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Pyridine → 4-(2-{[bis(benzyloxy)phosphoryl]oxy}ethyl)-2-methoxyphenyl (1R,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-((tert-butoxycarbonyl){[4'-fluoro-5'-propyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)propyl carbonate

HRID 1805932
ノート
印刷プレビュー

反応式

HRID 1805932 の反応式
N1C=CC=C[CH:2]=1.[P:7]([O:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([O:35][CH3:36])[CH:29]=1)([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl.[F:49][C:50]([F:97])([F:96])[C:51]1[CH:52]=[C:53]([C@@H:61]([OH:95])[C@@H:62]([N:64]([CH2:72][C:73]2[CH:78]=[C:77]([C:79]([F:82])([F:81])[F:80])[CH:76]=[CH:75][C:74]=2[C:83]2[CH:88]=[C:87]([CH:89]([CH3:91])C)[C:86]([F:92])=[CH:85][C:84]=2[O:93][CH3:94])[C:65](=[O:71])[O:66][C:67]([CH3:70])([CH3:69])[CH3:68])[CH3:63])[CH:54]=[C:55]([C:57]([F:60])([F:59])[F:58])[CH:56]=1>C(Cl)Cl.O>[C:38](=[O:40])([O:95][C@H:61]([C:53]1[CH:52]=[C:51]([C:50]([F:97])([F:49])[F:96])[CH:56]=[C:55]([C:57]([F:59])([F:58])[F:60])[CH:54]=1)[C@@H:62]([N:64]([C:65]([O:66][C:67]([CH3:68])([CH3:69])[CH3:70])=[O:71])[CH2:72][C:73]1[CH:78]=[C:77]([C:79]([F:81])([F:82])[F:80])[CH:76]=[CH:75][C:74]=1[C:83]1[CH:88]=[C:87]([CH2:89][CH2:91][CH3:2])[C:86]([F:92])=[CH:85][C:84]=1[O:93][CH3:94])[CH3:63])[O:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][CH2:26][O:25][P:7]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])=[CH:29][C:30]=1[O:35][CH3:36]
参加物反応条件実験手順後処理出典と根拠反応ノート

参加物

7

反応物 4

HCID 1049Pyridine2 回HCID 94429TriphosgeneHCID 67375221Dibenzyl 2-(4-hydroxy-3-methoxyphenyl)ethyl phosphateHCID 86657393tert-butyl {(1S,2R)-2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-1-methylethyl}{[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate2 回

生成物 1

HCID 123701204
4-(2-{[bis(benzyloxy)phosphoryl]oxy}ethyl)-2-methoxyphenyl (1R,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-((tert-butoxycarbonyl){[4'-fluoro-5'-propyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)propyl carbonate

試薬・触媒・溶媒 2

HCID 962Water溶媒HCID 6344Dichloromethane溶媒2 回

反応条件

温度
25 °C

実験手順

Pyridine (0,037 mL, 0.455 mmol) was added dropwise to a stirred solution of dibenzyl 2-(4-hydroxy-3-methoxyphenyl)ethyl phosphate (195 mg, 0.455 mmol) and triphosgene (49.3 mg, 0.166 mmol) in dry CH2Cl2 (4 mL) at 0° C. under N2. The reaction was stirred at 25° C. for 1.5 h. A solution of tert-butyl {(1S,2R)-2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-1-methylethyl}{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (INTERMEDIATE 7, 162.0 mg, 0.228 mmol) in dry CH2Cl2 (2 mL) was added via cannula followed by dropwise addition of pyridine (0.041 mL, 0.512 mmol). The reaction was stirred at 25° C. for 3 h. The reaction was diluted with water (15 mL) and extracted with EtOAc (3×20 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Biotage Horizon, 25M, Si, ˜20 mL/min, 100% hexanes for 144 mL, gradient to 50% EtOAc in hexanes over 2394 mL) to give 4-(2-{[bis(benzyloxy)phosphoryl]oxy}ethyl)-2-methoxyphenyl (1R,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-((tert-butoxycarbonyl){[4′-fluoro-5′-propyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)propyl carbonate, as a colorless oil. Rf=0.63 (50% EtOAc/hexanes). LCMS calc.=1166.4; found=1166.4 (M+H)+.

後処理

  1. stirringThe reaction was stirred at 25° C. for 3 h
  2. extractionextracted with EtOAc (3×20 mL)
  3. dry with materialThe combined extracts were dried (MgSO4)
  4. concentrationconcentrated in vacuo
  5. customto give the crude product
  6. customThis was purified by flash chromatography (Biotage Horizon, 25M, Si, ˜20 mL/min, 100% hexanes for 144 mL, gradient to 50% EtOAc in hexanes over 2394 mL)

出典と根拠

ORDレコード
ord-102c5d7d9c5a46e2b1718087e76973d4
出典データセット
uspto-grants-2013_01
DOI
10.6084/m9.figshare.5104873.v1
特許番号
US08354454B2

反応ノート

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