DK145080B - METHOD OF ANALOGUE FOR THE PREPARATION OF BENZYLAMINOALKANIC ACIDS OR SALTS OR OPTICALLY ACTIVE ISOMERS THEREOF - Google Patents
METHOD OF ANALOGUE FOR THE PREPARATION OF BENZYLAMINOALKANIC ACIDS OR SALTS OR OPTICALLY ACTIVE ISOMERS THEREOF Download PDFInfo
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- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
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Description
145080145080
Opfindelsen angår en analogifremgangsmåde til fremstilling af hidtil ukendte benzylaminoalkansyrer af den i krav 1's indledning angivne art eller salte eller optisk aktive isomere heraf, og fremgangsmåden er ejendommelig 5 ved det i krav 1's kendetegnende del angivne.The invention relates to an analogous process for the preparation of novel benzylaminoalkanoic acids of the kind or salts or optically active isomers thereof as defined in the preamble of claim 1, and the process is characterized by the characterizing part of claim 1.
Reduktionen .af den dannede schiffbase foretages ved at udføre kondensationen under reducerende betingelser, f.eks. under hydrogenerende betingelser under tilstedeværelse af en hydrogeneringskatalysator. Katalysatoren er 10 sædvanligvis et metal eller et derivat af et metal hørende til platingruppen, f.eks. platin, platinoxider, platinsalte, palladium, iridium, rhodium eller rhenium. De reducerende betingelser kan også tilvejebringes ved anvendelse af et blandet alkalimetalhydrid, f.eks. natriumbor-15 hydrid, lithiumborhydrid, kaliumborhydrid eller lithiumalu-miniumhydrid. De reducerende betingelser kan frembringes in situ eller indføres i reaktionsblandingen, efter at kondensationen har fundet sted.The reduction of the formed schiff base is done by conducting the condensation under reducing conditions, e.g. under hydrogenating conditions in the presence of a hydrogenation catalyst. The catalyst is usually a metal or a derivative of a metal belonging to the plate group, e.g. platinum, platinum oxides, platinum salts, palladium, iridium, rhodium or rhenium. The reducing conditions can also be provided using a mixed alkali metal hydride, e.g. sodium borohydride, lithium borohydride, potassium borohydride or lithium aluminum hydride. The reducing conditions can be produced in situ or introduced into the reaction mixture after the condensation has taken place.
Oxoalkansyrerne med den almene formel II kan frem-20 stilles ved at underkaste en cyklisk β-diketon med den almene formel: alk (IV) \ \ V 1 Γ hvor alk har den i krav 1 angivne betydning, en alkalisk spaltning og udvinde den tilsvarende oxoalkansyre.The oxoalkanoic acids of general formula II can be prepared by subjecting a cyclic β-diketone of the general formula: alk (IV) \ V 1 Γ wherein alk has the meaning of claim 1, an alkaline cleavage and recovering the corresponding oxoalkanoic acid.
Spaltningen udføres fortrinsvis ved hjælp af en 25 stærk alkalimetalbase, f.eks. natriumhydroxid, kaliumhydroxid eller lithiumhydroxid.The cleavage is preferably carried out by means of a strong alkali metal base, e.g. sodium hydroxide, potassium hydroxide or lithium hydroxide.
Der skal her navnlig anføres en fremgangsmåde til fremstilling af R-oxoalkansyrer med formlen: R1 CO - CH2CH2 - CHg - CH2 - CH2 - C00H (II1 ) 2 145080 hvor R1 har de i krav 1 anførte betydninger, hvor en cyclohexanon med formlen:In particular, a process for the preparation of R-oxoalkanoic acids of formula: R1 CO - CH2CH2 - CHg - CH2 - CH2 - C00H (II1) 2 145080 wherein R1 has the meanings set forth in claim 1, wherein a cyclohexanone of the formula:
- R- R
0 underkastes en alkalisk spaltning, og man derefter udvinder den ønskede oxoalkansyre.0 is subjected to an alkaline cleavage and then the desired oxoalkanoic acid is recovered.
5 De cykliske β-diketoner med den almene formel IV ' kan fremstilles ved kondensering af en cyeloalkenylamin med formlen:The cyclic β-diketones of general formula IV 'can be prepared by condensing a cyeloalkenylamine of the formula:
-----VV -----
f \y alk Y (V)f \ y alk Y (V)
VV
hvor alk har den i krav 1 angivne betydning, og X og Y, som kan være ens eller forskellige, hver betyder en la- 1Q vere alkylgruppe eller en phenylgruppe, eller de danner sammen med det nitrogenatom, hvortil de er bundne, en nitro-genholdig mættet heterocyclisk gruppe, hvis ring kan indeholde et andet hetero atom, med et funktionelt derivat af en organisk carboxylsyre med formlen: R1 - CO - Z (VI) 1 c- hvor R^ har de i krav 1 angivne betydninger og Z er et ha- 5 1 1 logenatom eller en R C00 gruppe, hvor R har de krav 1 angivne betydninger.wherein alk is as defined in claim 1 and X and Y, which may be the same or different, each represent a lower alkyl group or a phenyl group, or together with the nitrogen atom to which they are attached form a nitro group. containing saturated heterocyclic group, the ring of which may contain another hetero atom, with a functional derivative of an organic carboxylic acid of the formula: R 1 - CO - Z (VI) 1 c - wherein R 1 has the meanings given in claim 1 and Z is a have a 5 1 1 log atom or an R C00 group, wherein R has the meanings defined in claim 1.
Kondensationen af forbindelsen med formlen (V) med derivatet med formlen (VI) kan udføres under tilstedeværel- 20 se af en katalysator, f.eks. en lewissyre, f.eks. aluminium-chlorid eller bortrifluorid.The condensation of the compound of formula (V) with the derivative of formula (VI) can be carried out in the presence of a catalyst, e.g. a Lewis acid, e.g. aluminum chloride or boron trifluoride.
