反应详情

温度

25 °C

On a larger scale, 5-bromo-2-fluorobenzoyl chloride (4318 g, 4205 g active, 17.71 mol) was charged to the vessel as a solution in toluene (7.5 L). DIPEA (3150 mL, 18.08 mol) was added with no observed exotherm. Ethyl-3-(dimethylamino)acrylate (2532 g, 17.71 mol) was added portion wise over 30 minutes maintaining a batch temperature <40° C. An exotherm from 21-24° C. was noted over the 30 minute addition with a further slow rise to 38° C. over 1 h. The reaction was stirred at 20-30° C. for 16.5 h, 4-Methoxybenzylamine (2439 g, 17.78 mol) was added portionwise over 30 mins maintaining a batch temperature <40° C. An exotherm of 25-30° C. was observed over the addition with cooling provided by a reduced jacket temperature of 15° C. The reaction was stirred for 4 h at 20-30° C. after which HPLC indicated 93.2% of desired material. The batch was split for workup with each half of the mixture diluted with DCM (28.6 L) and washed with water (3×7.8 L). The organics were dried over MgSO4 (˜550 g) and filtered, washing with DCM (4 L). The combined organics were then concentrated to give 8444 g of die desired material as an oil (8434 g, 106% yield, 94.7% parity by HPLC). Analytical data was consistent with that obtained from previous batches.

1. temperaturemaintaining a batch temperature <40° C
2. additionAn exotherm from 21-24° C. was noted over the 30 minute addition with a further slow rise to 38° C. over 1 h
3. temperaturemaintaining a batch temperature <40° C
4. additionAn exotherm of 25-30° C. was observed over the addition
5. temperaturewith cooling
6. customprovided by a reduced jacket temperature of 15° C
7. stirringThe reaction was stirred for 4 h at 20-30° C. after which HPLC
8. customThe batch was split for workup with each half of the mixture
9. additiondiluted with DCM (28.6 L)
10. washwashed with water (3×7.8 L)
11. dry with materialThe organics were dried over MgSO4 (˜550 g)
12. filtrationfiltered
13. washwashing with DCM (4 L)
14. concentrationThe combined organics were then concentrated