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【结 构 式】 
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【分子编号】27559 【品名】(1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol 【CA登记号】 |
【 分 子 式 】C9H11NO 【 分 子 量 】149.19248 【元素组成】C 72.46% H 7.43% N 9.39% O 10.72% |
合成路线1
该中间体在本合成路线中的序号：(XXII)Alternatively, ecadotril can be obtained by an analogous route: Treatment of the already reported methyl beta-hydroxy-alpha-methylene-benzenepropionate (XVI) with sulfuric acid and acetic anhydride provides 2-benzylidene-3-acetoxypropionate methyl ester (XIXa-b), which is then subjected to hydrolysis with NaOH in MeOH/H2O to give carboxylic acid (XXa-b). Hydrogenation of (XXa-b) over Pd/C in MeOH/H2O in the presence of Et3N yields racemic 3-hydroxy-2-benzylpropionic acid (XXI), from which isomer (S)-(XXIII) is isolated by formation of a diastereomeric salt with (1R,2S)-(+)-cis-1-amino-2-indanol (XXII) in 2-propanol at 70 C followed by crystallization and decomposition of the salt with HCl. Coupling of compound (S)-(XXIII) with benzyl glycinate (XIV) by means of Et3N, HOBt and DCC in THF gives N-(3-hydroxy-2(S)-benzylpropionyl)-glycine benzyl ester (XXIV), which is then converted into the corresponding methanesulfonyloxy derivative (XXV) by reaction with methanesulfonyl chloride in toluene in the presence of pyridine followed by treatment with HCl. Finally, treatment of (XXV) with LiBr in refluxing acetone provides N-(3-bromo-2(S)-benzylpropionyl)glycine benzyl ester (XXVI), which is converted into ecadotril by reaction with potassium thioacetate in methyl isobutyl ether at 50 C.
| 【1】 Izawa, K.; Hamada, T.; Suzuki, T. (Ajinomoto Co., Inc.); Method for producing an optically active phenylpropionic acid deriv.. EP 0937710 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXa) | 49473 | (Z)-2-(hydroxymethyl)-3-phenyl-2-propenoic acid | C10H10O3 | 详情 | 详情 | |
| (XIXa) | 49474 | methyl (Z)-2-[(acetoxy)methyl]-3-phenyl-2-propenoate | C13H14O4 | 详情 | 详情 | |
| (XIXb) | 49475 | methyl (E)-2-[(acetoxy)methyl]-3-phenyl-2-propenoate | C13H14O4 | 详情 | 详情 | |
| (XXb) | 49476 | (E)-2-(hydroxymethyl)-3-phenyl-2-propenoic acid | C10H10O3 | 详情 | 详情 | |
| (S)-(XXIII) | 49481 | (2S)-2-benzyl-3-hydroxypropionic acid | C10H12O3 | 详情 | 详情 | |
| (XIV) | 13601 | benzyl 2-aminoacetate; Glycine benzyl ester hydrochloride | 1738-68-7 | C9H11NO2 | 详情 | 详情 |
| (XVI) | 49470 | methyl 2-[hydroxy(phenyl)methyl]acrylate | C11H12O3 | 详情 | 详情 | |
| (XXI) | 49480 | 2-benzyl-3-hydroxypropionic acid | C10H12O3 | 详情 | 详情 | |
| (XXII) | 27559 | (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol | C9H11NO | 详情 | 详情 | |
| (XXIV) | 49477 | benzyl 2-[[(2S)-2-benzyl-3-hydroxypropanoyl]amino]acetate | C19H21NO4 | 详情 | 详情 | |
| (XXV) | 49478 | benzyl 2-([(2S)-2-benzyl-3-[(methylsulfonyl)oxy]propanoyl]amino)acetate | C20H23NO6S | 详情 | 详情 | |
| (XXVI) | 49479 | benzyl 2-[[(2S)-2-benzyl-3-bromopropanoyl]amino]acetate | C19H20BrNO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)The enantioselective reduction of phenacyl bromide (I) with BH3.S(CH3)2 in THF catalyzed by the chiral borolidine (II) (obtained by reaction of (1R,2S)-1-amino-2-indanol (III) with BH3.S(CH3)2 in THF) gives the (R)-2-bromo-1-(4-benzyloxy-3-nitrophenyl)ethanol (IV), which is reduced with H2 over PtO2 in THF/toluene yielding the corresponding amino derivative (V). The reaction of (V) with formic acid and Ac2O affords the formamide (VI), which is condensed with the chiral (R)-N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine (VII) in THF/methanol providing the protected target compound (VIII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol. The intermediate the chiral (R)-N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine (VII) has been obtained by reductocondensation of 1-(4-methoxyphenyl)-2-propanone (IX) and benzylamine by hydrogenation with H2 over Pd/C in methanol yielding racemic N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine (X), which is submitted to optical resolution with (S)-mandelic acid to obtain the desired (R)-enantiomer (VII).