Forbindelserne med formlen V er fortrinsvis sådanne, i hvilke X og Y sammen danner en cyklisk struktur, f.eks. en pyrrolidin-, en piperidin- eller en morpholingruppe.Preferably, the compounds of formula V are those in which X and Y together form a cyclic structure, e.g. a pyrrolidine, a piperidine or a morpholine group.
25 De som udgangsmateriale anvendte ketoalkansyrer med den almene formel II kan også fremstilles efter en fremgangsmåde, som omfatter en esterificering af en dicarboxylsyre r 3 U5080 med formlen:The ketoalkanoic acids of general formula II used as starting material may also be prepared by a process which comprises esterifying a dicarboxylic acid r 3 U5080 of the formula:
COOHCOOH
alteverything
^COOH^ COOH
hvor alk har den i krav 1 angivne betydning, til fremstilling af en dialkylester deraf, selektiv forsæbning af denne sidstnævnte forbindelse til fremstilling af monoalkyl-5 esteren med formlen: . COOAlk alk-^wherein alk is as defined in claim 1 for the preparation of a dialkyl ester thereof, selectively saponifying this latter compound for the preparation of the monoalkyl ester of the formula:. COOAlk alk- ^
^ COOH^ COOH
hvor alk har den i krav 1 angivne betydning og Alk er en alkylgruppe, underkastelse af denne sidstnævnte forbindelse indvirkning af et halogenerende middel til fremstilling af et syrehalogenid med formlen: COOAlk alk ^*C0 Hal 10 hvor Hal er et halogenatom, Alk en alkylgruppe og alk er som angivet i krav 1, kondensering af dette halogenid med et organisk cadmiumderivat med formlen R Cd X', hvor S har de i krav 1 angivne betydninger og X* er en anion, til fremstilling af ketoalkylester med formlen: ^C00 Alk alk<^ 1wherein alk is as defined in claim 1 and Alk is an alkyl group, subjecting to this latter compound the action of a halogenating agent to produce an acid halide of the formula: COOAlk alk C0 C0 Hal 10 where Hal is a halogen atom, Alk an alkyl group and alk is, as defined in claim 1, condensing this halide with an organic cadmium derivative of the formula R Cd X ', wherein S has the meanings given in claim 1 and X * is an anion for the preparation of ketoalkyl ester of the formula: <^ 1
^ CO - RCO - R
15 i hvilken betydningen af substituenterne alk, Alk og R^ forbliver uændret, som til slut forsæbes i alkalisk medium til fremstilling af en ketoalkansyre med formlen II.15, in which the meaning of the substituents alk, Alk and R 2 remains unchanged, which is finally saponified in alkaline medium to produce a ketoalkanoic acid of formula II.
Opspaltningen kan om ønsket udføres på slutproduktet med formlen I. Fortrinsvis gennemføres opspaltningen 20 ved saltdannelse med en optisk aktiv syre, såsom d-vinsyre, dibenzoyl-d-vinsyre, d-kamfersyre eller abietinsyre, men opspaltningen kan også gennemføres med en optisk aktiv base.The cleavage may, if desired, be carried out on the final product of formula I. Preferably, the cleavage 20 is carried out by salt formation with an optically active acid such as d-tartaric acid, dibenzoyl-d-tartaric acid, d-camphoric acid or abietic acid, but the digestion can also be carried out with an optically active base. .
Anvendelige baser er f.eks. 1-ephedrin, brucinqui-25 nin, partein eller 2-dimethylamino-1-p-nitrophenylpropan- 1,3-diol.Useful bases are e.g. 1-ephedrine, brucine quinine, partein or 2-dimethylamino-1-p-nitrophenylpropane-1,3-diol.
Opfindelsen omhandler også fremstillingen af et salt af en forbindelse med den almene fprmel I med en uorganisk 145080 it eller organisk base eller syre.The invention also relates to the preparation of a salt of a compound of general formula I with an inorganic or organic base or acid.
Af salte med syrer er der fortrinsvis dem med stærke syrer, f.eks. saltsyre, svovlsyre eller myresyre. Der kan også nævnes salte med optisk aktive syrer.Of salts with acids, there are preferably those with strong acids, e.g. hydrochloric, sulfuric or formic acid. Salts with optically active acids may also be mentioned.
5 Som salte med uorganiske baser kan der navnlig næv nes f.eks. salte af alkalimetaller, f.eks. natriumsalte, kaliumsalte og lithiumsalte; ammoniumsalte; salte af jord-alkalimetaller; aluminiumsalte, ferrosalte og magnesiumsalte.In particular, salts with inorganic bases may be mentioned e.g. salts of alkali metals, e.g. sodium salts, potassium salts and lithium salts; ammonium salts; salts of alkaline earth metals; aluminum salts, ferrous salts and magnesium salts.
10 Som salte af organiske baser kan der navnlig nævnes salte med en primær, sekundær eller tertiær lavere alkyl-amin f.eks. ethylarain, triethylamin og diisobutylamin; salte med en substitueret lavere alkylamin, f.eks. aminoethanol og 3-dimetbylaminopropanol-1; salte med en lavere alkylen-15 diamin, f.eks. ethylendiamin, salte med en arylamin, f.eks. a-naphthylamin, o-anisidin og p-phenetidin; salte med en aryl-lavere-alkylamin, f.eks. phenylethylamin og a-methyl-benzylamin; salte med en quaternær ammoniumbase, en guani-dinbase, såsom glyocyamin eller agmatin, og salte med en 20 aminosyre, f.eks. glycin, alanin, 3-alanin, lysin, prolin og nor-valin.In particular, as salts of organic bases, salts having a primary, secondary or tertiary lower alkylamine are mentioned, e.g. ethylarain, triethylamine and diisobutylamine; salts with a substituted lower alkylamine, e.g. aminoethanol and 3-dimethbylaminopropanol-1; salts with a lower alkylene diamine, e.g. ethylenediamine, salts with an arylamine, e.g. α-naphthylamine, o-anisidine and p-phenetidine; salts with an aryl-lower-alkylamine, e.g. phenylethylamine and α-methylbenzylamine; salts with a quaternary ammonium base, a guanidine base such as glyocyamine or agmatine, and salts with a 20 amino acid, e.g. glycine, alanine, 3-alanine, lysine, proline and norvaline.
