Water → HCID 58109123, compound

HRID 2037470Notes

Reaction equation

HRID 2037470 reaction equation
[NH2:1][CH2:2][CH2:3][C@@:4]1([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.CCN(CC)CC.Cl[C:42]([O:44][CH3:45])=[O:43].O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[C:16]1[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@:4]([CH2:3][CH2:2][NH:1][C:42](=[O:43])[O:44][CH3:45])([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[O:9][C:8]2=[O:10])[CH3:12])=[CH:18][CH:17]=1

Participants

7

Reactant 4

HCID 962WaterHCID 6586Methyl chloroformateHCID 8471TriethylamineHCID 53473235HCID 53473235, compound

Product 1

HCID 58109123HCID 58109123, compoundYield 22.2%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
2.5 °C

Procedure

To a solution of (R)-6-(2-aminoethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (40 mg, 0.088 mmol) and DMAP (4 mg, 10%) in dry CH2Cl2 (3 mL), was added Et3N (27 mg, 0.264 mmol). The resulting mixture was cooled to 0-5° C. under ice-water bath, and a solution of methyl chloroformate (41 mg, 0.44 mmol) in dry CH2Cl2 (1 mL) was added dropwise. After addition, the reaction mixture was stirred for 1-2 h at 0˜5° C. After the starting material was disappeared, water (5 mL) was added. The layers were separated, and the aqueous layer was extracted with CH2Cl2 (3×5 mL). The combined organic layers were washed with 10% citric acid (2×10 mL) and brine, dried over Na2SO4, filtered and concentrated to give the residue, which was purified by preparative HPLC to afford methyl 2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethylcarbamate (10 mg, 22%). 1H NMR (CDCl3): 1.50 (m, 3H), 2.06 (m, 2H), 2.10-2.32 (m, 4H), 3.10 (m, 1H), 3.05-3.20 (m, 2H), 3.55 (s, 3H), 4.88 (s, 1H), 5.63 (m, 1H), 6.80-6.90 (m, 2H), 6.92-7.01 (m, 4H), 7.21 (m, 1H), 7.25 (m, 4H).

Workup

  1. additionAfter addition
  2. customThe layers were separated
  3. extractionthe aqueous layer was extracted with CH2Cl2 (3×5 mL)
  4. washThe combined organic layers were washed with 10% citric acid (2×10 mL) and brine
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customto give the residue, which
  9. customwas purified by preparative HPLC

Sources & evidence

ORD record
ord-3adffc4344d343c584994c8858749494
Source dataset
uspto-grants-2013_11
Patent number
US08575156B2

Reaction notes

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