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Diisopropylethylamine → 5-amino-2-(2,6-difluorophenyl)-N-(5-((2R,7R)-5-hydroxy-7-methyloxepan-2-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide

HRID 521948
Notes
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Reaction equation

HRID 521948 reaction equation
[CH3:1][CH:2]1[CH2:8][CH:7]([OH:9])[CH2:6][CH2:5][CH:4]([C:10]2[N:11]([CH3:18])[N:12]=[CH:13][C:14]=2[N+:15]([O-])=O)[O:3]1.[NH2:19][C:20]1[S:24][C:23]([C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[N:22][C:21]=1[C:33](O)=[O:34].CCN(C(C)C)C(C)C.CCCP(=O)=O>CO.[OH-].[OH-].[Pd+2]>[NH2:19][C:20]1[S:24][C:23]([C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[N:22][C:21]=1[C:33]([NH:15][C:14]1[CH:13]=[N:12][N:11]([CH3:18])[C:10]=1[C@H:4]1[CH2:5][CH2:6][CH:7]([OH:9])[CH2:8][C@@H:2]([CH3:1])[O:3]1)=[O:34]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 16167369Propylphosphoric anhydrideHCID 594556885-Amino-2-(2,6-difluorophenyl)thiazole-4-carboxylic acidHCID 867137752-Methyl-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-ol

Product 1

HCID 867138805-amino-2-(2,6-difluorophenyl)-N-(5-((2R,7R)-5-hydroxy-7-methyloxepan-2-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide
Yield 3%

Reagents, catalysts & solvents 2

HCID 9942167Palladium hydroxideCatalystHCID 887MethanolSolvent

Procedure

A solution of 2-methyl-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-ol (79 mg, 0.30 mmol) in MeOH (20 mL) was passed through the H-Cube® (full H2, 70° C., flow rate: 1 mL/min, 30 mm 20% Pd(OH)2/C cartridge). The solvent was removed under reduced pressure and the crude residue was re-dissolved in MeOH (1 mL). 5-Amino-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (94 mg, 0.37 mmol) and DIPEA (0.24 mL, 1.40 mmol) were added. Propylphosphonic anhydride solution (0.19 mL, 50% wt in EtOAc, 0.39 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 the residue was dissolved in EtOAc (10 mL). The organic layer was washed with 1 M aqueous NaOH (3×10 mL), 1 M aqueous HCl (2×10 mL) and brine (10 mL), separated, dried over Na2SO4 and concentrated under reduced pressure. Purification via silica gel chromatography (0-5% 7 M NH3 in MeOH/DCM) gave 108 as a white solid (4 mg, 3% over two steps). 1H NMR (400 MHz, CDCl3) δ 9.69 (d, J=11.8 Hz, 1H), 8.16 (d, J=5.6 Hz, 1H), 7.37-7.30 (m, 1H), 7.04-6.97 (m, 2H), 6.15 (s, 2H), 5.00-4.93 (m, 1H), 4.17 (s, 1H), 4.03 (dd, J=8.0, 6.9 Hz, 1H), 3.77 (s, 3H), 2.11-1.74 (m, 5H), 1.28 (d, J=3.3 Hz, 1H), 1.21 (dd, J=9.2, 6.3 Hz, 3H). Alkyl OH not observed. LCMS (ES+) m/z 464 (M+1).

Workup

  1. customThe solvent was removed under reduced pressure
  2. dissolutionthe crude residue was re-dissolved in MeOH (1 mL)
  3. concentrationThe reaction mixture was concentrated under reduced pressure
  4. dissolutionthe residue was dissolved in EtOAc (10 mL)
  5. washThe organic layer was washed with 1 M aqueous NaOH (3×10 mL), 1 M aqueous HCl (2×10 mL) and brine (10 mL)
  6. customseparated
  7. dry with materialdried over Na2SO4
  8. concentrationconcentrated under reduced pressure
  9. customPurification via silica gel chromatography (0-5% 7 M NH3 in MeOH/DCM)

Sources & evidence

ORD record
ord-23c2341186184f4ca28443bc7cfc2139
Source dataset
uspto-grants-2016_05
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09328106B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes