DE2007177A1 - Salts of amine bases and aryl substituted propionic acids and processes for making the same - Google Patents

Description

PATENT LAWYERS

dr. W. Schalk dipl.-ing. P. Wirth · dipl.-inc. G. Dannenberg DR.V. SCHMIED-KOWARZIK DR. P. WE I N HOLD DR.D.GUDEL

6 FRANKFURT AM MAIN
CR. ESCHENHEIMER STRASSE 39

Syn box Corporation
Apartado Postal 73% Panama / Panama

Salts of amine lines and aryl-substituted propionic acids and methods of making the same

The present lirfindurif !; refers to the salts of amine bases and aryl substituted ones Propionic acids and new processes for their preparation.

The present invention is particularly directed to the salts of

- bases
separated, optically active arair / and 2- (6-i'iethozy-2 '-naphthyl) -propionic acid

and to a process for the preparation of these salts, which is obtained by treating a 2- (6'-methoxy-2 ¹ -naphthyl) propionic acid with a separated,

optically active aminbaae. Λ

The salts of the separated, optically active amine bases and 2- (6'-methoxy-2 ¹ -naphthyl) propionic acid can be represented by the following formula:

COO ^w AH

in which A stands for a separated, optically active amine base.

009840/2307

BAO ORIGINAL

- 2. -

The separated, optically active amine bases include those naturally occurring Alkaloids and the separated, optically active primary, secondary and tertiary amines, such as 1-2-amino-1-propanol; 1-2-aminobutanol; d-2-aninobutanol; d-threo-2-amino-1-p-nitrophenyl-1,3-propanediol; d-anphetamine; d-menthylamine; Cholesterylamine; Urehydroabietylamine; 1-2-benzylamino-i-propanol; d-eesoxyephedrine; 1-lspheririne; d - ^ - dirnethylamino-1,2-diphenyl-3-methyl-2-butanol; 1 - ^ - dimethylamino-1 ^ -diphenyl-O-methyl - ^ - butaQol; ulucosamine; Solanidine; Quinine etc.

The salts are prepared by erfindungsgemäi3en Beha-MINATION a D- or L-2- (6 '-methoxy-2 ^1-naphthyl) propionic acid or a racemic mixture thereof with a separated, optically active amine base in an inert organic solvent, alone or in combination with an aqueous Lösungo ils such a solvent is preferably used sy stem, both the 2- (6'-methoxy-2-naphthyl ¹⁾ propionic acid are soluble in w-ELCHEM and the separated optically active amine base. Where the separate, optically active amine base is not readily soluble in the inert organic solvent, the reaction is carried out by combining a solution of the acid and an inert organic solvent with an aqueous solution of the base; In this case, a water-miscible, inert organic solvent is preferably used; at least 1 molar equivalent, preferably at least 1.01 molar equivalent, of base per mole of acid is used.

applies, iiis there is no upper limit on the amount of base used, however certain practical considerations, such as the cost of the base and its solution In particular, organic solvents used are the practical upper limit. Any inert organic solvent can be used in the above process can be used in which both the acid and the di base are soluble. Typical inert organic solvents include alkanols, such as methanol, Ethanol, isopropanol, butanol, tert-butanol, pentanol, etc .; Carboxylic acid

009840/2307 ¹ 8AD

or »tor, wio. ethyl acetate, amyl acetate, etc .; halo ^ cniurto KohlenwaiJ.Tirr w-ic l'-icthyl chloride, chloroform, carbon tetrachloride, methyl chloride, etc .; oaer hydrocarbon solvents such as benzene, toluene, xylene, pentane, Hexane, isooctane, cyclohexane, etc. According to the invention, mixed un.ejen can also be used above solvents can be used. The reaction can be from about Ü G. to to the boiling point of the reaction mixture, preferably at room temperature up to the boiling point of the solvent used or the solvent mixture be performed.

