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Preparation of Amides of Retinoic Acid Via Mixed Anhydride and Mixed Carbonate Intermediates

a technology of retinoic acid and amides, which is applied in the preparation of carboxylic acid amides, chemistry apparatus and processes, and organic chemistry, etc. it can solve the problems of unsuitable scale-up methods and achieve the effect of simple, scalable and less expensive processes

Inactive Publication Date: 2008-09-11
CEDARBURG PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention provides a process for preparing amides of retinoic acid, such as fenretinide, using simpler and scalable methods. The process involves reacting retinoic acid with a compound having the formula R-X, wherein R is alkyl or aryl, to produce an intermediate with the formula R-X', which is then reacted with 4-aminophenol to produce the amide of retinoic acid. The process can be carried out at temperatures between 0-10°C and is preferably performed in the presence of a solvent or a base. The invention also provides a compound having the formula R-X', wherein R is alkyl or aryl, and various isomers thereof. The process can be used to produce various forms of the amide of retinoic acid.

Problems solved by technology

However, these methods can be unsuitable for scale-up and therefore, there is a need for simpler, scaleable, and less expensive processes for preparing amides of retinoic acid such as fenretinide.

Method used

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  • Preparation of Amides of Retinoic Acid Via Mixed Anhydride and Mixed Carbonate Intermediates
  • Preparation of Amides of Retinoic Acid Via Mixed Anhydride and Mixed Carbonate Intermediates
  • Preparation of Amides of Retinoic Acid Via Mixed Anhydride and Mixed Carbonate Intermediates

Examples

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example 1

Preparation of the t-Butyl Mixed Anhydride of Retinoic Acid

[0029]To a 100 milliliter round bottom flask was added 2.00 grams (6.67 mmol) of retinoic acid and 40 milliliters of t-butyl methyl ether. The slurry was cooled to a bath temperature of about 0-10° C. To the slurry was added 1.02 milliliters (7.40 mmol) of triethylamine via syringe over about 1 minute. Trimethylacetyl chloride (0.86 milliliters, 7.0 mmol) was then added via syringe over about 10 minutes. The bright yellow slurry was then stirred for 3 hours at a bath temperature of about 0-10° C. and then held overnight in a refrigerator. The next day the reaction mixture was filtered, the filtered solids were washed thoroughly with t-butyl methyl ether, and the filtrate was concentrated via rotary evaporation (about 35-40° C. external temperature) to give 2.84 grams of the mixed anhydride as a gold oil. The NMR and IR of the oil corresponded to the assigned structure (t-butyl mixed anhydride of retinoic acid). The presence ...

example 2

Preparation of Fenretinide Via the t-Butyl Mixed Anhydride of Retinoic Acid

[0030]To a 5-Liter 4 neck round bottom flask equipped with a mechanical stirrer, temperature probe, addition funnel, and nitrogen inlet adapter was added 100.0 grams (333.3 mmol) of retinoic acid and 1.0 liter of ethyl acetate (EtOAc). The slurry was cooled to an internal temperature of 5° C. Triethylamine (50.7 milliliters, 366 mmol) was added all at once via graduated cylinder. To the thin slurry was then added trimethylacetyl chloride (45.1 milliliters, 366 mmol) via addition funnel over 23 minutes at an internal temperature of less than 5° C. After 3.5 hours, the reaction was judged to be complete by HPLC analysis. To the bright yellow slurry of the mixed anhydride was added a thin suspension of 4-aminophenol (76.3 grams, 700 mmol) in 500 milliliters of pyridine over 30 minutes at an internal temperature of 3-5° C. After 2 hours, the reaction was judged to be complete by HPLC analysis. To the slurry was a...

example 3

Preparation of Fenretinide Using 2,2-Dimethylbutyrlchloride

[0032]To a 250 milliliter round bottom flask was charged 2.00 grams (6.67 mmol) of retinoic acid and 20 milliliters of CH3CN. The slurry was cooled to an external temperature of 0-10° C. while 1.0 milliliters of Et3N (7.3 mmol) was charged via syringe. To the slurry was added 0.96 milliliters (7.0 mmol) of 2,2-dimethylbutyrlchloride via syringe over about 10 minutes. A thick, unstirrable slurry formed. Ten milliliters of additional CH3CN was added to improve the stirring. After about 3.5 hours, the activation was judged to be complete by HPLC analysis. To the slurry was added 2.0 milliliters of pyridine via syringe. 4-aminophenol (1.53 grams, 14.0 mmol) was then added as a solid in 2 portions over about 15 minutes. After stirring for 2 hours, the reaction was held overnight in the refrigerator (about 0-10° C.). The following morning the reaction was judged to be complete by HPLC analysis. At an external temperature of 0-10° ...

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Abstract

Processes for preparing amides of retinoic acid are disclosed. Intermediates useful in the preparation of amides of retinoic acid are also disclosed. In one version of the invention, fenretinide is produced via activation of retinoic acid (tretinoin) via its corresponding mixed anhydride or mixed carbonate followed by reaction of the activated intermediate with 4-aminophenol. Other amides of retinoic acid and isomers of retinoic acid, such as the 9-cis-form or 13-cis-form can also be made by this invention.

Description

CROSS-REFERENCES TO RELATED APPLICATIONS[0001]This application is a divisional of U.S. patent application Ser. No. 11 / 715,571 filed Mar. 8, 2007.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH[0002]Not Applicable.BACKGROUND OF THE INVENTION[0003]1. Field of the Invention[0004]The invention relates to processes for preparing amides of retinoic acid. In particular, the invention provides a procedure for producing N-(4-hydroxyphenyl)retinamide (fenretinide) on a production scale. In one version of the invention, fenretinide is produced via activation of retinoic acid (tretinoin) via its corresponding mixed anhydride or mixed carbonate followed by reaction of the activated intermediate with 4-aminophenol. Other amides of retinoic acid and isomers of retinoic acid, such as the 9-cis-form (alitretinoin) or 13-cis-form (isotretinoin), are also known to have useful properties and can be made by this invention.[0005]2. Description of the Related Art[0006]Fenretinide (CAS# 65646-68-6) is cur...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07C69/618
CPCC07C231/02C07C2101/16C07C233/28C07C2601/16
Inventor CABAJ, JOHN E.HUTCHISON, JEFF J.ZELLER, JAMES R.
Owner CEDARBURG PHARMA INC
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