Forbindelserne med den almene formel I og saltene deraf besidder værdifulde terapeutiske egenskaber. De udøver en anti-aggressiv virkning uden at have andre virk-25 ninger på det centrale nervesystem. De kan derfor anvendes terapeutisk i den menneskelige og veterinære medicin til behandling af psykisk depression forbundet med en tilstand af angst. Som det fremgår af de i det efterfølgende anførte terapeutiske undersøgelser udøver forbindelserne med 30 formlen I en virkning på det centrale nervesystem, der kan sammenlignes med den virkning man opnår ved intracereabral injektion af thyreotropin frigørende hormon (TRH) hos rotter. Fra E. Wei, Nature 253 (1975) 739~7^0 er det kendt, at TRH hos rotter fremkalder våd hunderysten (wet dog sha-35 kes) og nedsætter eller forebygger aggressivitet.The compounds of general formula I and their salts possess valuable therapeutic properties. They exert an anti-aggressive effect without having any other effects on the central nervous system. They can therefore be used therapeutically in human and veterinary medicine to treat mental depression associated with a state of anxiety. As will be seen in the therapeutic studies set forth below, the compounds of Formula I exert an effect on the central nervous system comparable to that achieved by intracereabral injection of thyroidotropin releasing hormone (TRH) in rats. From E. Wei, Nature 253 (1975) 739 ~ 7 ^ 0, it is known that TRH in rats induces wet canine (wet shaking) and reduces or prevents aggressiveness.
145080 5145080 5
Forbindelserne med formlen I kan anvendes som anti-aggressive midler uden nogen depressiv virkning på det centrale nervesystem. Forbindelserne forårsager dels en aktivering af encephalogrammet dels en nerveirritation af 5 samme art som TRH. Disse hinanden supplerende indikationer muliggør en differentiering mellem beroligende midler og midler mod angsttilstande på den ene side og forbindelserne med formlen I på den anden side.The compounds of formula I can be used as anti-aggressive agents without any depressive effect on the central nervous system. The compounds cause an activation of the encephalogram partly and a nerve irritation of the same kind as TRH. These complementary indications enable a differentiation between tranquilizers and antidepressants on the one hand and the compounds of formula I on the other.
Forbindelserne med formlen I har således en virkning, 10 der er forskellig fra virkningen af kendte antidepres Borer, således at det ikke er muligt at foretage nogen sammenligning. De er en ny art beroligende' midler uden hverken at være neurodepressive, såsom benzodiazepiner, f.eks. diazepam eller oxazepam, eller stimulerende midler, såsom amphe-15 taminer, eller ganglieblokkerende, såsom imipramin.Thus, the compounds of formula I have an effect different from the action of known antidepressant borers so that no comparison is possible. They are a new type of sedative without being neurodepressive, such as benzodiazepines, e.g. diazepam or oxazepam, or stimulants such as amphetamines, or ganglia blocking agents such as imipramine.
Den daglige dosis kan variere stærkt afhængigt af den terapeutiske anvendelse, patientens alder og vægt. Den kan f.eks. ligge fra 50 mg til 2000 mg pr dag opdelt i en til fire indgivelser for en mand.The daily dose may vary greatly depending on the therapeutic use, age and weight of the patient. It can e.g. range from 50 mg to 2000 mg per day divided into one to four administrations for one man.
20 Blandt forbindelserne med den almene formel I kan der, som foretrukne forbindelser, anføres: dl-7~(p-fluorbenzylamino)-9~methyldecansyre og dens optisk aktive isomere, dl-T-(p-fluorbenzylamino)-10-metbylundecansyre , 25 dl-?-(p-fluorbenzylamino)-9,9-dimethyldecansyre , dl-7~(p-fluorbenzylamino)-8-methylnonansyre.Among the compounds of general formula I, there may be mentioned as preferred compounds: dl-7 ~ (p-fluorobenzylamino) -9 ~ methyldecanoic acid and its optically active isomer, dl-T- (p-fluorobenzylamino) -10-methylbylundecanoic acid, 25 dl -? - (p-fluorobenzylamino) -9,9-dimethyldecanoic acid, dl-7 ~ (p-fluorobenzylamino) -8-methylnonanoic acid.
Der kan også anføres følgende forbindelser: dl-lt,it-dimethyl-7-(p-fluorbenzylamino )-8-methylnonansyre 30 dl-8-(p-fluorbenzylamino)-9-methyldecansyre , dl-9-(p-fluorbenzylamino)-10-methylundecansyre, og dl-2,8-dimethyl-7-(p-fluorbenzylamino)-nonansyre.The following compounds may also be listed: dl-lt, it-dimethyl-7- (p-fluorobenzylamino) -8-methylnonanoic acid dl-8- (p-fluorobenzylamino) -9-methyldecanoic acid, dl-9- (p-fluorobenzylamino) -10-methylundecanoic acid, and dl-2,8-dimethyl-7- (p-fluorobenzylamino) nonanoic acid.
Blandt forbindelserne med den almenen formel I er den racemiske form mindre aktiv end en af de optisk akti-35 ve former, mere nøjagtigt sagt end den højredrejende isomere.Among the compounds of general formula I, the racemic form is less active than one of the optically active forms, more accurately said than the right-turning isomer.
6 145080 I stedet for den frie syre kan basen eller syreadditionssaltene deraf også være af interesse. De mest interessante er de med en terapeutisk forenelig uorganisk eller organisk base eller med en terapeutisk forenelig uorganisk 5 eller organisk syre.Instead of the free acid, the base or acid addition salts thereof may also be of interest. Most interesting are those with a therapeutically compatible inorganic or organic base or with a therapeutically compatible inorganic or organic acid.
