2,6-Lutidine → HCID 67188926, compound

HRID 546079Notes

Reaction equation

HRID 546079 reaction equation
C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:49][CH:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)[C:40]([NH:42][C:43]2[CH:47]=[CH:46][N:45]([CH3:48])[N:44]=2)=[O:41])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[CH3:55][C:56]([CH3:65])=[CH:57]CN1C=CC(N)=N1.N1C(C)=CC=CC=1C>C(Cl)Cl.C(OCC)(=O)C>[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:49][CH:50]2[CH2:51][CH2:52][CH2:53][CH2:54]2)[C:40]([NH:42][C:43]2[CH:47]=[CH:46][N:45]([CH2:48][CH:55]=[C:56]([CH3:65])[CH3:57])[N:44]=2)=[O:41])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36]

Participants

8

Reactant 5

HCID 79372,6-LutidineHCID 11776TriphenylphosphineHCID 67184N-bromobutanimideHCID 671896933-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-1-methyl-pyrazoleHCID 67190134HCID 67190134, compound

Product 1

HCID 67188926HCID 67188926, compoundYield 39%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

Triphenylphosphine (224 mg, 0.85 mmol) was dissolved in methylene chloride (3 mL) and cooled to 0° C. To this solution was added N-bromosuccinimide (172 mg, 0.97 mmol) and was stirred at 0° C. until it was completely dissolved and became light purple in color. The 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1; 188 mg, 0.57 mmol) was then added and it was stirred at 0° C. for 20 min and then warmed to 25° C. and stirred for another 30 min. After such time 1-(3-methyl-but-2-enyl)-1H-pyrazol-3-ylamine (86 mg, 0.57 mmol) and 2,6-lutidine (198 μL, 1.71 mmol) were added and the reaction was stirred at 25° C. for 16 h. The reaction was then diluted with ethyl acetate (50 mL), washed with water (2×15 mL), saturated aqueous brine solution (1×15 mL), dried over magnesium sulfate and concentrated in vacuo to give an orange oil. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 20% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) followed by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% ethyl acetate/methylene chloride to 20% ethyl acetate/methylene chloride) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(3-methyl-but-2-enyl)-1H-pyrazol-3-yl]-propionamide (103 mg 39%) as an off white powder: ESI-LRMS m/e calcd for C23H30ClN3O3S [M+] 463.17, found 464.23 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.06-1.23 (m, 2H, CH2), 1.46-1.93 (m, 8H, 4×CH2), 1.76 (s, 3H, CH3), 1.80 (s, 3H, CH3), 2.05-2.35 (m, 1H, CH), 3.28 (s, 3H, SO2CH3), 3.53 (t, J=7.6 Hz, 1H, CH), 4.59 (d, J=7.1 Hz, 2H, NCH2), 531-5.43 (m, 1H, vinylic), 6.66 (d, J=2.3 Hz, 1H, Ar), 7.27 (d, J=2.3 Hz, 1H, Ar), 7.46 (dd, Jo=8.1, Jm=1.7 Hz. 1H, Ar), 7.59 (d, Jm=1.7 Hz, 1H, Ar), 7.83 (s, 1H, NH), 8.10 (d, Jo=8.1 Hz, 1H, Ar).

Workup

  1. dissolutionwas completely dissolved
  2. stirringit was stirred at 0° C. for 20 min
  3. temperaturewarmed to 25° C.
  4. stirringstirred for another 30 min
  5. stirringthe reaction was stirred at 25° C. for 16 h
  6. washwashed with water (2×15 mL), saturated aqueous brine solution (1×15 mL)
  7. dry with materialdried over magnesium sulfate
  8. concentrationconcentrated in vacuo
  9. customto give an orange oil
  10. customPurification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 20% ethyl acetate/hexanes to 100% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-1d81125d1b994bd7ba1c9694f4834b41
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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