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

HRID 1778050Notes

Reaction equation

HRID 1778050 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.[CH3:33][N:34]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[N:35]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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[CH:36]=[N:35][N:34]([CH3:33])[CH:38]=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

6

Reactant 3

HCID 10340Sodium CarbonateHCID 27600771-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 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 118036266N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 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, 290 mg, 0.574 mmol), 1-methylpyrazolboronicacid pinacol ester (190 mg, 0.886 mmol), PdCl2(dppf) (43 mg, 59 μmol) and saturated aqueous Na2CO3 (0.7 ml) in DME (2.1 ml) was sealed in a vial and purged with argon. The reaction mixture was stirred at 120° C. for 20 min in a microwave. The suspension was diluted with DCM and water, phases were separated and the aqueous layer was extracted with DCM (2×). The combined organic layers were dried using Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography eluting with a gradient of MeOH (1-10%) in DCM, followed by another purification eluting with a gradient of MeOH (1-5%) in DCM. Product containing fractions were combined, evaporated and dried to yield the title compound as an orange resin. (UPLC-MS 3) tR 0.95 min; ESI-MS 507.2 [M+H]+.

Workup

  1. customwas sealed in a vial and
  2. custompurged with argon
  3. additionThe suspension was diluted with DCM and water, phases
  4. customwere separated
  5. extractionthe aqueous layer was extracted with DCM (2×)
  6. customThe combined organic layers were dried
  7. filtrationfiltered
  8. customevaporated
  9. customThe crude product was purified by silica gel column chromatography
  10. washeluting with a gradient of MeOH (1-10%) in DCM
  11. customfollowed by another purification
  12. washeluting with a gradient of MeOH (1-5%) in DCM
  13. additionProduct containing fractions
  14. customevaporated
  15. customdried

Sources & evidence

ORD record
ord-a85be2e6fe324719b4291635e4439d05
Source dataset
uspto-grants-2016_02
Patent number
US09266883B2

Reaction notes

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