Tetrahydrofuran → 5-Ethoxy-4,5-dihydro-1,2-oxazole-3-carbonitrile

Temperature

2.5 °C

To a dried 10 L three-necked flask equipped with a thermometer controller, a mechanical stirrer, and a dropping funnel protected under nitrogen was charged 6966.7 g (7.3×) of tetrahydrofuran and 950.0 g (1.0×) of compound (1Z,2E)-N-hydroxy-2-(hydroxyimino)acetimidoyl chloride. The reaction mixture was cooled to 0-5° C. followed by drop wise addition of 1845.2 g (1.9×) thionyl chloride over 60-90 minutes at 0-5° C. After addition, the reaction mixture was stirred at 10-15° C. for 6-7 hours and deemed complete by HPLC. The reaction mixture was then concentrated under vacuum at 15-20° C. to about 1.0 L (1.0×) followed by addition of a total of 950 g (0.9×) of tetrahydrofuran and distillation to remove residual thionyl chloride. The resulting mixture was added drop wise into a solution of 2755 g (2.9×) of ethoxyethene, 6764 g (7.12×) of tetrahydrofuran and 715.0 g (0.75×) of sodium carbonate in 3200.0 g (3.4×) of water over 30-40 minutes at 0-5° C. After addition, the reaction mixture was stirred at 0-5° C. for 1-2 hours and deemed complete by HPLC. The resulting mixture was separated and the aqueous layer was extracted with 1900 g (2.0×) of methyl t-butyl ether, and then the combined organic layer was dried with 380 g (0.4×) of sodium sulfate, filtered and then concentrated to give 549.7 g yellow oil (Assay 60.3%, purity 97.0%, yield 30.5%). 1H NMR (CDCl3, 400 MHz) δ 5.76 (dd, J=2.0 Hz, 4.8 Hz, 1H), 3.86-3.90 (m, 1H), 3.60-3.65 (m, 1H), 3.21 (dd, J=6.8 Hz, 11.2 Hz, 1H), 3.00 (dd, J=2.0 Hz, 16 Hz, 1H), 1.21 (T, J=6.8 Hz, 1H).

1. customTo a dried 10 L three-necked flask equipped with a thermometer controller, a mechanical stirrer, and a dropping funnel
2. additionAfter addition
3. concentrationThe reaction mixture was then concentrated under vacuum at 15-20° C. to about 1.0 L (1.0×)
4. additionfollowed by addition of a total of 950 g (0.9×) of tetrahydrofuran and distillation
5. customto remove residual thionyl chloride
6. additionThe resulting mixture was added drop wise into a solution of 2755 g (2.9×) of ethoxyethene, 6764 g (7.12×) of tetrahydrofuran and 715.0 g (0.75×) of sodium carbonate in 3200.0 g (3.4×) of water over 30-40 minutes at 0-5° C
7. additionAfter addition
8. stirringthe reaction mixture was stirred at 0-5° C. for 1-2 hours
9. customThe resulting mixture was separated
10. extractionthe aqueous layer was extracted with 1900 g (2.0×) of methyl t-butyl ether
11. dry with materialthe combined organic layer was dried with 380 g (0.4×) of sodium sulfate
12. filtrationfiltered
13. concentrationconcentrated

ORD record

ord-1ce5327c17c541d2b8e83551c1f103f2

Source dataset

uspto-grants-2011_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07998994B2