Diisopropylethylamine → HCID 67439628, compound

HRID 1185313Notes

Reaction equation

HRID 1185313 reaction equation
[CH3:1][N:2]1[C:6]([O:7][CH2:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[C:5]([N+:15]([O-])=O)[CH:4]=[N:3]1.[C:18]([O:22][C:23]([NH:25][C:26]1[S:30][C:29]([C:31]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=2[F:38])=[N:28][C:27]=1[C:39](O)=[O:40])=[O:24])([CH3:21])([CH3:20])[CH3:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CO.C(Cl)Cl.[Pd].O>[F:38][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([F:37])[C:31]=1[C:29]1[S:30][C:26]([NH:25][C:23](=[O:24])[O:22][C:18]([CH3:20])([CH3:19])[CH3:21])=[C:27]([C:39](=[O:40])[NH:15][C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]=2[O:7][CH2:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:28]=1

Participants

9

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 58465096HCID 58465096, compoundHCID 674381985-((Tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid

Product 1

HCID 67439628HCID 67439628, compoundYield 69%

Reagents, catalysts & solvents 4

HCID 23938PalladiumCatalystHCID 887MethanolSolventHCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

A solution of 1-methyl-4-nitro-5-((tetrahydro-2H-pyran-4-yl)methoxy)-1H-pyrazole (0.143 g, 0.59 mmol) in MeOH (15 mL) was passed through the H-Cube® (70 bar, 60° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to afford the crude amine as a brown oil (0.115 g, 0.54 mmol). To a solution of this amine in DCM (8 mL) was added 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (0.206 g, 0.58 mmol), HATU (0.615 g, 1.62 mmol) and DIPEA (0.66 mL, 3.78 mmol). The mixture was stirred at room temperature for 18 hr. Water (30 ml) was added and stirring continued for 15 min. The layers were separated and the aqueous extracted with DCM. The combined organics were passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification of the residue via silica gel column chromatography (0-100% EtOAc/isohexane) gave tert-butyl 2-(2,6-difluorophenyl)-4-(1-methyl-5-((tetrahydro-2H-pyran-4-yl)methoxy)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a yellow solid (0.22 g, 69%). This solid (0.129 g, 0.25 mmol) was stirred in HCl in 1,4-dioxane (4.0 M, 4 mL) at room temperature for 18 hr. The solvents were removed under reduced pressure and the crude residue was re-dissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH and 0.3 M ammonia in MeOH to yield a coloured foam. Further purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 230 as a white solid (70 mg, 67%). 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.62 (s, 1H), 7.37-7.28 (m, 1H), 7.07-6.97 (m, 2H), 6.15 (s, 2H), 4.02 (d, J=6.5 Hz, 2H), 3.96 (dd, J=11.5, 4.5 Hz, 2H), 3.69 (s, 3H), 3.43-3.35 (m, 2H), 2.11-1.98 (m, 1H), 1.75-1.69 (m, 2H), 1.51-1.38 (m, 2H). LCMS (ES+) m/z 450 (M+1)

Workup

  1. customThe solvent was removed under reduced pressure
  2. customto afford the crude amine as a brown oil (0.115 g, 0.54 mmol)
  3. stirringstirring
  4. waitcontinued for 15 min
  5. customThe layers were separated
  6. extractionthe aqueous extracted with DCM
  7. customThe combined organics were passed through a phase separation cartridge
  8. customthe solvent removed under reduced pressure
  9. customPurification of the residue via silica gel column chromatography (0-100% EtOAc/isohexane)

Sources & evidence

ORD record
ord-ab32986340584319a274321a15bc27c1
Source dataset
uspto-grants-2014_03
Patent number
US08669361B2

Reaction notes

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