2,6-Lutidine → 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-hydroxy-propyl)-1H-pyrazol-3-yl]-propionamide

HRID 546134Notes

Reaction equation

HRID 546134 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]([OH:24])=O)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[C:31](Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.NC1C=CN(CC(O)C)N=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:25][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH:22]([OH:24])[CH3:31])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]

Participants

7

Reactant 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 552846691-(3-amino-1H-pyrazol-1-yl)propan-2-olHCID 67189335{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-acetic acid

Product 1

HCID 671908812(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-hydroxy-propyl)-1H-pyrazol-3-yl]-propionamideYield 61%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent4×

Conditions

Temperature
25 °C

Procedure

A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 106 mg, 0.32 mmol) was dissolved in methylene chloride (2 mL) and N,N-dimethylfomamide (two drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 170 μL, 0.33 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes. After this time, the reaction was cooled to 0° C. and 2,6-lutidine (80 μL, 0.64 mmol) was added to the flask and it was stirred for 15 min. To this was then added a solution of 1-(3-amino-pyrazol-1-yl)-propan-2-ol (45 mg, 0.32 mmol) in methylene chloride (1 mL) and the reaction was allowed to warm up to 25° C. and stirred for 45 minutes. After this time the reaction was diluted with a small amount of methanol in methylene chloride and washed with aqueous 1 N hydrochloric acid solution (1×15 mL) and then a saturated aqueous brine solution (1×15 mL). The organics were then dried over sodium sulfate, filtered and concentrated in vacuo with silica gel (2 g) and purified by Biotage Flash Chromatography (40S column, Silica gel, 50% ethyl acetate/hexanes to 100% ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(2-hydroxy-propyl)-1H-pyrazol-3-yl]-propionamide (88 mg, 61%, diastereomeric mixture 1:1) as a white foam: ES-HRMS m/e calcd for C21H28N3O4SCl (M+H)+ 454.1562, observed 454.1559.

Workup

  1. customat 25° C.
  2. customproduced gas evolution and it
  3. temperatureAfter this time, the reaction was cooled to 0° C.
  4. stirringwas stirred for 15 min
  5. temperatureto warm up to 25° C.
  6. stirringstirred for 45 minutes
  7. washwashed with aqueous 1 N hydrochloric acid solution (1×15 mL)
  8. dry with materialThe organics were then dried over sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo with silica gel (2 g)
  11. custompurified by Biotage Flash Chromatography (40S column, Silica gel, 50% ethyl acetate/hexanes to 100% ethyl acetate)

Sources & evidence

ORD record
ord-bfecfa30c6d14b4293c2ee4d8e1032e8
Source dataset
uspto-grants-2011_05
Patent number
US07935699B2

Reaction notes

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