Dichloromethane → Ethyl 3-amino-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridine-2-carboxylate

HRID 1948048Notes

Reaction equation

HRID 1948048 reaction equation
[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8](Br)[N:7]=1)=[O:5])[CH3:2].[O:14]1[C:18]2([CH2:23][CH2:22][C:21](B3OC(C)(C)C(C)(C)O3)=[CH:20][CH2:19]2)[O:17][CH2:16][CH2:15]1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[NH2:12][C:11]1[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[N:7][C:8]([C:21]2[CH2:22][CH2:23][C:18]3([O:17][CH2:16][CH2:15][O:14]3)[CH2:19][CH:20]=2)=[CH:9][CH:10]=1

Participants

7

Reactant 4

HCID 6344DichloromethaneHCID 11430Potassium CarbonateHCID 36970768-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dioxaspiro(4.5)dec-7-eneHCID 25137688Ethyl 3-amino-6-bromopicolinate2×

Product 1

HCID 67255067Ethyl 3-amino-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyridine-2-carboxylate

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Procedure

A mixture of 3-amino-6-bromopyridine-2-carboxylic acid ethyl ester-(Compound 232G, 0.31 g, 1.3 mmol), 1,4-dioxaspiro[4,5]dec-7-ene-8-boronic acid pinacol ester (0.406 g, 1.52 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(11), complex with dichloromethane (1:1) (0.10 g, 0.12 mmol) in a 35 mL sealable microwave tube was taken up in 1,4-Dioxane (4.9 mL). This mixture was treated with a solution of Potassium carbonate (0.52 g, 3.8 mmol) in H2O (1 mL), flushed with nitrogen, sealed and irradiated in a microwave reactor for 30 minutes at 100° C. The mixture was poured into water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 filtered and concentrated to a brown residue. This was taken up in DCM, treated with silica and concentrated. The resulting silica plug was loaded on to a sample cartridge and purified on an ISCO Combiflash system (0-50% EtOAc/Heptane) to isolate the desired product as 247 mg of an oil which crystallized upon standing. 1H NMR (400 MHz, DMSO-d6) d 1.30 (t, J=7.20 Hz, 3H), 1.77 (t, J=6.44 Hz, 2H), 2.32-2.40 (m, 2H), 2.60 (td, J=6.44, 1.52 Hz, 2H), 3.91 (s, 4H), 4.28 (q, J=7.07 Hz, 2H), 6.25 (t, J=4.04 Hz, 1H), 6.65 (s, 2H), 7.17 (d, J=8.84 Hz, 1H), 7.52 (d, J=8.84 Hz, 1H). MS (ES+): m/z=305.12 (100) [M+1]. HPLC: tR=3.50 min (ZQ3, polar—5 min).

Workup

  1. customflushed with nitrogen
  2. customsealed
  3. customirradiated in a microwave reactor for 30 minutes at 100° C
  4. additionThe mixture was poured into water
  5. extractionextracted twice with EtOAc
  6. washThe combined organic layers were washed with brine
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated to a brown residue
  10. additiontreated with silica
  11. concentrationconcentrated
  12. custompurified on an ISCO Combiflash system (0-50% EtOAc/Heptane)

Sources & evidence

ORD record
ord-b65d36a45da54953892219615f9da48e
Source dataset
uspto-grants-2013_03
Patent number
US08399433B2

Reaction notes

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