Alkylenkæden i forbindelsen med formlen I kan omfatte mindst et asymmetrisk carbonatom og kan derfor eksistere i en racemisk form eller, om nødvendigt efter at være 'blevet opspaltet, f.eks. ved hjælp af en optisk aktiv orga-10 nisk base eller en optisk aktiv organisk syre, i en optisk aktiv form.The alkylene chain of the compound of formula I may comprise at least one asymmetric carbon atom and may therefore exist in a racemic form or, if necessary after being decomposed, e.g. by an optically active organic base or an optically active organic acid, in an optically active form.
Som alkylgruppe for R^ kan f.eks. anføres n-propyl-, iso-propyl-, n-butyl-, iso-butyl- og tert-butylgrupper.As the alkyl group for R 1, e.g. n-propyl, iso-propyl, n-butyl, iso-butyl and tert-butyl groups are listed.
Substituenten R er fortrinsvis en alkylgruppe med 15 forgrenet kæde, f.eks. en iso-propylgruppe, en tertiær-butylgruppe, en iso-butylgruppe, eller en iso-pentylgrup-pe.The substituent R is preferably an alkyl group having a branched chain, e.g. an iso-propyl group, a tertiary-butyl group, an iso-butyl group, or an isopentyl group.
Alkoxygruppen indeholder fra 1 til 5 earbonatomer i en lige eller forgrenet kæde.The alkoxy group contains from 1 to 5 earbone atoms in a straight or branched chain.
20 Rår R er et halogenatom, er det fortrinsvis et fluor atom. Det kan imidlertid også være et chlor-, brom- eller . 3 lodatom. R kan være en methoxy-, ethoxy-, isopropoxy- eller isobutoxygruppe.If R is a halogen atom, it is preferably a fluorine atom. However, it can also be a chlorine, bromine or. 3 solder atom. R can be a methoxy, ethoxy, isopropoxy or isobutoxy group.
Benzylaminerne med den almene formel III, der anven-25 des som udgangsmaterialer, er omtalte i litteraturen og kan fremstilles efter kendte fremgangsmåder, nemlig ved kondensering af det tilsvarende benzaldehyd med en alkyl-amin under tilstedeværelse af et hydrogeneringsmiddel.The benzylamines of the general formula III used as starting materials are mentioned in the literature and can be prepared by known methods, namely by condensing the corresponding benzaldehyde with an alkyl amine in the presence of a hydrogenating agent.
De efterfølgende eksempler belyser opfindelsen nær- 30 mere.The following examples further illustrate the invention.
Eksempel 1.Example 1.
dl~7~p-fluorbenzylamino-10-methylundecansyre Trin A 1-morpholinocyclohex-1-en 295 g cyclohexanon og 261 g morpholin opløses i 800 35 ml benzen. lår alt er blevet opløst tilsættes 1,5 g p-to-luensulfonsyre, og blandingen opvarmes under tilbagesvaling. Det dannede vand ekstraheres kontinuert ved azeo-tropisk destillering. Efter 20 timers opvarmning er det 145080 τ tilbageværende opløsningsmiddel destilleret af, og den olieagtige rest udvindes. Man får 379 g enamin, der koger under 2 mm Hg ved 115—11T°C. Udbytte 76 %.dl ~ 7 ~ p-fluorobenzylamino-10-methylundecanoic acid Step A 1-morpholinocyclohex-1-ene 295 g cyclohexanone and 261 g morpholine are dissolved in 800 35 ml benzene. If all has been dissolved, add 1.5 g of p-to-luenesulfonic acid and the mixture is heated under reflux. The formed water is extracted continuously by azeotropic distillation. After 20 hours of heating, the remaining solvent is distilled off and the oily residue is recovered. 379 g of enamine are obtained which boils below 2 mm Hg at 115-111 ° C. Yield 76%.
Det rene 1-morpholinocyclohex-1-en har et refrak-5 tivt index på = 1,5122.The pure 1-morpholinocyclohex-1 has a refractive index of = 1.5122.
Trin B 2-(4'-methylvaleryl)cyclohexanonStep B 2- (4'-methylvaleryl) cyclohexanone
Til en opløsning af 16,7 g 1-morpholinocyelohex-1-en i ^ 5 ml chloroform sættes 10,1 g triethylamin. Over en periode på 1 time tilsættes under omrøring 13,4 g iso-10 caproylchlorid i 15 ml chloroform.To a solution of 16.7 g of 1-morpholinocyelohex-1-ene in 5 ml of chloroform is added 10.1 g of triethylamine. Over a period of 1 hour, with stirring, 13.4 g of iso-10 caproyl chloride in 15 ml of chloroform are added.
Blandingen omrøres i 2 timer ved stuetemperatur og opvarmes derefter til 6o°C i 3 timer. Den henstår natten over, hvorefter der tilsættes 150 ml saltsyre. Blandingen omrystes og henstår derefter til bundfældning. Chloro-15 formfasen skilles fra. Den vandige fase neutraliseres delvis med natriumcarbonat, indtil pH værdien når 6, hvorefter den ekstraheres med chloroform tre gange. De organiske faser samles, vaskes med vand, tørres over -iatriumsul-fat, filtreres og inddampes til tørhed.The mixture is stirred for 2 hours at room temperature and then heated to 60 ° C for 3 hours. It is left to stand overnight, after which 150 ml of hydrochloric acid is added. The mixture is shaken and then allowed to settle. The chloro-15 form phase is separated. The aqueous phase is partially neutralized with sodium carbonate until the pH reaches 6, then it is extracted with chloroform three times. The organic phases are combined, washed with water, dried over sodium sulfate, filtered and evaporated to dryness.
