ethyl 2-[(10S)-3-hydroxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl]acetate -Drug Synthesis Database

【结构式】

【分子编号】34523

【品名】ethyl 2-[(10S)-3-hydroxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl]acetate

【CA登记号】

【分子式】C₁₉H₂₀O₃

【分子量】296.366

【元素组成】C 77% H 6.8% O 16.2%

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：(X)

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2

该中间体在本合成路线中的序号：(X)

Condensation of 2-chloropyridine-N-oxide hydrochloride (XI) with 3-amino-1-propanol (XII) in boiling tert-amyl alcohol provided the aminopyridine N-oxide (XIII). Subsequent Mitsunobu coupling of (XIII) with the chiral phenol (X) in the presence of diisopropyl azodicarboxylate and triphenyl phosphine produced ether (XIV). The N-oxide group of (XIV) was then reduced by transfer hydrogenation using cyclohexene and Pd/C to yield pyridine (XV). Finally, saponification of the ethyl ester of (XV) furnished the title compound.

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
(X)	34523	ethyl 2-[(10S)-3-hydroxy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl]acetate		C₁₉H₂₀O₃	详情	详情
(XI)	34524	2-chloro-1-pyridiniumolate	2402-95-1	C₅H₄ClNO	详情	详情
(XII)	18522	3-amino-1-propanol	156-87-6	C₃H₉NO	详情	详情
(XIII)	34525	2-[(3-hydroxypropyl)amino]-1-pyridiniumolate		C₈H₁₂N₂O₂	详情	详情
(XIV)	34526	2-[(3-[[(10S)-10-(2-ethoxy-2-oxoethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-3-yl]oxy]propyl)amino]-1-pyridiniumolate		C₂₇H₃₀N₂O₄	详情	详情
(XV)	34527	ethyl 2-[(10S)-3-[3-(2-pyridinylamino)propoxy]-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl]acetate		C₂₇H₃₀N₂O₃	详情	详情

Extended Information