Aluminium lithium hydride → (3-methyl-1-((3-methylisoxazol-5-yl)methyl)-4-(6-(trifluoromethyl)-1H-indazol-4-yl)-1H-pyrazol-5-yl)methanol

HRID 58116Notes

Reaction equation

HRID 58116 reaction equation
[CH3:1][C:2]1[C:6]([C:7]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]3[C:8]=2[CH:9]=[N:10][NH:11]3)=[C:5]([C:20](OCC)=[O:21])[N:4]([CH2:25][C:26]2[O:30][N:29]=[C:28]([CH3:31])[CH:27]=2)[N:3]=1.CC1N(CC2ON=C(C)C=2)N=C(C(OCC)=O)C=1C1C=C(C(F)(F)F)C=C2C=1C=NN2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[CH3:1][C:2]1[C:6]([C:7]2[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[CH:13]=[C:12]3[C:8]=2[CH:9]=[N:10][NH:11]3)=[C:5]([CH2:20][OH:21])[N:4]([CH2:25][C:26]2[O:30][N:29]=[C:28]([CH3:31])[CH:27]=2)[N:3]=1

Participants

6

Reactant 3

HCID 21226445Aluminium lithium hydrideHCID 89782987HCID 89782987, compoundHCID 89783206HCID 89783206, compound

Product 1

HCID 89782965(3-methyl-1-((3-methylisoxazol-5-yl)methyl)-4-(6-(trifluoromethyl)-1H-indazol-4-yl)-1H-pyrazol-5-yl)methanol

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

A 40 ml, vial was charged with a mixture of ethyl 3-methyl-1-((3-methylisoxazol-5-yl)methyl)-4-(6-(trifluoromethyl)-1H-indazol-4-yl)-1H-pyrazole-5-carboxylate and ethyl 5-methyl-1-((3-methylisoxazol-5-yl)methyl)-4-(6-(trifluoromethyl)-1H-indazol-4-yl)-1H-pyrazole-3-carboxylate (0.210 g) in THF (6 mL). The mixture was cooled to 0° C. A 1M solution of lithium aluminum hydride (1.454 mL, 1.454 mmol) in ether was added and the reaction mixture was stirred for 30 minutes at room temperature. The reaction was quenched with 1N HCl (2 mL) at 0° C. The mixture was allowed to warm to room temperature and the product was extracted into EtOAc. The organic phase was washed with brine and dried over Na2SO4. The volatiles were evaporated and the crude residue was purified by LCMS, eluting with 35% ACN in H2O (containing 10 mM NH4HCO3) over a period of 10 minutes. The product-containing fractions were combined and the volatiles evaporated using a GeneVac™ to give the title compounds. The later-eluting peak was assigned to the regioisomer of EXAMPLE 411 (3.3 mg). 1H NMR (400 MHz, CD3OD) δ ppm 2.19 (s, 3H), 2.30 (s, 3H), 4.59 (s, 2H), 5.63 (s, 2H), 6.26 (s, 1H), 7.31 (d, J=1.26 Hz, 1H), 7.92 (s, 1H), 8.04 (d, J=0.76 Hz, 1H); ESI-MS m/z [M+H]+ calc'd for C18H16F3N5O2, 392.13. found 392.21. The earlier-eluting peak was assigned to the regioisomer of EXAMPLE 412 (2.8 mg). 1H NMR (400 MHz, CD3OD) δ ppm 2.30 (s, 3H), 2.31 (s, 3H), 4.50 (s, 2H), 5.55 (s, 2H), 6.28 (s, 1H), 7.34-7.43 (m, 1H), 7.90 (s, 1H), 7.96-8.05 (m, 1H); ESI-MS m/z [M+H]+ calc'd for C18H16F3N5O2, 392.13. found 392.21.

Workup

  1. customThe reaction was quenched with 1N HCl (2 mL) at 0° C
  2. temperatureto warm to room temperature
  3. extractionthe product was extracted into EtOAc
  4. washThe organic phase was washed with brine
  5. dry with materialdried over Na2SO4
  6. customThe volatiles were evaporated
  7. customthe crude residue was purified by LCMS
  8. washeluting with 35% ACN in H2O (containing 10 mM NH4HCO3) over a period of 10 minutes
  9. customthe volatiles evaporated

Sources & evidence

ORD record
ord-5109ab8d60a34e8c9b6aeebd5e21a360
Source dataset
uspto-grants-2016_09
Patent number
US09434743B2

Reaction notes

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