KR810000954B1 - Process for the preparation of 2-arylpropionic acid - Google Patents

Abstract

2-Arylpropionic acids were resolved with chiral amine in inert diluent at>=80oC, by isomerizing the more insol. isomer of 2-arylpropionic acid. Thus, flurbiprofen was treated in petroleum distillate b. 125oC with (-)-α-methylbenzyl amine, at 125oC for 72hr under N, the salt recrystallized from isopropanol, and cleaved with acid to give 2-(2-fluoro-4-biphenylyl)propionic acid[α D + 41o.

Description

Preparation of optically active 2-arylpropionic acid

The present invention relates to a process for preparing optically active 2-arylpropionic acid.

Several types of 2-arylpropionic acid have been found to have very valuable biological activity, in particular anti-inflammatory.

Conventional decomposition methods involving the separation of mixtures of salts, which are the isomers of acids, are undesirable because they require racemization of the enantiomers that are unnecessary to increase the various crystallization steps and yields.

Enantiomers of 2-arylpropionic acid can be obtained from mixtures of salts which are porous isomers by a simple method involving fewer steps than conventional decomposition methods.

The present invention relates to a process for increasing the yield of enantiomers of 2-arylpropionic acid, characterized by heating a mixture of an inert organodiluent and 2-arylpropionate with a chiral organonitride group at a temperature of at least 80 ° C, wherein the base And the diluent has a solubility of 0.1 to 10% w / v in the diluent at the operating temperature of the racemic acid, and in this method one optical isomer consisting of salt is converted into the enantiomer because the salt is not dissolved in the diluent. It is possible to recover salts which can increase the yield of the enantiomers of the acid component. 2-arylpropionic acid is generally a compound in which the aryl group is of the following structure.

는 같거나 다르며 알킬, 예를들면 메틸, 아르알킬, 예를들면 벤질; 사이클로알킬, 예를들면 탄소수 3 내지 7개의 사이클로알킬; 및 특히 사이클로헥실; 알킬 치환된 사이클로알킬, 예를들면 모노메틸 및 모노에틸 치환된 사이클로헥실; 아릴, 예를들면 페닐 및 알킬, 바람직하기로는 C₁-C₄알킬, 알콕시, 바람직하기로는 C₁-C₄알콕시, 알킬티오, 바람직하기로는 C₁-C₄알킬티오, 시아노 또는 할로겐으로 1 또는 2개가 치환된 페닐; 알콕시, 바람직하기로는 C₁-C₄알콕시; 사이클로알콕시, 예를들면 사이클로헥실옥시; 아릴옥시, 예를들면 페녹시 및 할로겐원자, 특히 불소 및 염소로하나 또는 두개가 치환된 페녹시; 알킬티오, 바람직하기로는 C₁-C₄알킬티오; 아르알킬티오; 사이클로알킬티오; 아릴티오, 예를들면 페닐티오; 아릴카보닐, 예를들면 벤조일 및 테노일; 사이클로알케닐, 예를들면 사이클로헥세닐; 트리플루오로메틸; 할로겐, 예를들면 불소 또는 염소; 푸릴; 피롤리디닐; 피롤일; 피롤리닐; 티에닐; 또는 1-옥소-2-이소인돌리닐으로 부터 선택되며, 두개의

그룹은 함께 카복실릭 또는 복소환링을 형성하며, 이 링은 방향족일 수가 있으며 치환될 수 있다. 벤젠과 함께 두개의 그룹이 형성한

그룹의 예로는 나프틸 및 치환된 나프틸, 특히 알콕시 나프틸, 플루오로에닐, 임의로 P-클로로페닐, 카바졸일, 임의로 염소에 의해서 치환된 벤족사졸일, 임의로 페닐로 치환된 벤조티아졸일, 임의로 알콕시 및 알킬로 치환된 페노티아지닐, 임의로 페닐로 치환된 벤조푸라닐, 벤조피라노 [2,3-b]-피리디닐, 및 9-옥산테닐 등이 있다.Where n is an integer from 1 to 4, preferably 1 or 2,

