Phosphorus oxychloride → HCID 86726337, compound

HRID 629737Notes

Reaction equation

HRID 629737 reaction equation
O=P(Cl)(Cl)Cl.[NH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([F:37])[C:12]=1[CH2:13][CH2:14][C@H:15]1[O:20][CH2:19][C@@H:18]([CH2:21][O:22][Si](C(C)(C)C)(C)C)[N:17]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:16]1.[C:38]([O:42][C:43]([NH:45][C@H:46]([C:62](O)=[O:63])[CH:47]([C:55]1[CH:60]=[CH:59][C:58]([F:61])=[CH:57][CH:56]=1)[C:48]1[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=1)=[O:44])([CH3:41])([CH3:40])[CH3:39].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>N1C=CC=CC=1.C1COCC1>[C:38]([O:42][C:43]([NH:45][C@H:46]([C:62]([NH:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([F:37])[C:12]=1[CH2:13][CH2:14][C@H:15]1[O:20][CH2:19][C@@H:18]([CH2:21][OH:22])[N:17]([C:30]([O:32][C:33]([CH3:36])([CH3:34])[CH3:35])=[O:31])[CH2:16]1)=[O:63])[CH:47]([C:55]1[CH:60]=[CH:59][C:58]([F:61])=[CH:57][CH:56]=1)[C:48]1[CH:53]=[CH:52][C:51]([F:54])=[CH:50][CH:49]=1)=[O:44])([CH3:40])([CH3:41])[CH3:39]

Participants

7

Reactant 4

HCID 24813Phosphorus oxychlorideHCID 2724141Tetrabutylammonium FluorideHCID 15981034(S)-2-((tert-butoxycarbonyl)amino)-3,3-bis(4-fluorophenyl)propanoic acidHCID 86726335Tert-butyl (2R,5S)-2-(2-(3-amino-5-fluoropyridin-4-YL)ethyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)morpholine-4-carboxylate

Product 1

HCID 86726337HCID 86726337, compoundYield 51.4%

Reagents, catalysts & solvents 2

HCID 1049PyridineSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

POCl3 (0.579 mL, 6.21 mmol) was added to a solution of tert-Butyl (2R,5S)-2-[2-(3-amino-5-fluoropyridin-4-yl)ethyl]-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)morpholine-4-carboxylate (2.65 g, 5.64 mmol) and N-(tert-butoxycarbonyl)-4-fluoro-β-(4-fluorophenyl)-L-phenylalanine [Patterson, D. E., et al. Org. Proc. Res. Dev. 2009, 13, 900-906.] (2.13 g, 5.64 mmol) in pyridine (28 mL) at −15° C. The reaction stirred for 30 min then warmed to 0° C. and stirred for 3 hours. The reaction was quenched with saturated aqueous KH2PO4, then brine and the mixture was extracted with ethyl acetate (×3). The combined organic fractions were dried (MgSO4), filtered and the solvent was evaporated under reduced pressure to afford a brown viscous oil. The resulting oil was dissolved in THF (28 mL) and a 1M solution of TBAF (11.3 mL, 11.3 mmol) in THF was added and the reaction stirred at ambient temperature overnight. The reaction was quenched with saturated aqueous KH2PO4 and the mixture was extracted with ethyl acetate (×3). The combined organic fractions were dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. Purification on silica gel (330 g) eluting with a gradient of 0-100% CHCl3 to 70:20:10 CHCl3/EtOAc/MeOH afforded the title compound (2.07 g, 2.90 mmol, 51% yield) as a white solid, MS (ESI): m/z=715.48 (MH+); 100% pure by LCMS.

Workup

  1. stirringstirred for 3 hours
  2. customThe reaction was quenched with saturated aqueous KH2PO4
  3. extractionbrine and the mixture was extracted with ethyl acetate (×3)
  4. dry with materialThe combined organic fractions were dried (MgSO4)
  5. filtrationfiltered
  6. customthe solvent was evaporated under reduced pressure
  7. customto afford a brown viscous oil
  8. stirringthe reaction stirred at ambient temperature overnight
  9. customThe reaction was quenched with saturated aqueous KH2PO4
  10. extractionthe mixture was extracted with ethyl acetate (×3)
  11. dry with materialThe combined organic fractions were dried (MgSO4)
  12. filtrationfiltered
  13. customthe solvent was evaporated under reduced pressure
  14. customPurification on silica gel (330 g)
  15. washeluting with a gradient of 0-100% CHCl3 to 70:20:10 CHCl3/EtOAc/MeOH

Sources & evidence

ORD record
ord-5539fa4f33974941a20c1d9c51dbd018
Source dataset
uspto-grants-2016_04
Patent number
US09315475B2

Reaction notes

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