2,6-Lutidine → HCID 24890000, compound

HRID 546111Notes

Reaction equation

HRID 546111 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[CH3:42][O:43][C:44]([CH:46]1[CH2:51][CH2:50][CH:49](CN2C=CC(N)=N2)[CH2:48][CH2:47]1)=[O:45]>C(Cl)Cl>[CH3:42][O:43][C:44]([CH:46]1[CH2:51][CH2:50][CH:49]([CH2:21][N:18]2[CH:19]=[CH:20][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]3[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([Cl:1])[CH:3]=3)[CH2:22][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)=[N:17]2)[CH2:48][CH2:47]1)=[O:45]

Participants

6

Reactant 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 671896933-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-1-methyl-pyrazoleHCID 67191702HCID 67191702, compound

Product 1

HCID 24890000HCID 24890000, compoundYield 38.3%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Conditions

Temperature
25 °C

Procedure

2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 125 mg, 0.38 mmol) was dissolved in methylene chloride (2 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (190 μL, 0.38 mmol) was added and the reaction stirred at 25° C. for 15 min. The solution was chilled to 0° C. and 2,6-lutidine (89 μL, 0.76 mmol) was added dropwise. The reaction continued to stir at 0° C. for 15 min. The 4-(3-amino-pyrazol-1-ylmethyl)-cyclohexanecarboxylic acid methyl ester (90 mg, 0.38 mmol) was added as a pre-dissolved reaction in methylene chloride (2 mL), the ice bath was removed and the reaction continued to stir at 25° C. for 25 min. The reaction was diluted with methylene chloride (100 mL), washed with water (2×30 mL), saturated aqueous brine solution (1×20 mL), dried over magnesium sulfate and concentrated in vacuo to a beige foam. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 0% ethyl acetate/methylene chloride to 15% ethyl acetate/methylene chloride) afforded 4-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-cyclohexanecarboxylic acid methyl ester (80 mg, 38%) as a white foam: ESI-LRMS m/e calcd for C27H36ClN3O5S [M+] 549.21, found 550.36 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 0.91-1.07 (m, 2H, CH2), 1.06-1.21 (m, 2H, CH2), 1.32-1.47 (m, 2H, CH2), 1.46-1.56 (m, 2H, CH2), 1.56-1.93 (m, 9H, CH and 4×CH2), 1.93-2.04 (m, 2H, CH2), 2.11-2.32 (m, 2H, 2×CH), 3.26 (s, 3H, SO2CH3), 3.54 (t, J=7.5 Hz, 1H, CH), 3.66 (s, 3H, CO2CH3), 3.80 (d, J=7.0 Hz, 2H, NCH2), 6.64 (d, Jo=2.2 Hz, 1H, Ar), 7.21 (d, Jo=2.2 Hz, 1H, Ar), 7.46 (dd, Jo=8.1, Jm=1.7 Hz. 1H, Ar), 7.59 (d, Jm=1.7 Hz, 1H, Ar), 7.58 (s, 1H, NH), 8.09 (d, Jo=8.1 Hz, 1H, Ar).

Workup

  1. temperatureThe solution was chilled to 0° C.
  2. stirringto stir at 0° C. for 15 min
  3. customthe ice bath was removed
  4. stirringto stir at 25° C. for 25 min
  5. additionThe reaction was diluted with methylene chloride (100 mL)
  6. washwashed with water (2×30 mL), saturated aqueous brine solution (1×20 mL)
  7. dry with materialdried over magnesium sulfate
  8. concentrationconcentrated in vacuo to a beige foam
  9. customPurification by flash column chromatography (Merck silica gel 60, 40-63 μm; 0% ethyl acetate/methylene chloride to 15% ethyl acetate/methylene chloride)

Sources & evidence

ORD record
ord-c08bd58b16ce48b9a0f488e7c69d2f09
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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