【结 构 式】 |
【分子编号】34898 【品名】(3aR,8aS)-2-methyl-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d][1,3,2]oxazaborole 【CA登记号】 |
【 分 子 式 】C10H12BNO 【 分 子 量 】173.02242 【元素组成】C 69.42% H 6.99% B 6.25% N 8.1% O 9.25% |
合成路线1
该中间体在本合成路线中的序号:(VI)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2
该中间体在本合成路线中的序号:(II)The enantioselective reduction of 2-benzoylacetonitrile (I) with BH3/Me2S complex catalyzed by the chiral catalyst (II) in THF gives 3(S)-hydroxy-3-phenylpropylamine (III), which is protected with tert-butyl dicarbonate and NaOH to yield the carbamate (IV). The condensation of (IV) with 4-(trifluoromethyl)phenol (V) by means of triphenylphosphine and diethyl azodicarboxylate (DEAD) in THF affords N-[3(S)-phenyl-3-[4-(trifluoromethyl) phenoxy]propyl]carbamic acid tert-butyl ester (VI), which is finally reduced with LiAlH4 in refluxing THF to give the target (S)-Fluoxetine.
【1】 Jurgens, A.R.; Hilborn, J.W. (Sepracor Inc.); Fluoxetine process from benzoylacetonitrile. WO 0007976 . |
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) | 34897 | 3-oxo-3-phenylpropanenitrile | 614-16-4 | C9H7NO | 详情 | 详情 |
(II) | 34898 | (3aR,8aS)-2-methyl-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d][1,3,2]oxazaborole | C10H12BNO | 详情 | 详情 | |
(III) | 34899 | (1S)-3-amino-1-phenyl-1-propanol | C9H13NO | 详情 | 详情 | |
(IV) | 34900 | tert-butyl (3S)-3-hydroxy-3-phenylpropylcarbamate | C14H21NO3 | 详情 | 详情 | |
(V) | 33607 | 4-(trifluoromethyl)phenol | 402-45-9 | C7H5F3O | 详情 | 详情 |
(VI) | 34901 | tert-butyl (3S)-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propylcarbamate | C21H24F3NO3 | 详情 | 详情 |