Trifluoroacetic acid → N-[3-[(3R)-5-Amino-3-(difluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl]-4-fluorophenyl]-5-cyano-3-methyl-2-pyridinecarboxamide

HRID 2196352Notes

Reaction equation

HRID 2196352 reaction equation
C(OC(=O)[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:17]2[CH:22]=[C:21]([NH:23][C:24]([C:26]3[C:31]([CH3:32])=[CH:30][C:29]([C:33]#[N:34])=[CH:28][N:27]=3)=[O:25])[CH:20]=[CH:19][C:18]=2[F:35])([CH:14]([F:16])[F:15])[N:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:17]2[CH:22]=[C:21]([NH:23][C:24]([C:26]3[C:31]([CH3:32])=[CH:30][C:29]([C:33]#[N:34])=[CH:28][N:27]=3)=[O:25])[CH:20]=[CH:19][C:18]=2[F:35])([CH:14]([F:16])[F:15])[N:13]=1

Participants

4

Reactant 2

HCID 6422Trifluoroacetic acidHCID 66665271((R)-5-{5-[(5-Cyano-3-methyl-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester

Product 1

HCID 58118873N-[3-[(3R)-5-Amino-3-(difluoromethyl)-3,6-dihydro-2H-1,4-oxazin-3-yl]-4-fluorophenyl]-5-cyano-3-methyl-2-pyridinecarboxamide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
25 °C

Procedure

To a solution of ((R)-5-{5-[(5-cyano-3-methyl-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester (23 g, 45.77 mmol) in DCM (615 ml) was added under argon TFA (23 ml, 302.27 mmol) below 25° C. After stirring for 18 h at 25° C., another TFA (12 ml, 151.13 mmol) was added. After stirring at 25° C. for another 6 h, cooled down to −5° C., quenched by 12.5% NH3 aqueous solution (110 ml). The DCM phase was collected and water (100 ml) was added. The DCM of the diphase solution was removed to provide a yellowish suspension. Filtered and dried to provide the title compound as yellowish crystals. ESIMS: 404 [(M+H)+]; 1H NMR (400 MHz, DMSO-d6): 10.72 (s, 1H), 8.96 (s, 1H), 8.38 (s, 1H), 7.99 (dd, 1H), 7.81 (m, 1H), 7.18 (d, 1H), 6.17 (br s, 2H), 6.15 (t, 1H), 3.98 (m, 4H), 2.53 (s, 3H).

Workup

  1. stirringAfter stirring at 25° C. for another 6 h
  2. temperaturecooled down to −5° C.
  3. customquenched by 12.5% NH3 aqueous solution (110 ml)
  4. customThe DCM phase was collected
  5. additionwater (100 ml) was added
  6. customThe DCM of the diphase solution was removed
  7. customto provide a yellowish suspension
  8. filtrationFiltered
  9. customdried

Sources & evidence

ORD record
ord-19d705045b6b45c1924485e559edd871
Source dataset
uspto-grants-2012_12
Patent number
US08338413B1

Reaction notes

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