COE JOTHAM WADSWORTH (US)
| US4026778A | 1977-05-31 |
| 1. | A method of preparing a compound of the formula comprising photolyzing a compound of the formula . |
| 2. | A method according to claim 1 , wherein the 9cis retinoic acid of formula II is crystallized directly from the reaction solution. |
| 3. | A method according to claim 1 , wherein the retinoic acid of formula I is trans retinoic acid. |
Background of the Invention The present invention relates to a process for the preparation of 9-cis retinoic acid. That compound is useful in the treatment of dermal, neoplastic and immunological disorders.
Traditionally, 9-cis retinoic acids have been obtained as a result of non-selective olefination reactions in retinoic acid syntheses. J. Am. Chem. Soc, 77, 4111 (1955), refers to the synthesis of the 6-cis-vitamin A acid through the Knoevenagel condensation reaction of onylideneacetaldehyde with an ester of ?-methylglutaconic acid catalyzed by a weak base. German Patent No. 1 ,050,763 and Rec. Trav. Chim., 68, 609 (1949) refer to the synthesis of the 9-cis form of vitamin A, as the minor isomer, utilizing the Reformatsky and Wittig condensation reactions, respectively.
The present method exploits the highly crystalline nature of 9-cis retinoic acid to enrich it from a mixture of isomers produced by the photolysis of any isomer of retinoic acid.
Summary of the Invention The present invention relates to a method for the preparation of a compound of the formula
comprising photolyzing a compound of the formula
The present invention also relates to a method of crystallizing 9-cis retinoic acid directly from the reaction solution.
Detailed Description of the Invention The following reaction scheme illustrates the preparation of the compound of the present invention.
The retinoic acid compound of formula I is converted to the corresponding 9-cis retinoic acid of formula II by refluxing and photolyzing I in solvent, preferably for a time period between about 19 hours to about 29 hours, more preferably about 24 hours, under inert reaction conditions. Photolysis of the trans retinoic acid compound of formula I occurs at wavelengths between about 250 nanometers to about 380 nanometers, preferably about 345 nanometers, through the use of a 150 watt to 300 watt tungsten filament lamp. Acetonitrile is the preferred solvent, however, other suitable solvents include C,-C 5 alkanol, ethyl acetate, tetrahydrofuran, dioxane, carbon tetrachloride, ethylene glycol dimethyl ether and dimethylacetamide. Upon completion of this reaction step, the reaction mixture is allowed to cool to room temperature and the desired 9-cis retinoic acid compound of formula II is recovered from solution in the form of a crystalline precipitate.
The 9-cis retinoic acid compound is useful in the treatment of dermal, neoplastic and immunological disorders. EXAMPLE 1
Trans-retinoic acid (4.0 grams, 13.3 mmol) was dissolved in high pressure liquid chromatography grade acetonitrile (1.5 liters) in a 3-liter single neck flask equipped with a condenser, a nitrogen inlet tube and a magnetic stirrer. The stirred dispersion dissolved at reflux under exposure to a 300 Watt tungsten filament lamp for 24 hours. After cooling, the solvent was removed on a rotary evaporator (bath temperature 35- 40°C, aspirator vacuum) until 800 mL of solvent has been collected. The reaction mixture was allowed to stand at ambient temperature for 30 minutes. Crystallization then began and was allowed to proceed for 10 minutes. Filtration provided 564 mg of a yellow solid. Recrystallization from ethanol provided 197 mg of 9-cis retinoic acid (m.p. 187-189° C, ethanol), 5% yield. Reequilibration of the mother liquors under the above conditions provided 177 mg of additional material.