Hydrochloric Acid → HCID 14939422, compound

Temperature

0 °C

The following is based on the procedure disclosed in B. Lygo, Tetrahedron, 51, pp. 12859-12868 (1995). To an oven dried 5 liter flask was added sodium hydride (60% dispersion in mineral oil, 1.21 mmoles, 48.55 g) under nitrogen gas. The hydride was washed with hexanes (4×250 mL). The hydride was then suspended in dry tetrahydrofuran (THF) (2000 mL) and the mixture cooled to 0° C. in an ice bath. To this solution was added t-butylacetoacetate (160 g, 1.01 mmol) via an addition funnel dropwise over 2 hours at 0° C. with a constant flow of nitrogen gas. After the addition was complete the reaction was allowed to stir at 0° C. under nitrogen for an additional 30 minutes. To this mixture was added n-butyllithium (2 M in cyclohexane, 556 mL, 1.11 mmol) via addition funnel dropwise over 3 hours. After the addition was complete the reaction mixture was allowed to stir at 0° C. for an additional 30 minutes. Ethylpropionate (85.94 mL, 1.01 mmol) was loaded into an addition funnel and added to reaction slowly over 1.5 hours. At this point the reaction was allowed to warm up to room temperature while stirring overnight. The reaction was once again cooled to 0° C. in an ice bath and 2 N HCl (1.15 liters, cooled to 0° C. before addition) was added dropwise via an addition funnel over 2 hours. The reaction pH was checked to ensure neutralization. If needed, more 2 N HCl was added by pipette to adjust the solution to pH 7. At this point the major portion of THF/cyclohexane was decanted away from the aqueous layer and the organic solvent was reduced by ˜75% using rotary evaporation. The aqueous layer was extracted with ethyl acetate (3×200 mL). The residue obtained from volume reduction was diluted with ethyl acetate (500 mL) and combined with the organic pool from aqueous extraction. This organic pool was washed with saturated sodium chloride (3×250 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation. The residue was then subjected to high vacuum distillation (140 microns, short path distillation head) to yield 131 g of crude compound U as a clear oil. 1H NMR CDCl3 δ: 15.16 (bs, 1H), 5.59 (s, 1H), 3.24 (s, 2H), 3.22 (q, 2H, J=8.0 Hz), 1.46 (s, 9H), 1.14 (t, 3H, J=8.0 Hz). ESMS m/z: 237 [M+Na+], 159 [M-t-butyl]+.

1. customTo an oven dried 5 liter flask
2. washThe hydride was washed with hexanes (4×250 mL)
3. additionAfter the addition
4. additionvia addition funnel dropwise over 3 hours
5. additionAfter the addition
6. stirringto stir at 0° C. for an additional 30 minutes
7. additionadded to reaction slowly over 1.5 hours
8. temperatureto warm up to room temperature
9. stirringwhile stirring overnight
10. temperatureThe reaction was once again cooled to 0° C. in an ice bath
11. customThe reaction pH
12. customAt this point the major portion of THF/cyclohexane was decanted away from the aqueous layer
13. customevaporation
14. extractionThe aqueous layer was extracted with ethyl acetate (3×200 mL)
15. customThe residue obtained from volume reduction
16. extractioncombined with the organic pool from aqueous extraction
17. washThis organic pool was washed with saturated sodium chloride (3×250 mL)
18. dry with materialdried over anhydrous sodium sulfate
19. filtrationfiltered
20. concentrationconcentrated by rotary evaporation
21. distillationThe residue was then subjected to high vacuum distillation (140 microns, short path distillation head)

ORD record

ord-d9ed4c9e32d54caead1a535cd54aad8e

Source dataset

uspto-grants-2011_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07879846B2