FI66828B - SAETT ATT OEKA ANDELEN AV EN SAODAN ENATIOMER VILKEN HAR EN HOG BIOLOGISK ACTIVITIES - Google Patents

Description

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(32) (33) (31) Pyr * «ty woHum Βΐ | Μ priorim 08.03.77 18.01.78 England-England (GB) 9697/77, 19A6 / 78 (71) The Boots Company PLC, 1 Thane Road West, Nottingham, England-England (GB).

(72) John Stuart Nicholson, Beeston, Nottingham,

James Gordon Tantum, Nuthal1, Nottinghamshire, England-England (GB) (7A) Oy Koister Ab '(5A) A way to increase the proportion of an enantiomer of 2-arylpropionic acid with high biological activity - Sätt att oka andelen av en. ädan enatiomer, vilken har en hög biologisk aktivitet

The invention relates to a process for increasing the proportion of the desired enantiomer of 2-arylpropionic acid in which the aryl group is 6-methoxy-2-naphthyl or a group of the formula R. Rc 4 where m is O or 1 and R 1, R 2 and R ^, which may be the same or different, denote hydrogen, chlorine, fluorine, hydroxy or methoxy. It is known that certain 2-arylpropionic acids have valuable biological properties and in particular anti-inflammatory properties.

66828

For some 2-arylpropionic acids, it is believed that the biological activity of one of their optical isomers is greater than that of its enantiomer, and it is desirable to have a simple method by which one enantiomer can be prepared essentially.

Conventional resolution methods to separate a mixture of diastereoisomeric salts of an acid are usually very laborious because they often require several recrystallization steps and also racemization of the undesired enantiomer to improve the yield.

It has now been found that the desired enantiomer of 2-arylpropionic acid can be obtained in a simple manner from a mixture of diastereoisomeric salts, generally requiring fewer steps than conventional decomposition methods.

In prior art processes, the desired isomer can be isolated only to the extent that it is present in the isomer mixture, whereas in the process of the invention conversion occurs.

The invention is characterized in that a mixture of a salt of 2-arylpropionic acid and an enantiomer of a chiral organic nitrogen-containing base is formed in an inert liquid hydrocarbon diluent in which part of the salt is insoluble, wherein the chiral organic nitrogen-containing base is oC-cyclamhexyl or o-cyclohexylamine substituted with C 1-4 alkyl, C 1-4 alkoxy or halogen, and wherein the salt and diluent are used in a ratio between 1: 1 and 1: 100 w / v, the choice of base and diluent such that the racemic 2- the solubility of the arylpropionic acid salt in the diluent is 0.1-10% (w / v), the mixture is heated to 90-150 ° C, whereby part of the second optical isomer of the acidic component is converted to its enantiomer, and after heating is separated the resulting solid salt is separated from the liquid phase and acidification to give a 2-arylpropionic acid containing an increased proportion of the desired enantiomer.

The invention is particularly suitable for 2- (2-fluoro-4-biphenylyl) -propionic acid and in particular for obtaining the (+) - isomer as the main component.

The invention can be carried out using racemic 2-arylpropionic acid either as the enantiomer of 2-arylpropionic acid or as mixtures containing mainly one of the two enantiomers. The process in question.

Depending on the salts of II 3 66828, either enantiomer of the acid may be formed. In the process, the material does not in all cases give the salt of only one enantiomer of the acid, so it is often desirable to treat the resulting material as infrequently as possible, usually in no more than two conventional recrystallization steps, or otherwise purified.

The desired acid may be expressed from the salt by conventional means, e.g. by acidifying the salt with dilute mineral acid and then extracting from the aqueous mixture as a suitable organic solvent. Acid recrystallization may further improve optical purity.

It should be noted that the choice of base depends on the 2-arylpropionic acid. The choice of diluent depends on 2-arylpropionic acid and base.

The base is generally o (-monosubstituted alkylamine and in particular oC-monosubstituted ethylamine, in particular o (-phenylethylamine), which may be substituted on the phenyl ring by one or more groups such as alkyl, e.g. C 1 -C 4 alkyl, especially isopropyl, halogen , e.g. chlorine or fluorine or alkoxy, e.g. C 1 -C 4 alkoxy, especially methoxy Particularly preferred bases are (-) - θ (-methylbenzylamine and (-) - ζ- (2-methoxyphenyl) ethylamine). Other suitable bases include (-) - (X- (4-isopropylphenyl) -ethylamine, (-) - - (3-chlorophenyl) -ethylamine, (-) - o (- (4-fluorophenyl) -ethylamine, {- ) - oC- (3-fluorophenyl) -ethylamine, (-) - oC- (2-fluorophenyl) -ethylamine, (-) - o (- (2-chlorophenyl) -ethylamine, (+) - o (- (2 -methoxyphenyl) -ethylamine, (-) - N - (- 2,6-dimethoxyphenyl) -ethylamine and also (+) - N-cyclohexylethylamine.

