2,6-Lutidine → 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-triethylsilanyloxy-ethylamino)-pyrazin-2-yl]-propionamide

HRID 719994Notes

Reaction equation

HRID 719994 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]([Si:30]([CH2:44][CH3:45])([CH2:42][CH3:43])[O:31][CH2:32][CH2:33][NH:34][C:35]1[CH:40]=[N:39][C:38]([NH2:41])=[CH:37][N:36]=1)[CH3:29].N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O.O1CCCC1.O>[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]([NH:41][C:38]2[CH:37]=[N:36][C:35]([NH:34][CH2:33][CH2:32][O:31][Si:30]([CH2:42][CH3:43])([CH2:28][CH3:29])[CH2:44][CH3:45])=[CH:40][N:39]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]

Participants

9

Reactant 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 12067655(R)-2-(3-Chloro-4-(methylsulfonyl)phenyl)-3-cyclopentylpropanoic acidHCID 21897274N-(2-triethylsilanyloxy-ethyl)-pyrazine-2,5-diamine

Product 1

HCID 674825802(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-triethylsilanyloxy-ethylamino)-pyrazin-2-yl]-propionamideYield 69%

Reagents, catalysts & solvents 4

HCID 6228DimethylformamideCatalystHCID 962WaterSolventHCID 6344DichloromethaneSolvent2×HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 500 mg, 1.51 mmol) in methylene chloride (20 mL) cooled to 0° C. was treated with a 2.0M solution of oxalyl chloride in methylene chloride (869 μL, 1.74 mmol) and N,N-dimethylformamide (1 drop). The reaction mixture was stirred at 0° C. for 30 min, concentrated in vacuo, and azeotroped with methylene chloride (2 mL) two times. The resulting oil was then dissolved in tetrahydrofuran (10 mL) at 25° C. and then treated dropwise with a solution of N-(2-triethylsilanyloxy-ethyl)-pyrazine-2,5-diamine (446 mg, 1.66 mmol) and 2,6-lutidine (211 μL, 1.81 mmol) in tetrahydrofuran (15 mL) via an addition funnel. The resulting cloudy solution was then stirred overnight for 16 h at 25° C. After this time, the reaction was diluted with water (10 mL) and then extracted with methylene chloride (3×25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 85/15 to 50/50 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-triethylsilanyloxy-ethylamino)-pyrazin-2-yl]-propionamide (606 mg, 69%) as a light yellow foam: (ES)+-HRMS m/e calcd for C27H41ClN4O4SSi (M+H)+ 581.2379, found 581.2386.

Workup

  1. concentrationconcentrated in vacuo
  2. customazeotroped with methylene chloride (2 mL) two times
  3. dissolutionThe resulting oil was then dissolved in tetrahydrofuran (10 mL) at 25° C.
  4. stirringThe resulting cloudy solution was then stirred overnight for 16 h at 25° C
  5. extractionextracted with methylene chloride (3×25 mL)
  6. dry with materialThe combined organic layers were dried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-df68467db763481cb40b03db44d526f3
Source dataset
uspto-grants-2006_11
Patent number
US07132425B2

Reaction notes

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