Water → (S)-methyl 2-(2-bromo-7-(4,4-dimethylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate

HRID 574354Notes

Reaction equation

HRID 574354 reaction equation
[Br:1][C:2]1[CH:25]=[C:5]2[N:6]=[C:7]([CH3:24])[C:8]([C:18](=[O:23])[C:19]([O:21][CH3:22])=[O:20])=[C:9]([N:10]3[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH2:12][CH2:11]3)[N:4]2[N:3]=1.C(#N)C.C(=O)=O.[B]1OC2C(=CC=CC=2)O1.O>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])([O-])=O.[K+].[K+]>[Br:1][C:2]1[CH:25]=[C:5]2[N:6]=[C:7]([CH3:24])[C:8]([C@H:18]([OH:23])[C:19]([O:21][CH3:22])=[O:20])=[C:9]([N:10]3[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH2:12][CH2:11]3)[N:4]2[N:3]=1

Participants

8

Reactant 4

HCID 962WaterHCID 6327445BenzcatechinboraneHCID 86587134Acetonitrile dry iceHCID 86695079Methyl 2-(2-bromo-7-(4,4-dimethylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate

Product 1

HCID 86695080(S)-methyl 2-(2-bromo-7-(4,4-dimethylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetateYield 92%

Reagents, catalysts & solvents 3

HCID 1140TolueneSolvent3×HCID 8857Ethyl AcetateSolventHCID 11430Potassium CarbonateSolvent

Procedure

To a solution of methyl 2-(2-bromo-7-(4,4-dimethylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-oxoacetate (6.15 g, 15.03 mmol, 1 equiv) in toluene (200 mL) was added (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,2,3]oxazaborole (9.0 mL of a 1M solution in toluene, 9.02 mmol, 0.6 equiv). The solution was cooled to −25° C. (acetonitrile/CO2) and catechol borane (8.7 mL of a 50% solution in toluene, 36.1 mmol, 2.4 equiv) was added. The cooling bath temperature was maintained between −15° C. and −25° C. for 4 h. The reaction was then diluted with EtOAc (35 mL) and 10% aqueous solution of K2CO3 (35 mL) and then allowed to warm to ambient temperature. The quenched solution was stirred for 45 min and then added to water. Extract with ether (×3). Combined ether extracts dried over MgSO4 and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (0-70% EtOAc/hexane) to provide (S)-methyl 2-(2-bromo-7-(4,4-dimethylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate as a pale yellow glass (5.68 g, 92%). 1H NMR (500 MHz, CDCl3) δ 6.58 (s, 1H), 5.54 (d, J=5.2 Hz, 1H), 4.51 (d, J=5.0 Hz, 1H), 3.81 (s, 3H), 3.73-3.14 (m very broad, 4H), 2.62 (s, 3H), 1.60-1.54 (m, 4H), 1.11 (s, 6H); LCMS (ESI, M+1): 411.05.

Workup

  1. additionwas added
  2. temperatureThe cooling bath temperature was maintained between −15° C. and −25° C. for 4 h
  3. extractionExtract with ether (×3)
  4. dry with materialCombined ether extracts dried over MgSO4
  5. concentrationconcentrated in vacuo
  6. customThe crude product was purified by silica gel flash chromatography (0-70% EtOAc/hexane)

Sources & evidence

ORD record
ord-b8635c78ada64409846857f9a3e3254f
Source dataset
uspto-grants-2015_05
Patent number
US09034882B2

Reaction notes

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