20 Den rå rest, der vejer 20,1 g renses ved destilla tion under nedsat tryk. Man får 10,3 g af den rene cyclohexanon, udbytte 55 %· 2-(4'-methylvaleryl)cyclohexanon er en væske, der koger ved 96-100°C under 0,3 mm Hg.The crude residue weighing 20.1 g is purified by distillation under reduced pressure. 10.3 g of pure cyclohexanone are obtained, yield 55% · 2- (4'-methylvaleryl) cyclohexanone is a liquid which boils at 96-100 ° C under 0.3 mm Hg.
25 = 1 ,489525 = 1, 4895
Analyse: C^E2Q02 = 196,28 C % H %Analysis: C ^ E₂O₂ = 196.28 C% H%
Beregnet: 73,43 10,27Calculated: 73.43, 10.27
Fundet: 72,91 10,13 30 Trin C 7~oxo-10-methylundecansyre.Found: 72.91 10.13 Step C7 ~ oxo-10-methylundecanoic acid.
10 g 2-(4'-methylvaleryl)cyclohexanon sættes til 70 ml af 5 %'s vandig opløsning af natriumhydroxid. Blandingen opvarmes under tilbagesvaling i 2 timer. Den vandige opløsning gøres derefter sur med en 4 N saltsyreopløsning og 35 ekstraheres med ether. Etherfasen skilles fra, vaskes med en mættet opløsning af natriumchlorid, tørres over natriumsulfat, filtreres og inddampes til tørhed. Den tilbageblivende faste rest, der vejer 9 g, henstår derefter ved 8 145080 stuetemperatur. Krystalliseringen begynder hurtigt. Krystallerne udvindes og omkrystalliseres i n-pentan; udbytte 6,2 g.10 g of 2- (4'-methylvaleryl) cyclohexanone are added to 70 ml of 5% aqueous solution of sodium hydroxide. The mixture is heated under reflux for 2 hours. The aqueous solution is then acidified with a 4N hydrochloric acid solution and extracted with ether. The ether phase is separated, washed with a saturated solution of sodium chloride, dried over sodium sulfate, filtered and evaporated to dryness. The remaining solid residue, weighing 9 g, is then left at room temperature. Crystallization begins quickly. The crystals are extracted and recrystallized from n-pentane; yield 6.2 g.
7-oxo-1O-methylundeeansyre smelter ved k9~51°C.7-Oxo-10-methylundeanic acid melts at k9 ~ 51 ° C.
5 Trin D dl-7-p-fluorbenzylamino-1O-methylundecansyre.Step D dl-7-p-fluorobenzylamino-10-methylundecanoic acid.
En frisk opløsning af 1,75 g p-fluorbenzylamin og 1,¾ g methylamin sættes til en opløsning af 3 g 7~oxo-10-methylundecansyre i 20 ml ethanol. Blandingen opvarmes til ij-0°C natten over. Derefter tilsættes 0,1 g platinoxid, 10 og blandingen hydrogeneres under normalt tryk ved 1i0°C. liår den teoretiske mængde hydrogen er blevet absorberet, filtreres katalysatoren fra, og opløsningsmidlet bortdampes under nedsat tryk. Den olieagtige rest udkrystalliserer hurtigt ved stuetemperatur. Man får k,2 g krystaller; 15 udbytte 9¾ %. Produktet renses ved omkrystallisering i 30 ml acetonitril og tørres over phosphoranhydrid i en lukket beholder. Udbytte 3 g.A fresh solution of 1.75 g of p-fluorobenzylamine and 1.1 g of methylamine is added to a solution of 3 g of 7 ~ oxo-10-methylundecanoic acid in 20 ml of ethanol. The mixture is heated to 0 ° C overnight. Then 0.1 g of platinum oxide is added, 10 and the mixture is hydrogenated under normal pressure at 100 ° C. After the theoretical amount of hydrogen has been absorbed, the catalyst is filtered off and the solvent is evaporated under reduced pressure. The oily residue crystallizes rapidly at room temperature. You get k, 2 g of crystals; 15 yield 9¾%. The product is purified by recrystallization in 30 ml of acetonitrile and dried over phosphoric anhydride in a sealed container. Yield 3 g.
7~(p-fluorbenzylamino)-10-methylundecansyre er et krystallinsk fast stof, der smelter ved 8^-85°C.7 ~ (p-Fluorobenzylamino) -10-methylundecanoic acid is a crystalline solid which melts at 8 ° -85 ° C.
20 Analyse: C^H^qFUO,, = 323,¾¾.Analysis: C ^H ^ qFUO ,, = 323, ¾¾.
C % Η $ Έ %C% Η $ Έ%
Beregnet: 70,56 9,3¾ ^33Calculated: 70.56 9.3¾ ^ 33
Fundet: 70,36 9,1 U^7 7-(p-fluorbenzylamino)-1O-methylundecansyre kan om-. 25 dannes til et salt ved tilsætning af en støkiometrisk mæng de natriumcarbonat og bortdampning af opløsningsmidlet.Found: 70.36 9.1 U 7 7- (p-Fluorobenzylamino) -1O-methylundecanoic acid can be converted to. 25 is formed into a salt by the addition of a stoichiometric amount of the sodium carbonate and evaporation of the solvent.
Eksempel 2 til 7.Examples 2 to 7.
dl-7~(pura-fluorbenzylamino)-9~methyldeeansyredl-7 ~ (pura-fluoro-benzylamino) -9 ~ methyldeeansyre
Ved at anvende den fremgangsmåde, der er beskrevet 30 i eksempel 1, har man fremstillet: 1- morpholinocyclohex-1-en 2- ( ¾' -methylvaleryl)cyclohexanon ; kogepunkt 102-10^0/Using the procedure described in Example 1, one has prepared: 1- morpholinocyclohex-1-ene 2- (¾'-methylvaleryl) cyclohexanone; boiling point 102-10
pQp Q
0,¾ mm Hg, n^ = 1^930, udbytte 60 % 7-oxo-9-methyldecansyre; smeltepunkt 32-36°C, udbyt-35 te 83 % dl-(7-p-fluorbenzylamino)-9_methyldecansyre, smeltepunkt = 79_83°C (acetonitril).0, ¾ mm Hg, n ^ = 1 ^ 930, yield 60% 7-oxo-9-methyldecanoic acid; mp 32-36 ° C, yield 83% dl- (7-p-fluorobenzylamino) -9-methyldecanoic acid, mp = 79_83 ° C (acetonitrile).
