DE2809794A1 - PROCESS FOR INCREASING THE PROPORTION OF A DESIRED ENANTIOMER OF A 2-ARYLPROPIONIC ACID - Google Patents

Description

DR. BEtIG DI? L -ING. STA? F DIPL.-ING. SCHWABE DR DR.SANDMAIR 2 8 Q 9 7 B 4

PATENTANWÄLTE PO Box 860245 8000 Munich 86

Dr. Berg Dipl.-Ing. Stapf and Partner, POBox 860245, 8000 Munich 86 '

Your sign Your ref.

Our reference 28 90 Our ref.

Mauerkircherstraße 45 8000 MUNICH 80

Lawyer file no .: 28

THE BOOTS COMPANY LIMITED Nottingham / Great Britain

Process for increasing the proportion of a desired enantiomer of a 2-arylpropionic acid

X / Ma

»(089) 988272 988273 988274 983310

584/591 809038/0899

Telegrams:

BERGSTAPFPATENT Munich TELEX: 0524560 BERG d Bank accounts: Hypo-Bank Munich 4410122850 (bank code 70020011) Swift code: HYPO DE MM Bayen Vereinsbank Munich 453100 (bank code 70020270) Postscheck Munich 65343-808 (bank code 70010080)

-JT-

Field of application of the invention

The present invention relates to the preparation of optically active 2-arylpropionic acids. Of certain 2-arylpropionic acids are known to have valuable biological properties, and particularly anti-inflammatory properties own.

Characteristics of the known technical solutions

The usual procedures for splitting by separating a mixture of the diastereoisomeric salts of an acid are usually very tedious, since they often require several crystallization stages and also a racemization of the undesired enantiomer to improve the yields.

Object of the invention

It is believed that with many 2-arylpropionic acids, the biological activity of one of the optical isomers is greater than that of its enantiomer, and therefore it exists a need for a simple process by which one enantiomer can be obtained in a predominant amount.

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Loan of the essence of the invention

It has now been found that a desired enantiomeric set of a 2-arylpropionic acid can be obtained from a ©? ¹ mixture d © r diastereois © · = mers salt © obtained in a simple way, _s b © required i the usual little ³ levels than in conventional methods sur splitting *

According to the present invention Uird a method% w increasing the proportion of a desired enantiomers? * A 2-Ary! Propionic acid created ₉ wherein a mixture comprising an inert ₉ liquid ©, organic diluent and a SaI ^ 2-aery! propionic acid with one enantiomer of a chiral, © rgani © © hen ₂ nitrogen-containing base, to a temperature of at least 80 ° C © rhitat _s where the base and the diluent are such that the salt of the racemic acid in the diluent at d @r working temperature a® solubility of 0.1 to 10 % w / v. has and a portion of the Salses in the diluent unsolved bleibts whereby © n optical isomers of the acid component is converted in proportion of a © of the salt in its Enamtiomeres i "j £ pd ₉ and to the Saiz _5, ¥ on dsm di © acidic component has an increased and predominant proportion of this enantiomer ^ ₉ collects "

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2-Ary! Propionic acid is usually one in which the ary! group the general formula

where the index η denotes an integer from 1 to k, preferably 1 or 2, and the radical Q is identical or different and is selected from C _1- ^ -AllCyI, for example methyl; Aralkyl, for example benzyl; Cycloalkyl, for example from three to seven carbon atoms, and especially cyclohexyl; Alkyl-substituted cycloalkyl, for example monomethyl- and monoethyl-substituted cyclohexyl; Aryl, for example phenyl, and phenyl which is substituted with, for example, 1 or 2 alkyl, preferably C 1-6 alkyl, alkoxy, preferably C _1-1 J-AlkOXy, alkylthio, preferably C 1-4 alkylthio, cyano or halogen; Alkoxy, preferably C _1- ^ -alkoxy; Cycloalkoxy, for example cyclohexyloxy; Aryloxy, for example phenoxy and phenoxy, which is substituted by, for example, 1 or 2 halogen atoms, in particular chlorine or fluorine; Alkylthio, preferably C _1- ^ .- alkylthio; Aralkylthio; Cycloalkylthio; Arylthio, for example phenylthio; Arylcarbonyl, for example benzoyl and thenoyl; Cycloalkenyl, for example cyclohexenyl; Trifluoromethyl; Halogen, for example fluorine or chlorine; Furyl; Pyrrolidinyl; Pyrrolyl; Pyrrolinyl. Thienyl; or