Are the same or different and are alkyl, eg methyl, aralkyl, eg benzyl; Cycloalkyl, such as cycloalkyl having 3 to 7 carbon atoms; And especially cyclohexyl; Alkyl substituted cycloalkyl such as monomethyl and monoethyl substituted cyclohexyl; Aryl, for example phenyl and alkyl, preferably C ₁ -C ₄ alkyl, alkoxy, preferably C ₁ -C ₄ alkoxy, alkylthio, preferably C ₁ -C ₄ alkylthio, cyano or halogen Phenyl substituted with one or two; Alkoxy, preferably C ₁ -C ₄ alkoxy; Cycloalkoxy such as cyclohexyloxy; Aryloxy, for example phenoxy and phenoxy substituted with one or two of the halogen atoms, in particular fluorine and chlorine; Alkylthio, preferably C ₁ -C ₄ alkylthio; Aralkylthio; Cycloalkylthio; Arylthio, such as phenylthio; Arylcarbonyls such as benzoyl and tenoyl; Cycloalkenyl such as cyclohexenyl; Trifluoromethyl; Halogen, for example fluorine or chlorine; Furyl; Pyrrolidinyl; Pyrroleyl; Pyrrolinyl; Thienyl; Or 1-oxo-2-isoindolinyl, two

The groups together form a cyclic or heterocyclic ring, which ring may be aromatic and may be substituted. Formed by two groups with benzene

Examples of groups include naphthyl and substituted naphthyl, in particular alkoxy naphthyl, fluoroenyl, optionally P-chlorophenyl, carbazolyl, benzoxazolyl optionally substituted by chlorine, benzothiazolyl optionally substituted by phenyl, Phenofiazinyl optionally substituted with alkoxy and alkyl, benzofuranyl optionally substituted with phenyl, benzopyrano [2,3-b] pyridinyl, 9-oxanthenyl and the like.

An aryl group instead of a substituted phenyl group may be a heteroaryl group which may be substituted by said group, for example benzothiazolyl, pyrroylyl, or thienyl.

Particularly preferred compounds are those in which the aryl group is of the structure

Wherein m is 0 or 1 and R ₂ , R ₄ and R ₅ are the same or different and are selected from hydrogen, chlorine, fluorine, hydroxy and methoxy. Especially preferred are compounds in which m is zero.

Other preferred are aryl groups having 2- (6-methoxy-2-naphthyl), n is 1 and is in the 3-position and the benzoyl is phenoxy, or is 4- and is 1-oxo-2- Isoindolinyl compound.

The invention is applicable to obtaining 2- (2-fluoro-4-biphenylyl) propionic acid, in particular the (+)-isomer.

The invention can be carried out using racemic 2-arylpropionic acid, two enantiomers of 2-arylpropionic acid or a mixture containing two enantiomers. Depending on the particular salt used, it is possible to increase both enantiomers of the acid. The use of racemic acid results in the formation of a salt containing one of the enantiomers of the acid. Since the plant does not convert to salts which are enantiomers of the acid of this substance, it is desirable in all cases to treat the obtained material by conventional recrystallization or other purification methods.

Preferred acids can be recovered from the salt by conventional methods, for example by acidifying the salt with a dilute inorganic acid and then extracting the liquid mixture with a suitable organic solvent. Recrystallization of the acid can further enhance optical purity.

It is preferable to select a base according to the 2-arylpropionic acid. Diluents are selected according to 2-arylpropionic acid and base.

Generally these bases are α-monosubstituted alkylamines, preferably as α-monosubstituted ethylamines, in particular α-phenylethylamine, the phenyl ring is alkyl, for example C ₁ -C ₄ alkyl, especially isopropyl , Halogen, for example chlorine or fluorine, alkoxy, for example C ₁ -C ₄ alkoxy, in particular one or two or more substituents such as methoxy. Particularly preferred bases are (-)-α-methylbenzylamine and (-)-α- (2-methoxyphenyl) ethylamine. Other suitable bases include (-)-α- (4-isopropylphenyl) ethylamine, (-)-α- (3-chlorophenyl) ethylamine, (-)-α- (4-fluorophenyl) ethyl Amine, (-)-α- (3-fluorophenyl) ethylamine, (-)-α- (2-fluorophenyl) ethylamine, (-)-α- (2-chlorophenyl) ethylamine, ( -)-α- (2-methoxyphenyl) ethylamine, (-)-α- (2,6-dimethoxyphenyl) ethylamine, and (+)-α-cyclohexylethylamine.

