Phosphoric Acid → Retinoic Acid

Temperature

5 °C

A 1-liter three-necked flask was charged under an atmosphere of nitrogen with 54.9 g of vitamin A aldehyde (69.1% purity, 133.6 mmoles, ratio of all trans form: 98.5%), 250 g of 2-methyl-2-butene, 100 ml of dioxane and 53.2 g of a 25% aqueous sodium chlorite solution. The mixture was mechanically stirred vigorously and, while the internal temperature was maintained at 5° C., 170 g of a 8.5% aqueous phosphoric acid solution was added thereto dropwise over 1.5 hours. After completion of the addition, the mixture was further stirred vigorously at 5° C. for 40 minutes. After confirming exhaustion of the starting material vitamin A aldehyde by thin layer chromatography, yellow solid that precipitated was filtered through a glass filter and then washed several times with water. The yellow solid was transferred to a 500-ml flask, and 200 ml of a 5% aqueous potassium hydroxide solution and 100 ml of ethanol were added thereto. The mixture was refluxed with heating for 1.5 hours. After cooling, the reaction mixture was transferred to a 1-liter separating funnel. To the mixture 200 ml of hexane was added and the funnel was shaken sufficiently. The bottom layer was separated and acidified with a 10% aqueous sulfuric acid solution. The yellow solid that precipitated was extracted with 500 ml of isopropyl ether and the extract was washed with water until the bottom layer became neutral. The isopropyl ether was distilled off under reduced pressure and 400 ml of ethanol was added to the yellow residue and the mixture was heated. After confirmation of complete dissolution, the solution was gradually cooled with stirring to 0° C. The vitamin A acid crystal that precipitated was filtered through a glass filter and then washed with cold ethanol. The crystal was dried under reduced pressure, to give 22.3 g of vitamin A acid having a purity of at least 99%. The yield was 55.9%. The vitamin A acid thus obtained had a all trans form ratio of 99.5%.

1. customform
2. additionAfter completion of the addition
3. stirringthe mixture was further stirred vigorously at 5° C. for 40 minutes
4. filtrationwas filtered through a glass
5. filtrationfilter
6. washwashed several times with water
7. customThe yellow solid was transferred to a 500-ml flask
8. addition200 ml of a 5% aqueous potassium hydroxide solution and 100 ml of ethanol were added
9. temperatureThe mixture was refluxed
10. temperaturewith heating for 1.5 hours
11. temperatureAfter cooling
12. customseparating funnel
13. additionTo the mixture 200 ml of hexane was added
14. stirringthe funnel was shaken sufficiently
15. customThe bottom layer was separated
16. customThe yellow solid that precipitated
17. extractionwas extracted with 500 ml of isopropyl ether
18. washthe extract was washed with water until the bottom layer
19. distillationThe isopropyl ether was distilled off under reduced pressure and 400 ml of ethanol
20. additionwas added to the yellow residue
21. temperaturethe mixture was heated
22. dissolutionAfter confirmation of complete dissolution
23. temperaturethe solution was gradually cooled
24. stirringwith stirring to 0° C
25. customThe vitamin A acid crystal that precipitated
26. filtrationwas filtered through a glass
27. filtrationfilter
28. washwashed with cold ethanol
29. customThe crystal was dried under reduced pressure

ORD record

ord-f44069506e194dd8ae8be692fd8bae89

Source dataset

uspto-grants-1994_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05312978