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l-oxo-2-isoindolinylj or two Q ~ groups together form a carbocyclic or heterocyclic ring xiobei _s · the rings is aromatic and may be substituted., Beispiel® of groups represented by Q groups Awei susammen with the benzene ,, to which they are bound ₉ can be formed _s include naphthyl and substituted naphthyl _s in particular alkoxynaphthyl, pluorenyl, ben ^ oxasolyl _s optionally substituted, for example by p-chlorophenyl ₉ carbazolyl _s optionally substituted by chlorine, benzthiazolyl _s optionally substituted by phenyl. » Phenothiaainyl _s optionally substituted by alkoxy and alkyl, bensofuranyl _s optionally substituted by phenyls BenzopyransE2 ₃ 3 = b3pyridinyl, and 9 ~ oxanthenyl.

Instead of a substituted phenyl group, the group can be a heteroary group ₂ ZoB. Be Bensothiagolyl _s pyrrolyl or thienyl, which groups may be substituted by _s s © l <sa © groups as listed above for Q warden.

Particularly preferred compounds are s © lehe _s in the n @ Ary! Group generally © formula

R ⁴ R ⁵ - / il

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in which m has the value O or 1, and the radicals R ^, R and R ^ are the same or different and are hydrogen, chlorine, fluorine, Hydroxy and / or methoxy mean, has. Those compounds in which m has the value 0 are particularly preferred.

Other preferred aryl groups include 2- (6-methoxy-2-naphthyl) and those in which η is 1 and Q is in the 3-position and is benzoyl or phenoxy, or is in the 4-position and is l-oxo-2-isoindolinyl.

The invention is particularly applicable to 2- (2-fluoro-4-biphenylyl) propionic acid, and in particular applicable for obtaining a predominant amount of the (+) isomer.

The inventive method can be carried out by one racemic 2-ary! propionic acid, any enantiomer a 2-ary! propionic acid, or mixtures which contain a predominant amount of any enantiomer, used. Depending on the particular salts used, the process according to the invention can lead to an increase in lead to any enantiomer of the acid. The use of a racemic acid leads to the formation of a salt that contains a predominant amount of one enantiomer of the acid. As the method is not exclusive to the material at all Cases converted into the salt of one enantiomer of the acid

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Therefore, it is often desirable to treat the contained material in a minimum number (usually not more than awei) from the usual steps of crystallization or other means of purification. Di © desired Säur® can be obtained from the salt in conventional manner, for example by acidification TUs Salaes Hiifc a dilute mineral acid and subsequent extraction of the aqueous mixture with a suitable organic solvent _o Recrystallization of the acid can further improve the optical purity "

It is j seen that di © selection of Bas © of the 2 = aryl = propionic acid depend wirdo Di © selection "of Verdünnungsmit = means of propionic acid is from 2 ~ ArjF! And Bas © depend _o

Usually, di © base is an east-monosubstituted Alkylam ± n _9, and preferably a am®n © substi £ u © RTEs ethylamine _s particular a ut-phenylethylamine in what @ md © r phenyl ring by one or more groups _s ui @ for example, alkyl _s e.g. C ^^ - alkyl, especially isopropyl _s Hal © g © n _s sB = chlorine or fluorine, Alk © sy _a gB _o C ^^^ - Allcosqfj, especially methoxy, can be substituted. Particularly preferred are © Bmssn

(-) - a-methylbenzylamine and others.

