Pyridine → 3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-1-methyl-pyrazole

HRID 545984

Reaction equation

HRID 545984 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]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[CH3:49][N:50]1[CH:54]=[CH:53][C:52]([NH2:55])=[N:51]1.N1C=CC=CC=1>C(Cl)Cl.O>[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([NH:55][C:52]2[CH:53]=[CH:54][N:50]([CH3:49])[N:51]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]

Participants

8

Reactant 5

HCID 1049PyridineHCID 11776TriphenylphosphineHCID 67184N-bromobutanimideHCID 1372541-Methyl-3-aminopyrazoleHCID 12067655(R)-2-(3-Chloro-4-(methylsulfonyl)phenyl)-3-cyclopentylpropanoic acid

Product 1

HCID 671896933-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-1-methyl-pyrazoleYield 48%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

Triphenylphosphine (1.190 g, 4.54 mmol) was dissolved in methylene chloride (40 mL) and cooled to 0° C. To this solution was added N-bromosuccinimide (914 mg, 5.14 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, 1.00 g, 3.02 mmol) was then added and it was stirred at 0° C. for 20 min and then warmed to 25° C. and stirred for 30 min. After such time, 1-methyl-1H-pyrazol-3-ylamine (441 mg, 4.54 mmol) and pyridine (740 μL, 4.53 mmol) were added and it was stirred at 25° C. for 16 h. The reaction was then diluted with water (30 mL) and then extracted with methylene chloride (3×15 mL). The organic layers were then combined and dried over magnesium sulfate, filtered and concentrated in vacuo. Flash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/hexanes) followed by reverse phase preparative HPLC purification (Column: Thomson C18 ODSA, 5 micron, 50×21.2 mm ID; 30% acetonitrile/water to 100% acetonitrile/water; 30 mL/min flow rate for 15 min run) afforded 3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-1-methyl-pyrazole (590 mg, 48%) as a white solid: ESI-LRMS m/e calcd for C19H24ClN3O3S [M+] 409.1. found 410.1 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 0.96-1.18 (m, 2H, CH2), 1.35-1.86 (m, 8H, 4×CH2), 2.10-2.21 (m, 1H, CH), 3.24 (s, 3H, SO2CH3), 3.57 (t, J=7.6 Hz, 1H, CH), 3.73 (s, 3H, NCH3), 6.59 (d, J=2.3 Hz, 1H, Ar), 7.21 (d, J=2.3 Hz, 1H, Ar), 7.38 (dd, Jo=8.2, Jm=1.7 Hz, 1H, Ar), 7.50 (d, Jm=1.7 Hz, 1H, Ar), 7.96 (d, Jo=8.2 Hz, 1H, Ar), 8.82 (s, 1H, NH).

Workup

  1. dissolutionwas completely dissolved
  2. stirringit was stirred at 0° C. for 20 min
  3. temperaturewarmed to 25° C.
  4. stirringstirred for 30 min
  5. stirringit was stirred at 25° C. for 16 h
  6. extractionextracted with methylene chloride (3×15 mL)
  7. dry with materialdried over magnesium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customFlash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/hexanes) followed by reverse phase preparative HPLC purification (Column: Thomson C18 ODSA, 5 micron, 50×21.2 mm ID; 30% acetonitrile/water to 100% acetonitrile/water; 30 mL/min flow rate for 15 min run)

Sources & evidence

ORD record
ord-3b05d9c6a7fb46dba98aff0a31b3ca32
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Linked notes

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