The salt, ie the salt of the separate, optically active amine base and 1- and / m

or d-2- (6 '-methoxy-2 ^1-naphthyl) propionic acid is isolated by conventional methods. For example, the reaction mixture can be allowed to cool slowly to room temperature and filtered. The salt is washed a few times and then dried. The filtrate is evaporated to dryness and yields further salt.

The novel salts according to the invention of the separated, optically active amine base and 2- (6'-methoxy-2 ¹ -naphthyl) -propionic acid are valuable intermediates for the separation of the optical isomers of 2- ( ^{6'-methoxy-2 1} -naphthyl) -

propionic acid. It was found that the different salts of the Λ

separate, optically active amine bases and the d- and II- (6'-Wethoxy-2 ¹ -naphthyl) propionic acid surprisingly different solubilities.

For example, it has been found Dais the salt of cinchonidine and 1-2 '~ (6' -Kethoxy ^{1-2-naphthyl)} -propionic acid in methanol at room temperature is substantially more soluble than the corresponding cinchonidine salt of d-2- (6'-methoxy -2 ¹ -naphthyljpropionsäure. in contrast, the salt of dehydroabietylamine and d-2- (6 '-i'lethoxy ^{1-2-naphthyl)} propionic acid in i'iothanol substantially more soluble than (iar> (intüfjrficncnOo iJOhydroabJcty'Liminnrilz dor l ~ 2- (6 '-hettoxy-'i ¹ -naphthyl) -f>-ro; / ionr ;; i: ir (j

der 2 - ('. j'-i ^/ iothfj / .. y-2 ^l -ria; jhthyl) -prop: lonc; auro to separate the d-2- (6' -. 'olh-

0098AO / 2307

oxy-2 ^1-naphthyl) -propionic acid and l-2- (6 '-methoxy-2 ^1-naphthyl) propionic acid.

The separation of the optical d- and 1-isomers of 2- (6'-methoxy-2 ¹ -nanhtthyl) -propionic acid is carried out by preparing a solution of the acid at elevated temperature in the solvent to be used for the separation; the temperature is preferably a few degrees below the boiling point of the solvent. A saturated solution of the base then becomes this warm solution

in about the same solvent, which is also heated to / the same temperature,

\ admitted. Use is at least 1 molar equivalent-nt, preferably

about 1.01 molar equivalents, base per molar equivalent of acid. the

the two solutions are preferably combined with stirring. The combined

ο ο

Mixture will slowly cool to a temperature of hOC to about 0C

calmly. During this time, the reaction mixture can optionally be seeded with the least soluble salt, which often improves the separation. After the reaction mixture is cooled, it is allowed to stand for about 1 hour or more and then filtered. The salt is washed a few times, dried and recrystallized one or more times; one obtains the salt of a resolved, optically active amine base and a Önanthiomorphs of 2- (6'-methoxy-2-naphthyl ¹⁾ propionic acid.

To split the salt, it is treated with an aqueous mineral acid such as 2N hydrochloric acid in a water-immiscible solvent such as ethyl acetate or ether. The organic layer is removed, washed neutral with water, dried and evaporated to give a separated optical isomer of 2- (6'-methoxy-2'-naphthyl) propionic acid. The aqueous layer can be treated with an inorganic base such as sodium hydroxide and extracted to give the separated optically active amine base which can be reused.

009840/2307

The'2- (b'-Hc thox.y-2 ¹ -iin.phth.yi) -propions; üircn .worden h or / lor; Loll t according to the registration in P ..166 <? 65 '+. 7 ■

described ancestors. Thus, for example, methoxynaphthalene is treated with acetyl chloride in the presence of aluminum chloride in mitrobenzene and gives 2-acetyl-b-methoxynaphthalene. Then we ^ d the orhalbone aoetyl product with f'ior-;> - holin heated to reflux in the presence of sulfur and the product obtained with conc. "ο al ze au ro to 2- (6 '-MobhoJcy-2 ¹ -naphthyl) -es. ^r jigsäur (-i h.yrJrolyslert. Lek' /. ore is rait Mobhanoi in the presence of boron trifluoride. The methylesber obtained is then with sodium hydride and methyl iodide

treated and gives a mixture of the optical d- and 1-isomers of the 2- (6'- i (

^{1-methoxy-2-naphthyl)} -propionic acid ester. The latter are hydrolyzed into the free acids by basic hydrolysis.

The d- and 1-isomers of 2- (6'-metho: xy-2-naphthyl) propionic acid and racemic mixtures thereof are anti-inflammatory, analgesic, antipyretic, antipruritic and antipruritic agents. Therefore, these compounds are suitable for treating and relieving inflammation of the skin-musculoskeletal system, joints and tissues. In cases where the above inflammation of pain, fever and itching is accompanied himself * compounds of the invention are also suitable to facilitate this Symptome-- Furthermore, the compounds are Suited per se in the treatment and relief of Sdmerzen, fever and itching. Therefore, the compounds erfindungsgemäüen ■ of formula 1 and Il for treatment of the above symptoms in combination with contact dermatitis, allergic rashes, rheumatism, lacerations can post-traumatic conditions, etc. are used in mammals and humans _t ircULn, 'in arthritis. The compounds according to the invention are administered in a known pharmaceutical way, such as orally, in doses of 1.0-60 mg per kg of body weight per day. Most diseases respond to treatment at a dose between 2-50 mg per kg of body weight. For oral use

0 098A072307

Abroichung is achieved through the incorporation of some common otreckmittfcln pharmaceutically acceptable, non-toxinous preparation. Suitable Extenders include lactose, magnesium stearate, dry skimmed milk, etc. These preparations! «Inside in the form of solutions, suspensions, tablets, capsules, Powders, depot formulierurigon, etc. can be used. Furthermore, the orf ind according to connections in connection with andorer / ncdiz in i see means given to treat the symptoms associated with the above disorders will.

■ The following examples illustrate the present invention without it

Example 1

By the addition of 68.7 g of d-2- (6 '-Hethoxy ^{1-2-naphthyl)} propionic acid to 1.2 1 of boiling methanol was added a saturated solution of the acid in methanol is manufactured •. The resulting solution was heated to boiling until it became cloudy; then sufficient methanol was added to make them clear again. Then this hot solution was stirred into a mixture of 8tf, 3g cinchoni

* 'din in 2.2 l of methanol (heated to about 6 ° C.) to pe. The received hot

The mixture was allowed to slowly come to room temperature with stirring.

™ Then it was left for 2 hours. The cold mixture was filtered,

the filtered salt washed with 5 parts ice-cold methanol and drunk under reduced pressure; There was thus obtained the cinchonidine salt of d-2- (6''methoxy-2-naphthyl ¹⁾ propionic acid.

By using ethanol, propanol or butanol instead of methanol in the above procedures the same results were obtained.

98.40 / 230

0AD ORfQINAl.

He is r> i ο 1

üine Löaunc from 22.9 g of l-2- (6'-methoxy-2-naphthyl ¹⁾ propionic acid in 6 ^l iO ecm heitfem methanol was added to a hot solution of 29>'+ ζ cinchonidine in 750 cc of methanol, the mixture obtained was allowed to come to room temperature with stirring and then evaporated to dryness; this gave the ginchonidine salt of l-2- (6'-ethoxy-2 ¹ -n.aphthy.1) -propionic acid.

By using ethyl acetate, butyl acetate, or amyl acetate instead of • Methanol in the above procedure gave the same results. ■

Example 3 ' M

Part A . -

A saturated 5O: 5O solution of d- and l-2- (6'-r-methoxy-2'-naphthyl) propionic acid in methanol was prepared by dissolving 230 g of the racemic mixture in 4.6 l of warm methanol . The solution obtained was heated to boiling until it became cloudy; then sufficient methanol was added to make the solution clear again. This hot solution was added to a solution of 296 g of cinchonidine in 7 μl of methanol (heated to about 60 ° C.). The solutions were combined without stirring and the combined mixture was then allowed to come to room temperature over 2 hours. During this ex λ cooling time the reaction mixture was 0t5 g of the pulverized Cichönidinsalzes of d-2- (6 '-i ^ ethoxy-2 ^1-naphthyl) propionic acid inoculated. After the reaction mixture reached room temperature, it was stirred for an additional 2 hours; the filtered salt was washed with 6 portions of ice-cold methanol and dried under vacuum. . ■ Part B,

