Ethyl Bromide → Cis pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {3-(5-chloro-2-difluoromethoxyphenyl)-1-[2-(5 ethyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2-oxoethyl]-1H-pyrazol-4-yl}amide hydrochloride

HRID 529757Notes

Reaction equation

HRID 529757 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:39])[F:38])=[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:28]3[CH2:35][C@@H:34]4[C@@H:30]([CH2:31][NH:32][CH2:33]4)[CH2:29]3)=[O:27])[N:9]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:47][CH3:48]>C(#N)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:39])[F:38])=[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:28]3[CH2:29][C@@H:30]4[C@@H:34]([CH2:33][N:32]([CH2:47][CH3:48])[CH2:31]4)[CH2:35]3)=[O:27])[N:9]=2)[CH:7]=1

Participants

5

Reactant 3

HCID 6332Ethyl BromideHCID 11430Potassium CarbonateHCID 118522653Cis-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {3-(5-chloro-2-difluoromethoxyphenyl)-1-[2-(hexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-oxoethyl]-1H-pyrazol-4-yl}amide

Product 1

HCID 131735621Cis pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {3-(5-chloro-2-difluoromethoxyphenyl)-1-[2-(5 ethyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2-oxoethyl]-1H-pyrazol-4-yl}amide hydrochloride

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
50 °C

Procedure

To a solution of cis-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {3-(5-chloro-2-difluoromethoxyphenyl)-1-[2-(hexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-oxoethyl]-1H-pyrazol-4-yl}amide (100 mg, 0.18 mmol) in acetonitrile (4 mL) was added potassium carbonate (37 mg, 0.27 mmol) and bromoethane (20 μL, 0.27 mmol). The reaction was heated at 50° C. for 2 hours and then allowed to cool to room temperature. The mixture was applied directly to an SCX-2 cartridge. Elution with 2M ammonia in MeOH gave the desired product. The product was purified by HPLC (Method 1) and the pure fractions were combined as passed through an SCX-2 cartridge. Elution with 2M ammonia in MeOH gave the free base on evaporation of the solvent. The solid was dissolved in 1.25M methanolic HCl and then the volatiles were evaporated. The HCl salt was crystallised from MeOH/Et2O and obtained as a white solid (32 mg, 40%). LCMS (Method 5) [M+H]+=585.0, RT=2.88 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 10.44 (d, 1H, J=35.0 Hz), 9.79-9.74 (m, 1H), 9.35 (dd, 1H, J=1.3, 7.0 Hz), 8.69 (dd, 1H, J=1.5, 4.2 Hz), 8.67 (s, 1H), 8.31 (d, 1H, J=3.8 Hz), 7.64 (dd, 1H, J=2.5, 8.8 Hz), 7.57 (d, 1H, J=2.6 Hz), 7.47 (d, 1H, J=8.9 Hz), 7.30 (dd, 1H, J=4.3, 7.0 Hz), 7.27 (t, 1H, J=73.6 Hz), 5.22-5.10 (m, 2H), 3.43 (s, 12H), 3.84-2.77 (m, 12H), 1.29-1.19 (m, 3H).

Workup

  1. temperatureto cool to room temperature
  2. washElution with 2M ammonia in MeOH

Sources & evidence

ORD record
ord-2767ec13e77046aca5f4326836e9a4c7
Source dataset
uspto-grants-2016_05
Patent number
US09346815B2

Reaction notes

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