| 【1】 Hett, R.; et al.; Large-scale synthesis of enantio- and diastereomerically pure (R,R)-formoterol. Org Process Res Dev 1998, 2, 2, 96. |
| 【2】 Hett, R.; Senanayake, C.H.; Fang, K.Q.; Wald, S.A.; Redmon, M.P.; Gao, Y. (Sepracor Inc.); Formoterol process. US 6040344 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 | |
| (I) | 32763 | 1-[4-(benzyloxy)-3-nitrophenyl]-2-bromo-1-ethanone | C15H12BrNO4 | 详情 | 详情 | |
| (II) | 32764 | (3aR,8aS)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d][1,3,2]oxazaborole | C9H10BNO | 详情 | 详情 | |
| (III) | 27559 | (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol | C9H11NO | 详情 | 详情 | |
| (IV) | 32765 | (1R)-1-[4-(benzyloxy)-3-nitrophenyl]-2-bromo-1-ethanol | 188690-82-6 | C15H14BrNO4 | 详情 | 详情 |
| (V) | 32766 | (1R)-1-[3-amino-4-(benzyloxy)phenyl]-2-bromo-1-ethanol | C15H16BrNO2 | 详情 | 详情 | |
| (VI) | 32767 | 2-(benzyloxy)-5-[(1R)-2-bromo-1-hydroxyethyl]phenylformamide | C16H16BrNO3 | 详情 | 详情 | |
| (VII) | 32738 | tert-butyl (2S,3S)-2-[(2-[[2-([[(1S,2S)-1-(tert-butoxycarbonyl)-2-methylbutyl]amino]carbonyl)phenyl]disulfanyl]benzoyl)amino]-3-methylpentanoate | C34H48N2O6S2 | 详情 | 详情 | |
| (VIII) | 32769 | 5-((1R)-2-[benzyl[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]-1-hydroxyethyl)-2-(benzyloxy)phenylformamide | C33H36N2O4 | 详情 | 详情 | |
| (IX) | 10038 | 4-Methoxyphenylacetone; 1-(4-Methoxyphenyl)acetone | 122-84-9 | C10H12O2 | 详情 | 详情 |
| (X) | 32770 | N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine; N-benzyl-1-(4-methoxyphenyl)-2-propanamine | C17H21NO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)The intermediate N-benzyl-N-[1(R)-methyl-2-(4-methoxyphenyl)ethyl]amine (IV) has been obtained as follows: The reductocondensation of 1-(4-methoxyphenyl)-2-propanone (I) with benzylamine (II) by H2 over Pd/C gives the N-benzyl-N-[1-methyl-2-(4-methoxyphenyl)ethyl]amine (III) as a racemic mixture, which is submitted to optical resolution with L-mandelic acid in methanol to obtain the desired (R)-enantiomer (IV). The reaction of cis-(1R,2S)-1-aminoindan-2-ol (V) with trimethylboroxine in toluene gives the (1R,2S)-oxazaborolidine (VI), which is used as chiral catalyst in the enantioselective reduction of 4-benzyloxy-3-nitrophenacyl bromide (VII) by means of BH3/THF, yielding the chiral bromoethanol derivative (VIII). The reaction of (VIII) with NaOH in aqueous methanol affords the epoxide (IX), which is condensed with the intermediate amine (IV) by heating the mixture at 90 C to provide the adduct (X). The reduction of the nitro group of (X) with H2 over PtO2 gives the corresponding amino derivative (XI), which is acylated with formic acid to afford the formamide compound (XII). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol, providing the target compound.
