ethyl 4-iodo-1-methyl-1H-pyrazole-5-carboxylate → tert-butyl 3-[(3-chloropyridin-2-yl){4-[5-(ethoxycarbonyl)-1-methyl-1H-pyrazol-4-yl]benzoyl}amino]piperidine-1-carboxylate

HRID 588374Notes

Reaction equation

HRID 588374 reaction equation
I[C:2]1[CH:3]=[N:4][N:5]([CH3:12])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C([Mg]Cl)(C)C.Br[C:19]1[CH:47]=[CH:46][C:22]([C:23]([N:25]([C:39]2[C:44]([Cl:45])=[CH:43][CH:42]=[CH:41][N:40]=2)[C@@H:26]2[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]2)=[O:24])=[CH:21][CH:20]=1>C1COCC1.CC1OCCC1.[Cl-].[Zn+2].[Cl-].[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[Cl:45][C:44]1[C:39]([N:25]([C:23](=[O:24])[C:22]2[CH:21]=[CH:20][C:19]([C:2]3[CH:3]=[N:4][N:5]([CH3:12])[C:6]=3[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:47][CH:46]=2)[CH:26]2[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]2)=[N:40][CH:41]=[CH:42][CH:43]=1

Participants

8

Reactant 3

HCID 60136698ethyl 4-iodo-1-methyl-1H-pyrazole-5-carboxylateHCID 117652956(R)-tert-butyl 3-(4-bromo-N-(3-chloropyridin-2-yl)benzamido)piperidine-1-carboxylateHCID 178418918HCID 178418918, compound

Product 1

HCID 117652911tert-butyl 3-[(3-chloropyridin-2-yl){4-[5-(ethoxycarbonyl)-1-methyl-1H-pyrazol-4-yl]benzoyl}amino]piperidine-1-carboxylate

Reagents, catalysts & solvents 4

HCID 3007855ZincchlorideCatalystHCID 178454861HCID 178454861, compoundCatalystHCID 73012-MethyltetrahydrofuranSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-52 °C

Procedure

Preparation 13 ethyl 4-iodo-1-methyl-1H-pyrazole-5-carboxylate (108.5 g, 387.4 mmol) was dissolved in 1 L of THF and the resulting solution was cooled to −52° C. Isopropylmagnesium chloride (2 mol/L solution in THF, 200 mL, 400 mmol) was added over 27 minutes keeping the internal temperature <−39° C., followed by addition of zinc chloride (1.9 mol/L in 2-MeTHF, 120 mL, 230 mmol) over 15 minutes keeping the internal temperature <−39° C. The reaction was then warmed to 40° C. followed by addition of Preparation 10 tert-butyl (3R)-3-[(4-bromobenzoyl)(3-chloropyridin-2-yl)amino]piperidine-1-carboxylate (158.27 g, 319.9 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (4.60 g, 6.92 mmol). The reaction was warmed further to 55° C. and held for 2 h. After cooling to room temperature, the crude reaction mixture was filtered through Celite® and the filtrate was concentrated to give a foam. This material was re-dissolved in 1 L of 2-MeTHF and washed with 400 mL of water followed by filtration of the biphasic mixture and phase separation. 2-MeTHF was removed in vacuo and replaced with EtOH, then the solution was concentrated to a final volume of 1.5 L, resulting in precipitation of solids which were collected via filtration. After drying, the title compound was isolated as a tan solid (141.5 g, 78% yield).

Workup

  1. customthe internal temperature <−39° C.
  2. customthe internal temperature <−39° C
  3. temperatureThe reaction was then warmed to 40° C.
  4. temperatureThe reaction was warmed further to 55° C.
  5. temperatureAfter cooling to room temperature
  6. customthe crude reaction mixture
  7. filtrationwas filtered through Celite®
  8. concentrationthe filtrate was concentrated
  9. customto give a foam
  10. washwashed with 400 mL of water
  11. filtrationfollowed by filtration of the biphasic mixture and phase separation
  12. custom2-MeTHF was removed in vacuo
  13. concentrationthe solution was concentrated to a final volume of 1.5 L
  14. customresulting in precipitation of solids which
  15. filtrationwere collected via filtration
  16. customAfter drying

Sources & evidence

ORD record
ord-5f9e6608ebe942eeb68a00fed2042237
Source dataset
uspto-grants-2016_01
Patent number
US09227956B2

Reaction notes

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