1,2-Dimethoxyethane → HCID 89544099, compound

HRID 1050947Notes

Reaction equation

HRID 1050947 reaction equation
Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:5]([O:7]C)=[O:6].B(O)O.[F:16][C:17]1[CH:37]=[CH:36][C:20]([O:21][C:22]2[CH:27]=[CH:26][C:25](CC(C(O)(C)C)(C)O)=[CH:24][CH:23]=2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>CCOC(C)=O.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.CCO>[F:16][C:17]1[CH:37]=[CH:36][C:20]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([CH3:12])[N:11]=3)[C:5]([OH:7])=[O:6])=[CH:24][CH:23]=2)=[CH:19][CH:18]=1

Participants

9

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 10340Sodium CarbonateHCID 2759833Methyl 2-Chloro-6-methylisonicotinateHCID 178459198HCID 178459198, compound

Product 1

HCID 89544099HCID 89544099, compoundYield 81.8%

Reagents, catalysts & solvents 4

HCID 178418476HCID 178418476, compoundCatalystHCID 702EthanolSolventHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

A 100 mL round bottom flask was charged with methyl 2-chloro-6-methylisonicotinate (3 g, 16.2 mmol), 2-[4-(4-fluoro-phenoxy)-phenyl pinacol boronate (5.1 g, 16.2 mmol), sodium carbonate (3.43 g, 32.4 mmol), PdCl2(PPh3)2 (569 mg, 0.81 mmol), DME (10 mL), EtOH (5 mL), and water (10 mL). The reaction mixture was heated to 80° C. for 16 h. The reaction mixture was then diluted with EtOAc (200 mL) and washed with 1M aq. HCl (2×200 mL). The organic layer was dried over MgSO4 and concentrated to a thick brown paste. The paste was suspended in EtOH (25 mL) and treated with 2N aq. NaOH (50 mL) at room temperature for 18 h, at which time the hydrolysis was complete. The mixture was concentrated under reduced pressure, suspended in water (50 mL), acidified with 4N aq. HCl (75 mL), and extracted with EtOAc (2×300 mL). The combined organic layers were dried over MgSO4 and concentrated to provide 2-(4-(4-fluorophenoxy)phenyl)-6-methylisonicotinic acid as a waxy brown solid (4.28 g, 13.25 mmol). 1H NMR (d6-DMSO): 8.15-8.09 (m, 2 H), 8.08-8.04 (s, 1 H), 7.67-7.63 (s, 1H), 7.32-7.24 (m, 2 H), 7.20-7.13 (m, 2 H), 7.11-7.05 (m, 2 H), 2.65-2.60 (s, 3 H). LCMS: m/z=324 [M+H+]+. Unless otherwise indicated all 1H NMR chemical shifts reported herein are denoted by the delta (δ) scale.

Workup

  1. washwashed with 1M aq. HCl (2×200 mL)
  2. dry with materialThe organic layer was dried over MgSO4
  3. concentrationconcentrated to a thick brown paste
  4. additiontreated with 2N aq. NaOH (50 mL) at room temperature for 18 h, at which time the hydrolysis
  5. concentrationThe mixture was concentrated under reduced pressure
  6. extractionextracted with EtOAc (2×300 mL)
  7. dry with materialThe combined organic layers were dried over MgSO4
  8. concentrationconcentrated

Sources & evidence

ORD record
ord-135bbbc41d114ddbba84ab268b887235
Source dataset
uspto-grants-2016_07
Patent number
US09388137B2

Reaction notes

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