A saturated solution of the above salt in methanol was prepared by initially dissolving 100 g of the salt in K 1 methanol (heated to about 60 ° C.). The mixture was then heated to reflux and additional salt added until the solution became cloudy; then methanol was added to the solution

009840/2307

& ■■

■ - 8 -

to make clear again. The crystallized mixture was allowed to cool to room temperature and during this time 0.1 g of the cinchonidine salt of ^! ^ - (o'-methojfy ^ '- naphthyl / propionic acid was inoculated. After the cooled mixture had been left to stand for 2 hours it was filtered. the filtered salts were washed and gave the cinchonidine salt of d-2- (6'-methoxy-2-naphthyl ¹⁾ propionic acid.

The above recrystallization was 9 times under Verwendimg of 2.5 1 of methanol instead of 4 1 was repeated to afford the cinchonidine salt of d-2- (6'-methoxy-2-naphthyl ¹⁾ propionic acid. The resulting salt was split according to the procedure of Example 4 to give d-2- (6 ' -He thoxy-2 ¹ -naphthyl) propionic acid having a mp of 152-154 ° C .; / <^ _ / _T) = - + 62. Part C.

The filtrates from parts A and B were combined and evaporated. The received 'Salt was added to 1,500 ecm of hot ethanol and the hot mixture was slowly added within 12 hours on OC. let cool down. The cooled mixture was filtered and the filtered salt crystals 5 times with ice-cold ethanol washed. Then the salt was recrystallized 4 more times, first

from 1350 ecm of a 26: 1 mixture of ethanol and water; second from II50 ecm ■ a 55 ^; 2 mixture of ethanol and water; third from 900 ecm a 27: 1-

Made from ethanol and water and finally from 675 ecm of a 26: 1 mixture of ethanol and water; in this way the salt of cinchonide and l »2- (6'-methyl-2i-naphthyl) propionic acid was obtained. The resulting salt was split according to the procedure of I ' Example 4 to give the l-2- (6'44ethoxy-2' -naphthyl) -prop ion-

^; . acid with a F. of 152-154 ⁰ C. Zo (I _n = -62 °.

0 0 98 40 »/ 230" 7O

BATH ORIGINAL

B e i S ρ i e 1

1 kg of the ginchonidinsalζes of d-2- (o'-methoxy-2 ¹ -naphthyl) propionic acid was added with stirring to a mixture of 6 1 of ethyl acetate and 4.5 1 of 2N aqueous hydrochloric acid. After the mixture had been stirred for 2 hours, the ethyl acetate layer was removed, washed neutral with water, dried over sodium sulfate and evaporated; the d-2- (6'-M & hoxy-2 ^l -naphthyl) propionic acid was obtained in this way. .

Similarly ", the l 2- (6'-methoxy-2-naphthyl ¹⁾ was prepared from the propionic acid cinchonidine salt of 1-2- (6 ^{1-methoxy-2'-naphthyl)} -propionic acid.

Example 5

. 732.8 g of a racemiseheη mixture of d- and l-2- (6'-methoxy-2'-naphthyl) propionic acid were added to a hot solution of 91H g of dehydroabietylamine, dissolved in 7 l of methanol, and the solution was added Stir for 3 hours and allow to cool to 20 ° C. After the cooled mixture had been left to stand for more than 10 hours, it was diluted with 5-5 liters of water. The mixture obtained was cooled to 10 ° C. and left to stand for 5 hours. It was then filtered and the salt obtained was washed with 5 portions of cold methanol. The ^r salt was obtained from a mixture of 8 1 of methanol and 3.5 ^ water at 10 C recrystallized ,, the salt was filtered off, dried and recrystallized from 6 1 of methanol and 5 1 of water at 1O ⁰ C. order; the dehydroabietylamine sal ζ of l-2- (6'-TMethox-y-2 ¹ -naphthyl) propionic acid was obtained in this way.

