DK154418B - PROCEDURE FOR INCREASING THE QUANTITY SHARE OF A DESIRED ENANTIOMER OF A 2-ARYL PROPIC ACID - Google Patents

Description

DK 154413B

The present invention relates to the preparation of optically active 2-arylpropionic acids, more particularly to a method of increasing the amount of a desired enantiomer of a 2-arylpropionic acid as defined in the preamble of claim 1. Certain 2-arylpropionic acids are known to have valuable biological properties, particularly anti-inflammatory properties.

It is believed that in some 2-arylpropionic acids, the biological activity of one of the optical ions is greater than the biological activity of its enantiomer, and it is therefore desirable to find a simple method to obtain the one enantiomer. .

Conventional cleavage technique involving separation of a mixture of diastereoisomeric salts of an acid is usually very cumbersome and slow because it often requires several recrystallization steps and also racemization of the undesirable enantiomer to improve yields.

Thus, for example, British Patent Specification no.

No. 1098878 and U.S. Patent No. 3686183 to conventional resolving processes for arylalkylacetic acids. The process of the present invention is quite different from a conventional resolution technique which involves separating a mixture of diastereomeric salts of an acid, both in terms of working conditions and in terms of the technical effect obtained.

The working conditions of a conventional resolving technique involve forming a hot complete solution of the diastereomeric salts and then cooling the solution to induce fractional crystallization. In contrast, in the present process - as explained later in the specification - continuous heating is carried out, a solid phase is present all the time and the solid product can be separated from the hot liquid phase.

The technical effect obtained is described in more detail 2

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at the end of the description.

Asymmetric rearrangements are also known, but mainly from theoretical and not practical points of view. For example, in "Molecular Asymmetry in Biology" 5 by Ronald Bentley, Academic Press 1969 pp. 94-95, a theoretical explanation of asymmetric rearrangements has been given.

This thesis also states that a strongly right-turning final solution is obtained when dinitrophenic acid is dissolved in alcohol and treated with quinine, although the starting acid 10 is optically inactive and the natural alkaloid is strongly left-turning. Results were obtained suggesting that only one diastereomer was present, but all attempts to regenerate an optically active form of the diphenyl acid failed. Thus, said thesis does not describe or suggest any practical method for obtaining a desired enantiomer of a 2-arylpropionic acid.

It has now been found that a desired enantiomer of certain 2-arylpropionic acids can be obtained from a mixture of 20 diastereoisomeric salts in a simple manner in which fewer steps are generally involved than in conventional cleavage technique. The process according to the invention is characterized by the characterizing part of claim 1.

The process of the invention is particularly applicable to 2- (2-fluoro-4-biphenylyl) propionic acid and particularly to obtain the excess weight of the (+) isomer.

The process of the invention can be carried out using a racemic 2-arylpropionic acid, any 30 enantiomer of a 2-arylpropionic acid, or mixtures containing an excess weight of one of the enantiomers. Depending on the particular salt used, the process can result in an increase of one or the other enantiomer of the acid. Use of a racemic 35 acid leads to the formation of a salt containing overweight of one enantiomer of the acid. In the process, transformation of material does not happen in all cases

DK 154418B

3, salt is obtained from only one enantiomer of the acid, so it is often desirable to subject the recovered material to a minimal number, usually not above two, conventional recrystallization steps or other purification processes.

The desired acid can be recovered from the salt in a conventional manner, for example by acidifying the salt with a dilute mineral acid followed by extraction from the aqueous mixture with a suitable organic solvent portion. Recrystallization of the acid can further enhance the optical purity.

It will be appreciated that the choice of base depends on the 2-aryl propionic acid. The choice of diluent depends on the 2-aryl propionic acid and the base.

In general, the base is an α-monosubstituted alkylamine, preferably an α-monosubstituted ethylamine, in particular an α-phenylethylamine, wherein the phenyl ring may be substituted by one or more groups such as alkyl, for example alkyl and especially isopropyl; halogen such as chlorine or fluorine; alkoxy such as C 1-4 alkoxy, especially methoxy.

