反应详情

温度

20 °C

Oxalyl chloride (15.1 ml, 173 mmol) was added over approx 1 minute to a stirred suspension of 5-{[(3-chlorophenyl)methyl]oxy}-2-methylbenzoic acid (31.8 g, 115 mmol) in dichloromethane (1.14 L) at 20° C. under argon. This was followed by the addition of N,N dimethylformamide (2 ml, 25.8 mmol) over 3 minutes with accompanying gas evolution but no noticeable temperature rise. Within approx 15 minutes the suspension dissolved and turned a darker brown. The mixture was stirred under argon at 20° C. for a total of 75 minutes. After 75 minutes the reaction mixture was evaporated in vacuo to a cream solid which was dried under vacuum at room temperature for 1 h. The solid was then redissolved in dichloromethane (900 ml) and to the stirred solution at 20° C. under argon was simultaneously added a solution of ethyl (4-amino-3-methylphenyl)acetate (24.4 g, 126 mmol) in dichloromethane (240 ml) and triethylamine (24 ml) over 10-15 minutes. The temperature rise in the reaction was from 20° C. to 30° C. over this time and thereafter slowly cooled to ambient. The brown solution was stirred under argon at room temperature for 14 h. After 14 h stirring the brown solution was washed with water (2×1 L). The combined aqueous washes were re-extracted with dichloromethane (500 ml) and all the organic extracts were combined, dried (MgSO4) and evaporated in vacuo to a brown oily solid which was dried at room temperature, under vacuum for 0.5 hours (wt=51.7 g). This material was dissolved in dichloromethane (200 ml) and the solution column chromatographed on Biotage 75 L system eluting with an ethyl acetate/iso-hexane gradient mixture and collecting 400 ml fractions as follows:

1. dissolutionWithin approx 15 minutes the suspension dissolved
2. customAfter 75 minutes the reaction mixture was evaporated in vacuo to a cream solid which
3. customwas dried under vacuum at room temperature for 1 h
4. dissolutionThe solid was then redissolved in dichloromethane (900 ml) and to the stirred solution at 20° C. under argon
5. customwas from 20° C. to 30° C. over this time
6. temperatureslowly cooled
7. stirringThe brown solution was stirred under argon at room temperature for 14 h
8. stirringAfter 14 h stirring the brown solution
9. washwas washed with water (2×1 L)
10. extractionThe combined aqueous washes were re-extracted with dichloromethane (500 ml) and all the organic extracts
11. dry with materialdried (MgSO4)
12. customevaporated in vacuo to a brown oily solid which
13. customwas dried at room temperature, under vacuum for 0.5 hours (wt=51.7 g)
14. dissolutionThis material was dissolved in dichloromethane (200 ml)
15. customthe solution column chromatographed on Biotage 75 L system
16. washeluting with an ethyl acetate/iso-hexane gradient mixture
17. customcollecting 400 ml fractions