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3,3-Difluoroazetidine hydrochloride → HCID 71279873, compound

HRID 246419
Notes
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Reaction equation

HRID 246419 reaction equation
[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH:32]=O)[N:18]=3)[N:15]=2)[N:10]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:43][C:44]1([F:48])[CH2:47][NH:46][CH2:45]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C([O-])(O)=O.[Na+]>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][N:46]4[CH2:47][C:44]([F:48])([F:43])[CH2:45]4)[N:18]=3)[N:15]=2)[N:10]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:40])([CH3:39])[CH3:41])[CH:9]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 3

HCID 27582473,3-Difluoroazetidine hydrochlorideHCID 5049666Sodium triacetoxyborohydrideHCID 86677979HCID 86677979, compound

Product 1

HCID 71279873HCID 71279873, compoundYield 98.8%

Reagents, catalysts & solvents 2

HCID 63651,1-DichloroethaneSolvent
HCID 516892
Sodium Bicarbonate
Solvent

Conditions

Temperature
25 °C

Procedure

To a solution of N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-oxopropyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (34 mg, 58.0 μmol) in dichloroethane (6 mL) was added 3,3-difluoroazetidine hydrochloride (9.76 mg, 75.3 μmol.30). The mixture was stirred at 25° C. for 15 min, then sodium triacetoxyborohydride (18.4 mg, 86.9 μmol0) was added and stirring was continued for 18 h. The reaction mixture was diluted with saturated NaHCO3 solution and extracted with dichloromethane (5×20 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 20 min (MeOH containing 10% ammonium hydroxide)/dichloromethane to give N-tert-butyl-2-(1-(3-(3,3-difluoroazetidin-1-yl)propyl)-5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (38 mg, 57.2 μmol, 98.8%) as an off-white solid. MS (M+Na)+=686; 1H NMR (CDCl3) δ: 9.22 (s, 1H), 8.36 (s, 1H), 8.32 (d, J=2.3 Hz, 1H), 8.05 (s, 1H), 7.59 (d, J=9.1 Hz, 1H), 7.36 (dd, J=9.1, 2.3 Hz, 1H), 6.55 (t, J=74.0 Hz, 1H), 5.75 (s, 2H), 4.61 (t, J=6.6 Hz, 2H), 3.53-3.72 (m, 6H), 2.64 (t, J=6.0 Hz, 2H), 2.14 (dq, J=6.8, 5.7 Hz, 2H), 1.64 (s, 9H), 0.91-1.08 (m, 2H), 0.00 (s, 9H).

Workup

  1. stirringstirring
  2. waitwas continued for 18 h
  3. extractionextracted with dichloromethane (5×20 mL)
  4. dry with materialThe organic layer was dried (MgSO4)
  5. concentrationconcentrated in vacuo
  6. customThe resultant residue was purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco)
  7. washeluting with 0 to 5% over 20 min (MeOH containing 10% ammonium hydroxide)/dichloromethane

Sources & evidence

ORD record
ord-9c7212d620344acc917f85c5da9595cf
Source dataset
uspto-grants-2014_02
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08658646B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes