Triethylamine → HCID 178502986, compound

Temperature

41 °C

A 500 mL, 3-neck flask equipped with an overhead mechanical stirrer and pressure equalizing addition funnel was charged with L-alaninol (12.5 g, 166.4 mmol), triethylamine (29 mL, 208 mmol, 1.25 equiv) and dichloromethane (125 mL). The reaction solution was cooled to +2° C. and treated with dimethoxyphosphoryl chloride (20 mL, 183 mmol, 1.10 equiv) over 40 minutes while maintaining an internal temperature >+8° C. The reaction mixture was stirred with ice bath cooling for 1 hour at which point the reaction was complete by TLC analysis (silica gel, 93:6:1 DCM/MeOH/NH4OH and 6/3/1 CHCl3/MeOH/NH4OH; KMnO4 stain). Additional triethylamine (25.5 mL, 182.5 mmol, 1.10 equiv) was added to the reaction mixture and methanesulfonyl chloride (14.9 mL, 191 mol, 1.15 equiv) was added drop-wise over 45 minutes while maintaining an internal temperature <+10° C. The resulting reaction mixture was stirred with ice bath cooling for 1.0 hour after which time TLC analysis indicated the reaction was complete. Potassium hydroxide solution (3 M, 220 mL, 650 mmol, 4.0 equiv) was slowly added to the stirred reaction mixture while maintaining an internal temperature <+16° C. The reaction was continued with agitation for 6 hours, after which time the aqueous layer was separated and discarded. Saturated NaHCO3 solution (35 mL) was added and the biphasic mixture heated to 40-42° C. Distillation was started and a first fraction of 90 mL of dichloromethane was collected. When the temperature reached 50° C., a second fraction was collected until the batch temperature was 65° C. The mixture was heated at 65° C. for another 1 hour and then cooled to ambient temperature. Dichloromethane (90 mL) was added and the mixture stirred for 10 minutes before separation. The dichloromethane layer was concentrated under reduced pressure. The residue was dissolved in heptanes (15 mL) and concentrated under reduced pressure to remove the residual water. This azeotropic drying was repeated two more times. The resulting 4a was obtained as a light yellow liquid (20.9 g, 76% yield, 95.40% GC purity). A colorless sample was prepared by short path distillation (80-85° C.@15 mm Hg vacuum). Optical rotation c=1.00, ethanol, 25.0° C., +39.3°. 1H NMR (300 MHz, CDCl3) δ 3.80 (s, 3H), 3.76 (s, 3H), 2.65-2.50 (m, 1H), 2.42-2.31 (m, 1H), 1.92 (dt, J=3.6, 1.2 Hz, 1H), 1.28 (dd, J=5.4, 1.2 Hz, 3H).

1. customA 500 mL, 3-neck flask equipped with an overhead mechanical stirrer
2. additionaddition funnel
3. temperatureThe reaction solution was cooled to +2° C.
4. temperaturewhile maintaining an internal temperature >+8° C
5. temperaturecooling for 1 hour at which
6. additionwas added drop-wise over 45 minutes
7. temperaturewhile maintaining an internal temperature <+10° C
8. customThe resulting reaction mixture
9. stirringwas stirred with ice bath
10. temperaturecooling for 1.0 hour after which time TLC analysis
11. temperaturewhile maintaining an internal temperature <+16° C
12. customafter which time the aqueous layer was separated
13. additionSaturated NaHCO3 solution (35 mL) was added
14. distillationDistillation
15. customa first fraction of 90 mL of dichloromethane was collected
16. customreached 50° C.
17. customa second fraction was collected until the batch temperature
18. customwas 65° C
19. temperatureThe mixture was heated at 65° C. for another 1 hour
20. temperaturecooled to ambient temperature
21. additionDichloromethane (90 mL) was added
22. stirringthe mixture stirred for 10 minutes before separation
23. concentrationThe dichloromethane layer was concentrated under reduced pressure
24. dissolutionThe residue was dissolved in heptanes (15 mL)
25. concentrationconcentrated under reduced pressure
26. customto remove the residual water
27. customThis azeotropic drying

ORD record

ord-60a3fee85c0844d58a3c389fb64d7c94

Source dataset

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09278904B2