Sodium Carbonate → N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-(1,3-dimethyl-1H-pyrazol-4-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

HRID 1778048Notes

Reaction equation

HRID 1778048 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:15][CH3:16])[O:13][CH3:14])[N:8]([C:17]([NH:19][C:20]1[CH:25]=[C:24]([NH:26][CH2:27][CH2:28][O:29][CH3:30])[C:23]([C:31]#[N:32])=[CH:22][N:21]=1)=[O:18])[CH2:7][CH2:6][CH2:5]2.C[N:34]1[C:38]([CH3:39])=[C:37](B(O)O)[CH:36]=[N:35]1.[C:43]([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(Cl)Cl.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:31]([C:23]1[C:24]([NH:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:25][C:20]([NH:19][C:17]([N:8]2[C:9]3[C:4](=[CH:3][C:2]([C:37]4[C:38]([CH3:39])=[N:34][N:35]([CH3:43])[CH:36]=4)=[C:11]([CH:12]([O:15][CH3:16])[O:13][CH3:14])[N:10]=3)[CH2:5][CH2:6][CH2:7]2)=[O:18])=[N:21][CH:22]=1)#[N:32]

Participants

8

Reactant 3

HCID 10340Sodium CarbonateHCID 532165971,5-Dimethylpyrazole-4-boronic acid2×HCID 1180366576-bromo-N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide2×

Product 1

HCID 118036571N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-(1,3-dimethyl-1H-pyrazol-4-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
120 °C

Procedure

A suspension of 6-bromo-N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 315, 41 mg, 0.081 mmol), 1,5-dimethyl-1H-pyrazole-4-boronic acid pinacolester (19 mg, 0.083 mmol), PdCl2(dppf) (6 mg, 8.20 μmol) and saturated aqueous Na2CO3 (100 μl) in DME (300 μl) was sealed in a vial and purged with argon. Then reaction mixture was stirred at 120° C. for 15 min in a microwave. Additional 1,5-dimethyl-1H-pyrazole-4-boronic acid pinacolester (5 mg, 0.022 mmol) was added and the reaction mixture was stirred at 120° C. for 5 min in a microwave. The suspension was diluted with DCM and water, phases were separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with water, dried using Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography eluting with a gradient of MeOH (1-5%) in DCM. Product fractions were combined, evaporated and dried to yield the title compound as an orange film. (UPLC-MS 3) tR 0.94 min; ESI-MS 521.3 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 8.24 (s, 1H), 7.58 (s, 1H), 7.47 (s, 1H), 7.29 (s, 1H), 5.34 (s, 1H), 5.24 (s, 1H), 4.09-4.04 (m, 2H), 3.86 (s, 3H), 3.63 (t, 2H), 3.51-3.45 (m, 2H), 3.41 (s, 9H), 2.85 (t, 2H), 2.18 (s, 3H), 2.06-1.99 (m, 2H).

Workup

  1. customwas sealed in a vial and
  2. custompurged with argon
  3. customThen reaction mixture
  4. stirringthe reaction mixture was stirred at 120° C. for 5 min in a microwave
  5. customwere separated
  6. extractionthe aqueous layer was extracted with DCM
  7. washThe combined organic layers were washed with water
  8. customdried
  9. filtrationfiltered
  10. customevaporated
  11. customThe crude product was purified by silica gel column chromatography
  12. washeluting with a gradient of MeOH (1-5%) in DCM
  13. customevaporated
  14. customdried

Sources & evidence

ORD record
ord-bc964d3b14b34c5aa788a845962c0dac
Source dataset
uspto-grants-2016_02
Patent number
US09266883B2

Reaction notes

Loading…