JPS6252736B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula (wherein A is either a simple aryl group or an aryl group substituted with an electropositive or electronegative group, provided that A does not contain a ketone or aldehyde group) It relates to a new, easy, economical and therefore industrially effective method for the production of. Furthermore, in particular, the method of the present invention allows A to

[Formula] and

Manufacture of the compound () of the formula, a substance already widely known in the pharmaceutical field as an anti-inflammatory, analgesic and antipyretic agent and marketed as Naproxen (2018) and Flurbiprofen (2009), respectively. Therefore, it is industrially useful. Due to the importance of said substances in the pharmaceutical field, many synthetic methods have been proposed for their production. Most of these are purely theoretical synthetic methods, and only a small number of them have been implemented in practice. The synthesis method currently most widely used in industry consists of Darzens condensation of chloro-ethyl acetate with the corresponding methyl-aryl ketone, followed by hydrolysis and decarboxylation of the resulting epoxy acid ether. Finally, the aldehyde undergoes controlled oxidation to form the acid. Therefore, this is a four-step synthesis method with relatively low overall yield;
In particular, the initial Dalzens condensation step and the final controlled oxidation step are quite difficult to carry out. A new and highly industrial process has now been found for the preparation of compounds of formula (), in particular () and (), and this is the object of the present invention. Compared to the known best methods mentioned above, this new process has the advantage that it consists of only two stages, each stage being carried out industrially under moderate conditions and therefore without particular operational difficulties. Furthermore, all of these stages provide high yields of reaction products with respect to the converted materials, while unconverted starting materials and used catalyst can be recovered and recycled in an economically advantageous manner. The new process consists essentially of the following steps: (A) reacting a methyl-aryl ketone with chloroform or bromoform in the presence of an alkaline hydrate and a phase transfer catalyst according to the following reaction scheme; (wherein A is an aryl group as defined above, and
is Cl or Br, and Me is K or Na) (B) Both α-aryl lactic acid and α-aryl crotonic acid obtained as a mixture are reduced with concentrated HI according to the reaction formula below to obtain a high yield. Obtaining the desired α-arylpropionic acid, As mentioned above, step (A) is a quaternary ammonium salt,
It is carried out in the presence of a phase transfer catalyst selected from the group consisting of quaternary phosphonium salts, quaternary arsonium salts and corona ethers. Suitable catalysts include triethylbenzylammonium chloride, tetrabutylammonium chloride, triethylcetylammonium chloride, triphenylbenzylphosphonium chloride, triphenylbenzylarsonium chloride, dibenzo-18-corona-6 and 18-corona- 6 can be given. The method is successfully carried out using NaOH or KOH as the alkaline base. However, potassium is preferred. This is because the potassium salt is less soluble in the solvent used in the catalyst recovery step and is therefore more easily separated. Chloroform or bromoform are also commonly used. However, it should be noted that if chloroform is used, LiCl must be used as cocatalyst to obtain good yields. LiCl may be replaced with other soluble Li salts such as Li ₂ SO ₄ , Li ₂ CO ₃ and the like. However, in terms of yield, LiCl
It is always advantageous to operate in the presence of Methyl-aryl ketones and chloroform or bromoform react in nearly stoichiometric proportions. In all cases, the conversion of ketones is ephemeral (less than 60%), but the unreacted ketones are recovered and recycled with a yield of 90-95%, which results in extremely high yields of the final product calculated as converted ketones. It is about 70-90%. The ratio of the two acids produced in step (A), α-aryl lactic acid and α-aryl crotonic acid, depends on the nature of the aryl group A. For example, if A , the product obtained at this stage is essentially all hydroxy acid, whereas A is , the amount of unsaturated acid is 20 and 20 of the total product.
Between 30% and 30%. In any case this aspect of the reaction can be ignored. This is because α-aryl lactic acid and α-aryl crotonic acid are HI under the same conditions in the next step.
This is because all of them are converted into α-arylpropionic acid in high yields by reacting with. However, for a reaction that selectively converts a ketone in a mixture of two acids without producing substantial by-products, the temperature of the reaction mixture should be between 0° and 5°C until the end of the reaction. must be preserved. The phase transfer catalyst is 0.1:1 to 0.1:1 for the first ketone.
It is added into the reaction mixture in a molar ratio of 0.3:1.
The Li salt cocatalyst is added in a molar ratio of 1:1 to 1.5:1 with respect to the ketone. A large excess of alkaline base is used such that the concentration in the aqueous phase does not fall below 40% by weight. The acid mixture is reduced with concentrated HI in glacial acetic acid (B)
The stage is carried out at a temperature between 60° and 70°C. HI is used in stoichiometric proportions or in excess of up to 10% with respect to the mixture of acids to be reduced. Unreacted HI and product I ₂ are recovered in good yield. The reduction yields for the initial acid mixture are 50 and 85
%. Therefore, the overall yield of α-arylpropionic acid of formula ( ) for the first converted methyl-aryl ketone is between 35 and 77-78%. In order to make the process of the invention easier to reproduce and to explain in more detail the operation for recovering unreacted materials, non-limiting examples are given below. Example 1 (A) 90 g of KOH dissolved in 100 ml of H ₂ O are placed in a three-necked flask equipped with a stirrer, thermometer and feeding funnel. Reduce the temperature to 0°C, then add 50ml
