Diisopropylethylamine → HCID 67437983, compound

HRID 1185320Notes

Reaction equation

HRID 1185320 reaction equation
[CH3:1][N:2]1[C:6]([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[C:5]([NH2:13])[CH:4]=[N:3]1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:56]([O:60][C:61]([NH:63][C:64]1[S:68][C:67]([C:69]2[C:74]([F:75])=[CH:73][CH:72]=[CH:71][C:70]=2[F:76])=[N:66][C:65]=1[C:77](O)=[O:78])=[O:62])([CH3:59])([CH3:58])[CH3:57]>C(Cl)Cl>[F:76][C:70]1[CH:71]=[CH:72][CH:73]=[C:74]([F:75])[C:69]=1[C:67]1[S:68][C:64]([NH:63][C:61](=[O:62])[O:60][C:56]([CH3:58])([CH3:57])[CH3:59])=[C:65]([C:77](=[O:78])[NH:13][C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]=2[CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[N:66]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2724699PyBOPHCID 674381985-((Tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acidHCID 67438275HCID 67438275, compound

Product 1

HCID 67437983HCID 67437983, compoundYield 59.5%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

A solution of 5-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-4-nitro-1H-pyrazole (80 mg, 0.38 mmol) in MeOH (20 mL) was passed through the H-Cube® (30 bar, 25° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to afford crude 1-methyl-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine as a light yellow oil (64 mg, 0.35 mmol). To a solution of this amine (60 mg, 0.33 mmol) in DCM (20 mL) was added DIPEA (0.5 mL, 2.87 mmol), PyBOP (0.34 g, 0.66 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (124 mg, 0.35 mmol) and the mixture was stirred at room temperature for 18 hr. The mixture was diluted with DCM and washed with water. The organic layer was separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-80% EtOAc/isohexane) gave tert-butyl 2-(2,6-difluorophenyl)-4-(1-methyl-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as an off-white solid (102 mg, 59%). This solid (100 mg, 0.19 mmol) was stirred in HCl in 1,4-dioxane (4.0 M, 1.9 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 7 N ammonia in MeOH to yield 301 as a peach solid (59 mg, 73%). 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.69 (s, 1H), 7.34-7.29 (m, 1H), 7.02 (t, J=8.7 Hz, 2H), 6.11 (s, 2H), 4.09 (dd, J=11.6, 4.2 Hz, 2H), 3.88 (s, 3H), 3.50 (t, J=11.6 Hz, 2H), 3.02-2.95 (m, 1H), 2.17-2.08 (m, 2H), 1.78 (d, J=13.4 Hz, 2H). LCMS (ES+) m/z 420 (M+1)

Workup

  1. washwashed with water
  2. customThe organic layer was separated
  3. dry with materialdried over MgSO4
  4. customthe solvent removed under reduced pressure
  5. customPurification via silica gel column chromatography (0-80% EtOAc/isohexane)

Sources & evidence

ORD record
ord-18352382681c46ecb4fb2f70ddab47d3
Source dataset
uspto-grants-2014_03
Patent number
US08669361B2

Reaction notes

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