* 145080 9* 145080 9
Analyse: CiøH28FIi02 = 3°9,41Analysis: CøHH₂FFiO₂ = 3 ° 9.41
Cl Η % Ν %Cl Η% Ν%
Beregnet: 69,87 9,12 Η,53Calculated: 69.87 9.12 53, 53
Fundet: 69,85 9,09 4,71 5 ai-7-(para-fluorbenzylamino)-8-methylnonansyreFound: 69.85 9.09 4.71 α-7- (para-fluorobenzylamino) -8-methylnonanoic acid
Ved at anvende den fremgangsmåde, der er beskrevet i eksempel 1, har man fremstillet: 2-(isobutyroyl)-cyclohexanon 7-oxo-8-methylnonansyre 10 dl-7”(para-fluorbenzylamino)-8-methylnonansyre · smel tepunkt 88-89°C (ethylacetat)Using the procedure described in Example 1, 2- (isobutyroyl) -cyclohexanone 7-oxo-8-methylnonanoic acid 10d-7 ”(para-fluorobenzylamino) -8-methylnonanoic acid · melting point 88- 89 ° C (ethyl acetate)
Analyse: C1TH26FN02 = 294,38 C% H % N %Analysis: C1TH26FNO2 = 294.38 C% H% N%
Beregnet: 69,3 9 8,56 4,76 15 Fundet: 69,21 8,76 *1,52 dl-7-(para-fluorbenzylamino)-9,9~dimethyldecansyreCalculated: 69.3 9 8.56 4.76 Found: 69.21 8.76 * 1.52 dl-7- (para-fluorobenzylamino) -9.9 ~ dimethyldecanoic acid
Ved at anvende den fremgangsmåde, der er beskrevet i eksempel 1, har man fremstillet: 1-morpholinocyclohex-1-en 20 2-(2,2-dimethyl-4-oxobutyl)cyclohexanon kogepunkt 82—8U°C/0,1 mm Hg; udbytte 61 %, njp = 1 ,U885 7-OXO-9,9_dimethyldecansyre, smeltepunkt 25_26°C, udbytte 80 % dl-7-(para-fluorbenzylamino)~9,9-dimethyldecansyre, 25 smeltepunkt = 63-65°C (acetonitril).Using the procedure described in Example 1, one has prepared: 1-morpholinocyclohex-1-ene 2- (2,2-dimethyl-4-oxobutyl) cyclohexanone boiling point 82-8U ° C / 0.1 mm Hg; yield 61%, njp = 1, U885 7-OXO-9.9-dimethyldecanoic acid, m.p. 25_26 ° C, yield 80% dl-7- (para-fluorobenzylamino) ~ 9,9-dimethyldecanoic acid, m.p. = 63-65 ° C acetonitrile).
Analyse: C19H3C)FN02 = 323,44Analysis: C 19 H 3 C) FNO 2 = 323.44
Cl H I I ICl H I I I
Beregnet: 70,56 9,3¾ 4,33Calculated: 70.56 9.3¾ 4.33
Fundet: 70,18 9,18 4,52 30 dl-6-(para-fluorbenzylamino)-7-methylpctansyreFound: 70.18 9.18 4.52 dl-6- (para-fluorobenzylamino) -7-methylpectanoic acid
Ved at anvende den fremgangsmåde, der er beskrevet i eksempel 1, har man fremstillet: 1- morpho1inocyclopent-1-enon 2- isobutyroylcyclopentanon 35 kogepunkt = 98-100°C/13 mm Hg, udbytte 56 l n^3 '= 1 ,4790 145080 ίο 6-oxo-7-methyloetansyre kogepunkt = 12l+-127°C/0,05 mm Hg, udbytte 77 %, n21 = ]fkk60 dl-6-(para-fluorbenzylamino)-7-methyloctansyre 5 Analyse: C^H^FHO,, = 281 ,36 C % H % IS %Using the procedure described in Example 1, one has prepared: 1-morpholinocyclopent-1-enone 2-isobutyroylcyclopentanone boiling point = 98-100 ° C / 13 mm Hg, yield 56 ln ^ 3 '= 1, 4790 Boiling point = 12l + -127 ° C / 0.05 mm Hg, yield 77%, n21 =] fkk60 dl-6- (para-fluorobenzylamino) -7-methyloctanoic acid Analysis: C FHO, = 281, 36 C% H% IS%
Beregnet: 68,30 8,60 li, 98Calcd: 68.30 8.60 li, 98
Fundet: 67*89 8,1+8 5,19 smeltepunkt = 109-115°C (aeetonitril) 10 Denne forbindelse er opløselig i en H/10 saltsyre opløsning .Found: 67 * 89 8.1 + 8 5.19 Melting point = 109-115 ° C (aeetonitrile) 10 This compound is soluble in a H / 10 hydrochloric acid solution.
