Ammonium Chloride → N-(2-t-Butyl-5-methoxycarbonylphenyl)-3-(4-hydroxymethyl-2-methoxyphenyl)octanamide

One drop of dimethylformamide and then 3.0 ml (34.5 mmol) of oxalyl chloride were added to a solution of 6.06 g (18.8 mmol) of 3-(4-acetoxymethyl-2-methoxyphenyl)octanoic acid (prepared as described in Preparation 41) in 40 ml of methylene chloride, and the resulting mixture was stirred at room temperature for 50 minutes. At the end of this time, the reaction mixture was freed from excess reagents and the solvent by distillation under reduced pressure. The resulting residue was dissolved in 20 ml of methylene chloride, and this solution was added to a solution of 4.12 g (19.9 mmol) of 2-t-butyl-5-methoxycarbonylaniline (prepared as described in Preparation 5) and 5 ml of pyridine in 20 ml of methylene chloride, whilst ice-cooling. The resulting mixture was then stirred at the same temperature for 20 minutes. At the end of this time, the reaction mixture was mixed with water, and the aqueous mixture was extracted with ethyl acetate. The extract was washed with 2 N aqueous hydrochloric acid, with water, with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was dissolved in 200 ml of absolute methanol. 2.0 ml (2.0 mmol) of a 1.0 M methanolic sodium methoxide solution were then added to the resulting solution. The resulting mixture was then stirred at room temperature for 2.5 hours. In order to terminate the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction mixture, after which it was freed from methanol by distillation under reduced pressure. It was then extracted with ethyl acetate. The extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 250 g of silica gel using a 1:1 by volume mixture of ethyl acetate and hexane as the eluent, to give 7.80 g (yield 88%, based on the compound of Preparation 41)of the title compound as a foam-like substance.

1. distillationthe solvent by distillation under reduced pressure
2. dissolutionThe resulting residue was dissolved in 20 ml of methylene chloride
3. temperaturecooling
4. stirringThe resulting mixture was then stirred at the same temperature for 20 minutes
5. extractionthe aqueous mixture was extracted with ethyl acetate
6. washThe extract was washed with 2 N aqueous hydrochloric acid, with water, with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order
7. dry with materialafter which it was dried over anhydrous magnesium sulfate
8. customThe solvent was then removed by distillation under reduced pressure
9. dissolutionthe resulting residue was dissolved in 200 ml of absolute methanol
10. addition2.0 ml (2.0 mmol) of a 1.0 M methanolic sodium methoxide solution were then added to the resulting solution
11. stirringThe resulting mixture was then stirred at room temperature for 2.5 hours
12. customIn order to terminate
13. customthe reaction
14. distillationafter which it was freed from methanol by distillation under reduced pressure
15. extractionIt was then extracted with ethyl acetate
16. washThe extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order
17. dry with materialafter which it was dried over anhydrous magnesium sulfate
18. customThe solvent was then removed by distillation under reduced pressure
19. customthe resulting residue was purified by column chromatography through 250 g of silica gel using a 1:1
20. additionby volume mixture of ethyl acetate and hexane as the eluent
21. customto give 7.80 g (yield 88%

ORD record

ord-0cdb80f67d0b447dbc5bf895d1b47a6a

Source dataset

uspto-grants-2000_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06040339