Particularly preferred bases are (-) - α-methylbenzylamine and (-) - α- (2-methoxyphenyl) ethylamine. Other suitable bases are (-) - α- (4-isopropylphenyl) -ethylamine, (-) - α- (3-chlorophenyl) -ethylamine, (-) - α- (4-fluorophenyl) -ethylamine, (-) - α- (3-fluorophenyl) -ethylamine, (-) - α- (2-fluorophenyl) -ethylamine, (-) - α- (2-chlorophenyl) -ethylamine, (+) - α- (2-methoxyphenyl) -ethylamine, (-) - α- (2,6-dimethoxyphenyl) -ethylamine and also (+) - α-cyclohexylethylamine.

Preferably, the mixture of the diluent and salt is heated to a temperature of 95-130 ° C.

It is preferred that the amount ratio of the salt to the diluent be from 1: 5 to 1:15 weight / volume (v / r).

Preferably, the solubility of the salt of the racemic acid in the diluent at the working temperature is 0.5-2% v / r.

Preferably, 50-98% by weight of the salt, in particular

DK 154418 B

4 80-95% undissolved in the diluent at the working temperature.

The inert diluent is a liquid at the temperature to which the mixture is heated and may consist of one or more organic compounds. Usually, the diluent has low polarity and may for example contain one or more hydrocarbons. The diluent is preferably a mixture of hydrocarbons which are predominantly aliphatic, and preferably has a boiling point in the range of 110-135 ° C. Polar compounds may be present in amounts of, for example, up to 1% in the diluent.

It is preferred that the diluent is such that the reaction can be carried out under reflux conditions.

In order to avoid by-product formation, it may be desirable for the heating to be carried out under an inert atmosphere, e.g., nitrogen.

The method according to the invention will now be elucidated in more detail below some examples; in these, the word flurbiprofen stands for (+) - 2- (2-fluoro-4-biphenylyl) propionic acid. Unless otherwise specified, specific turns are measured in ethanol at a concentration of 1% v / r and at room temperature.

Examples 1-31

Various mixtures containing an amine salt of a 2-arylpropionic acid and a diluent consisting of one or more liquid organic compounds 2g were stirred and heated. At the end of the heating, the hot mixtures were filtered through a steam-heated Buchner funnel and the salts washed with the hot diluent, dried in vacuo and acidified with thin sulfuric acid or hydrochloric acid, and the acidic mixtures extracted with ether. The ether extracts were washed with water, dried and evaporated to give 2-arylpropionic acids with a different optical activity than the acid component of the salt from 5

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the beginning of the search.

The details of the results of the various examples are shown in Table I.

5 10 15 20 25 30 35 6

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DK 154418 B

Key to Table I

2-arylpropionic acids

Al = (+) - 2- (2-fluoro-4-biphenylyl) -propionic acid = 2- (2-fluoro-4-biphenylyl) -propionic acid with Yflurbiproprot. OO / phen has [α] + = -44.7 irio, D '[αJD pa + A 4-biphenylyl) propionic acid with j or [«] D = + 8.9 ° J -44'7 B = (+) - 2- (2'-fluoro-4-biphenylyl) propionic acid: optically pure (+ ) -isomer has [cx] + = + 50.3 ° C = (+) -2- (2,2 ', 4 * -trifluoro-4-biphenylyl) propionic acid: optically pure (+' isomer has [o ] D = + 35.9 ° D = (+) - 2- (6-methoxy-2-naphthyl) propionic acid: optically pure (+) - isomer has [a] D = + 66 ° E = (+) -2- [4- (2-fluorophenoxy) -phenyl] -propionic acid: optically pure (+) - isomer has Ια] β = + 42.0 ° F = (+) - 2- (2-hydroxy-4-biphenylyl) ) -propionic acid: optically pure (+) - isomer has [a] D = + 47.6 ° x Specific rotation of this acid was measured in chloroform at a concentration of 1% v / r.

