Toluene → HCID 90233275, compound

HRID 1748839Notes

Reaction equation

HRID 1748839 reaction equation
C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(C)C=CC=CC=1.[OH:18][C@:19]1([C:47]([F:50])([F:49])[F:48])[CH2:35][C:24]2[N:25]([CH3:34])[N:26]=[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[C:23]=2[C@@H:22]([C:36]2[CH:45]=[CH:44][C:39]([C:40]([O:42]C)=O)=[CH:38][C:37]=2[CH3:46])[CH2:21][CH2:20]1.[CH3:51][C:52]1[C:57]([NH2:58])=[CH:56][CH:55]=[CH:54][N:53]=1>C1COCC1>[OH:18][C@:19]1([C:47]([F:49])([F:48])[F:50])[CH2:35][C:24]2[N:25]([CH3:34])[N:26]=[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[C:23]=2[C@@H:22]([C:36]2[CH:45]=[CH:44][C:39]([C:40]([NH:58][C:57]3[C:52]([CH3:51])=[N:53][CH:54]=[CH:55][CH:56]=3)=[O:42])=[CH:38][C:37]=2[CH3:46])[CH2:21][CH2:20]1

Participants

6

Reactant 4

HCID 1140Toluene2×HCID 5726163-Amino-2-methylpyridine2×HCID 2733832Lithium Hexamethyldisilazide2×HCID 90234048HCID 90234048, compound

Product 1

HCID 90233275HCID 90233275, compoundYield 5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

1 M lithium bis(trimethylsilyl)amide in toluene (0.13 mL, 0.13 mmol) was added dropwise to a solution of rac-methyl 4-((4R,7S)-7-hydroxy-1-methyl-3-(pyridin-2-yl)-7-(trifluoromethyl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)-3-methylbenzoate (0.018 g, 0.04 mmol) and 2-methylpyridin-3-amine (6.4 mg, 0.06 mmol, Appollo) in THF (1 mL) at 0° C. The mixture was allowed to warm to rt. After about 2 h, the mixture was cooled to about 0° C. 2-Methylpyridin-3-amine (4.2 mg, 0.04 mmol) and 1 M lithium bis(trimethylsilyl)amide in toluene (0.04 mL, 0.04 mmol) were added then the mixture was allowed to warm to rt. After about 5 h a saturated aqueous NH4 Cl solution (20 mL) was added and then mixture was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (20 mL), dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 2-6% MeOH/DCM) to give rac-4-((4R,7S)-7-hydroxy-1-methyl-3-(pyridin-2-yl)-7-(trifluoromethyl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)-3-methyl-N-(2-methylpyridin-3-yl)benzamide (0.001 g, 5%): LC-MS (Table 1, Method g) Rt=1.94 min, m/z 536 (M+H)+; 1H-NMR (DMSO, Bruker 400 MHz) δ 9.81 (s, 1H), 8.37-8.34 (m, 1H), 8.31-8.27 (m, 1H), 7.79-7.75 (m, 1H), 7.71-7.62 (m, 3H), 7.56-7.51 (m, 1H), 7.26-7.22 (m, 1H), 7.13-7.08 (m, 1H), 6.97 (d, J=8.0 Hz, 1H), 6.32 (s, 1H), 5.28-5.21 (m, 1H), 3.86 (s, 3H), 3.36-3.32 (m, 2H), 2.65 (s, 3H), 2.39 (s, 3H), 2.22-2.12 (m, 1H), 2.00-1.90 (m, 1H), 1.88-1.76 (m, 2H).

Workup

  1. temperaturethe mixture was cooled to about 0° C
  2. temperatureto warm to rt
  3. extractionmixture was extracted with EtOAc (2×20 mL)
  4. washThe combined organic extracts were washed with brine (20 mL)
  5. dry with materialdried with Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified by column chromatography (SiO2, 2-6% MeOH/DCM)

Sources & evidence

ORD record
ord-fcd515c504a343bd91cac674f2f1533c
Source dataset
uspto-grants-2015_10
Patent number
US09150592B2

Reaction notes

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