m-Chloroperbenzoic acid → HCID 178465310, compound

HRID 1474057Notes

Reaction equation

HRID 1474057 reaction equation
[CH2:1]([NH:3][C:4]([NH:6][C:7]1[NH:11][C:10]2[C:12]([C@H:27]3[CH2:31][CH2:30][CH2:29][O:28]3)=[C:13]([F:26])[C:14]([C:16]3[CH:17]=[N:18][C:19]([C:22]([OH:25])([CH3:24])[CH3:23])=[N:20][CH:21]=3)=[CH:15][C:9]=2[N:8]=1)=[O:5])[CH3:2].N1C=NN=N1.CC(N([P:44]([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)C(C)C)C.C1C=C(Cl)C=C(C(OO)=[O:69])C=1>CN(C=O)C>[P:44]([O:25][C:22]([C:19]1[N:18]=[CH:17][C:16]([C:14]2[C:13]([F:26])=[C:12]([C@H:27]3[CH2:31][CH2:30][CH2:29][O:28]3)[C:10]3[NH:11][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[N:8][C:9]=3[CH:15]=2)=[CH:21][N:20]=1)([CH3:24])[CH3:23])([O:45][CH2:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)([O:53][CH2:54][C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)=[O:69]

Participants

6

Reactant 4

HCID 70297m-Chloroperbenzoic acidHCID 196621Bis(benzyloxy)(diisopropylamino)phosphine2×HCID 178418441HCID 178418441, compoundHCID 178465307HCID 178465307, compound

Product 1

HCID 178465310HCID 178465310, compoundYield 85.27%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To 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 (23) (10.24 g, 23.66 mmol) in a 1 L round bottom flask under N2 at 23° C. was added DMF (200 mL) followed by a solution of tetrazole (105.2 mL of 0.45 M in MeCN, 47.32 mmol) followed by N-dibenzyloxyphosphanyl-N-isopropyl-propan-2-amine (12.26 g, 11.93 mL, 35.49 mmol). After 4.5 h more N-dibenzyloxyphosphanyl-N-isopropyl-propan-2-amine (4 mL) was added. After stirring a further 16 h the reaction was cooled to 0° C. (ice-water bath) then treated with mCPBA (15.17 g, 61.52 mmol). The mixture was stirred at 0° C. for 30 min then at 23° C. for 30 min after which the reaction mixture was partitioned between water (400 mL) and EtOAc (700 mL). The organic layer was separated, washed with saturated aqueous sodium bicarbonate (500 mL), 10% aqueous sodium bisulfate (500 mL), saturated aqueous sodium bicarbonate (500 mL), and brine (500 mL) then dried (magnesium sulfate), filtered and concentrated. The residue was purified by MPLC using an ISCO COMBIFLASH brand flash chromatography purification system (330 g column) eluting with a 0-10% EtOH in DCM linear gradient over 16.5 column volumes at a 200 mL/min flow rate. After concentration in vacuo, (R)-dibenzyl 2-(5-(2-(3-ethylureido)-6-fluoro-7-(tetrahydrofuran-2-yl)-1H-benzo[d]imidazol-5-yl)pyrimidin-2-yl)propan-2-ylphosphate (24) (13.89 g, 20.17 mmol, 85.27%) was obtained as a white solid. ESMS (M+1)=689.5; 1H NMR (300 MHz, CD3OD) δ8.88 (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. stirringThe mixture was stirred at 0° C. for 30 min
  2. customat 23° C. for 30 min after which the reaction mixture was partitioned between water (400 mL) and EtOAc (700 mL)
  3. customThe organic layer was separated
  4. washwashed with saturated aqueous sodium bicarbonate (500 mL), 10% aqueous sodium bisulfate (500 mL), saturated aqueous sodium bicarbonate (500 mL), and brine (500 mL)
  5. dry with materialthen dried (magnesium sulfate)
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe residue was purified by MPLC
  9. customan ISCO COMBIFLASH brand flash chromatography purification system (330 g column)
  10. washeluting with a 0-10% EtOH in DCM linear gradient over 16.5 column volumes at a 200 mL/min flow rate
  11. concentrationAfter concentration in vacuo

Sources & evidence

ORD record
ord-9b35b2f6792a4af9b9e969696b6db0b1
Source dataset
uspto-grants-2015_04
Patent number
US09018216B2

Reaction notes

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