Aluminium lithium hydride → 1-(1-Methyl-3-pyrrolidinyl)-1H-pyrazol-4-amine

HRID 577688Notes

Reaction equation

HRID 577688 reaction equation
[H-].[H-].[H-].[H-].[Li+].[Al+3].[NH2:7][C:8]1[CH:9]=[N:10][N:11]([CH:13]2[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[CH2:14]2)[CH:12]=1>C1COCC1.CCOC(C)=O>[CH3:18][N:15]1[CH2:16][CH2:17][CH:13]([N:11]2[CH:12]=[C:8]([NH2:7])[CH:9]=[N:10]2)[CH2:14]1

Participants

5

Reactant 2

HCID 21226445Aluminium lithium hydrideHCID 46738147tert-Butyl 3-(4-amino-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate

Product 1

HCID 679816411-(1-Methyl-3-pyrrolidinyl)-1H-pyrazol-4-amineYield 51%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

A reaction flask containing a suspension of LAH (499 mg, 13.2 mmol) in THF (22 mL) was evacuated and back-filled with nitrogen three times. A solution of tert-butyl 3-(4-amino-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (830 mg, 3.3 mmol) in THF (11 mL) was added dropwise, via an addition funnel and the reaction mixture was stirred at rt under nitrogen overnight. The reaction was quenched sequentially with water (1 mL), 1N NaOH (1 mL), and water (3 mL) to afford a suspension. The precipitate was filtered off and washed with ethyl acetate. The combined filtrates were diluted with a small amount of water and transferred to a separatory funnel. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The organics were combined and concentrated to give crude material (137 mg). To recover product in the aqueous layer, the aqueous extraces were lyophilized to give a solid residue. This was suspended in EtOAc and filtered. The filtrate was evaporated to give additional crude material (287 mg). The combined crude was purified via Biotage flash chromatography (25S column, eluting with 7 N NH3/MeOH in DCM (1%-4%)) to give the title compound (279 mg, 51% yield). m/z (APCI+) for C8H14N4 167.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.89-2.00 (m, 1H) 2.20-2.31 (m, 1H) 2.26 (s, 3H) 2.42 (td, J=8.40, 6.19 Hz, 1H) 2.60 (dd, J=9.60, 4.80 Hz, 1H) 2.64-2.77 (m, 2H) 3.79 (br. s., 2H) 4.67 (m, J=9.44, 7.23, 4.67, 4.67 Hz, 1H) 6.87 (s, 1H) 7.07 (s, 1H).

Workup

  1. additionA reaction flask containing
  2. customwas evacuated
  3. additionback-filled with nitrogen three times
  4. customThe reaction was quenched sequentially with water (1 mL), 1N NaOH (1 mL), and water (3 mL)
  5. customto afford a suspension
  6. filtrationThe precipitate was filtered off
  7. washwashed with ethyl acetate
  8. additionThe combined filtrates were diluted with a small amount of water
  9. customtransferred to a separatory funnel
  10. customThe layers were separated
  11. extractionthe aqueous layer was extracted with ethyl acetate
  12. concentrationconcentrated
  13. customto give crude material (137 mg)
  14. customTo recover product in the aqueous layer
  15. customto give a solid residue
  16. filtrationfiltered
  17. customThe filtrate was evaporated
  18. customto give additional crude material (287 mg)
  19. customwas purified via Biotage flash chromatography (25S column, eluting with 7 N NH3/MeOH in DCM (1%-4%))

Sources & evidence

ORD record
ord-ce9d4f7beaac405487b45095582deb6b
Source dataset
uspto-grants-2015_05
Patent number
US09040547B2

Reaction notes

Loading…