4-Methylmorpholine → 5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(5-methyl-5-((2,2,2-trifluoroacetamido)methyl)-1,3-dioxan-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide

HRID 521959Notes

Reaction equation

HRID 521959 reaction equation
[F:1][C:2]([F:24])([F:23])[C:3]([NH:5][CH2:6][C:7]1([CH3:22])[CH2:12][O:11][CH:10]([C:13]2[N:17]([CH3:18])[N:16]=[CH:15][C:14]=2[N+:19]([O-])=O)[O:9][CH2:8]1)=[O:4].C([O-])=O.[NH4+].[NH2:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43](O)=[O:44].CN1CCOCC1.CCCP(=O)=O>CO.[Pd]>[NH2:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43]([NH:19][C:14]1[CH:15]=[N:16][N:17]([CH3:18])[C:13]=1[CH:10]1[O:11][CH2:12][C:7]([CH3:22])([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:24])([F:23])[F:1])[CH2:8][O:9]1)=[O:44]

Participants

8

Reactant 5

HCID 79724-MethylmorpholineHCID 2723923Ammonium formateHCID 16167369Propylphosphoric anhydrideHCID 594556885-Amino-2-(2,6-difluorophenyl)thiazole-4-carboxylic acidHCID 867138262,2,2-trifluoro-N-((5-methyl-2-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,3-dioxan-5-yl)methyl)acetamide2×

Product 1

HCID 867138875-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(5-methyl-5-((2,2,2-trifluoroacetamido)methyl)-1,3-dioxan-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 887MethanolSolvent

Procedure

2,2,2-trifluoro-N-((5-methyl-2-(1-methyl-4-nitro-1H-pyrazol-5-yl)-1,3-dioxan-5-yl)methyl)acetamide (171 mg, 0.49 mmol, intermediate 84) was dissolved in MeOH (30 mL) and ammonium formate (170 mg, 2.69 mmol) and 10% Pd/C (140 mg, 0.13 mmol) were added. The mixture was heated at reflux for 18 hr before being cooled to room temperature. The suspension was filtered, the cake washed with EtOAc (100 mL) and the filtrate concentrated under reduced pressure. The crude residue was dissolved in EtOAc (10 mL) and 5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (131 mg, 0.51 mmol) was then added followed by N-methylmorpholine (0.11 mL, 1.46 mmol). Propylphosphonic anhydride solution (50% wt in EtOAc, 338 mg, 0.53 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure and purified via silica gel chromatography (0-5% 7 N NH3 in MeOH/DCM) to give 5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(5-methyl-5-((2,2,2-trifluoroacetamido)methyl)-1,3-dioxan-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide as a white solid (102 mg, 18% over three steps). A mixture of 5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(5-methyl-5-((2,2,2-trifluoroacetamido)methyl)-1,3-dioxan-2-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide (101 mg, 0.18 mmol) in MeOH (6 mL) and aqueous saturated K2CO3 solution (0.6 mL) was heated in a microwave at 100° C. for 1 hr. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and purified via silica gel chromatography (0-20% MeOH/DCM) to give 175 as a white solid (4 mg, 5%). 1H NMR (400 MHz, CDCl3) δ 9.80 (s, 1H), 8.24 (s, 1H), 7.34-7.27 (m, 1H), 7.05-6.97 (m, 2H), 6.15 (s, 2H), 5.70 (s, 1H), 3.98-3.91 (m, 2H), 3.86 (s, 3H), 3.80 (d, J=11.0 Hz, 2H), 2.54 (s, 2H), 1.26 (s, 3H). Alkyl NH2 not observed. LCMS (ES+) m/z 465 (M+1).

Workup

  1. temperatureThe mixture was heated
  2. temperatureat reflux for 18 hr
  3. filtrationThe suspension was filtered
  4. washthe cake washed with EtOAc (100 mL)
  5. concentrationthe filtrate concentrated under reduced pressure
  6. dissolutionThe crude residue was dissolved in EtOAc (10 mL)
  7. concentrationThe reaction mixture was concentrated under reduced pressure
  8. custompurified via silica gel chromatography (0-5% 7 N NH3 in MeOH/DCM)

Sources & evidence

ORD record
ord-4b7121180f17494cb761994b20c36cc9
Source dataset
uspto-grants-2016_05
Patent number
US09328106B2

Reaction notes

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