Sodium Bicarbonate → (S)-2-(1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl)-7-nitroisoindolin-1-one

Temperature

72.5 °C

(1S)-7-nitro-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindolin-1-one was prepared by the following procedure. A mixture of methyl 2-bromomethyl-6-nitrobenzoate (100.0 g, 365 mmol, prepared previously in Example 6.5.2.), (1S)-1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethylamine (104.7 g, 383 mmol, prepared previously in Example 6.5.3.), sodium hydrogen carbonate (67.5 g, 8.03 moles, from Aldrich Chemicals) and dimethyl formamide (500 mL) was charged into a 1-L 3-necked flask at room temperature under nitrogen. The reaction mixture was gradually heated to an internal temperature of 70-75° C. for two hours until there was less than <2% of unreacted methyl 2-bromomethyl-6-nitrobenzoate. The reaction mixture was gradually heated to an internal temperature of 95-100° C. for 18 hours. The reaction mixture was cooled to 20-25° C. and transferred to an 1-L addition funnel. After purified water (1500 mL) was charged into a 5-L 3-necked flask, the reaction mixture in the addition funnel was added into water in the 5-L 3-necked flask at room temperature over 1-2 hours maintaining an internal temperature below 30° C. The reaction mixture was stirred for 2 hours at room temperature. The solid was filtered out under vacuum, washed with water (3×300 mL) and methanol (2×400 mL), and then charged into a 2-L 3-necked flask followed by methanol (1000 mL). The mixture was refluxed for 1 hour. The mixture was cooled to room temperature. The solid was collected by filtration under vacuum, washed with 200 mL methanol (2 vol), and dried to a constant weight at 40-45° C. under a vacuum at 100-120 torr. The yield of (1S)-7-nitro-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindolin-1-one was 123.0 g (78%), based on 100.0 g input of methyl 2-bromomethyl-6-nitrobenzoate. The product was found to have a purity of >99% measured by HPLC based on area percentage, and a water content of <0.1% measured by Karl Fisher titration.

1. customprepared previously in Example 6.5.2
2. temperatureThe reaction mixture was gradually heated to an internal temperature of 95-100° C. for 18 hours
3. temperatureThe reaction mixture was cooled to 20-25° C.
4. customAfter purified water (1500 mL)
5. additionwas charged into a 5-L 3-necked flask
6. additionthe reaction mixture in the addition funnel was added into water in the 5-L 3-necked flask at room temperature over 1-2 hours
7. temperaturemaintaining an internal temperature below 30° C
8. filtrationThe solid was filtered out under vacuum
9. washwashed with water (3×300 mL) and methanol (2×400 mL)
10. additioncharged into a 2-L 3-necked flask
11. temperatureThe mixture was refluxed for 1 hour
12. temperatureThe mixture was cooled to room temperature
13. filtrationThe solid was collected by filtration under vacuum
14. washwashed with 200 mL methanol (2 vol)
15. customdried to a constant weight at 40-45° C. under a vacuum at 100-120 torr

ORD record

ord-c1b0a1841851498880bcdcbc62293a6b

Source dataset

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09272035B2