Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
  • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
  • C07C51/353—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by isomerisation; by change of size of the carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
  • C07C51/41—Preparation of salts of carboxylic acids
  • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part

Definitions

• This invention relates to a novel synthetic approach to compounds of Formula I.
• Phenylbutyric acid and its pharmaceutically acceptable derivatives are particularly preferred targets of the present invention.
• Sodium phenylbutyrate has been used extensively for the treatment of urea cycle disorders (Batshaw et al., Brusilow et al. (Ped. Research), Brusilow et al. (New Eng. J. Med.), Finkelstein et al., Maestri et al., Redonnet-Vernhet et al., Rowe et al.).
• Phenylbutyrate derivatives have also shown promising pharmaceutical properties in the treatment of sickle cell anemia (Collins et al., Dover et al. (New Eng. J. Med.), Dover et al.
• cystic fibrosis (Bradbury et al., Loffing et al.), AIDS (Roberts et al , and several types of cancer (Carducci et al., Darmanun et al., Englehard et al., Gorospe et al.).
• phenylbutyrate derivatives have been prepared by the Arndt-Einstert reaction, using diazomethane with silver oxide and sodium thiosulfate (J. Chem. Soc, 1997-99 (1938)).
• thianapthene-2-acetic acid and thianapthene-3 -acetic acid have been used to prepare ⁇ -phenylbutyric acid (J. Am. Chem. Soc, 70, 3768 (1948)).
• the Gignard reagent, benzyl magnesium chloride has also been used in the synthesis of phenylbutyric acid, resulting in a yield of 16.1 % (J. Am. Chem. Soc, 71, 2807-2808 (1949)).
• One aspect of the present invention is a method of preparing a compound of Formula I:
• the method comprises the steps of, a) reacting a compound of Formula II;
• a particularly suitable compound of Formula IV is sodium hydroxide.
• the reaction of a compound of Formula I with the compound of Formula II is conducted in the presence of a catalyst.
• catalysts are Lewis acids, including, but not limited to aluminum chloride, zinc chloride, iron chloride, stannous chloride, boron tribromide, boron trifluoride, or sulfuric acid.
• a particular aspect of the present invention is a method of preparing a 4-phenylbutyric acid by reacting benzene with butyrolactone.
• R is independently selected from hydrogen, halo, C1 -C4 alkyl, alkenyl, alkynyl, C3-C6 cycloalkyl, C1 -C4 alkoxy, alkenoxy, alkynoxy; and X is hydrogen, an alkali metal cation, an ammonium or a substituted ammonium.
• the method of the present invention comprises the steps of a) reacting a compound of Formula II;
• a particularly preferred compound of Formula II is benzene. According to one embodiment of the present invention, the reaction is conducted in a solvent. According to an alternative embodiment, the compound of Formula II is itself the solvent for the reaction.
• a catalyst may be used to facilitate the reaction of the compound of Formula II with the compound of Formula III.
• One preferred class of catalysts is Lewis acids. Examples of particularly preferred catalysts are aluminum chloride, zinc chloride, iron chloride, stannous chloride, boron tribromide, boron trifluoride, and sulfuric acid.
• the catalyst is added to a mixture of a compound of Formula II and an appropriate solvent or to neat compound of Formula II, if no solvent is used.
• This mixture is maintained, preferably with stirring, at a temperature between about -80 °C and the boiling point of the solvent at ambient pressure.
• the mixture is maintained between 0 °C and the boiling point of the solvent.
• the mixture of a compound of Formula II and catalyst can be stirred for a time ranging from several seconds to several days before a compound of Formula III is added to the mixture.
• the mixture of a compound of Formula II and catalyst is stirred for a time ranging from about 1 min to about 30 min before a compound of Formula III is added.
• the compound of Formula III can be added to the mixture of a compound of Formula II and catalyst as a neat reagent, or can be added as a solution in an appropriate solvent.
• the compound of Formula III is added dropwise, in small aliquots, or as a large portion.
• the reaction mixture is maintained, preferably with stirring, at a temperature between about -80 °C and the boiling point of the solvent at ambient pressure.
• the mixture is maintained between 0 °C and the boiling point of the solvent.
• the reaction mixture can be so maintained for a time ranging from a few seconds to about 24 hr.
• the reaction mixture is maintained about 10 min to about 180 min, more preferably from about 60 min to about 120 min.
• the reaction mixture can be quenched via the addition of a quenching agent.
• Suitable quenching agents are of Formula IV:
• Quenching agent can be added neat or as a solution in an appropriate solvent.
• a particularly preferable quenching agent is an aqueous solution of base.
• a preferred base is sodium hydroxide.
• Another preferred quenching agent is a mixture of a solution of aqueous base and ice.
• the quenched solution can be maintained at a temperature from about 0 to about 50 °C for a time ranging from a few minutes to about 10 hr, preferably from about 1 hr to about 3 hr.
• the pH of the solution can be maintained from about 6.5 to about 10, preferably from about 9 to about 9.5.
• the pH of the solution can be further raised by the addition of base.
• the quenched solution can be purified by filtration to remove any particulate that can be present.
• the quenched solution can be further purified by contacting it with an organic solvent to extract remaining starting materials, side products, and impurities. Examples of suitable extraction solvents include chloroform, dichcloromethane, trichloromethane, carbontetrachloride, and diethyl ether.
• the product can be precipitated from the aqueous solution by the addition of acid.
• the product can be isolated by filtration, or extracted into a suitable organic solvent. If the product is extracted into an organic solvent, it can be recovered
• Powdered aluminum chloride (200 g) was added to benzene (400 g) and stirred for 10 min at 50 °C.
• Butyrolactone (86 g) was added in small portions. The temperature was maintained between 50 and 60 °C for 90 min and then the reaction mixture was added, with stirring, to a mixture of ice and 5 % sodium hydroxide. The temperature was maintained below 35 °C and the pH was maintained between 9 and 9.5 for 2 hr. The mixture was filtered under vacuum. Phenylbutyric acid was precipitated from the aqueous fraction by the addition of ice and hydrochloric acid. Crude (93.7 % - 94.3 %) 4-phenylbutyric acid was isolated by vacuum filtration. Crude 4-phenylbutyric acid was purified by vacuum distillation (120-125°C, 1mm Hg).
• the acid was dissolved in 5 % sodium hydroxide and agitated.
• the acid was dissolved in 5 % sodium hydroxide and agitated with carbon tetrachloride for 15 minutes.
• Carbon tetrachloride was removed and the 4-phenylbutyric solution was mixed with acetone, methanol and a small amount of activated charcoal for 15 minutes at ambient temperature.
• the mixture was filtered and acidified by the addition of HCI. Crystals of 4-phenylbutyric acid (81.15 % yield) were isolated and dried by lyophilization. HPLC analysis indicates 99.87 % purity of the final product.

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• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
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