Pyridine → 5-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazine-2-carboxylic acid methyl ester

HRID 719902Notes

Reaction equation

HRID 719902 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[CH3:28][O:29][C:30]([C:32]1[CH:37]=[N:36][C:35]([NH2:38])=[CH:34][N:33]=1)=[O:31].N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O>[CH3:28][O:29][C:30]([C:32]1[CH:37]=[N:36][C:35]([NH:38][C:13](=[O:15])[C@@H:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=2)[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:34][N:33]=1)=[O:31]

Participants

7

Reactant 4

HCID 1049PyridineHCID 65578Oxalyl chlorideHCID 12067655(R)-2-(3-Chloro-4-(methylsulfonyl)phenyl)-3-cyclopentylpropanoic acidHCID 14536427Methyl 5-aminopyrazine-2-carboxylate

Product 1

HCID 674828615-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazine-2-carboxylic acid methyl esterYield 82.2%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideCatalystHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 196.4 mg, 0.59 mmol) in methylene chloride (3 mL) was cooled to 0° C. The reaction mixture was then treated with N,N-dimethylformamide (1 drop) and oxalyl chloride (109 μL, 1.25 mmol). The reaction mixture was stirred at 0° C. for 15 min and then at 25° C. for 2 h. The solution was then concentrated in vacuo. The yellow slurry was dissolved in methylene chloride (1 mL) and cooled to 0° C. To this solution was added a suspension of 5-amino-pyrazine-2-carboxylic acid methyl ester (100.0 mg, 0.65 mmol) and pyridine (53 μL, 0.6529 mmol) in warm methylene chloride (2 mL). The reaction mixture was stirred at 0° C. for 30 min and then at 25° C. for 3 h. The reaction mixture was then concentrated in vacuo. The reaction material was diluted with ethyl acetate (50 mL) and washed with a saturated aqueous sodium bicarbonate solution (100 mL), a saturated aqueous sodium chloride solution (100 mL), a 1N aqueous hydrochloric acid solution (100 mL), and a saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 ethyl acetate/hexanes) afforded 5-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazine-2-carboxylic acid methyl ester (225.9 mg, 82%) as a white foam: mp 94–97° C. (foam to gel); (ES)+-HRMS m/e calcd for C21H24ClN3O5S (M+H)+466.1198, found 466.1204.

Workup

  1. waitat 25° C. for 2 h
  2. concentrationThe solution was then concentrated in vacuo
  3. dissolutionThe yellow slurry was dissolved in methylene chloride (1 mL)
  4. temperaturecooled to 0° C
  5. additionTo this solution was added
  6. stirringThe reaction mixture was stirred at 0° C. for 30 min
  7. waitat 25° C. for 3 h
  8. concentrationThe reaction mixture was then concentrated in vacuo
  9. additionThe reaction material was diluted with ethyl acetate (50 mL)
  10. washwashed with a saturated aqueous sodium bicarbonate solution (100 mL)
  11. dry with materiala saturated aqueous sodium chloride solution (100 mL), a 1N aqueous hydrochloric acid solution (100 mL), and a saturated aqueous sodium chloride solution (100 mL), dried over sodium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-e1415eb8bb104ddbb3edb0d036ce7947
Source dataset
uspto-grants-2006_11
Patent number
US07132425B2

Reaction notes

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