Hydrochloric Acid → HCID 57891190, compound

HRID 1913261Notes

Reaction equation

HRID 1913261 reaction equation
[CH3:1][C:2]#[N:3].[Li]CCCC.CO[C:11](=[O:26])[CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.Cl>C1COCC1>[C:22]([O:21][C:19]([N:16]1[CH2:15][CH2:14][CH:13]([CH2:12][C:11](=[O:26])[CH2:1][C:2]#[N:3])[CH2:18][CH2:17]1)=[O:20])([CH3:23])([CH3:24])[CH3:25]

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 6342AcetonitrileHCID 1514280tert-Butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylateHCID 178418339Butyllithium

Product 1

HCID 57891190HCID 57891190, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-78 °C

Procedure

At −78° C., CH3CN in THF (1505 uL, 28.82 mmoL) was added dropwise to n-BuLi (2.5 M in hexane, 11.52 mL) in THF (40 mL). After stirring at −78° C. for 1 h, tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (Int-12a, 3708 mg, 14.41 mmoL) in THF (10 mL) was added dropwise in 5 min. The mixture was stirred at −78° C. for 1 h and −45° C. for 1 h. At 0° C., 1N HCl was added carefully to adjust the pH to about 7. The mixture was then extracted with ethyl acetate (x2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation afforded tert-butyl-4-(3-cyano-2-oxopropyl)piperidine-1-carboxylate (Int-12b) which was then heated at 100° C. overnight with 1H-pyrazol-5-amine (1197 mg, 14.41 mmoL) in HOAc (25 mL). Concentration provided crude tert-butyl 4-((7-aminopyrazolo[1,5-a]pyrimidin-5-yl)methyl)piperidine-1-carboxylate (Int-12c) which was treated with SEMCl (72.05 mmoL, 12.71 mL) and DIEA (144.4 mmoL, 25.05 mL) in DCE (100 mL) at 50° C. for 1 h. The mixture was diluted with H2O and then extracted with CH2Cl2 (x2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation and purification by column chromatography afforded tert-butyl 4-((7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)piperidine-1-carboxylate (Int-12d): LCMS tR=3.05 Min (5 min run, UV254nm). Mass calculated for, M+591.3, observed m/z 592.3 (M+H).

Workup

  1. stirringThe mixture was stirred at −78° C. for 1 h and −45° C. for 1 h
  2. extractionThe mixture was then extracted with ethyl acetate (x2)
  3. washThe combined organic layers were washed with brine
  4. dry with materialdried with Na2SO4
  5. customEvaporation

Sources & evidence

ORD record
ord-443e8667000f4f3cb6d8356c9c9256b7
Source dataset
uspto-grants-2013_12
Patent number
US08609675B2

Reaction notes

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