1-[(3aR,8aS)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-1-propanone -Drug Synthesis Database

【结构式】

【分子编号】27554

【品名】1-[(3aR,8aS)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-1-propanone

【CA登记号】

【分子式】C₁₅H₁₉NO₂

【分子量】245.3214

【元素组成】C 73.44% H 7.81% N 5.71% O 13.04%

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：(VII)

Preparation of the precursor alcohol (XI) is outlined in Scheme 1. Reduction of 2-bromo-5-methoxybenzoic acid (I) with borane-dimethylsulfide complex gave benzylic alcohol (II). After conversion of (II) to the corresponding mesylate, treatment with NaBr provided bromide (III). (1R,2S)-Aminoindanol (IV) was acylated with propionyl chloride to afford amide (V), which was converted to acetonide (VII) with 2-methoxypropene (VI) using pyridinium tosylate as the acid catalyst. Acetonide (VII) was then alkylated with bromide (III) in the presence of lithium hexamethyldisilazide at -35 C to give the chiral intermediate (VIII). Hydrolysis of acetonide at 10 C, followed by amide hydrolysis under reflux furnished a mixture of acid (IX) and methyl ester (X). This mixture was then reduced with LiAlH4 to provide the chiral alcohol (XI).

参考文献中间体

合成目标

【1】 Frey, L.F.; Devine, P.N.; Tschaen, D.M.; Dolling, U.H.; Tillyer, R.D.; Kato, Y. (Banyu Pharmaceutical Co., Ltd.; Merck & Co., Inc.); Stereoselective deoxygenation reaction. EP 0923557; JP 1999514676; WO 9806700 .

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)	17819	2-bromo-5-methoxybenzoic acid	22921-68-2	C₈H₇BrO₃	详情	详情
(II)	27551	(2-bromo-5-methoxyphenyl)methanol		C₈H₉BrO₂	详情	详情
(III)	27552	1-bromo-2-(bromomethyl)-4-methoxybenzene		C₈H₈Br₂O	详情	详情
(IV)	27559	(1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol		C₉H₁₁NO	详情	详情
(V)	27553	N-[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]propanamide		C₁₂H₁₅NO₂	详情	详情
(VI)	17354	isopropenyl methyl ether; 2-methoxy-1-propene	116-11-0	C₄H₈O	详情	详情
(VII)	27554	1-[(3aR,8aS)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-1-propanone		C₁₅H₁₉NO₂	详情	详情
(VIII)	27555	(2S)-1-[(3aR,8aS)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-3-(2-bromo-5-methoxyphenyl)-2-methyl-1-propanone		C₂₃H₂₆BrNO₃	详情	详情
(IX)	27556	(2S)-3-(2-bromo-5-methoxyphenyl)-2-methylpropionic acid		C₁₁H₁₃BrO₃	详情	详情
(X)	27557	methyl (2S)-3-(2-bromo-5-methoxyphenyl)-2-methylpropanoate		C₁₂H₁₅BrO₃	详情	详情
(XI)	27558	(2S)-3-(2-bromo-5-methoxyphenyl)-2-methyl-1-propanol		C₁₁H₁₅BrO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(X)

The intermediate 3-(2-bromo-5-methoxyphenyl)-2(S)-methyl-1-propanol tert-butyldimethylsilyl ether (XIV) has been obtained as follows: the reduction of 2-bromo-5-methoxybenzoic acid (VII) with NaBH4/BF3 gives the expected benzyl alcohol (VIII), which by treatment with SOCl2 is converted into the benzyl chloride (IX). The condensation of (IX) with the chiral auxiliary (X) by means of LIHMDS provides the 2(S)-methylpropionic acid derivative (XI). Elimination of the chiral auxiliary with sulfuric acid gives 3-(2-bromo-5-methoxyphenyl)-2(S)-methylpropionic acid (XII), which is reduced with NaBH4/BF3 to the corresponding alcohol (XIII). Finally, this compound is silylated to afford the intermediate (XIV) with TBDMS-Cl and imidazole.

参考文献中间体

合成目标

【1】 Song, Z.J.; et al.; Practical asymetric synthesis of an endothelin receptor antagonist. J Org Chem 1999, 64, 26, 9658.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	17819	2-bromo-5-methoxybenzoic acid	22921-68-2	C₈H₇BrO₃	详情	详情
(VIII)	27551	(2-bromo-5-methoxyphenyl)methanol		C₈H₉BrO₂	详情	详情
(IX)	38553	1-bromo-2-(chloromethyl)-4-methoxybenzene; 4-bromo-3-(chloromethyl)phenyl methyl ether		C₈H₈BrClO	详情	详情
(X)	27554	1-[(3aR,8aS)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-1-propanone		C₁₅H₁₉NO₂	详情	详情
(XI)	27555	(2S)-1-[(3aR,8aS)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-3-(2-bromo-5-methoxyphenyl)-2-methyl-1-propanone		C₂₃H₂₆BrNO₃	详情	详情
(XII)	27556	(2S)-3-(2-bromo-5-methoxyphenyl)-2-methylpropionic acid		C₁₁H₁₃BrO₃	详情	详情
(XIII)	27558	(2S)-3-(2-bromo-5-methoxyphenyl)-2-methyl-1-propanol		C₁₁H₁₅BrO₂	详情	详情
(XIV)	27567	4-bromo-3-((2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methylpropyl)phenyl methyl ether		C₁₇H₂₉BrO₂Si	详情	详情

Extended Information