2,6-Lutidine → HCID 67482886, compound

HRID 719931Notes

Reaction equation

HRID 719931 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.[CH2:28]([O:30][C:31](=[O:45])[CH:32]([C:38]1[CH:43]=[N:42][C:41]([NH2:44])=[CH:40][N:39]=1)[C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH3:29].N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O.O1CCCC1>[CH2:28]([O:30][C:31](=[O:45])[CH:32]([C:38]1[CH:43]=[N:42][C:41]([NH:44][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:40][N:39]=1)[C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH3:29]

Participants

8

Reactant 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 12067655(R)-2-(3-Chloro-4-(methylsulfonyl)phenyl)-3-cyclopentylpropanoic acidHCID 67482815HCID 67482815, compound

Product 1

HCID 67482886HCID 67482886, compoundYield 26.6%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
25 °C

Procedure

A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 170 mg, 0.51 mmol) in methylene chloride (10 mL) cooled to 0° C. was treated with a 2.0M solution of oxalyl chloride in methylene chloride (385 μL, 0.77 mmol) and catalytic N,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 30 min and at 25° C. for 2 h. The solution was then concentrated in vacuo. The residue was dissolved in methylene chloride (10 mL), cooled to 0° C., and then treated with a solution of 2-(5-amino-pyrazin-2-yl)-malonic acid diethyl ester (130 mg, 0.51 mmol) and 2,6-lutidine (120 μL, 1.03 mmol) in tetrahydrofuran (10 mL). The reaction mixture was then stirred at 0° C. for 15 min and at 25° C. for 16 h. The reaction was then concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 1/1 ethyl acetate/hexanes) afforded the 2(R)-{5-[2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazin-2-yl}-malonic acid diethyl ester (76.9 mg, 26%) as a pale yellow oil. This material was further purified by dissolving it in methylene chloride and washing with a 1N aqueous hydrochloric acid solution (25 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the 2(R)-{5-[2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazin-2-yl}-malonic acid diethyl ester (51.3 mg, 18%) as a pale yellow oil: (ES)+-HRMS m/e calcd for C26H32ClN3O7S (M+H)+ 566.1722, found 566.1726.

Workup

  1. concentrationThe solution was then concentrated in vacuo
  2. dissolutionThe residue was dissolved in methylene chloride (10 mL)
  3. temperaturecooled to 0° C.
  4. stirringThe reaction mixture was then stirred at 0° C. for 15 min and at 25° C. for 16 h
  5. concentrationThe reaction was then concentrated in vacuo

Sources & evidence

ORD record
ord-4388cf52525d4f169375260aeb317f64
Source dataset
uspto-grants-2006_11
Patent number
US07132425B2

Reaction notes

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