Acetic Acid → HCID 54343789, compound

Temperature

-78 °C

A solution of oxalyl chloride (1.81 ml, 20.8 mmol) in dichloromethane (180 ml) was cooled to -78° C. A solution of dimethylsulfoxide (2.15 ml, 27.8 mmol) in dichloromethane (2 ml) was added dropwise. The solution was stirred for 15 min at -78° C. A solution of N-((1R)-1-(hydroxymethyl)-2-(2-thienyl)ethyl)-N-methylcarbamic acid tert-butyl ester (3.78 g, 13.9 mmol) in dichloromethane (10 ml) was added dropwise. The solution was stirred for 20 min at -78° C. Triethylamine (7.71 ml, 55.6 mmol) was added. The solution was stirred for 5 min at -78° C. and warmed to -35° C. As soon as -35° C. was reached it was cooled to -78° C. Acetic acid (3.50 ml, 61.2 mmol) was added. The solution was warmed to room temperature and was washed with brine (200 ml). The organic phase was dried over magnesium sulfate. The solvent was removed in vacuo. The residue was dissolved in methanol (180 ml). 4 Å mol (20 g) sieves was added. Acetic acid (5.5 ml, 97.3 mmol) was added. An 8.0M solution of methylamine in ethanol (5.2 ml, 41.7 mmol) was added. Solid sodium cyano borohydride (0.57 g, 9.1 mmol) was added. The solution was stirred at room temperature for 1 h, before another portion of solid sodium cyano borohydride (0.57 g, 9.1 mmol) was added. The reaction mixture was stirred for 16 h at room temperature and filtered through a plug of celite. The celite was washed with methanol (150 ml). The solvent of the filtrate was removed in vacuo. The residue was dissolved in 1N sodium hydroxide solution (200 ml). The solution was extracted with tert-butyl methyl ether (3×100 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (150 g), using dichloromethane/methanol/25% aqueous ammonia 100:10:1 as eluent, to give 1.72 g of N-methyl-N-((1R)-2-methylamino-1-((2-thienyl)methyl)ethyl)carbamic acid tert-butyl ester.

1. stirringThe solution was stirred for 20 min at -78° C
2. stirringThe solution was stirred for 5 min at -78° C.
3. temperaturewarmed to -35° C
4. customsoon as -35° C.
5. temperaturewas cooled to -78° C
6. temperatureThe solution was warmed to room temperature
7. washwas washed with brine (200 ml)
8. dry with materialThe organic phase was dried over magnesium sulfate
9. customThe solvent was removed in vacuo
10. dissolutionThe residue was dissolved in methanol (180 ml)
11. addition4 Å mol (20 g) sieves was added
12. additionwas added
13. stirringThe reaction mixture was stirred for 16 h at room temperature
14. filtrationfiltered through a plug of celite
15. washThe celite was washed with methanol (150 ml)
16. customThe solvent of the filtrate was removed in vacuo
17. dissolutionThe residue was dissolved in 1N sodium hydroxide solution (200 ml)
18. extractionThe solution was extracted with tert-butyl methyl ether (3×100 ml)
19. dry with materialThe combined organic layers were dried over magnesium sulfate
20. customThe solvent was removed in vacuo
21. customThe crude product was purified by flash chromatography on silica (150 g)

ORD record

ord-8045ca21cfbc44908df38ba9fb8d8170

Source dataset

uspto-grants-1999_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05977178