3-Aminopropionitrile → pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (3-(5-chloro-2-difluoromethoxy-phenyl)-1-{2-[4-(2-cyano-ethylamino)-piperidin-1-yl]-2-oxo-ethyl}-1H-pyrazol-4-yl)-amide

HRID 529764Notes

Reaction equation

HRID 529764 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH:36]([F:38])[F:37])=[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:34])[N:27]3[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]3)[N:9]=2)[CH:7]=1.O1CCOCC1.[NH2:45][CH2:46][CH2:47][C:48]#[N:49].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH:36]([F:37])[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:27]3[CH2:32][CH2:31][CH:30]([NH:49][CH2:48][CH2:47][C:46]#[N:45])[CH2:29][CH2:28]3)=[O:34])[N:9]=2)[CH:7]=1

Participants

8

Reactant 4

HCID 16473-AminopropionitrileHCID 312751,4-DioxaneHCID 5049666Sodium triacetoxyborohydrideHCID 118522668N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-(4-oxo-1-piperidyl)ethyl]pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Product 1

HCID 118522443pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (3-(5-chloro-2-difluoromethoxy-phenyl)-1-{2-[4-(2-cyano-ethylamino)-piperidin-1-yl]-2-oxo-ethyl}-1H-pyrazol-4-yl)-amideYield 91%

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolventHCID 887MethanolSolvent2×HCID 6344DichloromethaneSolvent

Procedure

A solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {3-(5-chloro-2-difluoromethoxy-phenyl)-1-[2-oxo-2-(4-oxo-piperidin-1-yl)-ethyl]-1H-pyrazol-4-yl}-amide.dioxane (36 g, 57.0 mmol) in DCM (500 mL) was treated with 3-amino-propionitrile (5.0 mL, 68.4 mmol) and acetic acid (50 mL). The mixture was cooled in an ice bath before the addition of sodium triacetoxyborohydride (18.1 g, 85.4 mmol) portionwise. The reaction was allowed to warm to room temperature and stirred for 1.5 hours. The mixture was diluted with methanol and loaded onto a pad of Isolute® SCX-2 which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH. The basic fractions were combined and evaporated to afford pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (3-(5-chloro-2-difluoromethoxy-phenyl)-1-{2-[4-(2-cyano-ethylamino)-piperidin-1-yl]-2-oxo-ethyl}-1H-pyrazol-4-yl)-amide as a pale brown solid (31.1 g, 91%). LCMS (Method 3) [M+H]+=598.2, RT=2.25 min. 1H NMR (400 MHz, CDCl3) δ: (ppm) 9.84 (s, 1H), 8.78 (dd, 1H, J=1.6, 6.9 Hz), 8.69 (s, 1H), 8.58-8.55 (m, 1H), 8.40 (s, 1H), 7.68 (d, 1H, J=2.5 Hz), 7.41 (dd, 1H, J=2.7, 8.7 Hz), 7.28 (d, 1H, J=8.7 Hz), 7.28 (s, 1H), 7.00 (dd, 1H, J=4.2, 6.9 Hz), 6.50 (t, 1H, J=74.1 Hz), 5.08 (d, 1H, J=15.4 Hz), 5.02 (d, 1H, J=15.5 Hz), 4.37 (d, 1H, J=13.4 Hz), 3.88 (d, 1H, J=13.4 Hz), 3.22-3.12 (m, 1H), 3.02 (t, 1H, J=6.4 Hz), 2.98-2.86 (m, 2H), 2.82-2.72 (m, 1H), 2.52-2.46 (m, 2H), 1.96-1.83 (m, 2H), 1.36-1.20 (m, 2H).

Workup

  1. customAfter flushing with MeOH
  2. washthe product was eluted with 2M ammonia in MeOH
  3. customevaporated

Sources & evidence

ORD record
ord-ed79b5c3cdf743fab39f8f20b5bf1c7f
Source dataset
uspto-grants-2016_05
Patent number
US09346815B2

Reaction notes

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