| 【1】 Wilkinson, H.S.; et al.; Modulation of catalyst reactivity for the chemoselective hydrogenation of functionalized nitroarene: Preparation of a key intermediate in the synthesis of (R,R)-formoterol tartrate. Org Process Res Dev 2000, 4, 6, 567. |
| 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) | 10038 | 4-Methoxyphenylacetone; 1-(4-Methoxyphenyl)acetone | 122-84-9 | C10H12O2 | 详情 | 详情 |
| (II) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (III) | 32770 | N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine; N-benzyl-1-(4-methoxyphenyl)-2-propanamine | C17H21NO | 详情 | 详情 | |
| (IV) | 32768 | (2R)-N-benzyl-1-(4-methoxyphenyl)-2-propanamine; N-benzyl-N-[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amine | C17H21NO | 详情 | 详情 | |
| (V) | 27559 | (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol | C9H11NO | 详情 | 详情 | |
| (VI) | 34898 | (3aR,8aS)-2-methyl-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d][1,3,2]oxazaborole | C10H12BNO | 详情 | 详情 | |
| (VII) | 32763 | 1-[4-(benzyloxy)-3-nitrophenyl]-2-bromo-1-ethanone | C15H12BrNO4 | 详情 | 详情 | |
| (VIII) | 32765 | (1R)-1-[4-(benzyloxy)-3-nitrophenyl]-2-bromo-1-ethanol | 188690-82-6 | C15H14BrNO4 | 详情 | 详情 |
| (IX) | 50312 | (2R)-2-[4-(benzyloxy)-3-nitrophenyl]oxirane; benzyl 2-nitro-4-[(2R)oxiranyl]phenyl ether | C15H13NO4 | 详情 | 详情 | |
| (X) | 50313 | (1R)-2-[benzyl[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]-1-[4-(benzyloxy)-3-nitrophenyl]-1-ethanol | C32H34N2O5 | 详情 | 详情 | |
| (XI) | 50314 | (1R)-1-[3-amino-4-(benzyloxy)phenyl]-2-[benzyl[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]-1-ethanol | C32H36N2O3 | 详情 | 详情 | |
| (XII) | 32769 | 5-((1R)-2-[benzyl[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]-1-hydroxyethyl)-2-(benzyloxy)phenylformamide | C33H36N2O4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)The synthesis of the chiral borolidine catalyst (II) starting from indoline (I), as well as the enantioselective reduction of 4'-(benzyloxy)-3'-nitrophenacyl bromide (III), catalyzed by borolidine (II), and using various borane complexes (borane/dimethylsulfide, borane/THF and borane/diethylaniline), has been studied in order to solve the problems presented in large-scale synthesis. The conclusions of the study are that the complex borane/diethylaniline (DEANB) is the most suitable reagent for large-scale reduction of phenacyl bromide (III) since the chemical hazards and inconsistent reagent quality of the borane/THF and borane/dimethylsulfide complexes disqualified their use in large-scale processes. The best reaction conditions of the reduction with this complex are presented.
| 【1】 Wilkinson, H.S.; et al.; Diethylanilineborane: A practical, safe, and consistent-quality borane source for the large-scale enantioselective reduction of a ketone intermediate in the synthesis of (R,R)-formoterol. Org Process Res Dev 2002, 6, 2, 146. |
| 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) | 27559 | (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol | C9H11NO | 详情 | 详情 | |
| (II) | 32764 | (3aR,8aS)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d][1,3,2]oxazaborole | C9H10BNO | 详情 | 详情 | |
| (III) | 32763 | 1-[4-(benzyloxy)-3-nitrophenyl]-2-bromo-1-ethanone | C15H12BrNO4 | 详情 | 详情 | |
| (IV) | 32765 | (1R)-1-[4-(benzyloxy)-3-nitrophenyl]-2-bromo-1-ethanol | 188690-82-6 | C15H14BrNO4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)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).
| 【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 |