Hydrochloric Acid → Tert-butyl6-amino-2-chloro-4-methylnicotinate

HRID 1481960Notes

Reaction equation

HRID 1481960 reaction equation
[Cl:1][C:2]1[N:14]=[C:13](Cl)[CH:12]=[C:11]([CH3:16])[C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+].C(=[NH:78])(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])=O.[Na+].Cl.[OH-].[Na+]>O1CCOCC1.CCOC(C)=O.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]>[NH2:78][C:13]1[CH:12]=[C:11]([CH3:16])[C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[C:2]([Cl:1])[N:14]=1

Participants

11

Reactant 7

HCID 313Hydrochloric AcidHCID 10796Cesium carbonateHCID 14798Sodium HydroxideHCID 136809Benzophenone imineHCID 517045Sodium AcetateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 117632239Tert-butyl 2,6-dichloro-4-methylnicotinate

Product 1

HCID 117631130Tert-butyl6-amino-2-chloro-4-methylnicotinateYield 77.1%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

tert-butyl 2,6-dichloro-4-methylnicotinate (10.5 g, 40.1 mmol, 1 equiv), Pd2(dba)3 (1.84 g, 2.01 mmol, 0.05 equiv), xantphos (2.32 g, 4.01 mmol, 0.1 equiv), and Cs2CO3 slurried in dioxane (deoxygenated by bubbling nitrogen through it for 10 min) added. Benzophenone imine (8.0 mL, 48.1 mmol, 1.2 equiv) added and the mixture was heated at 90° C. for 1 h. Upon cooling to ambient temperature, the reaction was diluted with EtOAc and washed with water, dried (Na2SO4), and concentrated in vacuo. The crude product was taken up in MeOH (200 mL) and NaOAc (9.87, 120 mmol, equiv) and hydroxlamine hydrochloride (5.57 g, 80 mmol, 2 equiv) was added. After 30 min, the reaction was added to 1 N NaOH and extracted with DCM (×2). The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (0-30% EtOAc/hex) to afford tert-butyl 6-amino-2-chloro-4-methylnicotinate (7.5 g, 77%). 1H NMR (400 MHz, CDCl3) δ 6.22 (d, J=0.8 Hz, 1H), 4.58 (br. s., 2H), 2.27 (d, J=0.8 Hz, 3H), 1.60 (s, 9H); LCMS (ESI, M+1): 243.1.

Workup

  1. additionadded
  2. temperatureUpon cooling to ambient temperature
  3. washwashed with water
  4. dry with materialdried (Na2SO4)
  5. concentrationconcentrated in vacuo
  6. extractionextracted with DCM (×2)
  7. dry with materialThe combined DCM extracts were dried (Na2SO4)
  8. concentrationconcentrated in vacuo
  9. customThe crude product was purified by flash column chromatography (0-30% EtOAc/hex)

Sources & evidence

ORD record
ord-eb57974a061d442f97b3775b60355abd
Source dataset
uspto-grants-2016_08
Patent number
US09409922B2

Reaction notes

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