Amines G = (-) - α-methylbenzylamine H = (-) - α- (4-isopropylphenyl) -ethylamine J = (+) - α-cyclohexylethylamine K = (-) - α- (3-chlorophenyl) -ethylamine L1 = (+) - α- (2-methoxyphenyl) -ethylamine L2 = (-) - α- (2-methoxyphenyl) -ethylamine M = (-) - α- (4-fluorophenyl) -ethylamine N = (+ ) -a- (2-fluorophenyl) -ethylamine O = (-) - α- (2-chlorophenyl) -ethylamine P = (-) - α- (3-fluorophenyl) -ethylamine 35

DK 154418 B

9

Solvents R = petroleum fraction, initial boiling point 112 ° CS = (-) - α-pinene T = myrcene 5 U1 = 85% R + 15% toluene U2 = 67% R + 33% toluene V = petroleum fraction, boiling range 120-160 ° CW = petroleum fraction, initial boiling point 125 ° CX = octane 10 Y = petroleum fraction, initial boiling point 115 ° C, containing 1% n-butanol Z = toluene

Example 32 15 4.75 kg of flurbiprofen was mixed with 48 liters of a petroleum fraction with kp. 125 ° C and the mixture is stirred under nitrogen and heated to form a solution. 2.35 kg of (-) - cc-2Q methylbenzylamine in 23 liters of the same petroleum fraction was added with stirring and then the mixture was heated under reflux under nitrogen for 72 hours. The internal temperature was 125 ° C.

Then the mixture was filtered and the salt washed with the hot gasoline and dried to give 5.4 kg of the (-) - α-methyl-benzylamine salt of 2- (2-fluoro-4-biphenylyl) propionic acid, corresponding to a yield of 76%. A small portion of this was acidified to give 2- (2-fluoro-4-biphenylyl) propionic acid with [cc] D = + 33 °. The residue was recrystallized from isopropanol and a portion was acidified to give 2- (2-fluoro-4-biphenylyl) propionic acid with [α] D = + 41 °.

The rest of the recrystallized salt (4.3 kg) was mixed with 35 liters of petroleum ether (bp 102-120 ° C) and 37 liters of water and the mixture was stirred under nitrogen.

1 kg of concentrated hydrochloric acid was added and the mixture was refluxed for 1 hour. The hot organic layer was separated, washed with water, filtered and cooled and the product collected by filtration,

DK 154418 B

10 was separated with hexane and dried to give 2- (2-fluoro-4-biphenyllyl) propionic acid with [α] D = + 43.7 °, corresponding to 98% optical purity.

The filtrate after the initial 72 hours of heating the salt together with the solid recovered from the mother liquor from the isopropanol recrystallization of the salt and the gasoline crystallization with the acid were all recycled for treatment with an additional amount of flurbiprofen.

The amine salt of the racemic acid had a solubility in the petroleum fraction of 124 ml / g at 125 ° C.

Example 33 1 Weight portion of the (-) - α-methylbenzylammonium salt of the γ-flurbiprofen was mixed with 10 volumes of petroleum ether (b.p. 40-60 ° C) and heated to 116 ° C in a closed autoclave for 72 hours. Then the mixture was cooled and filtered and the salt washed with petroleum ether and dried in vacuo; 93.5% yield of a salt 2q was obtained which gave 2- (2-fluoro-4-biphenylyl) propionic acid with [oc] D = + 21.9 °.

Technical effect

From the data listed in the preceding Table I 2, the proportion of the dominant enantiomer in the acid recovered in each experiment can be calculated using the following equation: [ot] m + [ot] e% dominant enantiomer in the acid = -x 100 2 x [oc] e 30 where m is the optical rotation of extracted acid and e the optical rotation of pure enantiomer It is instructive to express the percentage of the dominant enantiomer in the salt (which of course is 2 ^ identical to the percentage of the dominant enantiomer in the recovered acid) as the percent yield calculated from the original weight of acid; so that 1 1

DK 154418 B

y - P x S

where Y is% yield of dominant enantiomer in the salt, P is% dominant enantiomer in the salt and 5 S is S yield of salt.