(-) - α- (2-Methoxyphenyl) -äthy lamin »

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Other suitable bases include

(-) - <* - (4-lBopropylphenyl) -ethy lamin, (-) - α- (3-chloropheny1) ethylamine, (-) - α- (4-fluoropheny1) ethylamine, (-) - a- (3-fluorophenyl) ethylamine, (-) - o- (2-fluorophenyl) ethylamine, (-) - α- (2-chlorophenyl) ethylamine, (+) - α- (2-methoxyphenyl) ethylamine,

(-) - a- (2,6-Dimethoxyphenyl) ethylamine, and also

(+) - a-Cyclohexylethylamine.

Preferably the mixture of diluent and salt is heated to a temperature in the range of 90 ° to 150 ° C, e.g. heated in the range from 95 ° to 130 ° C. The heating is usually carried out for a period of at least 1 hour, e.g. up to 96 hours.

It is preferred that the ratio of the salt to the diluent be in the range of 1: 1 to 1: 100 w / v, e.g. in the range from 1: 5 to 1: 15 w / v lies.

Preferably the solubility of the salt of the racemic acid in the diluent at operating temperature is in the range of 0.5 to 2% w / v.

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Preferably 50 to 98 weight percent of SaIsOS _5, gB "are 80 to 95 Gewichtsproseat _s unsolved in the diluent at the operating temperature"

The inert diluent is at the temperature to which the mixture is heated _s tfirdj, a liquid and _s, one or more organic compounds © "usually has the diluent © © ine low polarity and may for example include one or more hydrocarbons. The diluent is preferably a © mixture of hydrocarbons _s which are predominantly aliphatic, and it preferably has a boiling point in the Bereden of 110 ° to 135 ° C. Polar compounds in amounts of at = - game, up to 1% may be contained in the diluent .

It is preferred that that

is that the reaction be carried out under reflux can.

It may be desirable since ₉ © Erhitsea avoid be under an atmosphere, for example under Stickstof £ _s durehsufUfSTSa ₅ to formation of by-product shown below.

The invention will be in the following

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refines, in which flurbiprofen is (±) -2- (2-fluoro ~ 4-biphenyl) propionic acid. Unless expressly stated otherwise, the specific rotations in ethanol at a concentration of 1 % w / v. and measured at room temperature.

Working examples Examples 1 to 31

Various mixtures containing an amine salt of a 2-aryi propionic acid and a diluent which consisted of one or more liquid organic compounds were stirred and heated. After the heating was stopped, the hot mixtures were filtered through a steam-heated Buchner funnel, the salts were washed with the hot diluent _3, dried in vacuo, acidified with dilute sulfuric acid or hydrochloric acid, and the acidic mixtures extracted with ether. The ether extracts were washed with water, dried and concentrated, whereby 2-arylpropionic acids were obtained with an optical activity different from the acidic component of the salt at the beginning of the experiment.

The details and the results of the various examples are set out in the table below.

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Tabel

At- thin-

game acid amination no.

Solubility

thin salt

the (±) acid

with- in thinner

telecommunication means

per g with reaction = salt

Reak Reak the end [aJ _D der functional ions prey won temp. Time of salt acid ( ⁰ C) (Hours.) (%) (O)

to
approx 5

7th 8th

10
11
12th

A2
A2

G G

Al J
BG

C G

Al

R.
R.

S.
T

10 10 10 10 10 10 10 10 10 10 10

110 110 110

85

100 100

90

26th

68, J 186 352

115 2 * 5 58.0 +23.6 115 72 71.0 +35.3 115 72 80 _fl 0 +31.3 115 72 61.2 +34.2 115 72 61.3 +29.3 115 72 7I ₉ O +34.9 115 72 69.0 +27.9 117 72 73.3 +33.4 117 72 74.5 +33.0 113 72 75.3 +33.4 108 72 7β, 5 +25.5 97 72 77.0 +15.8

