Carbon Dioxide → HCID 136348437, compound

HRID 1748771Notes

Reaction equation

HRID 1748771 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:14][CH2:13][C:12](=O)[NH:11][C:10]3[N:16]([CH3:20])[N:17]=[C:18]([CH3:19])[C:9]2=3)=[C:4]([CH3:21])[CH:3]=1.BrC1C=CC(C=O)=C(C)C=1.CN1C(N)=CC(C)=N1.[Li]CCCC.[C:45](=[O:47])=[O:46]>C1COCC1>[CH3:20][N:16]1[C:10]2[NH:11][CH2:12][CH2:13][CH2:14][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([C:45]([OH:47])=[O:46])=[CH:3][C:4]=3[CH3:21])[C:9]=2[C:18]([CH3:19])=[N:17]1

Participants

7

Reactant 5

HCID 280Carbon Dioxide2×HCID 5207211,3-Dimethyl-1H-pyrazol-5-amineHCID 135551504-Bromo-2-methylbenzaldehydeHCID 136348438HCID 136348438, compoundHCID 178418339Butyllithium

Product 1

HCID 136348437HCID 136348437, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

A solution of 4-(4-bromo-2-methylphenyl)-1,3-dimethyl-4,5,6,8-tetrahydropyrazolo[3,4-b]azepin-7(1H)-one (0.143 g, 0.41 mmol, prepared using W from 4-bromo-2-methylbenzaldehyde (Ark Pharm, Inc), X from 1,3-dimethyl-1H-pyrazol-5-amine, Y, Z, then AA) in dry THF (20 mL) was cooled to about −78° C. under nitrogen. A solution of n-BuLi (0.66 mL, 1.64 mmol) (2.5M in THF) was added dropwise maintaining the reaction temperature below about −70° C. The mixture was stirred for about an additional 10 min at about −78° C. and then a stream of CO2 generated from dry ice was bubbled through the solution for about 15 min. Cooling was removed and the reaction was allowed to warm to rt. The reaction was concentrated to solids and then acidified with 2N HCl (2 mL) and extracted with EtOAc (2×10 mL). The EtOAc extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified on silica gel using a gradient of 0-10% MeOH in DCM. Product fractions were combined and concentrated in vacuo and dried on vacuum pump to yield 4-(1,3-dimethyl-1,4,5,6,7,8-hexahydropyrazolo[3,4-b]azepin-4-yl)-3-methylbenzoic acid as an off white solid (0.055 g, 0.18 mmol, 53%); LC-MS (Table 1, Method g) Rt=1.37 min, m/z 312 (M−H)−. The carboxylate was used in the next step without further manipulation.

Workup

  1. temperaturemaintaining the reaction temperature below about −70° C
  2. customwas bubbled through the solution for about 15 min
  3. temperatureCooling
  4. customwas removed
  5. temperatureto warm to rt
  6. concentrationThe reaction was concentrated to solids
  7. extractionextracted with EtOAc (2×10 mL)
  8. dry with materialThe EtOAc extracts were dried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customThe residue was purified on silica gel using a gradient of 0-10% MeOH in DCM
  12. concentrationconcentrated in vacuo
  13. customdried on vacuum pump

Sources & evidence

ORD record
ord-c171ba1129b34b8bbca40d444d4edbac
Source dataset
uspto-grants-2015_10
Patent number
US09150592B2

Reaction notes

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