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Sodium hydride → 4-[5-amino-4-benzoyl-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-1H-pyrazol-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester

HRID 1959506
Notes
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Reaction equation

HRID 1959506 reaction equation
[H-].[Na+].[NH2:3][C:4]1[N:8]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12]([NH:14][CH:15]2[CH2:17][CH2:16]2)=[O:13])[N:7]=[CH:6][C:5]=1[C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25](CO)[CH:24]=1.C(O[C:35](=O)[C:36]1[CH:41]=CC=C(OCCN2CCOCC2)[CH:37]=1)C.FC(F)(F)[C:54]([OH:56])=[O:55].C1(NC(=O)[C:64]2[CH:69]=[CH:68][C:67](C)=[C:66]([NH:71]N)C=2)CC1.[O:74]1CCOCC1>>[C:36]([O:56][C:54]([N:71]1[CH2:66][CH2:67][CH:68]([O:74][C:6]2[C:5]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:4]([NH2:3])[N:8]([C:9]3[CH:10]=[C:11]([C:12](=[O:13])[NH:14][CH:15]4[CH2:16][CH2:17]4)[CH:18]=[CH:19][C:20]=3[CH3:21])[N:7]=2)[CH2:69][CH2:64]1)=[O:55])([CH3:41])([CH3:37])[CH3:35]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 5

HCID 24758Sodium hydrideHCID 312751,4-DioxaneHCID 114066393-[5-amino-4-(3-hydroxymethyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamideHCID 58089039Ethyl 3-{[2-(4-morpholinyl)ethyl]oxy}benzoateHCID 67024207N-cyclopropyl-3-hydrazinyl-4-methylbenzamide 2,2,2-trifluoroacetate

Product 1

HCID 11157237
4-[5-amino-4-benzoyl-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-1H-pyrazol-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester
Yield 16%

Procedure

Dry sodium hydride (41.0 mg, 1.60 mmol) was added to a solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester 7 (0.565 g, 2.81 mmol) in dioxane (2 ml) at 0° C. The mixture was stirred at room temperature for 45 min. 2-Benzoyl-3,3-bis-methylsulfanyl-acrylonitrile 2 (0.20 g, 0.80 mmol) was added, and the mixture was stirred at 65° C. for 4 h. The mixture was cooled to room temperature. N-Cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoroacetic acid salt (0.26 g, 0.80 mmol) was added and the reaction was heated to 80° C. for another 3 h. After the reaction mixture was cooled to room temperature, solvents were removed in vacuo. The residue was diluted in saturated NaHCO3 solution and was extracted three times with EtOAc. Combined organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography (SiO2, gradient of 65 to 85% EtOAc/hexanes). The product was further purified by washing the with warm EtOAc to give the desired 4-[5-amino-4-benzoyl-1-(5-cyclopropylcarbamoyl-2-methyl-phenyl)-1H-pyrazol-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester 8 as an off-white solid (70 mg, 16%). HPLC (4 minute 10-90 gradient) tR 2.63 min; MS m/z 559.9 [M+H]+; 1H NMR (DMSO-d6, 300 MHz) δ 8.49 (d, J=3.6, 1H), 7.90 (d, J=8.1, 1H), 7.84 (s, 1H), 7.59 (d, J=7.7, 2H), 7.40-7.51 (m, 4H), 6.99 (bs, 2H), 4.75 (m, 1H), 3.18 (m, 2H), 2.99 (m, 2H), 2.87 (m, 1H), 2.19 (s, 3H), 1.68 (m, 2H), 1.43 (m, 2H), 1.37 (s, 9H), 0.71 (m, 2H), 0.58 (m, 2H) ppm.

Workup

  1. stirringthe mixture was stirred at 65° C. for 4 h
  2. temperatureThe mixture was cooled to room temperature
  3. temperaturethe reaction was heated to 80° C. for another 3 h
  4. temperatureAfter the reaction mixture was cooled to room temperature
  5. customsolvents were removed in vacuo
  6. additionThe residue was diluted in saturated NaHCO3 solution
  7. extractionwas extracted three times with EtOAc
  8. dry with materialCombined organic layers were dried over MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe crude product was purified by flash chromatography (SiO2, gradient of 65 to 85% EtOAc/hexanes)
  12. customThe product was further purified
  13. washby washing the with warm EtOAc

Sources & evidence

ORD record
ord-b10037ccf5e54b64937cc7d921a592d3
Source dataset
uspto-grants-2013_04
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08410160B2

Reaction notes

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