1,2-Dichloroethane → 4-Hydroxy-4-methyl-[1,4']bipiperidinyl-1'-carboxylic acid tert-butyl ester

HRID 60244ノート

反応式

HRID 60244 の反応式
[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1CCN[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1([OH:22])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl[CH2:38][CH2:39]Cl>>[C:1]([O:5][C:6]([N:7]1[CH2:39][CH2:38][CH:10]([N:19]2[CH2:20][CH2:21][C:16]([OH:22])([CH3:15])[CH2:17][CH2:18]2)[CH2:9][CH2:8]1)=[O:14])([CH3:4])([CH3:3])[CH3:2]

参加物

5

反応物 4

HCID 111,2-DichloroethaneHCID 7238334-(N-Boc-amino)piperidineHCID 5049666Sodium triacetoxyborohydrideHCID 156491744-Methylpiperidin-4-ol

生成物 1

HCID 672987574-Hydroxy-4-methyl-[1,4']bipiperidinyl-1'-carboxylic acid tert-butyl ester

実験手順

To a suspension of piperidin-4-yl-carbamic acid tert-butyl ester (723 mg, 3.6 mmol) in DCE (20 mL) was added 4-methylpiperidin-4-ol (500 mg, 4.4 mmol). After 30 minutes, sodium triacetoxyborohydride (1.54 g, 7.3 mmol) was added portionwise. After 20 hours at ambient temperature, the reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate solution (50 mL) and dichloromethane (75 mL). The organic phase was separated, dried (Na2SO4), filtered and evaporated in-vacuo. The resultant residue was purified by flash chromatography (silica, Biotage 100 g column, 0-10% methanol in dichloromethane) to afford crude 4-hydroxy-4-methyl-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester. This crude material was dissolved in dichloromethane (10 mL) and TFA (2 mL) added. After 30 minutes at ambient temperature, the reaction mixture was concentrated in-vacuo and the resultant residue loaded onto a 20 g SCX-2 cartridge which was washed with methanol, then 2N ammonia in methanol. Concentration of the combined basic fractions in-vacuo afforded the title compound as a colourless oil (285 mg, 40% over two steps). 1H NMR (300 MHz, CDCl3): 3.15 (d, J=12.3 Hz, 2H), 2.62-2.60 (m, 6H), 2.42-2.39 (m, 1H), 1.84 (d, J=12.6 Hz, 2H), 1.67-1.64 (m, 5H), 1.46-1.44 (m, 2H), 1.24 (s, 3H).

後処理

  1. waitAfter 20 hours at ambient temperature
  2. customthe reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate solution (50 mL) and dichloromethane (75 mL)
  3. customThe organic phase was separated
  4. dry with materialdried (Na2SO4)
  5. filtrationfiltered
  6. customevaporated in-vacuo
  7. customThe resultant residue was purified by flash chromatography (silica, Biotage 100 g column, 0-10% methanol in dichloromethane)

出典と根拠

ORDレコード
ord-77d445b8f82f4c349215f08892e7a2bd
出典データセット
uspto-grants-2016_09
特許番号
US09440976B2

反応ノート

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