Diisopropylethylamine → {(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(6-cyano-pyridazin-3-yl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid 4-fluoro-phenyl ester

HRID 587373Notes

Reaction equation

HRID 587373 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:32])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:24]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.Cl[C:34]1[N:39]=[N:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:32])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:24]([CH:26]3[CH2:31][CH2:30][N:29]([C:34]4[N:39]=[N:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=4)[CH2:28][CH2:27]3)=[O:25])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 133828716-Chloropyridazine-3-carbonitrileHCID 58303156[(3S,4R)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester

Product 1

HCID 58303191{(3S,4R)-4-(4-Chloro-phenyl)-1-[1-(6-cyano-pyridazin-3-yl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid 4-fluoro-phenyl esterYield 74.2%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of [(3S,4R)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester (186 mg, 0.40 mmol) in DMF (2 mL) was added 6-chloro-3-pyridazinecarbonitrile (67 mg, 0.48 mmol) and N,N-diisopropyl ethyl amine (208, 1.21 mmol). The resulting dark brown solution was stirred for 3 h at 80° C. After cooling to ambient temperature the reaction mixture was diluted with ethyl acetate (15 mL) and washed with aqueous sodium carbonate (1M, 15 mL), water (15 mL) and brine (15 mL). The aqueous layers were extracted with ethyl acetate (15 mL) and the combined organic layers dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=50:50 to 0:100) afforded the title compound (167 mg, 73%) as a white foam. MS m/e: 563.3 [M]+.

Workup

  1. temperatureAfter cooling to ambient temperature the reaction mixture
  2. washwashed with aqueous sodium carbonate (1M, 15 mL), water (15 mL) and brine (15 mL)
  3. extractionThe aqueous layers were extracted with ethyl acetate (15 mL)
  4. dry with materialthe combined organic layers dried over sodium sulfate
  5. concentrationConcentration and purification by chromatography (SiO2, heptane:ethyl acetate=50:50 to 0:100)

Sources & evidence

ORD record
ord-79254aaf3568414086f94436e9b51d7a
Source dataset
uspto-grants-2016_01
Patent number
US09226916B2

Reaction notes

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