Ammonium Chloride → (R)-5-(2-(3-carbamoyl-5-fluorophenyl)-4,4-difluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

HRID 513047Notes

Reaction equation

HRID 513047 reaction equation
[C:1]([C:4]1[CH:5]=[C:6]([C@H:11]2[CH2:15][C:14]([F:17])([F:16])[CH2:13][N:12]2[C:18]2[CH:23]=[CH:22][N:21]3[N:24]=[CH:25][C:26]([C:27]([OH:29])=O)=[C:20]3[CH:19]=2)[CH:7]=[C:8]([F:10])[CH:9]=1)(O)=[O:2].CC[N:32](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH4+:63].[Cl-]>CN(C=O)C.[NH4+].[OH-].CCOC(C)=O>[C:1]([C:4]1[CH:5]=[C:6]([C@H:11]2[CH2:15][C:14]([F:17])([F:16])[CH2:13][N:12]2[C:18]2[CH:23]=[CH:22][N:21]3[N:24]=[CH:25][C:26]([C:27]([NH2:32])=[O:29])=[C:20]3[CH:19]=2)[CH:7]=[C:8]([F:10])[CH:9]=1)(=[O:2])[NH2:63]

Participants

8

Reactant 4

HCID 25517Ammonium ChlorideHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 68282203(R)-5-(2-(3-carboxy-5-fluorophenyl)-4,4-difluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid

Product 1

HCID 60171439(R)-5-(2-(3-carbamoyl-5-fluorophenyl)-4,4-difluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolventHCID 14923Ammonium HydroxideSolvent

Procedure

To a solution of (R)-5-(2-(3-carboxy-5-fluorophenyl)-4,4-difluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (I-52) (54 mg, 0.13 mmol) in DMF (2 mL) was added DIEA (116 μL, 0.67 mmol) and HATU (126 mg, 0.33 mmol). The reaction was stirred for 30 minutes, then a solution of NH4Cl (29 mg, 0.52 mmol) in NH4OH (0.25 mL) was added and stirring continued for 2 hours. The crude reaction mixture was diluted with EtOAc and washed with water, brine, dried over magnesium sulfate, filtered and reduced to dryness. Purification by column chromatography on silica gel with DCM/MeOH gradient as eluant gave (R)-5-(2-(3-carbamoyl-5-fluorophenyl)-4,4-difluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (X-9). 1H NMR (400 MHz, CD3OD) δ 8.24 (d, J=7.6 Hz, 1 H), 8.19 (s, 1 H), 7.65 (s, 1 H), 7.46 (d, J=8.4 Hz, 1 H), 7.22 (d, J=9.2 Hz, 1 H), 7.04 (d, J=2.4 Hz, 1 H), 6.44 (dd, J=2.8, 7.6 Hz, 1 H), 5.25 (dd, J=4.4, 8.8 Hz, 1 H), 4.26 (q, J=11.6 Hz, 1 H), 3.99 (q, J=14.0 Hz, 1 H), 3.20-3.02 (m, 1 H), 2.52-2.40 (m, 1 H). MS m/z 404.1 (M+1)+.

Workup

  1. stirringstirring
  2. waitcontinued for 2 hours
  3. customThe crude reaction mixture
  4. washwashed with water, brine
  5. dry with materialdried over magnesium sulfate
  6. filtrationfiltered
  7. customPurification by column chromatography on silica gel with DCM/MeOH gradient as eluant

Sources & evidence

ORD record
ord-5f3474a925884d82a8f90d05e4835b3b
Source dataset
uspto-grants-2015_08
Patent number
US09102671B2

Reaction notes

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