6-bromo-N-(5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide → Tert-butyl 2-(8-((5-cyanopyridin-2-yl)carbamoyl)-2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acetate

HRID 1777903Notes

Reaction equation

HRID 1777903 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]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][N:21]=1)=[O:18])[CH2:7][CH2:6][CH2:5]2.[Cl-].[C:29]([O:33][C:34](=[O:37])[CH2:35][Zn+])([CH3:32])([CH3:31])[CH3:30]>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].C1([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)C=CC=CC=1.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[Fe+2].O>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:17]([N:8]2[C:9]3[N:10]=[C:11]([CH:12]([O:15][CH3:16])[O:13][CH3:14])[C:2]([CH2:35][C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:37])=[CH:3][C:4]=3[CH2:5][CH2:6][CH2:7]2)=[O:18])=[N:21][CH:22]=1)#[N:27]

Participants

6

Reactant 2

HCID 1180363436-bromo-N-(5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide2×HCID 178451183HCID 178451183, compound

Product 1

HCID 118036371Tert-butyl 2-(8-((5-cyanopyridin-2-yl)carbamoyl)-2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acetate

Reagents, catalysts & solvents 3

HCID 6505921(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladiumCatalystHCID 129828017Ditert-butyl(cyclopenta-2,4-dien-1-yl)phosphane;iron(2+);(2,3,4,5-tetraphenylcyclopenta-1,4-dien-1-yl)benzeneCatalystHCID 962WaterSolvent

Conditions

Temperature
70 °C

Procedure

A tube was charged with 6-bromo-N-(5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 2H, 41.7 mg, 0.096 mmol), Pd(dba)2 (2.8 mg, 4.8 μmol) and 1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene (3.4 mg, 4.8 μmol), flushed with argon, then THF (1 ml) was added followed by 2-tert-butoxy-2-oxoethylzinc chloride (0.5 M in Et2O, 0.386 ml, 0.193 mmol) and the reaction mixture was stirred at 70° C. under argon for 1 h. The reaction mixture was poured into water and extracted with DCM (2×). The organic phase was then dried over Na2SO4, filtered and evaporated. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 95:5 to 50:50) followed by a reverse phase chromatography (13 g C18 cartridge, 0.1% TFA in water/acetonitrile 95:5 to 5:95) to give the title compound as a red resin. (UPLC-MS 3) tR 1.33 min; ESI-MS 468.2 [M+H]+.

Workup

  1. customflushed with argon
  2. additionTHF (1 ml) was added
  3. extractionextracted with DCM (2×)
  4. dry with materialThe organic phase was then dried over Na2SO4
  5. filtrationfiltered
  6. customevaporated
  7. customThe crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 95:5 to 50:50)

Sources & evidence

ORD record
ord-39e69b3d7277473bbf66a294dc886ea5
Source dataset
uspto-grants-2016_02
Patent number
US09266883B2

Reaction notes

Loading…