The salt was treated according to Example 4 and gave the l-2- (6 ^l -methoxy-2'-naphthyl) -propionic acid.

BADORIOINAt

0 0984071 ^

If so i ο 1 6

Tune mixture of 284 g of dehydroabietylamine acetate and 1.3 g of ethanol was prepared and heated to the reflux and allowed to cool by 5 ° C. 230 g of l-2- (6 '-hethoxy ^{1-2-naphthyl)} propionic acid is added to this mixture and the hot erhaltemiteaktionsmischung with stirring to room temperature, allowed to warm. Then it was diluted with 2 liters of water and left to stand at about 10 ° C. for 8 hours. The crystals were filtered off, washed with cold methanol and dried under vacuum; there was prepared the Dehydroabietylaminsalz of 1-2- (6 '-methoxy-2 ^1-naphthyl) propionic acid.

Was in the above method, the l-2- (6 '-methoxy-2 ^1-naphthyl) propionic acid is replaced by d-2- (6'-methoxy-2-naphthyl ¹⁾ propionic acid, there was prepared the corresponding dehydroabietylamine salt of the d-2- (6'-4 ^v iethoxy-2 ^l-naphthyl) -rpropionsäure.

Using ethanol, butanol, methylene chloride, chloroform, bromoform, Trichloroethane or tetrachloropropane in the above process instead of methanol similar results were obtained.

example "] _

A saturated solution of the d-2- (ö'-methoxy-2-naphthyl ¹⁾ propionic acid and ethanol produced by the addition of 230 g of the above acid to 1.2 1 of boiling ethanol. The resulting solution was heated to boiling until it became cloudy; then sufficient ethanol was added to make the solution clear again. This solution was then heiiJe Kühren su a mixture of 325 g quinine in 500 cc of ethanol (to about 60 ⁰ C. heated) added. Which he-

keep hot (the 3rd mixture was slowly brought to room temperature with stirring left and then left to stand for 2 hours. The mixture had cooled down on Monday and was concentrated by evaporation, and the salt was added to diethyl ether and Mobhanoi urakriaballi «iort {uo

BAD ORiQINAt

one obtained the quinine salt of d-2- (6'-methoxy-2 ¹ -naphthyl) -propionic acid * -

By. Use; 230 g l-2- (6'-methoxy-2-naphthyl ¹⁾ propionic acid, the d-2- (6'-methoxy-2 ^1-naphthyl) propionic acid in place in the above procedure to give the corresponding quinine salt of l-2 - (6'-Fiethoxy-2 ¹ -naphöiyl) propionic acid.

The above procedure was carried out using the following resolved optically active amine bases in place of quinine and sufficient amounts of ethanol to dissolve the base to give the corresponding salts of the resolved. optically active amine bases and 2- (6'-methoxy-2 ¹ -naphthyl) propionic acid again,

■ '■ ■ ■ + i

fetches: 163 g anabasine, 398 g brucine, 36O g conessin, 297 g cinchonidine, 297 g / - '*

327 g epi, 288 g of morphine, quinidine 327 g, 327 g quinicine, 3i5 Chinamin g, 337 g strychnine, 181 g of glucosamine, solanidine 400 g ,, ¹ 175 g do (- (1-naphthyl) ethylamine, 175 g l -ö (- (I-naphthyl) ethylamine, 122 g d-./& -Methylbenzylamine, 122 g 1-Ok-methylbenzylarain, 76 g 1-2-amino-1-propanol, 90 g d-2-aminobutanol, 90 g 1-2-aminobutanol, 214 g d-threo-2-amino-l-p-nitrophenyl-1,3-popanediol, 136 g d-amphetamine, I56 gd ^ -menthylamine, I56 g 1-menthylamine, 388 g cholesterylamine , 475 g N-cholesterylaniline, 166 g d-2-benzylamino-1-propanol, 166 g 1-2-benylamino-1-propanol, 1665 g 1-ephedrine, 149 g d-deoxyephedrine, 286 g

d-dimethylamino-1,2-diphenyl-3-methyl-2-butanol and 286 g of l-dimethylamino-1,2- U

diphenyl-S-methyl ^ -butanoi. · ·

Virtually the same results were obtained using other inert ones organic solvent instead of ethanol in the above statute of limitations. So can instead of ethanol e.g. methanol, isopropanol, isobutanol, butanol or isopentanol (in sufficient quantities to dissolve the acid and base in the above Way) can be used. .

