Ammonium Bicarbonate → 2-(methylsulfanyl)ethyl 2-[(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]ethyl)amino]acetate

HRID 529845Notes

Reaction equation

HRID 529845 reaction equation
Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH2:8][S:9][CH3:10])=[O:5].Br[CH2:12][CH2:13][N:14]1[CH:18]=[C:17]([NH:19][C:20]([C:22]2[CH:23]=[N:24][N:25]3[CH:30]=[CH:29][CH:28]=[N:27][C:26]=23)=[O:21])[C:16]([C:31]2[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=2[O:38][CH:39]([F:41])[F:40])=[N:15]1.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[NH4+]>CC#N.C(O)=O.O>[Cl:37][C:35]1[CH:34]=[CH:33][C:32]([O:38][CH:39]([F:41])[F:40])=[C:31]([C:16]2[C:17]([NH:19][C:20]([C:22]3[CH:23]=[N:24][N:25]4[CH:30]=[CH:29][CH:28]=[N:27][C:26]=34)=[O:21])=[CH:18][N:14]([CH2:13][CH2:12][NH:2][CH2:3][C:4]([O:6][CH2:7][CH2:8][S:9][CH3:10])=[O:5])[N:15]=2)[CH:36]=1

Participants

8

Reactant 4

HCID 14013Ammonium BicarbonateHCID 81531DiisopropylethylamineHCID 1185225552-(methylsulfanyl)ethyl 2-aminoacetate HCl saltHCID 118522619N-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy) phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Product 1

HCID 1185227932-(methylsulfanyl)ethyl 2-[(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]ethyl)amino]acetate

Reagents, catalysts & solvents 3

HCID 284Formic AcidSolventHCID 962WaterSolventHCID 6342AcetonitrileSolvent3×

Conditions

Temperature
75 °C

Procedure

To a solution of 2-(methylsulfanyl)ethyl 2-aminoacetate HCl salt (792 mg, 3.57 mmol) in CH3CN was added N-[1-(2-bromoethyl)-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (364 mg, 0.71 mmol) and DIEA (1.57 g, 12.15 mmol). The resulting solution was stirred at 75° C. overnight and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (2#-Waters 2767-2 (HPLC-08)): Column, Xbridge Prep Phenyl, 5 um, 19×150 mm; mobile phase, Water with 50 mmol ammonium bicarbonate and acetonitrile (10.0% acetonitrile up to 33.0% in 2 min, up to 53.0% in 8 min, up to 100.0% in 1 min, down to 10.0% in 1 min); Detector, UV 220 nm. This resulted in 53.1 mg (2%) of the formic acid salt of 2-(methylsulfanyl)ethyl 2-[(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]ethyl)amino]acetate as light yellow oil. LCMS (Method 20): [M+H]+=580.15, RT=2.76 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.73 (s, 1H), 9.33 (dd, 1H, J=1.5, 6.9 Hz), 8.67 (dd, 1H, J=1.5, 4.2 Hz), 8.66 (s, 1H), 8.36 (s, 1H), 7.65-7.61 (m, 2H), 7.44 (d, 1H, J=9.3 Hz), 7.23 (dd, 1H, J=4.5, 7.2 Hz), 6.99 (t, 1H, J=73.5 Hz), 4.27-4.18 (m, 4H), 3.38 (s, 2H), 2.99 (t, 2H, J=6.0 Hz), 2.67 (t, 2H, J=6.6 Hz), 2.07 (s, 3H).

Workup

  1. concentrationconcentrated under vacuum
  2. customThe crude product was purified by Prep-HPLC with the following conditions (2#-Waters 2767-2 (HPLC-08))
  3. waitup to 53.0% in 8 min
  4. waitup to 100.0% in 1 min
  5. waitdown to 10.0% in 1 min)

Sources & evidence

ORD record
ord-900b8ed033b84a39b314f91398a0912b
Source dataset
uspto-grants-2016_05
Patent number
US09346815B2

Reaction notes

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