (XIII), which is reduced with NaBH4 in methanol to yield the ethanol derivative (XIV). The hydrogenolysis of the Br substituent of (XIV) by means of H2 over Pd/C in methanol/TEA affords the dihydroxy compound (XV), which is treated with MsCl and pyridine to provide the mesylate (XVI). Finally, this compound is cyclized by means of TEA in refluxing ethyl acetate to furnish the target indeno[5,4-b]furan derivative.

参考文献中间体

合成目标

【1】 Chilman-Blair, K.; Castaner, J.; Silvestre, J.S.; Bayes, M.; TAK-375. Drugs Fut 2003, 28, 10, 950.
【2】 Uchikawa, O.; Fukatsu, K.; Tokunoh, R.; et al.; Synthesis of a novel series of tricyclic indan derivatives as melatonin receptor agonists. J Med Chem 2002, 45, 19, 4222.

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)	34515	6-methoxy-1-phenyl-1-indanol		C₁₆H₁₆O₂	详情	详情
(II)	10045	Diethyl cyanomethylphosphonate	2537-48-6	C₆H₁₂NO₃P	详情	详情
(III)	62218	2-(6-methoxy-2,3-dihydro-1H-inden-1-ylidene)acetonitrile		C₁₂H₁₁NO	详情	详情
(IV)	62219	2-(6-methoxy-2,3-dihydro-1H-inden-1-ylidene)ethylamine; 2-(6-methoxy-2,3-dihydro-1H-inden-1-ylidene)-1-ethanamine		C₁₂H₁₅NO	详情	详情
(V)	15967	propanoyl chloride; propionyl chloride	79-03-8	C₃H₅ClO	详情	详情
(VI)	62220	N-[2-(6-methoxy-2,3-dihydro-1H-inden-1-ylidene)ethyl]propanamide		C₁₅H₁₉NO₂	详情	详情
(VII)	62221	N-{2-[(1S)-6-methoxy-2,3-dihydro-1H-inden-1-yl]ethyl}propanamide		C₁₅H₂₁NO₂	详情	详情
(VIII)	62222	N-{2-[(1S)-5-bromo-6-methoxy-2,3-dihydro-1H-inden-1-yl]ethyl}propanamide		C₁₅H₂₀BrNO₂	详情	详情
(IX)	62223	N-{2-[(1S)-5-bromo-6-hydroxy-2,3-dihydro-1H-inden-1-yl]ethyl}propanamide		C₁₄H₁₈BrNO₂	详情	详情
(X)	11463	3-Bromo-1-propene; 3-Bromopropene；allyl bromide	106-95-6	C₃H₅Br	详情	详情
(XI)	62224	N-{2-[(1S)-6-(allyloxy)-5-bromo-2,3-dihydro-1H-inden-1-yl]ethyl}propanamide		C₁₇H₂₂BrNO₂	详情	详情
(XII)	62225	N-{2-[(1S)-7-allyl-5-bromo-6-hydroxy-2,3-dihydro-1H-inden-1-yl]ethyl}propanamide		C₁₇H₂₂BrNO₂	详情	详情
(XIII)	62226	N-{2-[(1S)-5-bromo-6-hydroxy-7-(2-oxoethyl)-2,3-dihydro-1H-inden-1-yl]ethyl}propanamide		C₁₆H₂₀BrNO₃	详情	详情
(XIV)	62227	N-{2-[(1S)-5-bromo-6-hydroxy-7-(2-hydroxyethyl)-2,3-dihydro-1H-inden-1-yl]ethyl}propanamide		C₁₆H₂₂BrNO₃	详情	详情
(XV)	62228	N-{2-[(1S)-6-hydroxy-7-(2-hydroxyethyl)-2,3-dihydro-1H-inden-1-yl]ethyl}propanamide		C₁₆H₂₃NO₃	详情	详情
(XVI)	62229	2-{(3S)-5-hydroxy-3-[2-(propionylamino)ethyl]-2,3-dihydro-1H-inden-4-yl}ethyl methanesulfonate		C₁₇H₂₅NO₅S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

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

Extended Information