Diisopropylethylamine → 5-amino-2-(2,6-difluorophenyl)-N-(5-((5R,6S)-5,6-dihydroxyoxepan-2-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide

HRID 521949Notes

Reaction equation

HRID 521949 reaction equation
[CH3:1][N:2]1[C:6]([CH:7]2[O:13][CH2:12][CH:11]([OH:14])[CH:10]([OH:15])[CH2:9][CH2:8]2)=[C:5]([N+:16]([O-])=O)[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(OC([NH:68][C:69]1[S:73][C:72]([C:74]2[C:79]([F:80])=[CH:78][CH:77]=[CH:76][C:75]=2[F:81])=[N:71][C:70]=1[C:82](O)=[O:83])=O)(C)(C)C>CO.C(Cl)Cl.Cl.O1CCOCC1.[Pd]>[NH2:68][C:69]1[S:73][C:72]([C:74]2[C:79]([F:80])=[CH:78][CH:77]=[CH:76][C:75]=2[F:81])=[N:71][C:70]=1[C:82]([NH:16][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[CH:7]1[CH2:8][CH2:9][C@@H:10]([OH:15])[C@@H:11]([OH:14])[CH2:12][O:13]1)=[O:83]

Participants

10

Reactant 4

HCID 81531DiisopropylethylamineHCID 2724699PyBOPHCID 674381985-((Tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acidHCID 867138827-(2-Methyl-4-nitro-pyrazol-3-yl)oxepane-3,4-diol2×

Product 1

HCID 867138815-amino-2-(2,6-difluorophenyl)-N-(5-((5R,6S)-5,6-dihydroxyoxepan-2-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamideYield 9.4%

Reagents, catalysts & solvents 5

HCID 23938PalladiumCatalystHCID 313Hydrochloric AcidSolventHCID 887MethanolSolvent2×HCID 6344DichloromethaneSolvent2×HCID 312751,4-DioxaneSolvent

Procedure

A solution of 7-(2-methyl-4-nitro-pyrazol-3-yl)oxepane-3,4-diol (Intermediate 10) (165 mg, 0.64 mmol) in MeOH (13 mL) was passed through the H-Cube (full H2 mode, 80° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solvent was removed under reduced pressure. To a solution of the resulting amine in DCM (10 mL) was added DIPEA (0.33 mL, 1.92 mmol), PyBOP (499 mg, 0.96 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)-thiazole-4-carboxylic acid (249 mg, 0.70 mmol). The mixture was stirred at room temperature for 18 hr, diluted with DCM (5 mL) and washed with water (3×5 mL). The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel chromatography (0-10% MeOH/EtOAc) gave a pink solid. This solid (65 mg, 0.11 mmol) was dissolved in a solution of HCl in dioxane (4 M, 8.6 mL) and MeOH (2 mL) and stirred at room temperature for 18 hr. The solvents were removed under reduced pressure. Purification via preparative HPLC gave 111 as an off-white solid (28 mg, 9% over three steps). 1H NMR (400 MHz, CDCl3) δ 9.75 (br s, 1H), 8.17 (s, 1H), 7.39-7.32 (m, 1H), 7.10-7.00 (m, 2H), 6.25 (br s, 2H), 5.14-5.10 (m, 1H), 4.23 (dd, J=13.7, 4.0 Hz, 1H), 3.90-3.85 (m, 1H), 3.79 (s, 3H), 3.75-3.56 (m, 2H), 2.12-2.00 (m, 3H), 1.76-1.70 (m, 1H). OH protons not observed. LCMS (ES+) m/z 466 (M+1).

Workup

  1. customThe solvent was removed under reduced pressure
  2. washwashed with water (3×5 mL)
  3. customThe organic layer was passed through a phase separation cartridge
  4. concentrationconcentrated under reduced pressure
  5. customPurification via silica gel chromatography (0-10% MeOH/EtOAc)
  6. customgave a pink solid
  7. stirringstirred at room temperature for 18 hr
  8. customThe solvents were removed under reduced pressure
  9. customPurification via preparative HPLC

Sources & evidence

ORD record
ord-6330a540ed3a4a4f93bb871bba6b5eaa
Source dataset
uspto-grants-2016_05
Patent number
US09328106B2

Reaction notes

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