The mixture of diluent and salt is preferably heated to a temperature of 90-150 ° C, e.g. 95-130 ° C. Usually the heating is continued for at least one hour, e.g. 8-96 hours.

It is recommended that the ratio of salt to diluent be 1: 1 to 1: 100 w / v, e.g. 1: 5 to 1:15 w / v.

The solubility of the racemic acid salt in the diluent at the working temperature is preferably 0.5 to 2% w / w.

At the working temperature, preferably 50-98% by weight, e.g. 80-95%, remains insoluble in the diluent.

τπ: 66828

The unreacted diluent is a liquid at the heating temperature of the mixture and may consist of one or more organic compounds. Usually the diluent is of low polarity and may consist of e.g. one or more hydrocarbons. The diluent is preferably a mixture of aliphatic hydrocarbons, preferably having a boiling point of 110-135 ° C. The diluent may contain up to 1% of polar compounds.

The diluent is preferably such that the reaction can be carried out under reflux conditions.

It may be desirable to perform heating in an unreacted atmosphere, e.g., nitrogen, to prevent the formation of by-products.

The following examples illustrate the invention. In them, fluorobiprofen is (-) - 2- (2-fluoro-4-biphenylyl) -propionic acid. Unless otherwise stated, the specific rotation is measured in ethanol at a concentration of 1% w / w at ambient temperature.

Examples 1-31

Various mixtures of the amine salt of 2-arylpropionic acid and a diluent containing one or more liquid organic compounds were stirred and heated. At the end of the heating, the hot mixtures were filtered through a steam-heated Buchner funnel, the salts were washed with hot diluent, dried in vacuo, acidified with dilute sulfuric or hydrochloric acid and the acid mixtures were extracted with ether. The ether extracts were washed with water, dried, evaporated to give 2-arylpropionic acid, the optical activity of which differed from that of the acid component of the salt at the beginning of the experiment.

Details and results of the various examples are shown in Table I.

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Explanations for Table I: 2-arylpropionic acids

A1 = (-) - 2- (2-fluoro-4-biphenylyl) -propionic acid A2 = 2- (2-fluoro-4-biphenylyl) -propionic acid, = = 303 A3 = 2- (2-fluoro-4- biphenylyl) propionic acid, / gl / q = “44.7 A4 = 2- (2-fluoro-4-biphenylyl) -propionic acid, / ° (/ D = + 8.9 ° These optically pure isomers / o // D is + or -44.7 ° B = (-) - 2- (2'-fluoro-4-biphenylyl) -propionic acid, optically pure (+) -isomer / <X> = + 50.3 ° C = ( -) - 2- (2,2 ', 4'-trifluoro-4-biphenylyl) -propionic acid, optically pure (+) - isomer / <X / O = + 35.9 ° D = (-) - 2- ( 6-Methoxy-2-naphthyl) -propionic acid, optically pure (+) - isomer (+) = + 66 ° E = (-) - 2- [4- (2-fluorophenoxy) -phenyl] -propionic acid; (+) - isomer (+) + 42.0 ° F = (-) - 2- (2-hydroxy-4-biphenylyl) -propionic acid, optically pure (+) - isomer / + +, 6 ° xThe specific rotation of this acid was measured in chloroform at a concentration of 1% w / w

amines; G = (-) - N-methylbenzylamine H = (-) - c- (4-isopropylphenyl) -ethylamine J = (+) - o (-cyclohexylethylamine) K = (-) - O- (3-chlorophenyl) -ethylamine L1 = (+) - (2-methoxyphenyl) -ethylamine L2 = (-) - CV- (2-methoxyphenyl) -ethylamine M = (-) - oC- (4-fluorophenyl) -ethylamine N = (+) -oC- (2-fluorophenyl) -ethylamine O = (-) - N- (2-chlorophenyl) -ethylamine P = (-) - o <i- (3-fluorophenyl) -ethylamine Solvents: R = petroleum fraction, boiling point 112 ° CS = (-) - oC-pinene T = myrcene

UI = 85% R + 15% toluene U2 = 67% R + 33% toluene V = petroleum fraction, boiling range 120-160 ° C W = petroleum fraction, initial boiling point 125 ° C

66828 8 X = octane Y = petroleum fraction, initial boiling point 115 ° C, containing 1% n-butanol Z = toluene

Example 32

4.75 kg of flurbiprofen and 48 l of petroleum fraction were mixed, b.p. 125 ° C, and the mixture was stirred under nitrogen and heated to give a solution. 2.35 kg of (-) - methyl-benzylamine in 23 liters of the same petroleum were added with stirring and the mixture was heated under reflux under nitrogen for 72 hours. The internal temperature was 125 ° C. The mixture was filtered, the salt was washed with hot gasoline, dried to give 5.4 kg (yield 76%) of the (-) - N-methylbenzylamine salt of 2- (2-fluoro-4-biphenylyl) -propionic acid. A small portion of this was acidified to 2- (2-fluoro-4-biphenylyl) -propionic acid, / ° C / D = + 41 °.

