Sodium Carbonate → (R)-{1-[4-(2-methoxy-pyridin-3-yl)-phenyl]-ethyl}carbamic acid tert-butyl ester

HRID 2422853Notes

Reaction equation

HRID 2422853 reaction equation
C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][O:8][C:9]1[C:14](B(O)O)=[CH:13][CH:12]=[CH:11][N:10]=1.[C:18]([O:22][C:23](=[O:34])[NH:24][C@@H:25]([C:27]1[CH:32]=[CH:31][C:30](Br)=[CH:29][CH:28]=1)[CH3:26])([CH3:21])([CH3:20])[CH3:19]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:18]([O:22][C:23](=[O:34])[NH:24][C@@H:25]([C:27]1[CH:28]=[CH:29][C:30]([C:14]2[C:9]([O:8][CH3:7])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:31][CH:32]=1)[CH3:26])([CH3:19])([CH3:20])[CH3:21]

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 2762709(2-Methoxypyridin-3-yl)boronic acidHCID 52987808(R)-tert-Butyl (1-(4-bromophenyl)ethyl)carbamate

Product 1

HCID 67244774(R)-{1-[4-(2-methoxy-pyridin-3-yl)-phenyl]-ethyl}carbamic acid tert-butyl esterYield 83.5%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
95 °C

Procedure

2M Aqueous sodium carbonate solution (3.25 ml, 6.50 mmol) was added to a mixture of 2-methoxypyridine-3-boronic acid (994 mg, 6.50 mmol), (R)-[1-(4-bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (650 mg, 2.16 mmol) and tetrakis(triphenylphosphine)palladium (0) (125 mg, 0.108 mmol) in 1,2 dimethoxyethane (27 ml). The mixture was heated at 95° C. for 16 h under nitrogen atmosphere. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed twice with brine, dried over anhydrous magnesium sulfate and the solvent evaporated. The resulting gum was chromatographed over silica gel eluting with heptane/dichloromethane and the solvent evaporated to give (R)-{1-[4-(2-methoxy-pyridin-3-yl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (593 mg, 1.71 mmol, 83.5%) as a crystalline solid. Trifluoroacetic acid (6.45 ml, 86.8 mmol) was added dropwise to a solution of (R)-{1-[4-(2-methoxy-pyridin-3-yl)-phenyl]-ethyl}carbamic acid tert-butyl ester (645 mg, 1.97 mmol) in dichloromethane (6.45 ml) under a nitrogen atmosphere at 0° C. After stirring for 1 h at 0° C. the solvent was evaporated. Methanol (20 ml) was added and the mixture added to a Strata™ 5 g/20 ml SCX column. The intermediate amine was eluted with 2M ammonia in methanol. The solvent was evaporated to give (R)-1-[4-(2-methoxy-pyridin-3-yl)-phenyl]-ethylamine as a gum (425 mg, 1.86 mmol, 94.6%). The title compound was then prepared in a similar manner to (R)-2,5-dimethyl-furan-3-sulfonic acid [1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethyl]-amide (Example 10) using 4-bromo-3-thiophenesulfonyl chloride and 1-[4-(2-Methoxy-pyridin-3-yl)-phenyl]-ethylamine. Title compound: 1H NMR (400 MHz, CDCl3): δ 8.17 (d, 1H), 7.56 (d, 1H), 7.41, 7.20 (a/b, 4H), 7.38 (m, 1H), 6.99-6.92 (m, 2H), 5.27 (d, 1H), 4.60 (m, 1H), 3.97 (s, 3H), 1.54 (d, 3H) ppm; MS (ESI) m/z: 453 [M+H]+.

Workup

  1. customThe solvent was evaporated
  2. customthe residue partitioned between ethyl acetate and water
  3. washThe organic phase was washed twice with brine
  4. dry with materialdried over anhydrous magnesium sulfate
  5. customthe solvent evaporated
  6. customThe resulting gum was chromatographed over silica gel eluting with heptane/dichloromethane
  7. customthe solvent evaporated

Sources & evidence

ORD record
ord-5062526e602b4b0bbf781a8819b39877
Source dataset
uspto-grants-2011_06
Patent number
US07960365B2

Reaction notes

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