Methanol → HCID 178465310, compound

HRID 1474059Notes

Reaction equation

HRID 1474059 reaction equation
[CH2:1]([O:8][P:9]([OH:19])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:27]([CH2:56][CH3:57])[C:28]([NH:30][C:31]1[NH:35][C:34]2[C:36]([C@H:51]3[CH2:55][CH2:54][CH2:53][O:52]3)=[C:37]([F:50])[C:38]([C:40]3[CH:41]=[N:42][C:43]([C:46](O)([CH3:48])[CH3:47])=[N:44][CH:45]=3)=[CH:39][C:33]=2[N:32]=1)=[O:29])(OC(C)(C)C)=O.O.C(O)(C(F)(F)F)=O.CO>C(Cl)Cl>[P:9]([O:19][C:46]([C:43]1[N:42]=[CH:41][C:40]([C:38]2[C:37]([F:50])=[C:36]([C@H:51]3[CH2:55][CH2:54][CH2:53][O:52]3)[C:34]3[NH:35][C:31]([NH:30][C:28]([NH:27][CH2:56][CH3:57])=[O:29])=[N:32][C:33]=3[CH:39]=2)=[CH:45][N:44]=1)([CH3:47])[CH3:48])([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]

Participants

6

Reactant 4

HCID 887MethanolHCID 962WaterHCID 6422Trifluoroacetic acid2×HCID 178465309HCID 178465309, compound

Product 1

HCID 178465310HCID 178465310, compoundYield 98.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of Boc-1-ethyl-3-[6-fluoro-5-[2-(1-hydroxy-1-methyl-ethyl)pyrimidin-5-yl]-7-[(2R)-tetrahydrofuran-2-yl]-1H-benzimidazol-2-yl]urea dibenzyl phosphate (26) (11.9 g, 15.09 mmol) in DCM (300 mL) at 23° C. was added water (2.325 mL, 129.1 mmol) then TFA (3.441 g, 2.325 mL, 30.18 mmol). After 1 h, only partial conversion was observed by tlc, so more TFA (3.441 g, 2.325 mL, 30.18 mmol) was added. After a further 2.5 h, MeOH (2 mL) was added and the mixture stirred a further 18 hours. The reaction mixture was washed with 1:1 brine:saturated aqueous sodium bicarbonate (200 mL). The aqueous layer was re-extracted with DCM (150 mL), the organic layers combined, then dried (over magnesium sulfate), filtered and concentrated in vacuo. The resulting residue was re-dissolved in EtOAc (200 mL) washed with water (150 mL) and brine (100 mL), then dried (magnesium sulfate) filtered and concentrated to give (R)-dibenzyl 2-(5-(2-(3-ethylureido)-6-fluoro-7-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)propan-2-yl phosphate (24) (10.21 g, 14.83 mmol, 98.27%) as a white solid. ESMS (M+1)=689.4; 1H NMR (300 MHz, CD3OD) δ 8.88 (d, J=1.6 Hz, 2H), 7.37 (d, J=6 Hz, 1H), 7.30 (m, 10H), 5.38-5.33 (m, 1H), 5.12-5.01 (m, 4H), 4.24 (dd, J=6.8, 14.9 Hz, 1H), 3.98 (dd, J=6.9, 15.1 Hz, 1H), 3.35-3.27 (m, 3H), 2.52 (q, J=5.9 Hz, 1H), 2.14-2.05 (m, 2H), 1.91 (s, 6H) and 1.22-1.14 (m, 3H) ppm.

Workup

  1. additionwas added
  2. waitAfter a further 2.5 h
  3. washThe reaction mixture was washed with 1:1 brine
  4. extractionThe aqueous layer was re-extracted with DCM (150 mL)
  5. dry with materialdried (over magnesium sulfate)
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. dissolutionThe resulting residue was re-dissolved in EtOAc (200 mL)
  9. washwashed with water (150 mL) and brine (100 mL)
  10. dry with materialdried (magnesium sulfate)
  11. filtrationfiltered
  12. concentrationconcentrated

Sources & evidence

ORD record
ord-78e8e13992a1407fbeba1e0c030fca5b
Source dataset
uspto-grants-2015_04
Patent number
US09018216B2

Reaction notes

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