Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C253/00—Preparation of carboxylic acid nitriles
  • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/275—Nitriles; Isonitriles
  • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C253/00—Preparation of carboxylic acid nitriles
  • C07C253/32—Separation; Purification; Stabilisation; Use of additives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C255/00—Carboxylic acid nitriles
  • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
  • C07C255/24—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton
  • C07C255/26—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton containing cyano groups, amino groups and singly-bound oxygen atoms bound to the carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C255/00—Carboxylic acid nitriles
  • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
  • C07C255/24—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton
  • C07C255/27—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton containing cyano groups, amino groups and doubly-bound oxygen atoms bound to the carbon skeleton

Definitions

• the invention relates to a process for the preparation of 2-cyano-3-hydroxy-N- (phenyl) but-2-enamides from 2-cyano-N- (phenyl) acetamide, in particular the preparation of 2-cyano-3-hydroxy N - [(4-trifluoromethyl) -phenyl] but-2-enamide from 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide.
• 2-cyano-3-hydroxy-N- [phenyl] but-2-enamides can be prepared from 2-cyano-N- (phenyl) acetamide in the presence of acetic anhydride and sodium hydroxide.
• the invention therefore relates to a process for obtaining the compound of the formula I.
• R1 is a) -CF3, b) -0-CF 3, c) -S-CF 3, d) -OH, e) -N0 2 f) halo, g) benzyl, h) phenyl, i) -O-phenyl, k) -CN,
• R 2 represents a) - (C 1 -C 4 ) -alkyl, b) halogen or c) represents a hydrogen atom,
• R1 and R2 are as defined above, in the presence of at least one base, reacting acetic anhydride and at least one solvent and then isolating the compound of formula I formed.
• the invention further relates to a process for obtaining the compound of formula III
• the procedure is such that initially the compound of the formula II or (2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide) is introduced into a solvent and the resulting solution or suspension is cooled , Thereafter, the addition of aqueous sodium hydroxide and acetic anhydride and the resulting reaction mixture is stirred or shaken with cooling.
• the compound of formula I is precipitated with an acid.
• the isolation of the compound of formula I is carried out for example by crystallization or extraction, for example with ethyl acetate or toluene.
• the crystallization is promoted by cooling the suspension or further evaporating the solvents.
• solvent are, for example, water, organic solvents, for example: ketonic solvents such as acetone, methyl ethyl ketone or methyl isobutyl ketone; halogenated hydrocarbons such as dichloromethane;
• Alcohols such as ethanol, isopropanol or n-butanol;
• Ethers such as diisopropyl ether, diethoxymethane or diethylene glycol dimethyl ether;
• Hydrocarbons such as toluene; Esters, such as ethyl acetate; aprotic solvents such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide or N-ethylpyrrolidinone or
• Phase transfer catalysts such as quaternary ammonium or phosphonium salts, for example dimethylditetradecylammonium bromide, benzyltriethylammonium chloride, Alliquat ® 336 (3-methyltrioctylammonium chloride), tetrabutylammonium hydrogen sulfate, or tetrabutylphosphonium chloride;
• bases is understood as meaning alkali metal hydroxides, for example sodium hydroxide or potassium hydroxide, caustic soda in solid form or in the form of alkalis of different concentrations, alkali metal hydrides and alkaline earth metal hydrides, for example sodium hydride, calcium hydride, amides, for example sodium amide, alcoholates, for example sodium methoxide, potassium tert-butoxide.
• organometallic compounds for example n-butyllithium, or amines, for example diethylisopropylamine, or mixtures of the abovementioned inorganic bases
• halogen refers to fluorine, chlorine, bromine and iodine understood.
• - (C-j-C / jJ-alkyl are hydrocarbon radicals such as methyl, ethyl, propyl, n-butyl or
• Suitable acids are, for example, hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid or mixtures of the acids.
• the amount of solvent used is generally from 3 kg to 11 kg per kg of the compound of the formula II or IV, preferably from 4 kg to 6 kg.
• the reaction time is generally between a few minutes and 24 hours, preferably 1 to 3 hours, depending on the composition of the mixture and the selected temperature range.
• the reaction temperature is from -5 ° C to 50 ° C, preferably from 0 ° C to 30 ° C, especially 10 ° C.
• the residual content of the starting substrate of the compound of the formula II or 2-cyano-N- (4-trifluoromethyl-phenyl) -acetamide could be determined in isolated 2-cyano-3-hydroxy-N - [(4-trifluoromethyl) -phenyl] but-2-one. enamide are reduced below a level of 0.5%.
• the starting material for the reaction according to the invention can be prepared by processes known from the literature, for example DE 1 900947.
• the process product is biologically active and is suitable, for example, for the treatment of rheumatoid arthritis or multiple sclerosis.
• Advantageous in the process according to the invention are the very short reaction times, the omission of additional purification steps, the high yields and the high purity of the product produced.
• Advantage of the method according to the invention is the substantially complete reaction to the compound of formula I or 2-cyano-3-hydroxy-N - [(4-trifluoromethyl) phenyl] but-2-enamide and a total by-product content of less than 1%.
• Triethylamine Adjust 5 mL with H 3 P0 4 85% to pH 6.0 5
• Test solution Dissolve 12.5 mg of the substance in acetonitrile R to 25 mL.
• FN ' peak area of the respective by-product in the chromatogram of the test solution
• ⁇ F sum of all peak areas in the chromatogram of the test solution except for the injection peak
• PTC phase transfer catalyst
• Example 9 In a 200 ml four-necked flask, 9.1 g of 2-cyano-N- (4-trifluoromethyl-phenyl) acetamide were weighed and then suspended by addition of 49 ml of methyl isobutyl ketone (slightly yellow thin suspension), which was then cooled to 10 ° C. At this temperature, 17.8 ml of 33% NaOH was added directly from the graduated cylinder. The temperature rose to 12 ° C and there was a difficult to stir kremepme suspension. This was vigorously stirred for 10 minutes. Thereafter, 9.7 ml of acetic anhydride are added dropwise at 7 to 12 ° C within 1 h and 20 min.
• the mixture was stirred for 50 minutes and cooled to 3 to 5 ° C. Then 11.5 ml of water were added dropwise within 10 min at this temperature, the mixture had a pH of 7.1. Subsequently, 16 ml of 37% HCl were added dropwise within 1 h, so that at a constant temperature, a pH of 1.1 was reached. After further stirring for 25 minutes, the pH was still at 1.1 (cream-colored, non-homogeneous stirrable suspension, already after about 7 ml of HCl). Within the next 20 minutes, 47.5 ml of water were added dropwise, the temperature rising to 10 ° C. The pH rose to 1.7. The mixture was then stirred for 40 min.

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• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

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• 2003
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