4.3 kg of the remaining recrystallized salt, 35 l of petroleum ether (b.p. 102-120 ° C) and 37 l of water were mixed and the mixture was stirred under a nitrogen blanket. 1 kg of concentrated hydrochloric acid was added and the mixture was heated under reflux for one hour. The hot organic layer was isolated by filtration, washed with hexane, dried to give 2- (2-fluoro-4-biphenylyl) -propionic acid, / <X / D = + 43.7 °, which represents 98% optical purity.

After heating the salt for the first 72 hours, the filtrate and solid isolated from the mother liquor recrystallization and acid from gasoline crystallization mother liquors were recycled for further treatment with flurbiprofen.

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

Example 33

1 part by weight of the (-) -? - methylbenzylammonium salt of flurbiprofen and 10 parts by volume of petroleum ether (b.p. 40 ° -60 ° C) were mixed and heated at 116 ° C for 72 hours in a closed autoclave. The mixture was cooled, filtered, the salt washed with petroleum ether, dried in vacuo to give the salt, yielding 2- (2-fluoro-4-biphenylyl) -propionic acid, in 93.5% yield, [(+ = + 21.9 °).

9 66828

Technical power

From the values in Table I above, the proportion of the predominant enantiomer in the recovered acid in each experiment can be calculated according to the following formula: 100% of the predominant r,, r / = L * Jx & + - * e enantiomer in the acid-x x where = optical rotation of the recovered acid, and Jee (Je = optical rotation of the pure enantiomer.

It is illustrative to express the percentage of the predominant enantiomer in the salt (which is, of course, the same as the percentage of the predominant enantiomer in the recovered acid) as a percentage of the yield based on the initial weight of the acid.

Thus V = p x s 100 where Y = yield of the predominant enantiomer in the salt%, P = amount of the predominant enantiomer in the salt%, S = yield of the salt% S The values of S are obtained from the examples and P and Y are calculated and shown in the following Table II. indicating that the yield of the predominant enantiomer is generally greater than 50%. This is a clear difference from the conventional resolution method, where the maximum theoretical yield is 50% based on the initial weight of the racemic acid.

___ "Γ“. ____ 10

Table II 6 6 8 2 8

Predominant in salt

Example No. Salt yield% Amount of enantiomer of the predominant enantiomer (S)% yield (P) (Y) _ 1 · 58.0 76.4 44.3 2 71T0 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 6 71.0 84t7 '60.1 7 69.0 88.9 61.3 8 73.3 87.4 64 .0 9 74.5 86.9 64.7 10 75.5 87.4 65.8 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 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 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 26 69.5 89.4 62.1 27 80.1 97.1 77.8 • 28 57.6 '92, 1 53.0 29 53.0 89.0 51.6 30 65.4 65.0 42.5 31 57.7 83.9 48.4 32 76.0 86.9 66.0 33 93.5 74 4 69 * 6

Claims (11)

1. A method of increasing the proportion of such anantiomer of 2-arylpropionic acid, where the aryl group is 6-methoxy-2-naphthyl or a group of formula R 3 - <RTI ID = 0.0> R4 </RTI> where m is 0 or 1 and R 2, R 2 and R 2, which may be the same or different, represent hydrogen, chlorine, fluoro, hydroxy or methoxy, characterized in that a mixture of a 2-arylpropionic acid and an enantiomer is formed. of a chiral organic base containing nitrogen in an inert hydrocarbon diluent, wherein a portion of the salt is insoluble, the chiral organic base containing nitrogen being fl 1 -cyclohexylamine or a 2-phenyl-ethylamine in which the phenyl ring may be substituted by C ^ alkyl alkylalkyl, C ^ _ ^ alkoxy or halogen, and the diluent is used in a ratio of 1: 1 to 1: 100% w / v, the base and diluent being selected so that the salt of the racemic 2- the arylpropionic acid has a solubility of 0.1-10% (w / v) in the diluent, the mixture is heated at a temperature of 90-150 ° C, v wherein part of one of the acidic component's optical isomers is converted to its enantiomer and upon completion of heating, the obtained solid salt is separated from the liquid phase and acidified to obtain 2-arylpropionic acid containing an increased proportion of the desired enantiomer. 2. A process according to claim 1, characterized in that the 2-arylpropionic acid is 2- (2-fluoro-4-biphenylyl) propionic acid, 2- (21-fluoro-4-biphenylyl) propionic acid, 2- (2,2 '). 4'-trifluoro-4-biphenylyl) propionic acid, 2- [4- (2-fluorophenoxy) phenyl] propionic acid or 2- (6-methoxy-2-naphthyl) propionic acid. 3. A process according to claim 2, characterized in that the 2-arylpropionic acid is 2- (2-fluoro-4-biphenylyl) propionic acid.