/ Cinchonine. ·

0 09840/2307

BATH ORIGINAL

Claims (1)

Godparents t α η π ρ rü che
.f Connections of the r'oxmel 1: Ke in which A Jir is a separate, optically active amine base. i ,, 2, - Viu'biiiduri ^ nn according to claim 1, thereby fjekennzeiphnot, dai3 A for Anabnüin, P Brucin, Conessin, Cinchonicin, Cinchonidin, Cinchonin, h'pichinin, Morphine, ^ f quinidn, quinine, strychnine, üehydriabietylamin, ülucosamin, solanin, dt <- (l- i ^ hthyl) -äthylaniin, 1 - & - (l-Naphthyl) -äthylarain, d- C { - ^ methylbenzylamine, 1-θ (- rtethylbenzylamin, 1-2-Amino-l-propanol, 1-2-aminobutanol, d-2-aminobutanol, d-threo ^ -amino-lp-nitrophenyl-l ^ -propanediol, d-araphethamine, dM en thy la min, 1-t-lenthylamine, cholesterylamine, N-cholesterylaniline, 1-2-benzylamino- l-propanol, d-uesoxyephedrine, 1-i'jphedrine, d-dimethylatlino-1,2-diphenyl-3-lllethyl-2-butanol, l-dimethylamine-1,2-diphenyl-3-diethyl-2-butanol or Dihydroabietylamine stands. _ ₍ '} .- cinchonidine salts of d- and / or l-2- (6' -i ^v iethoxy-2 '-naphthyl) -prop.ion- acid. ™ k.- D ehyd ro ab ie ty lam in s al ze der d- and / or l-2- (6'-methoxy-2 ¹ -naphthyl) - propionic acid. 5 · Quinine salts of d- and / or l-2- (6'-methoxy-2 ¹ -laphthyl) propionic acid. 6.- d- £ <- (l-naphthyl) -äthyla'ninsalze of the d- and / or l-2- (6 '-Üethoxy ^1-2 naphthyl) propionic acid. 6.- lC \ .'- (l-Kai ^ hthyl) -; ith.ylaminsalze of the d- and / or l-2- (6 '-methoxy-2 ¹ naphthyl) -propionsäuro. 09840/2307 bad mm ^α '/. Ancestors to. Making connections of the l'O: rmel 1: CUU -Q AH in which Ä stands for a separated, optically active amiri base, thereby marked, daläman a connection: the i-'orme-l II ;: OH) H I II I with at least 1, ul molar equivalents edner on separate, optically active Amine base in an inert organic solvent alone or in combination with an aqueous solution in which the compound of .Formel II and the optically active amine bases are soluble at a temperature from G C. to treated to the boiling point of the reaction mixture. 8.- method according to claim? _t characterized by the fact that the optically active amine bases are ginchonidine, quinidine, quinine, d- ^ - (1-naphthyl) -ethylarain, l -? (- (l-naphthyl) -ethylamine, d-bimethylamino-l ^ -diphenyl ^ -niethyl ^ - butanol or l-diinethylamino-1,2-diphenyl-3-niethyl-2-butanol is used. 9 · - method according to claim? and 8, characterized in that the inert organic solvent an alkanol, carboxylic acid ester, a halogenated Hydrocarbon or a hydrocarbon solvent is used. 10 .-- Method according to claim 7 to 9 »characterized in that the connection of the formula II with a separated, optically active amine base at a Temperature from about room temperature to the boiling point of the reaction mixture is treated. The patent attorney: ^ 09840/2307 : BATH