Hydrazine → HCID 67232495, compound

HRID 1409677Notes

Reaction equation

HRID 1409677 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]([OH:16])=[O:15])[C@H:10]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=O)[CH3:32])=[CH:27][CH:26]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Li].[NH2:45][NH2:46]>C1COCC1.CCO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]([OH:16])=[O:15])[C@H:10]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3].[F:23][C:20]1[CH:21]=[CH:22][C:17]([C@H:10]2[C@H:11]([C:14]3[CH:32]=[C:31]([C:28]4[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=4)[NH:46][N:45]=3)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]2)=[CH:18][CH:19]=1

Participants

9

Reactant 5

HCID 9321HydrazineHCID 98284'-FluoroacetophenoneHCID 2733832Lithium HexamethyldisilazideHCID 3028194LithiumHCID 67232495HCID 67232495, compound

Product 2

HCID 67232495HCID 67232495, compoundHCID 178452024HCID 178452024, compound

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

The starting material (3R,4R)-1-tert-butoxycarbonyl-3-(4-fluorophenyl)piperidine-4-carboxylic acid was prepared as an enantiomeric mixture according to the procedure disclosed in WO 2002/068387. The resulting enantiomers were separated via SFC (Instrument: Berger MG II preparative SFC; Column: ChiralPak AD-H, 250×30 mm I.D.; Mobile phase: CO2: Methanol (with 0.01% DEA), 95:5; Flow rate: 70 mL/min; Sample preparation: dissolved in Methanol, 20 mg/ml; Injection: 2 ml per injection.). The faster eluting enantiomer of (3R,4R)-1-tert-butoxycarbonyl-3-(4-fluorophenyl)piperidine-4-carboxylic acid (300 mg, 0.928 mmol) in THF (4.0 ml) was treated with CDT (165 mg, 1.021 mmol) and heated at 60° C. for 20 min. A solution of 4′-fluoroacetophenone (513 mg, 3.71 mmol) in a separate vial was treated at rt with solid lithium bis(trimethylsilyl)amide (621 mg, 3.71 mmol) and the mixture was stirred at rt for 10 min. This lithium mixture was then treated dropwise with the CDT-activated carboxylic acid solution. The combined mixture was stirred for 30 min at rt and then quenched with saturated aqueous NaHCO3. The mixture was diluted with water and extracted with MTBE. The combined organic layers were dried with anhydrous Na2SO4, and then filtered. The filtrate was concentrated to give a residue. The residue was dissolved in EtOH, and treated with hydrazine (0.25 ml, 7.97 mmol). The reaction was heated at 60° C. for 1 h, then cooled to rt and concentrated. Purification of the resulting residue by chromatography on SiO2 (0 to 10% MeOH/DCM) afforded tert-butyl (3R,4R)-3-(4-fluorophenyl)-4-[5-(4-fluorophenyl)-1H-pyrazol-3-yl]piperidine-1-carboxylate, which was dissolved in DCM (1 mL) and treated with TFA (1 mL), followed by stirring at rt for 12 h and concentrating under vacuum. Purification of the resulting residue by RP-HPLC(C18, 15% to 100% water/acetonitrile over 12 min, 0.1% TFA) afforded the title compound. HPLC/MS: 340.1 (M+1), R=1.45 min (LC-4 HPLC conditions). Racemic material can be obtained in a similar manner by using racemic starting material.

Workup

  1. customThe resulting enantiomers were separated via SFC (Instrument: Berger MG II preparative SFC; Column: ChiralPak AD-H, 250×30 mm I.D.; Mobile phase: CO2: Methanol (with 0.01% DEA), 95:5; Flow rate: 70 mL/min; Sample preparation: dissolved in Methanol, 20 mg/ml; Injection: 2 ml per injection.)
  2. additionwas treated with CDT (165 mg, 1.021 mmol)
  3. stirringThe combined mixture was stirred for 30 min at rt
  4. customquenched with saturated aqueous NaHCO3
  5. additionThe mixture was diluted with water
  6. extractionextracted with MTBE
  7. dry with materialThe combined organic layers were dried with anhydrous Na2SO4
  8. filtrationfiltered
  9. concentrationThe filtrate was concentrated
  10. customto give a residue
  11. temperatureThe reaction was heated at 60° C. for 1 h
  12. temperaturecooled to rt
  13. concentrationconcentrated
  14. customPurification of the resulting residue by chromatography on SiO2 (0 to 10% MeOH/DCM)

Sources & evidence

ORD record
ord-91fee4f2ad9b4f65af6df9b20e30f63f
Source dataset
uspto-grants-2014_12
Patent number
US08921394B2

Reaction notes

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