dl-l+ ,l+-dimethyl-7-p ara-f luorb en zylamino-8-metIiylnonansyre Ved at anvende den fremgangsmåde, der er beskrevet i eksempel 1, er følgende forbindelser blevet fremstillet: 15 1-morpholino-b,l+-dimethyleyclohex-1-en 2-isobutyroyl-l+, l+-dimethylcyclohexanon kogepunkt = 76-80°C/0,1 mm Hg, udbytte = bo %, n23 = 1,1+81+0 1+, l+-dimetbyl-7-oxo-8-methylnonansyre 20 kogepunkt = 136-1 l+0°C/0,05 mm Hg, udbytte = 55 %, n22 = 1,1+550 dl-l+,l+-dimethyl-7~(para-fluorbenzylamino)-8-methyl-nonansyre, smeltepunkt = ll+5~ll+80C (methyl-2-ethoxy-ethanol) . 25 Analyse: C^H FHOg = 323,1+5 C % Η % II %dl-l +, l + -dimethyl-7-p ara-fluorob a zylamino-8-methylnonanoic acid Using the procedure described in Example 1, the following compounds have been prepared: 1-morpholino-b, l + -dimethylleyclohex -1-en 2-isobutyroyl-l +, l + -dimethylcyclohexanone boiling point = 76-80 ° C / 0.1 mm Hg, yield = bo%, n23 = 1.1 + 81 + 0 + 1, 1 + -dimethylbyl-7- oxo-8-methylnonanoic acid boiling point = 136-1 l + 0 ° C / 0.05 mm Hg, yield = 55%, n22 = 1.1 + 550 dl-l +, l + -dimethyl-7 ~ (para-fluorobenzylamino) -8-methyl nonanoic acid, m.p. = 11 + 5 ~ 11 + 80C (methyl 2-ethoxy-ethanol). Analysis: C ^H FHOg = 323.1 + 5 C% Η% II%
Beregnet: 70,56 9,35 1+,33Calc'd: 70.56 9.35 +1, 33
Fundet: 70,1+2 9,21 1+, 52 dl~7~(p-chlorbenzylamino)-8-methylnonansyre 30 Ved at anvende fremgangsmåden, der er beskrevet i eksempel 1, og anvende p-chlorbenzylamin som udgangsmateriale fås den ovennævnte forbindelse med et smeltepunkt = 79-85°C (aeetonitril).Found: 70.1 + 2 9.21 1+, 52 dl ~ 7 ~ (p-chlorobenzylamino) -8-methylnonanoic acid 30 Using the procedure described in Example 1 and using p-chlorobenzylamine as starting material, the above compound having a melting point = 79-85 ° C (aeetonitrile).
Analyse: C^H^Cl HOg = 311,8¼ 35 C % E % 1 ? Cl faAnalysis: C ^H ^ClHOg = 311.8¼ 35% C% E% 1? Cl fa
Beregnet: 65,1+9 8,1+1 1+,50 1 1 ,37Calculated: 65.1 + 9 8.1 + 1 1 +, 50 1 1, 37
Fundet: 65,56 8,35 U,81 11,06 145080 1 1Found: 65.56 8.35 U, 81 11.06 145080 1 1
Denne forbindelse er opløselig i en N/10 saltsyreopløsning og giver en svag sur opløsning.This compound is soluble in a N / 10 hydrochloric acid solution and gives a slightly acidic solution.
Eksempel 8.Example 8.
7~(p~fluorbenzylamino)-8-methylnonansyre (venstredrej ende 5 isomer)7 ~ (p ~ fluorobenzylamino) -8-methylnonanoic acid (left-side 5 isomer)
Trin AStep A
Man går ud fra 2k0 g dl-7~(p-fluorbenzylamino )-8-methylnonansyre og ethanol under tilstedeværelse af svovlsyre ved tilbagesvalingstemperatur, og man får 188,67 g 10 ethylester af dl-7-(p-fluorbenzylamino)-8-methylnonansyre.2k0 g of dl-7 ~ (p-fluorobenzylamino) -8-methylnonanoic acid and ethanol in the presence of sulfuric acid at reflux temperature are obtained and 188.67 g of ethyl ester of dl-7- (p-fluorobenzylamino) -8- methylnonansyre.
Udbytte = 67 !’, kogepunkt = 1U2 — 1 l+7°C/0 ,01 mm Hg.Yield = 67 °, boiling point = 1U2 - 1l + 7 ° C / 0.1 mm Hg.
Trin BStep B
I en kolbe opløses 125 g ethylester af dl-7-(p-fluorbenzylamino )-8-methylnonansyre i 550 ml ethanol. Derefter 15 tilsættes 8 g palladiseret trækul, og blandingen befries for atmosfærisk oxygen ved gennembobling af nitrogen. Hydrogeneringen gennemføres derefter ved atmosfærisk tryk og opvarmning til ca 60°C. Efter 1 time er den teoretiske mængde hydrogen blevet absorberet, og katalysatoren filtre-20 res fra ved sugning og vaskes derefter med ethanol. De ethanoliske filtrater forenes, affarves med trækul, filtreres og inddampes. Man får 92 g af ethylesteren af dl-7~ amino-8-methylnonansyre. Dette råprodukt renses yderligere ved fraktioneret destillation, udbytte 93 %. Ethylesteren 25 af 7-amino-8-methylnonansyre er en væske, der koger ved 81+-87°C/0,0 1 mm Hg, n^° = 1,1+1+70, protometrisk titrering: 102 - 2 %.In a flask, 125 g of ethyl ester of dl-7- (p-fluorobenzylamino) -8-methylnonanoic acid are dissolved in 550 ml of ethanol. Then, 8 g of palladized charcoal is added and the mixture is freed from atmospheric oxygen by bubbling nitrogen. The hydrogenation is then carried out at atmospheric pressure and heated to about 60 ° C. After 1 hour, the theoretical amount of hydrogen has been absorbed and the catalyst is filtered off by suction and then washed with ethanol. The ethanolic filtrates are combined, decolorized with charcoal, filtered and evaporated. 92 g of the ethyl ester of dl-7 ~ amino-8-methylnonanoic acid are obtained. This crude product is further purified by fractional distillation, yield 93%. The ethyl ester 25 of 7-amino-8-methylnonanoic acid is a liquid boiling at 81 + -87 ° C / 0.0 1 mm Hg, n + = 1.1 + 1 + 70, protometric titration: 102 - 2% .
