Diisopropylethylamine → Cis-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {3-(5-chloro-2-difluoromethoxyphenyl)1-[2-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-oxoethyl]-1H-pyrazol-4-yl}amide

HRID 529755Notes

Reaction equation

HRID 529755 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](O)=[O:27])[N:9]=2)[CH:7]=1.CCN(C(C)C)C(C)C.[CH3:42][N:43]1[CH2:50][C@@H:49]2[C@@H:45]([CH2:46][NH:47][CH2:48]2)[CH2:44]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:47]3[CH2:48][C@@H:49]4[C@@H:45]([CH2:44][N:43]([CH3:42])[CH2:50]4)[CH2:46]3)=[O:27])[N:9]=2)[CH:7]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 12958532(3aR,6aS)-2-methyl-octahydropyrrolo[3,4-c]pyrroleHCID 118522370{3-(5-Chloro-2-difluoromethoxy-phenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid

Product 1

HCID 118522535Cis-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {3-(5-chloro-2-difluoromethoxyphenyl)1-[2-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-oxoethyl]-1H-pyrazol-4-yl}amideYield 69.3%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 11430Potassium CarbonateSolvent

Procedure

A solution of {3-(5-chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (20.0 g, 43.2 mmol) in DMF (150 mL) was treated with DIPEA (6.7 g, 5.2 mmol), cis-2-methyloctahydropyrrolo[3,4-c]pyrrole (6.27 g, 49.7 mmol) and HATU (18.9 g, 49.7 mmol) and the mixture left to stir at room temperature for 1 hour. The reaction mixture was diluted with 0.5M aqueous K2CO3 solution and extracted with ethyl acetate (×2). The combined organic extract was washed with water (×2) and brine, dried (Na2SO4) and evaporated to afford a solid. The resultant solid was purified by flash chromatography on silica eluting with 0-10% 2M NH3/MeOH in DCM. Collecting appropriate fractions, followed by evaporation gave the title compound as a cream solid (17.1 g, 69%). LCMS (Method 5) [M+H]+=570.9, RT=2.82. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.70 (s, 1H), 9.30 (dd, 1H, J=7.0, 1.6 Hz), 8.62-8.63 (m, 2H), 8.27 (s, 1H), 7.59 (dd, 1H, J=8.8, 2.7 Hz), 7.52 (d, 1H, J=2.7 Hz), 7.42 (d, 1H, J=8.8 Hz), 7.25 (dd, 1H, J=7.0, 4.2 Hz), 7.11 (t, 1H, J=73.3 Hz), 5.07 (d, 2H, J=5.9 Hz), 3.69 (dd, 1H, J=10.8, 8.6 Hz), 3.56 (dd, 1H, J=12.2, 8.8 Hz), 3.36 (dd, 1H, J=10.8, 4.4 Hz), 3.22 (dd, 1H, J=12.3, 4.5 Hz), 2.45-2.46 (m, 3H), 2.37-2.39 (m, 3H), 2.17 (s, 3H).

Workup

  1. waitthe mixture left
  2. extractionextracted with ethyl acetate (×2)
  3. extractionThe combined organic extract
  4. washwas washed with water (×2) and brine
  5. dry with materialdried (Na2SO4)
  6. customevaporated
  7. customto afford a solid
  8. customThe resultant solid was purified by flash chromatography on silica eluting with 0-10% 2M NH3/MeOH in DCM
  9. customCollecting appropriate fractions
  10. customfollowed by evaporation

Sources & evidence

ORD record
ord-0fe702de65714573bf0257880edc150f
Source dataset
uspto-grants-2016_05
Patent number
US09346815B2

Reaction notes

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