1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → AFN-1252

Temperature

40 °C

A 22-L three-necked round-bottomed flask with a mechanical stirrer, a thermocouple, a reflux condenser and a nitrogen inlet was flushed with N2. The flask was charged with DMF (7.5 L, 5 v) and (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid (1.49 kg, 4.98 mol, 1.0 eq.). To the yellow suspension, HOBT (0.74 kg, 5.48 mol, 1.1 eq.), EDCI (1.15 kg, 5.98 mol, 1.2 eq) and N-methyl-1-(3-methylbenzofuran-2-yl)methanamine (0.96 kg, 5.48 mol, 1.1 eq) were added. During the addition an exotherm was observed and the temperature increased from 20.3° C. to 36.4° C. To the resulting thick suspension was added DIPEA (1.93 kg, 14.94 mol, 3 eq.) and an exotherm was observed to 41.9° C. During the addition the suspension changed to a clear brown solution. The resulting solution was stirred at 38-42° C. After about 45 min a new solid started to form. After stirring for 1.5 h, ˜1 mL of suspension was taken, the progress of the reaction was monitored by HPLC and the results indicated >95% reaction completion. After another 16 hours of stirring at the same temperature, 1H NMR and HPLC analysis indicated the reaction was complete. Half of the reaction mixture was transferred to another 22-L three-necked round-bottomed flask containing a mechanical stirrer, a thermocouple, a reflux condenser and a nitrogen inlet. The contents of both flasks were allowed to cool to 20-25° C. and each reaction mixture was diluted with H2O (8 L, 5.3 v) over 15 min. Both reaction mixtures showed an exotherm during the water addition to 30-35° C. The resulting suspensions were allowed to stir at 20-25° C. for 3.5 h. Solid was collected by filtration using a Buchnner funnel with a cloth filter and 20-L glass receiver under vacuum. The solids were washed with water (4×1.4 v), heptane (1×1.4 v) and ethyl acetate (3×1 v). The damp solid was dried under vacuum at 30-35° C. with a slow N2 bleed for 120 h to a constant weight to give 1.67 kg of the title compound as yellow solid. The material was analyzed indicating 98.48 area % HPLC purity with 146 ppm residual Pd.

1. customA 22-L three-necked round-bottomed flask with a mechanical stirrer, a thermocouple, a reflux condenser and a nitrogen inlet was flushed with N2
2. additionDuring the addition an exotherm
3. temperaturethe temperature increased from 20.3° C. to 36.4° C
4. customwas observed to 41.9° C
5. additionDuring the addition the suspension
6. customto form
7. stirringAfter stirring for 1.5 h
8. custom>95% reaction completion
9. stirringAfter another 16 hours of stirring at the same temperature, 1H NMR and HPLC analysis
10. customHalf of the reaction mixture was transferred to another 22-L three-necked round-bottomed flask
11. additioncontaining a mechanical stirrer
12. customThe contents of both flasks were allowed
13. temperatureto cool to 20-25° C.
14. customBoth reaction mixtures
15. stirringto stir at 20-25° C. for 3.5 h
16. filtrationSolid was collected by filtration
17. filtrationfilter
18. washThe solids were washed with water (4×1.4 v), heptane (1×1.4 v) and ethyl acetate (3×1 v)
19. dry with materialThe damp solid was dried under vacuum at 30-35° C. with a slow N2
20. waitbleed for 120 h to a constant weight

ORD record

ord-ded8e0963f694e9aae64ba8906b4caf0

Source dataset

uspto-grants-2012_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08263613B2