Lithium Hydroxide → Benzoic Acid

Temperature

0 °C

Chlorosulfonyl isocyanate (1.7 mL, 19.5 mmol) was dissolved in 20 mL of methylene chloride and cooled to 0° C. Methyl 4-aminobenzoate (2.5 g, 16.2 mmol) dissolved in 20 mL of methylene chloride was added dropwise to the chlorosulfonyl isocyanate solution. Upon stirring, a precipitate slowly formed. After 2 hours, the mixture was filtered, and the solid collected and dried; yield 4.21 g. A portion of this solid (1.0 g, 3.4 mmol) was placed in a flask containing 3-amino-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide (0.95 g, 3.4 mmol), triethylamine (1.2 mL, 8.5 mmol), and 50 mL of tetrahydrofuran. The mixture was stirred overnight. The tetrahydrofuran was evaporated under reduced pressure, and the resulting solid was dissolved in methylene chloride (50 mL). The methylene chloride was sequentially washed with 25 mL of 1N hydrochloric acid, water, and brine. A precipitate was formed, which was recovered by filtration and triturated with a mixture of methylene chloride and methanol. The solid was dried under vacuum; yield 0.67 g. A portion of this solid (0.30 g, 0.6 mmol) was suspended in a 9:1 mixture of tetrahydrofuran and water (10 mL). Lithium hydroxide (48.3 mg, 2.0 mmol) was added, and the resulting mixture was refluxed overnight. The mixture was diluted with 1N hydrochloric acid (50 mL) and extracted with diethyl ether (1×50 mL) and ethyl acetate (1×50 mL). The organics were combined, dried with magnesium sulfate, and filtered. The resulting filtrate was evaporated under reduced pressure to give a white foam. The foam was triturated with hot ethyl acetate and ether, then dried under vacuum to give 0.12 g of benzoic acid, 4-[[[[[[5-[[(3,4-difluorophenyl)amino]carbonyl]-2-methoxyphenyl]amino]-sulfonyl]amino]carbonyl]amino]-. Microanalysis for C22H18F2N4O7S.0.25 H2O.0.1 C4H8O2; calculated C=50.40; H=3.64; N=10.50. found: C=50.29; H=3.71; N=10.14.

1. customa precipitate slowly formed
2. filtrationthe mixture was filtered
3. customthe solid collected
4. customdried
5. stirringThe mixture was stirred overnight
6. customThe tetrahydrofuran was evaporated under reduced pressure
7. dissolutionthe resulting solid was dissolved in methylene chloride (50 mL)
8. washThe methylene chloride was sequentially washed with 25 mL of 1N hydrochloric acid, water, and brine
9. customA precipitate was formed
10. filtrationwhich was recovered by filtration
11. customtriturated with a mixture of methylene chloride and methanol
12. customThe solid was dried under vacuum
13. temperaturethe resulting mixture was refluxed overnight
14. extractionextracted with diethyl ether (1×50 mL) and ethyl acetate (1×50 mL)
15. dry with materialdried with magnesium sulfate
16. filtrationfiltered
17. customThe resulting filtrate was evaporated under reduced pressure
18. customto give a white foam
19. customThe foam was triturated with hot ethyl acetate and ether
20. customdried under vacuum

ORD record

ord-d6c9511ba0144b07aca28855d7eeb5ce

Source dataset

uspto-grants-2005_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06906094B2