Table (continuation)

at acid Amine Ver Ver solubility React Reak the end Γ / ν 1 A λίί game thin thin of the salt functional ions prey L οι j tv eggs No. nunga- potential the (±) -Säu- temp. Time of salt won with- with- re in thinner ( ⁰ C) (Hours.) (Ji) acid tel tel resources (°) A3 α per g at reaction 13th salt temperature 115 72 66.5 Al K V (ml) (ml / g) +27.6 14th Al 0 10 72 115 72 49.0 σ 15th Al α R. 125 θ 71.0 +37.0 CD 16 W. 10 33 125 96 73.5 +22.5! CO Al 0 W. 10 124 +33.6 β * "Xs, 17th Al Q 10 124 126 72 70.0 O 18th Al Ll X 115 72 76.0 +35.4 19th Al M. Ϊ 10 57 115 72 84.3 +32.4 ■ ο 20th A4 α R. 10 114 115 72 64.0 -41.45 21st Al α R. 14.4 160 115 72 80.5 +37.3 22nd D. Q R. 9.4 94 112 72 66.0 +35.0 23 Al α U2 10 110 115 72 67.7 +32.4 & 24 R. 10 57 117 72 87.0 +27.3 <x T 6.7 58 +33.3 i 3 15.5 I. OO
t

Table (continued)

Ver Ver solubility thin thin of the salt at Acid amine potential the (±) -Säu- game with with- re in thinner No. tel tel resources per g at reaction salt temperature Al G S (ml) (ml / g) 25th Al M E 5 26th 26th Al L2 R 6th ββ 27 Al O R 15.2 160 28 Al P R 4th 40 29 6th 59

Reactiong "
temp.
(°

Response time (hrs ₃ )

Yield of salt

[a] _D the

recovered acid

90

72 72 72 72 72 72 72

79 _p

69 _S 5 8O ₃ I.

57.6

65 »*

57.7

-35.2 ' +42.1 ^

+ 37.6

CC; CD

Key to the table 2-Arylpropi onsäuren

Al * (±) -2- (2-fluoro-4-biphenylyl) propionic acid A2 * 2- (2-fluoro-4-biphenylyl) propionic acid; [α] ~ * -30 ° A3 * 2- (2-fluoro-4-biphenyIyI) propionic acid; [aJ _D «-44.7 ° A4 s 2- (2-fluoro-4-biphenylyl) propionic acid; [o] _D * + 8.9 °

The optically pure isomers of the compounds Al, A2, A3 and A4 have [a] _n values of + 44.7 ° or -44.7 °.

B * (±) -2- (2 ^l -Pluoro-4-biphenylyl) -propionic acid: The optically pure (+) - isomer has a value of

[a] _D * + 50.3 ° C s (±) -2- (2.2 ^f , 4'-trifluoro-4-biphenyIyI) -propionic acid:

The optically pure (+) - isomer has a value of

Co] ₀ χ + 35.9 ° D * (±) -2- (6-methoxy-2-naphthyl) propionic acid:

The optically pure (*) isomer has a value of

[a] _D * + 66 ° (The specific rotation of this acid was in chloroform at a concentration of 1 %

Weight / volume measured.) E »(±) -2- [4- (2-Pluophenoxy) -phenyl] -propionic acid:

The optically pure (4 -) isomer has a value of

Eo] _n «+ 42.0 °

¹ D

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P s (±) -2- (2-hydroxy-4-biphenylyl) propionic acid:

The optically pure (+) - isomer has a value of [a] _D = + 47.6 °

Amines

G = (-) - α-methylbenzylamine

H = (-) - α- (4-isopropylphenyl) ethylamine J = (+) - o-cyclohexylethylamine

K = (-) - a- (3-chlorophenyl) ethylamine Ll = (+) - a- (2-methoxyphenyl) ethylamine L2 s (-) - o- (2-methoxyphenyl) ethylamine M s (-) - a- (4-fluorophenyl) ethylamine N = (+) - a- (2-? Luophenyl) -ethylamine 0 β (-) - a- (2-chlorophenyl) ethylamine ρ = (-) - a- (3-fluorophenyl) ethylamine

