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

HRID 1778052Notes

Reaction equation

HRID 1778052 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12](OC)[O:13]C)[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.[S:33]1[CH:37]=[CH:36][CH:35]=[C:34]1B1OC(C)(C)C(C)(C)O1.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:34]4[S:33][CH:37]=[CH:36][CH:35]=4)=[C:11]([CH:12]=[O:13])[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 107036284,4,5,5-Tetramethyl-2-(thiophen-2-yl)-1,3,2-dioxaborolaneHCID 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 118036430N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-(thiophen-2-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, 50 mg, 0.099 mmol), thiophene-2-boronic acid pinacol ester (25 mg, 0.119 mmol), PdCl2(dppf) (8 mg, 10.9 μmol) and saturated aqueous Na2CO3 (140 μl) in DME (420 μl) was sealed in a vial and purged with argon. The reaction mixture was stirred at 120° C. for 15 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 (2-4%) in DCM, followed by another purification eluting with a gradient of EtOAc (70-100%) in hexanes. Product fractions were combined, evaporated and dried to yield the title compound as a white solid. (UPLC-MS 3) tR 1.23 min; ESI-MS 509.2 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 8.31 (s, 1H), 7.62-7.55 (m, 2H), 7.44 (d, 1H), 7.31 (d, 1H), 7.18-7.13 (m, 1H), 5.57 (s, 1H), 5.33 (s, 1H), 4.10 (t, 2H), 3.66 (t, 2H), 3.48 (s, 11H), 2.91 (t, 2H), 2.09-2.00 (m, 2H).

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 (2-4%) in DCM
  11. customfollowed by another purification
  12. washeluting with a gradient of EtOAc (70-100%) in hexanes
  13. customevaporated
  14. customdried

Sources & evidence

ORD record
ord-5e1e7659a2494018beec62e75d103580
Source dataset
uspto-grants-2016_02
Patent number
US09266883B2

Reaction notes

Loading…