Ethanolamine → (+/-) 3-[5-chloro-4-((2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-N-(2-hydroxyethyl)-4-methylbenzamide

Temperature

-20 °C

To a cold solution of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (4.0 g, 9.5 mmol) in anhydrous dimethylacetamide (20 mL, −20° C.) and N-methylmorpholine (1.56 mL, 14.25 mmol) was added a solution of isobutyl chloroformate (1.84 mL, 14.25 mmol) in anhydrous dichloromethane (5 mL). The reaction mixture stirred under nitrogen atmosphere at −20° C. for 10 min and then at room temperature for 30 min. At which time it was cooled back down to 0° C. and ethanolamine (0.86 mL, 14.25 mmol) and DMAP (ca.) were added. The reaction mixture stirred for 30 min at 0° C., then at room temperature overnight. The solvent was removed by vacuum distillation and the residue was diluted with acetonitrile/water (1:1 v/v) to be purified by reverse phase HPLC using a 10–90% acetonitrile in water containing 0.5% TFA (30 min) gradient at a 80 mL/min flow rate. The appropriate fractions (M+H m/z=464) were collected, concentrated to a reduced volume, freeze-dried and lyophilized. The resulting white solid was diluted with dichloromethane (30 mL) and washed with 5% NaHCO3 (2×50 mL). The organic extracts were washed with water (2×25 mL) and dried over Na2SO4 (anhydrous). The organic extracts were concentrated under reduced pressure and dried in vacuo to afford the desired product (2.625 g, 59%) as a white solid. 1H-NMR (CD3OD, 400 MHz) δ 7.9 (dd, 1H, J=2 Hz), 7.69 (d, 1H, J=2 Hz), 7.62 (m, 1H), 7.55 (d, 1H, J=8.4 Hz), 7.01 (m, 2H), 5.58 (q, 2H, J=12.4 Hz), 3.68 (t, 2H, J=5.6 Hz), 3.46 (t, 2H, J=5.6 Hz), 2.17 (s, 3H), 2.12 (s, 3H); ES-HRMS m/z 464.1153 (M+H C22H21ClF2N3O4 requires 464.1183).

1. waitat room temperature for 30 min
2. additionwere added
3. stirringThe reaction mixture stirred for 30 min at 0° C.
4. customat room temperature
5. customovernight
6. customThe solvent was removed by vacuum distillation
7. additionthe residue was diluted with acetonitrile/water (1:1 v/v)
8. customto be purified by reverse phase HPLC
9. customa 10–90% acetonitrile in water containing 0.5% TFA (30 min) gradient
10. customThe appropriate fractions (M+H m/z=464) were collected
11. concentrationconcentrated to a reduced volume
12. customfreeze-dried
13. additionThe resulting white solid was diluted with dichloromethane (30 mL)
14. washwashed with 5% NaHCO3 (2×50 mL)
15. washThe organic extracts were washed with water (2×25 mL)
16. dry with materialdried over Na2SO4 (anhydrous)
17. concentrationThe organic extracts were concentrated under reduced pressure
18. customdried in vacuo

ORD record

ord-f8ddcb0a6f9642c98939832cc17b9171

Source dataset

uspto-grants-2007_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07183287B2