Cesium carbonate → benzyl (3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylate

HRID 1063268Notes

Reaction equation

HRID 1063268 reaction equation
[NH2:1][C@H:2]1[C@@H:6]([OH:7])[CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3]1.Cl[C:19]1[C:24]([CH2:25][CH3:26])=[N:23][CH:22]=[C:21]([CH2:27][CH3:28])[N:20]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C([O-])([O-])=O.[Cs+].[Cs+].C([O-])(O)=O.[Na+]>CCOCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].COCCOC>[CH2:25]([C:24]1[C:19]([NH:1][C@H:2]2[C@@H:6]([OH:7])[CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:3]2)=[N:20][C:21]([CH2:27][CH3:28])=[CH:22][N:23]=1)[CH3:26]

Participants

9

Reactant 5

HCID 10796Cesium carbonateHCID 2373953-Chloro-2,5-diethylpyrazineHCID 516892Sodium BicarbonateHCID 27342172-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenylHCID 58583507benzyl (3R,4S)-3-amino-4-hydroxypyrrolidine-1-carboxylate

Product 1

HCID 60044796benzyl (3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylateYield 60%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 3283Diethyl EtherSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
80 °C

Procedure

A 250 ml round bottom flask was charged with benzyl (3R,4S)-3-amino-4-hydroxypyrrolidine-1-carboxylate (4.97 g, 21.04 mmol), 2-chloro-3,6-diethylpyrazine (3.95 g, 23.15 mmol), Pd2(dba)3 (10 mol %, 1.926 g), 2-dicyclohexylphosphino-2′-(N, N-dimethyl amino)biphenyl (20 mol %, 1.66 g), ethylene glycol dimethyl ether (110 mL), and Cs2CO3 (9.57 g) respectively. The reaction mixture was stirred at 80° C. for 20 hr. It was cooled, diluted with Et2O (100 ml), poured into NaHCO3 (80 ml), extracted with CH2Cl2 (150 ml×3), dried (MgSO4), and concentrated. Purification with Biotage MPLC (35% EtOAc in heptane) provided 4.6 g (60%) of benzyl (3R,4S)-3-[(3,6-diethylpyrazin-2-yl)amino]-4-hydroxypyrrolidine-1-carboxylate as an oil. IR (liq.) 2969, 2344, 1996, 1952, 1703, 1691, 1546, 1499, 1449, 1426, 1395, 1359, 1175, 1133, 1095, cm−1. HRMS (FAB) calcd for C20H26N4O3+H1 371.2083. found 371.2089.

Workup

  1. temperatureIt was cooled
  2. extractionextracted with CH2Cl2 (150 ml×3)
  3. dry with materialdried (MgSO4)
  4. concentrationconcentrated
  5. customPurification with Biotage MPLC (35% EtOAc in heptane)

Sources & evidence

ORD record
ord-097b26f077314d139d221bffe6dba56e
Source dataset
uspto-grants-2005_11
Patent number
US06964965B2

Reaction notes

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