solvent

R a petroleum fraction, initial boiling point 112 ° C S s (-) - a-pinene

T * myrcene

ül = 65 % R ♦ 15 % toluene

U2 = 67 Ϊ R + 33 * toluene

V * petroleum fraction, boiling point range 120 ° to 160 ° C

W s petroleum fraction, initial boiling point 125 ° C

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-χι - SSL

X s octane

Y = petroleum fraction, initial boiling point 115 ° C, with a

Content of 1 % n-butanol.
Z = toluene

Example 32

Flurbiprofen (4.75 kg) was mixed with a petroleum fraction boiling at 125 ° C (48 liters) and the mixture was stirred and heated under nitrogen to make a solution. (-) - α-Methylbenzylarain (2.35 kg) in the same solvent (23 liters) was added with stirring and the mixture was then heated under reflux and under nitrogen for 72 hours. The internal temperature was 125 ° C. The mixture was then filtered and the salt washed with the hot solvent (as above) and dried. The (-) - a-methylbenzylarain salt of 2- (2-fluoro-4-biphenylyl) propionic acid (5.4 kg) was obtained in 76% yield. A small part of this salt was acidified and 2- (2-fluoro-4-biphenyIyI) propionic acid was obtained with a value of [α] ^ ^s + 33 °. The remainder was recrystallized from isopropanol and some of it was acidified, giving 2- (2-fluoro-4-biphenyIyI) propionic acid with a value of lot] -. * Received + 41 °.

The remainder of the recrystallized salt (4.3 kg) was with petroleum ether (boiling point 102 ° to 120 ° C; 35 liters) and water (37 liters) mixed and the mixture under nitrogen

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touched. Concentrated hydrochloric acid (1 kg) was added and the mixture was refluxed for 1 hour. The hot organic layer was separated, washed with water, filtered, cooled and the product collected by filtration, washed with hexane and dried. 2- (2-fluoro-4-biphenyIyI) propionic acid was obtained with a value of α] _β * +43 »7 °, which means 98% optical purity.

The filtrate after the initial heating of the salt for 72 hours became together with that from the mother liquors solid obtained from isopropanol recrystallization of the salt and petroleum ether recrystallization of the acid again returned for treatment with another 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 53

The (-) - a-Methylbenzylammoniumsalz (1 part by weight) of flurbiprofen was mixed with petroleum ether (boiling point 40 ° to 60 ⁰ C; 10 parts by volume) and heated for 72 hours at 116 ° C in a sealed autoclave. The mixture was then cooled and filtered and the salt washed with petroleum ether

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washed and dried in vacuo. A 93.5% yield of salt was obtained, which gave 2- (2-fluoro-4-bipheny-IyI) propionic acid, which had a value for the rotation [a] _D - + 21.9 °.

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Claims (21)

