Ethanol → 6-[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid

HRID 872954Notes

Reaction equation

HRID 872954 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]#N)=[CH:17][N:16]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][CH:3]=1.C(O)C.[OH-:27].[Na+].[OH2:29]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]([OH:29])=[O:27])=[CH:17][N:16]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][CH:3]=1

Participants

5

Reactant 4

HCID 702EthanolHCID 962WaterHCID 14798Sodium HydroxideHCID 86681906HCID 86681906, compound

Product 1

HCID 684418986-[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acidYield 83%

Conditions

Temperature
52.5 °C

Procedure

6-[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinonitrile (58.8 g, 190 mmol) was suspended in water (440 mL) and ethanol (600 mL) and treated with 32% sodium hydroxide solution (178 mL 1.92 mol). The mixture was heated to 50-55° C. and subsequently stirred at this temperature for 15 hour. The slightly turbid mixture was polish filtered to remove the ether by-product 6-[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxymethyl-3-(4-fluoro-phenyl)-5-methyl-isoxazole. The first vessel and the transfer lines were rinsed with a mixture of water (50 mL) and ethanol (50 mL). The filtrate was treated at 20-25° C. within one hour with 25% hydrochloric acid (approx. 280 mL) until the pH was <2.0. The resulting suspension was stirred for one hour at room temperature. The crystals were filtered off, washed with a mixture of ethanol (200 mL) and water (200 mL) and subsequently dried at 50° C./<25 mbar until constant weight to afford 52.0 g (83%) of the title acid as an off-white solid with a purity of 99.5%.

Workup

  1. filtrationfiltered
  2. customto remove the ether by-product 6-[3-(4-Fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxymethyl-3-(4-fluoro-phenyl)-5-methyl-isoxazole
  3. washThe first vessel and the transfer lines were rinsed with a mixture of water (50 mL) and ethanol (50 mL)
  4. additionThe filtrate was treated at 20-25° C. within one hour with 25% hydrochloric acid (approx. 280 mL) until the pH was <2.0
  5. stirringThe resulting suspension was stirred for one hour at room temperature
  6. filtrationThe crystals were filtered off
  7. washwashed with a mixture of ethanol (200 mL) and water (200 mL)
  8. customsubsequently dried at 50° C./<25 mbar until constant weight

Sources & evidence

ORD record
ord-426eead7bc3f4f3fb7cb3807eddd4201
Source dataset
uspto-grants-2015_03
Patent number
US08975397B2

Reaction notes

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