2.5 g LiCl, 7 g triethylbenzylammonium chloride and 50 g 2 dissolved in CHCl ₃
- Add methoxy-6-acetonaphthene.
Stir the mixture vigorously and slowly add 77.7 g of _CHBr3 . The reaction mixture was heated between 0° and 5°C for 10
Hold for ~15 hours, then increase the temperature to 25 °C while stirring the entire mixture for 24 hours. The mixture is diluted with 1000 ml of ether, then shaken and the two layers are separated. Remove the ether phase while reducing the aqueous phase to 30%
Acidify with H ₂ SO ₄ to pH 2. The oily layer was separated and dissolved in _a 10% aqueous solution of _Na2CO3 , then concentrated.
Acidify with HCl to PH1. After extraction with ether, separating the ether phase and removing the solvent, 26g
A product is obtained, which is confirmed to be only 2-methoxy-6-naphthyl lactic acid by 1 Hn.mr analysis. 20 g of 2-methoxy-6-acetonaphthene are recovered from the previously removed ether phase and can be recycled. The yield of dimethoxy-6-naphthyl lactic acid is therefore 70% based on converted material. After separation of the oily layer containing 2-methoxy-6-naphthyl lactic acid, LiCl and triethylbenzylammonium chloride are recovered from the residual aqueous solution. (B) Dissolve 26 g of 2-methoxy-6-naphthyl lactic acid in 150 ml of glacial acetic acid in a three-necked flask equipped with a reflux condenser, stirrer and thermometer and add 50 ml of 57
Add %HI (d=1.71). The mixture is stirred at 65° C. for 5-6 hours, after which time the reaction appears to be complete. Cool the mixture, dilute with _H2O ,
Neutralize to pH 6 and reduce iodine with excess Na ₂ SO ₃ . The mixture is then extracted with ether and the ether extract is evaporated to dryness. 10% residue
Dissolve in Na ₂ CO ₃ solution and then extract with ether. Evaporation to dryness and crystallization from isopropyl ether give 20 g of 2-methoxy-6-propionic acid, melting point 155-158°, in the ether phase. The yield in step (B), which involves the reduction of 2-methoxy-6-naphthyl lactic acid, is 84%, and the overall yield of the process is about 60% in terms of converted 2-methoxy-6-acetonaphthene. A similar example uses tetrabutylammonium chloride, triphenylbenzylphosphonium chloride and triphenylbenzylarsonium chloride as catalysts in step (A), and instead of ethyl ether, benzene, chloroform and methylene chloride are used. The steps were separated using one and repeated. The overall yield was between 35 and 60%. Example 2 (A) 100 g of KOH dissolved in 100 ml of H ₂ O are placed in a three-necked flask equipped with a stirrer, thermometer and feed funnel. Lower the temperature to 0℃ and add 30ml
13 g of LiCl and 7.5 g of triethyl-benzylammonium chloride dissolved in CHCl ₃ are added. With continued stirring, 56 g of 2-fluoro-4-acetyldiphenyl dissolved in 50 ml of _CHCl3 are added. 80 g of CHBr ₃ are added while keeping the temperature between 0° and 5° C. and with constant stirring. After 15 hours the temperature is raised to 25° C. and the mixture is allowed to react for a further 24 hours with stirring. dilute with water,
Extract with ether. The ether phase is removed while the aqueous phase is acidified with 30% H ₂ SO ₄ to a pH of 2. Separate the oily layer and dissolve in _a 10% aqueous solution of _Na2CO3 . When acidified with concentrated HCl to a pH of 1,
The crystalline product is separated and recrystallized from ether to give 24 g of 2-fluoro-diphenyl-4-lactic acid. 26 g of 2-fluoro-4-acetyldiphenyl are recovered from the previously removed ether phase and can be recycled. LiCl and triethylbenzylammonium chloride are recovered from the aqueous phase remaining after separation of the oily phase containing 2-fluoro-diphenyl-4-lactic acid. The yield of 2-fluoro-diphenyl-4-lactic acid is 66% based on the initial methyl-aryl ketone converted. (B) 140 ml of glacial acetic acid and 24 g of 2-fluoro-diphenyl-4-lactic acid are placed in a three-necked flask equipped with a stirrer, thermometer and reflux condenser. Heat the solution to 60 °C with stirring and add 57% of 50 ml
Add HI (d=1.71). The mixture is heated to 65° C. for 6 hours under constant stirring. Cool and 600ml
Dilute with _H2O , neutralize to PH 5-6 and reduce _iodine with excess _Na2SO3 . The mixture is extracted with ether and the ether phase is evaporated to dryness, giving 20 g of 2-fluoro-diphenyl-4-propionic acid with a melting point of 109 DEG C. The reduction yield obtained in this step (B) is 89%, with 2-fluoro-diphenyl-4- for the converted 2-fluoro-4-acetyl-diphenyl.
The overall yield of propionic acid is about 59%. A similar example uses triethylcetylammonium chloride or dibenzo-18-corona-6 as the catalyst in step (A) and salt instead of LiCl.
_Repeated with _{Li2SO4 and Li2CO3} . The yields obtained were between 40 and 59%.

Claims (1)

[Claims] 1 formula (wherein A is selected from the group consisting of [formula] and [formula]) In the production of α-arylpropionic acid represented by the _formula ) is a methyl-aryl ketone of formula CHX ₃ (where,
X is Cl or Br. ) in the presence of an alkaline hydrate and a phase transfer catalyst at a temperature between 0 and 5 °C, the reaction (wherein A and X are as defined above,
Me is an alkali metal. ) to produce aryl fatty acids at 60°C and 70°C.
By HI in glacial acetic acid at a temperature between A method for producing α-arylpropionic acid, which comprises reducing the α-arylpropionic acid. 2 reacting the methyl-aryl ketone with the compound CHX ₃ in the presence of a cocatalyst consisting of a soluble Li salt,
Method of Section 1. 3 The phase transfer catalyst is a quaternary ammonium salt, a quaternary
2. The method of claim 1, wherein the salt is selected from the group consisting of class arsonium salts, corona ethers, and quaternary phosphonium salts.