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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
Notizen
Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 1805932
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]
KomponentenReaktionsbedingungenVersuchsvorschriftAufarbeitungQuellen und NachweiseNotizen zur Reaktion

Komponenten

7

Edukt 4

HCID 1049Pyridine2×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×

Produkt 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

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 962WaterLösungsmittelHCID 6344DichloromethaneLösungsmittel2×

Reaktionsbedingungen

Temperatur
25 °C

Versuchsvorschrift

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)+.

Aufarbeitung

  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)

Quellen und Nachweise

ORD-Eintrag
ord-102c5d7d9c5a46e2b1718087e76973d4
Quelldatensatz
uspto-grants-2013_01
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US08354454B2

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