Sodium Carbonate → methyl 3-[bis(tert-butoxycarbonyl)amino]-6-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)pyrazine-2-carboxylate

HRID 1959474Notes

Reaction equation

HRID 1959474 reaction equation
CC1(C)C(C)(C)OB([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH:14]=2)O1.C(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)(C)C.[C:41]([O:45][C:46]([N:48]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[C:49]1[C:50]([C:56]([O:58][CH3:59])=[O:57])=[N:51][C:52](Br)=[CH:53][N:54]=1)=[O:47])([CH3:44])([CH3:43])[CH3:42].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.Cl[Pd]Cl.O>[C:63]([O:62][C:60]([N:48]([C:46]([O:45][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:47])[C:49]1[C:50]([C:56]([O:58][CH3:59])=[O:57])=[N:51][C:52]([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH:14]=2)=[CH:53][N:54]=1)=[O:61])([CH3:66])([CH3:65])[CH3:64]

Participants

9

Reactant 4

HCID 10340Sodium CarbonateHCID 4642098Tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylateHCID 11714598(4-(N,N-Dimethylamino)phenyl)di-tert-butyl phosphineHCID 86660188Methyl 3-(bis(tert-butoxycarbonyl)amino)-6-bromopyrazine-2-carboxylate

Product 1

HCID 66745644methyl 3-[bis(tert-butoxycarbonyl)amino]-6-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)pyrazine-2-carboxylateYield 97.6%

Reagents, catalysts & solvents 4

HCID 24290Palladium ChlorideCatalystHCID 962WaterSolventHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Procedure

A suspension of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (858 mg, 2.8 mmol), 4-ditert-butylphosphanyl-N,N-dimethyl-aniline; dichloropalladium (164 mg, 0.23 mmol), methyl 3-[bis(tert-butoxycarbonyl)amino]-6-bromo-pyrazine-2-carboxylate (1.0 g, 2.3 mmol), and Na2CO3 (490 mg, 4.6 mmol) under an atmosphere of nitrogen in toluene (15 mL) and water (2 mL) was heated to 95° C. for 2 h. The reaction mixture was diluted with ethyl acetate, washed with 1N HCl, 50% saturated sodium bicarbonate solution, and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified via silica gel column chromatography using 10-50% ethyl acetate/hexane to provide methyl 3-[bis(tert-butoxycarbonyl)amino]-6-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)pyrazine-2-carboxylate (1.2 g, 97%) as a amber oil. 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 6.97 (s, 1H), 4.12 (s, 2H), 3.89 (s, 3H), 3.57 (t, J=5.2 Hz, 2H), 2.61 (s, 2H), 1.43 (s, 9H), 1.34 (s, 18H). LC/MS m/z 535.5 [M+H]+.

Workup

  1. washwashed with 1N HCl, 50% saturated sodium bicarbonate solution, and brine
  2. dry with materialThe organic layer was dried over anhydrous Na2SO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe crude product was purified via silica gel column chromatography

Sources & evidence

ORD record
ord-f2210440f10c49128aad07dd52024595
Source dataset
uspto-grants-2013_04
Patent number
US08410112B2

Reaction notes

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