Claims 1. A process for increasing the proportion of a desired enantiomer of a 2-ary propionic acid _s characterized!
characterized in that one is a mixture, which is an inert, liquid, organic diluent and a
Salt of 2-arylpropionic acid with one enantiomer of a
Contains chiral, organic, nitrogen-containing base, heated to a temperature of at least 80 C, the base and the diluent are such that the
Salt of the racemic acid in the diluent at the working temperature has a solubility of 0.1 to 10 % GeWo / Vol »and a proportion of the salt in the diluent
remains undissolved, whereby a portion of the one optical iso- ORIGINAL INSPECTED 809830/08 ^ 0 «(089) 988272 988273 988274 983310 Telegrams: BERGSTAPF PATENT Munich TELEX: 0524560 BERG d Bank accounts: Hypo-Bank Munich 4410122850 (BLZ 70020011) Swift Code: HYPO DE MM Bayer. Vereinsbank Munich 453100 (bank code 70020270) Post check Munich 65343-808 (bank code 70010080) -z- merging the acidic component of the salt into its enantiomer is converted, and one the salt, of which the acidic component has an increased and predominant proportion of this Has enantiomers, collects. 2. The method according to claim 1, characterized in that that 2-ary! propionic acid is one in which the aryl group has the general formula -z h in which m has the value 0 or 1, and the radicals R, R and B? are identical or different and are hydrogen, chlorine, fluorine, hydroxy and / or methoxy. 3. The method according to claim 2, characterized in that the 2-ary! Propionic acid 2- (2-fluoro-4-biphenylyl) propionic acid, 2- (2 * -Fluoro-4-biphenylyl) -propionic acid, 2- (2,2 ', 4'-trifluoro-4-biphenylyl) propionic acid, 2- (2-Hydroxy-4-biphenyIyI) propionic acid or 2- [4- (2-fluorophenoxy) phenyl] propionic acid is. - / 3 ORIGINAL INSPECTED 4. The method according to claim 1, characterized in, that 2-arypropionic acid is 2- (6-methoxy-2-naphthyl) propionic acid is. 5. The method according to any one of claims 1 to 4 _S, characterized in that the chiral, organic, nitrogen-containing base is an α-monosubstituted alkylamine. 6. The method according to claim 5, characterized., that the α-monosubstituted alkylamine is an α-monosubstituted ethylamine. 7. The method according to claim 6, characterized in that the α-monosubstituted ethylamine an a-phenylethylamine is ₃ in which the phenyl ring _i by one or more C ₁ _ alkyl. C. _S | may be substituted alkoxy. Or halogen groups . 8. The method according to claim 7 _3, characterized in that the enantiomer of α-phenylethylamine from (-) - a-methylbenzylamine _s (-) - a- (2-methoxyphenyl) ethylamine, (-) »a- (4-isopropylphenyl ) ~ ethylamine _s (-) - α- (3-chlorophenyl) ethylamine, (-) - α- (4-fluorophenyl) ethylamine, (-) - α- (3-fluorophenyl) ethylamine, (-) - α- (2-Pluorpheny1) -äthy1 80 ^ 818/0890 - / 4 - 2BÜ9794 - 4 amiri and (-) - a- (2-chlorophenyl) ethylamine is selected. 9. The method according to any one of claims 1 to 8, characterized in that the mixture is heated to a temperature of 90 ° to 150 ° C. 10. The method according to claim 9 »characterized that the temperature is 95 ° to 130 ° C. 11. The method according to any one of claims 1 to 10, characterized in that the mixture Is heated for 8 to 96 hours. 12. The method according to any one of claims Ibis 11, characterized characterized in that the ratio of the salt to the diluent is in the range of 1: 1 to 1: 100 w / v lies. 13. The method according to claim 12, characterized in that that the ratio is in the range of 1: 5 to 1:15 w / v. lies. 14. The method according to any one of claims 1 to 13, characterized in that the Lösiich- 809838/0090 - / 5 - speed of the salt of the racemic acid in the range of O ₃ 5 to 2 % w / v. lies. 15. The method according to any one of claims 1 to 14 characterized gekennzeichne ₃ t _s that 50 to 98 weight percent of the salt are solved in the diluent at the operating temperature. 16. The method according to claim 15 characterized gekennzeichne ₃ t _s that 80 to 95 weight percent of the salt are unresolved. 17. The method according to any one of claims 1 to 16 _3, characterized in that the diluent is liquid at the temperature to which the mixture is heated and that it has a lower polarity. 18. The method according to claim 17 characterized chnet _s ge kennzei that the diluent is a mixture of hydrocarbons is _s which are predominantly aliphatic and a boiling point in the range of 110 ° has to 135 ° C. 19. The method according to claim l _s thereby ge - indicates that it is carried out essentially as described in the examples. 20. Salts of 2-ary! Propionic acid with an optically active, organic, nitrogen-containing base, provided they have been obtained by the process according to any one of claims 1 to 19. 21. 2-Ary! Propionic acid, containing predominantly one enantiomer, provided that it was obtained from a salt according to claim 20. 80983S / ÖS90 - / 7 -