p-Toluenesulfonic acid → HCID 136348447, compound

HRID 1748780Notes

Reaction equation

HRID 1748780 reaction equation
[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[C:16]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[N:17][N:18]([CH2:28][CH3:29])[C:19]=2[NH:20]C(OC(C)(C)C)=O)[CH2:9][CH2:10][C:11](OC)=[O:12])=[C:4]([CH3:36])[CH:3]=1.BrC1C=CC(C=O)=CC=1.C(N1C(N)=CC(C2C=CC=CN=2)=N1)C.C(O)(C(F)(F)F)=O.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:12])[NH:20][C:19]3[N:18]([CH2:28][CH3:29])[N:17]=[C:16]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[C:15]2=3)=[C:4]([CH3:36])[CH:3]=1

Participants

8

Reactant 5

HCID 6101p-Toluenesulfonic acidHCID 6422Trifluoroacetic acidHCID 707414-BromobenzaldehydeHCID 86724121HCID 86724121, compoundHCID 86724123HCID 86724123, compound

Product 1

HCID 136348447HCID 136348447, compoundYield 67%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

A solution of methyl 4-(4-bromo-2-methylphenyl)-4-(5-((tert-butoxycarbonyl)amino)-1-ethyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)butanoate (0.072 g, 0.129 mmol, Prepared using W from 4-bromobenzaldehyde, X from 1-ethyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine, Y then Z) in DCM (3 mL) was treated with TFA (3 mL) and the reaction was stirred for about 20 min at rt. Solvents were removed in vacuo and the residue was taken up in toluene (5 mL) containing p-TSA (0.049 g, 0.26 mmol) and the reaction was heated at about 100° C. for about 3 h. The reaction was cooled to rt, diluted with EtOAc (5 mL) to solubilize the product and washed with sat. aq. NaHCO3 (5 mL), then water (5 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Crude product was further purified on silica gel (4 g) using a gradient of 60-90% EtOAc in heptane. Product fractions were combined and concentrated to solids and dried in the vacuum oven overnight to yield 4-(4-bromo-2-methylphenyl)-1-ethyl-3-(pyridin-2-yl)-4,5,6,8-tetrahydropyrazolo[3,4-b]azepin-7(1H)-one as an off-white solid (0.037 g, 0.087 mmol, 67%); LC-MS (Table 1, Method g) Rt=2.31 min, m/z 425/427 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 8.37-8.30 (m, 1H), 7.84 (br. s, 1H), 7.63 (d, J=8.1 Hz, 1H), 7.58-7.48 (m, 1H), 7.14 (s, 1H), 7.06-6.94 (m, 2H), 6.61 (d, J=8.3 Hz, 1H), 5.30-5.20 (m, 1H), 4.20 (q, J=7.3 Hz, 2H), 2.74-2.66 (m, 2H), 2.47 (s, 3H), 2.41-2.30 (m, 1H), 1.94-1.83 (m, 1H), 1.50 (t, J=7.2 Hz, 3H).

Workup

  1. customSolvents were removed in vacuo
  2. temperaturethe reaction was heated at about 100° C. for about 3 h
  3. temperatureThe reaction was cooled to rt
  4. washwashed with sat. aq. NaHCO3 (5 mL)
  5. dry with materialThe organic layer was dried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customCrude product was further purified on silica gel (4 g)
  9. concentrationconcentrated to solids
  10. customdried in the vacuum oven overnight

Sources & evidence

ORD record
ord-518ff11c5b3947cea53f125585ffaea6
Source dataset
uspto-grants-2015_10
Patent number
US09150592B2

Reaction notes

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