Sodium Bicarbonate → benzyl (3R,4S)-3-({3,6-diethyl-5-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]pyrazin-2-yl}amino)-4-ethoxypyrrolidine-1-carboxylate

HRID 1297289Notes

Reaction equation

HRID 1297289 reaction equation
I[C:2]1[C:3]([C:10]([F:13])([F:12])[F:11])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.C([Li])(C)(C)C.[CH2:19]([C:21]1[C:22]([NH:30][C@H:31]2[C@@H:35]([O:36][CH2:37][CH3:38])[CH2:34][N:33]([C:39]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:40])[CH2:32]2)=[N:23][C:24]([CH2:28][CH3:29])=[C:25](I)[N:26]=1)[CH3:20].C(=O)(O)[O-].[Na+]>C1COCC1.[Cl-].[Zn+2].[Cl-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:19]([C:21]1[C:22]([NH:30][C@H:31]2[C@@H:35]([O:36][CH2:37][CH3:38])[CH2:34][N:33]([C:39]([O:41][CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)=[O:40])[CH2:32]2)=[N:23][C:24]([CH2:28][CH3:29])=[C:25]([C:2]2[C:3]([C:10]([F:13])([F:12])[F:11])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=2)[N:26]=1)[CH3:20]

Participants

8

Reactant 4

HCID 516892Sodium BicarbonateHCID 534256993-Iodo-6-methoxy-2-(trifluoromethyl)pyridineHCID 58914564benzyl (3R,4S)-3-[(3,6-diethyl-5-iodopyrazin-2-yl)amino]-4-ethoxypyrrolidine-1-carboxylateHCID 178418306HCID 178418306, compound

Product 1

HCID 58914566benzyl (3R,4S)-3-({3,6-diethyl-5-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]pyrazin-2-yl}amino)-4-ethoxypyrrolidine-1-carboxylateYield 53%

Reagents, catalysts & solvents 3

HCID 3007855ZincchlorideCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 3-iodo-6-methoxy-2-(trifluoromethyl)pyridine (162 mg, 3 eq.) and Zinc chloride (0.5 M THF, 9 eq.) in THF (2.67 ml) under N2 at −78° C. was added t-butyl lithium (9 eq.). After 5 min, the reaction mixture was warmed to ambient temperature and cannula'd into a flask containing benzyl (3R,4S)-3-[(3,6-diethyl-5-iodopyrazin-2-yl)amino]-4-ethoxypyrrolidine-1-carboxylate (120 mg) and palladium tetrakis (31 mg). The reaction mixture was heated at reflux for 16 h, poured into saturated sodium bicarbonate (50 ml), extracted 3×50 ml of CH2Cl2, dried MgSO4, filtered and concentrated. Purification via MPLC chromatography eluting with 20–45% ethyl acetate/heptane afforded the title compound as an amorphous solid (63 mg, 53%):

Workup

  1. temperatureThe reaction mixture was heated
  2. temperatureat reflux for 16 h
  3. extractionextracted 3×50 ml of CH2Cl2, dried MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customPurification via MPLC chromatography
  7. washeluting with 20–45% ethyl acetate/heptane

Sources & evidence

ORD record
ord-d36c1473a9894608ba8555d3b4009911
Source dataset
uspto-grants-2007_07
Patent number
US07250418B2

Reaction notes

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