Values of S (from the examples) and of P and Y are calculated in the manner calculated above and the results are given in Table II.

It can be seen from Table II that the yields of the dominant enantiomer are generally above 50%. This is in marked contrast to a conventional resolution process where the maximum theoretical yield is 50%, calculated from the original weight of the acid.

15 20 25 30 35

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12

Table II

Ex. % Yield of% Dominant% Yield of No. Salt (S) Enantiomer in the Dominant Salt (P) Enantiomer _ (Y) _ 5 1 58.0 76.4 44.3 2 71.0 89.5 63.5 3 80.0 85.0 68.0 4 61.2 88.3 54.0 5 61.3 82.8 50.7 10 6 71.0 84.7 60.1 7 69.0 88.9 61.3 8 73.3 87.4 64.0 9 74.5 86.9 64.7 10 75.3 87.4 65.8 15 11 76.5 78.5 60.1 12 77.0 67.7 52, 1 13 66.5 80.9 53.8 14 49.0 91.4 44.8 15 71.0 75.2 53.4 20 16 73.5 87.6 64.4 17 70.0 89.6 62 , 7 18 76.0 86.2 65.5 19 84.3 96.4 81.2 20 64.0 91.7 58.7 25 21 80.5 89.1 71.7 22 66.0 86.2 56.9 23 67.7 70.7 47.9 24 87.0 87.3 75.9 25 79.0 89.6 70.8 30 26 69.5 89.4 62.1 27 80.1 97, 1 77.8 28 57.6 92.1 53.0 29 58.0 89.0 51.6 30 65.4 65.0 42.5 35 31 57.7 83.9 48.4 32 76.0 86 , 9 66.0 33 _93.5_74.4_69.6

Claims (8)

A process for increasing the amount of a desired enantiomer of a 2-arylpropionic acid whose aryl group is 6-methoxy-2-naphthyl or a group of the formula 5 are the number O or 1 and R, R and R, which may be the same or different, each represent a hydrogen, 3 chlorine or fluorine atom or a hydroxy group, wherein R, 4,5 and R cannot simultaneously be hydrogen characterized in that a mixture of a salt of the 2-aryl propionic acid is formed with an enantiomer of a chiral organic nitrogen-containing base and an inert organic diluent in which a proportion of the salt is insoluble and a ratio of the salt and diluent from 1: 1 to 1: 100 w / v, the base and diluent being selected such that the salt 20 of the racemic 2-arylpropionic acid has a solubility of 0.1% to 10% w / v in the diluent, the mixture is heated to a temperature of 90-150 ° C for 8-96 hours whereby a portion of an optical isomer of the salt sews recombinant will be converted to the enantiomer thereof, upon completion of the heating, the solid salt is collected and acidified and the acid thus formed is worked up in known manner to isolate the desired isomer of the 2-arylpropionic acid. Process according to claim 1, characterized in that 2- (2-fluoro-4-biphenylyl) -propionic acid is used as 2-arylpropionic acid. Process according to claim 1 or 2, characterized in that as an chiral organic nitrogen-containing base an alpha-phenylethylamine is used, wherein the phenyl ring can be substituted by an alkyl or C 1-4 alkoxy group or a halogen atom. DK 154418 B Process according to any one of the preceding claims, characterized in that the mixture is heated to 95-130 ° C. Process according to any one of the preceding claims, characterized in that a ratio of salt to diluent of 1: 5 to 1:15 weight / volume is used. Process according to any one of the preceding claims, characterized in that a salt of the racemic acid whose solubility is 0.5-2% w / v is used. Process according to any one of the preceding claims, characterized in that 80-95% by weight of the salt is undissolved in the diluent at the working temperature. Process according to any one of the preceding claims, characterized in that a diluent is used which is a mixture of hydrocarbons which are predominantly aliphatic and have a boiling point 20. range 110-135 ° C. 25 30 35