3,6-Dihydro-2H-pyran-4-boronic acid pinacol ester → 6-(3,6-dihydro-2H-pyran-4-yl)-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine

HRID 1778047Notes

Reaction equation

HRID 1778047 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])[NH:8][CH2:7][CH2:6][CH2:5]2.[O:17]1[CH2:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>C([O-])([O-])=O.[Na+].[Na+].COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:17]1[CH2:18][CH:19]=[C:20]([C:2]2[CH:3]=[C:4]3[C:9](=[N:10][C:11]=2[CH:12]([O:15][CH3:16])[O:13][CH3:14])[NH:8][CH2:7][CH2:6][CH2:5]3)[CH2:21][CH2:22]1

Participants

6

Reactant 2

HCID 112180533,6-Dihydro-2H-pyran-4-boronic acid pinacol esterHCID 1180362976-Bromo-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine2×

Product 1

HCID 1180369276-(3,6-dihydro-2H-pyran-4-yl)-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine

Reagents, catalysts & solvents 3

HCID 178418476HCID 178418476, compoundCatalystHCID 80711,2-DimethoxyethaneSolventHCID 10340Sodium CarbonateSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 6-bromo-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 12, 1.0 g, 3.48 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.49 g, 6.96 mmol) and Pd(PPh3)2Cl2 (0.24 g, 0.35 mmol) in aqueous Na2CO3 solution (2 M, 5.2 ml) and 1,2-dimethoxyethane (40 ml) was heated for 1.5 h at 100° C. under an atmosphere of argon. The cooled reaction mixture was then partitioned between aqueous NaHCO3 solution and EtOAc, the organic layer washed with brine, dried over MgSO4 and evaporated. The residue was then purified by normal phase chromatography using a 40 g RediSep® column, eluting with a gradient from DCM to 10% MeOH in DCM. Product containing fractions were then combined and evaporated to give the title compound as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 6.96 (s, 1H), 6.52 (s, br, 1H), 5.54 (s, br, 1H), 5.11 (s, 1H), 4.17-4.14 (m, 2H), 3.77 (t, 2H), 3.28-3.21 (m, 2H), 3.25 (s, 6H), 2.65 (t, 2H), 2.26-2.20 (m, 2H), 1.80-1.72 (m, 2H). (UPLC-MS 3) tR 0.55 min; ESI-MS 291.2 [M+H]+.

Workup

  1. customThe cooled reaction mixture
  2. customwas then partitioned between aqueous NaHCO3 solution and EtOAc
  3. washthe organic layer washed with brine
  4. dry with materialdried over MgSO4
  5. customevaporated
  6. customThe residue was then purified by normal phase chromatography
  7. washeluting with a gradient from DCM to 10% MeOH in DCM
  8. additionProduct containing fractions
  9. customevaporated

Sources & evidence

ORD record
ord-bf12d7116367437eaa8f5b6d1d7a258a
Source dataset
uspto-grants-2016_02
Patent number
US09266883B2

Reaction notes

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