Preferably the mixture of diluent and salt is heated at a temperature of 90 to 150 ° C, for example 95 to 130 ° C. Heating is generally carried out for at least 1 hour, for example 8 to 96 hours.

The ratio of salt to diluent is preferably from 1: 1 to 1: 100 W / V, for example from 1: 5 to 1:15 W / V. The solubility of the racemic acid salt in the diluent under operating temperature is preferably from 0.5 to 2% W / V.

50 to 98% (W / V), for example 80 to 95% of salt, are not dissolved in the diluent at the operating temperature. Inert diluents are liquid at the temperature at which the mixture is heated and consist of one or more organic compounds. Diluents are generally of low polarity and consist of one or more hydrocarbons, preferably of a mixture of aliphatic hydrocarbons, having a boiling point in the range of 110 to 135 ° C. Up to 1% of the polar material may be included in the diluent, and such a diluent that can proceed the reaction while refluxing is preferred. It is desirable to heat in an inert atmosphere such as nitrogen to prevent the formation of by-products. The present invention is illustrated in the following examples where the flubipropene is (±) -2 (2-fluoro-4-biphenylyl) propionic acid. Unless stated otherwise, specific light was measured at ambient temperature with a concentration of 1% W / V in ethanol.

[Examples 1 to 31]

The 2-arylpropionic acid and one or more liquid organic compounds are heated with stirring of the various mixtures. Once the heating is complete, the salt obtained by filtration of the hot mixture with a Buchner funnel heated with steam is washed with a hot diluent and then dried in vacuo. Acidify with dilute hydrochloric acid or sulfuric acid and extract the acid mixture with ether. The ether extract is washed with water and evaporated to dryness to yield 2-arylpropionic acid, which differs in optical activity from the acid of the salt of the starting material.

The detailed results of the various embodiments are described in Table 1 below.

TABLE 1

Example 32

The solution is obtained by mixing flubiprofen (4.75 kg) with a petroleum fraction (48 L) with a boiling point of 125 ° C. and stirring under nitrogen atmosphere. To this was added (-)-α-methylbenzylamine in the same petroleum (23 L) with stirring and the solution was heated under reflux for 78 hours under nitrogen atmosphere. The internal temperature is 125 ° C. The mixture was filtered, the obtained salt was washed with hot petroleum and dried to give (-)-α-methylbenzylamine salt of 2- (2-fluoro-4-biphenylyl) propionic acid in 76% yield. Acidification of this small amount yields 2- (2-fluoro-4-biphenylyl) propionic acid with [α] _D being + 33 °. Acidification and the remaining residue are recrystallized with isopropanol and acidified to yield 2- (2-fluoro-4-biphenylyl) propionic acid of [α] _D , +41. The recrystallized residue (4.3 kg) is mixed with light oil (boiling point: 102-120 ° C., 35 L) and concentrated hydrochloric acid (1 kg) is added while stirring the water and the mixture under nitrogen atmosphere and the mixture is refluxed for 1 hour. The hot organic layer is separated, washed with water, filtered and cooled. The collected material by filtration was washed with hexane and dried to obtain 2- (2-fluoro-4-biphenylyl) propionic acid having 98% optical purity of [α] _D , + 43.7 °.

After the solids and salts recovered from the mother liquor are heated together for 72 hours by isopropanol recrystallization of the salt and petroleum crystallization of the acid, the filtrate is all recycled to treat a greater amount of flubiprofen.

Example 33

One minute of (-)-α-methylbenzyl ammonium salt of flubiprofen is mixed with case (melting point 40-60 ° C.) and heated for 72 hours in a closed autoclave. The mixture was then cooled, filtered and the resulting salt was washed with light oil and filtered in vacuo to give [a] _D , 2- (2-fluoro-4-biphenylyl) propionic acid at + 21.9 ° in 93.5% yield. Obtained.

Claims (1)

The mixture of the inert organodiluent and the 2-arylpropionic acid salt is heated together with the enantiomer of the chiral organic nitrogen base at a temperature of at least 80 ° C., and the solubility of the racemic salt is from 0.1 to 10% W / V in the diluent at this temperature and the 2-aryl propionic acid The salt is insoluble in the diluent and thus converts one optical isomer composed of the salt to its enantiomer, thereby increasing and recovering the yield of the desired enantiomer of the 2-arylpropionic acid, which is optically active 2-arylpropionic acid. Method for the preparation of enantiomers.