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4-Bromophenacyl bromide → (1R,3S,5R)-tert-butyl 3-(5-(4-bromophenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate

HRID 625575
ノート
印刷プレビュー

反応式

HRID 625575 の反応式
CC[N:3]([CH:7]([CH3:9])[CH3:8])C(C)C.BrCC(C1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1)=O.[C:21]([O:25][C:26]([N:28]1[C@H:33]([C:34](O)=O)[CH2:32][C@@H:31]2[C@H:29]1[CH2:30]2)=[O:27])([CH3:24])([CH3:23])[CH3:22].C([O-])(=O)C.[NH4+:41]>CC#N>[Br:20][C:17]1[CH:18]=[CH:19][C:9]([C:7]2[NH:3][C:34]([C@@H:33]3[CH2:32][C@@H:31]4[C@@H:29]([CH2:30]4)[N:28]3[C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])=[N:41][CH:8]=2)=[CH:15][CH:16]=1
参加物実験手順後処理出典と根拠反応ノート

参加物

6

反応物 4

HCID 74544-Bromophenacyl bromideHCID 81531DiisopropylethylamineHCID 517165Ammonium AcetateHCID 11020613(1R,3S,5R)-2-(tert-Butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid

生成物 1

HCID 57816594(1R,3S,5R)-tert-butyl 3-(5-(4-bromophenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate収率 88.9%

試薬・触媒・溶媒

1
HCID 6342Acetonitrile溶媒

実験手順

Hunig's Base (7.69 mL, 44.0 mmol) was added to a stirred solution of 2-bromo-1-(4-bromophenyl)ethanone (12.23 g, 44.0 mmol) and (1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (10 g, 44 mmol) in dry MeCN (400 mL). The mixture was stirred for 16 h at RT. The solvent was removed in vacuo and the residue was taken up in ethyl acetate and washed with saturated sodium bicarbonate solution and brine, dried (sodium sulfate), filtered and concentrated. In a pressure vessel the residue was taken up in xylene (400 mL) and ammonium acetate (33.9 g, 440 mmol) was added. The vessel was sealed and heated at 140° C. for 2 h. The solvent was removed in vacuo and the residue was taken up in ethyl acetate and washed with saturated sodium bicarbonate solution (pH=9), brine, dried over sodium sulfate and concentrated. The crude product, as a reddish orange foam, was dissolved in methylene chloride and placed onto a 300 g Thompson silica gel cartridge (eluted with 20% B to 100% B for 4000 mL where Solvent B=ethyl acetate and Solvent A=hexanes) to yield (1R,3S,5R)-tert-butyl 3-(5-(4-bromophenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (16.67 g, 39.1 mmol, 88.8% yield) as a golden-brown foam. LC-MS retention time 1.762 min; m/z 403.94 [M+H]+. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna S10 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min and an analysis time of 5 min where Solvent A was 5% methanol/95% water/0.1% TFA and Solvent B was 95% methanol/5% water/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD) δ ppm 7.62 (br d, J=8.6 Hz, 2H), 7.50 (br d, J=8.6 Hz, 2H), 7.37 (s, 1H), 4.66 (br s, 1H), 3.58 (br s, 1H), 2.56-2.47 (m, 1H), 2.36-2.27 (m, 1H), 1.75-1.67 (m, 1H), 0.97 (br s, 9H), 0.88-0.81 (m, 1H), 0.64-0.57 (m, 1H).

後処理

  1. customThe solvent was removed in vacuo
  2. washwashed with saturated sodium bicarbonate solution and brine
  3. dry with materialdried (sodium sulfate)
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customIn a pressure vessel the residue was taken up in xylene (400 mL)
  7. customThe vessel was sealed
  8. temperatureheated at 140° C. for 2 h
  9. customThe solvent was removed in vacuo
  10. washwashed with saturated sodium bicarbonate solution (pH=9), brine
  11. dry with materialdried over sodium sulfate
  12. concentrationconcentrated
  13. dissolutionThe crude product, as a reddish orange foam, was dissolved in methylene chloride
  14. washplaced onto a 300 g Thompson silica gel cartridge (eluted with 20% B to 100% B for 4000 mL where Solvent B=ethyl acetate and Solvent A=hexanes)

出典と根拠

ORDレコード
ord-83340487231447f881aae40a61b2314c
出典データセット
uspto-grants-2016_04
DOI
10.6084/m9.figshare.5104873.v1
特許番号
US09303007B2

反応ノート

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