Trin CStep C
60,5 g dl-ethylester af 7-amino-8-methylnonansyre 30 opløses i 1+00 ml ethanol. Til denne opløsning sættes 1+2 g d(+) vinsyre under omhyggelig omrøring. Krystalliseringen indledes ved skrabning, og opløsningen henstår natten over på et koldt sted. Den krystallinske blanding skilles fra ved filtrering, tørres, og omkrystalliseres i ethanol, hvor-35 ved man får 26 g af et råprodukt, der smelter ved 100-103°C. Drejningen af d(+) tartratet er: 1450*0 12 - C«] 5?8 = + 20’^° (C = 1 % vand) [α]^5 = + ^7,9° (C = 1 % vand) optisk renhed målt ved VPC er højere end 95 %·60.5 g of dl-ethyl ester of 7-amino-8-methylnonanoic acid are dissolved in 1 + 00 ml of ethanol. To this solution is added 1 + 2 g of d (+) tartaric acid with careful stirring. The crystallization is initiated by scraping and the solution is left to stand overnight in a cold place. The crystalline mixture is separated by filtration, dried and recrystallized in ethanol to give 26 g of a crude product melting at 100-103 ° C. The rotation of the d (+) tartrate is: 1450 * 0 12 - C «] 5? 8 = + 20 ° C (C = 1% water) [α] 5 = + ^ 7.9 ° (C = 1% water) optical purity measured by VPC is higher than 95% ·
Trin DStep D
5 Det højredrejende d(+) tartrat omdannes til hasen med en natriumhydroxidopløsning, og efter bortdampning af opløsningsmidlet fås 12,8 g højredrejende ethylester af 7" amino-8-methylnonansyre.The right-turning d (+) tartrate is converted to the rabbit with a sodium hydroxide solution, and after evaporation of the solvent, 12.8 g of right-turning ethyl ester of 7 "amino-8-methylnonanoic acid is obtained.
Kogepunkt = 85-89°C/0,05 mm Hg.Boiling point = 85-89 ° C / 0.05 mm Hg.
10 [a3578 = + 14’7° (C = 1 1ΰ ethano1) [a]gg5 = + U1,3° (C = 1 % ethanol)[A3578 = + 14'7 ° (C = 1ΰΰ ethano1) [a] gg5 = + U1.3 ° (C = 1% ethanol)
Trin EStep E
10 g af den højredrejende ethylester af 7~amino-8-methylnonansyre opløses i 50 ml ethanol, hvorefter der til 15 denne opløsning sættes 12 g p-fluorbenzaldehyd. Blandingen opvarmes under tilbagesvaling i 1^ time og bringes derefter tilbage til stuetemperatur. Der tilsættes 10 g triethyl" amin og 0,5 g platinoxid, og hele blandingen hydrogeneres ved atmosfærisk tryk under opvarmning til ca 60°C. Hydro-20 generingen er tilendebragt, når den teoretiske mængde hydrogen er blevet absorberet. Katalysatoren skillesfra ved filtrering, vaskes mange gange med ethanol, og de alkoholiske filtrater forenes. Opløsningsmidlet destilleres fra, og man får en hvid krystallinsk masse. Efter omkrystal-25 lisation i isopropylether fås et udbytte på 89 % af den venstredrej ende ethylester af 7~(para-fluorbenzylamino)-8-methylnonansyre. Kogepunkt = 128-13^°C/0,02 mm Hg. ίαή2η = - 3,U° (C * 1 ί ethanol) [a]^g5 = - 13,6° (C = 1 % ethanol)Dissolve 10 g of the right-turning ethyl ester of 7-amino-8-methylnonanoic acid in 50 ml of ethanol and add 12 g of p-fluorobenzaldehyde to this solution. The mixture is heated at reflux for 1 hour and then brought back to room temperature. 10 g of triethylamine and 0.5 g of platinum oxide are added and the whole mixture is hydrogenated at atmospheric pressure under heating to about 60 ° C. Hydrogenation is completed when the theoretical amount of hydrogen has been absorbed. The solvent is distilled off to give a white crystalline mass. After recrystallization in isopropyl ether, 89% of the left-end ethyl ester of 7 ~ (para-fluorobenzylamino) is obtained -8-methylnonanoic acid Boiling point = 128-13 ° C / 0.02 mm Hg ίαή2η = -3, U ° (C * 1 ethanol) [a] + g5 = - 13.6 ° (C = 1% ethanol)
30 Trin FStep F
6,2 g venstredrej ende ethylester af 7-(para-fluor-benzylamino)-8-methylnonansyre opløses i 25 ml ethanol.6.2 g of left-turn ethyl ester of 7- (para-fluoro-benzylamino) -8-methylnonanoic acid are dissolved in 25 ml of ethanol.
Til denne opløsning sættes 100 ml af en 2 N natriumhydroxidopløsning i ethanol, og hele blandingen holdes under 145090 13 omrøring ved ca 10°Ci 2 timer. Reaktionsmediet gøres derefter let surt ved tilsætning af eddikesyre og henstår natten over. Det uopløselige uorganiske materiale filtreres fra, og filtratet inddampes og giver venstredrej ende 5 7“(p-fluorbenzylamino)-8-methylnonansyre. Udbytte = 90 %.To this solution is added 100 ml of a 2N sodium hydroxide solution in ethanol and the whole mixture is kept under stirring at about 10 ° C for 2 hours. The reaction medium is then made slightly acidic by the addition of acetic acid and left overnight. The insoluble inorganic material is filtered off and the filtrate is evaporated to give left-hand end 7 7 '(p-fluorobenzylamino) -8-methylnonanoic acid. Yield = 90%.
Syren omkrystalliseres i acetonitril og giver krystaller, der smelter ved 91-100°C.The acid is recrystallized from acetonitrile to give crystals melting at 91-100 ° C.
= 5,1° (C = 1 % buffer pH 7) ία]^5 = 16,5° (0=1* buffer pH 10) 1q Eksempel 9·= 5.1 ° (C = 1% buffer pH 7) δα = 5.5 = 16.5 ° (0 = 1 * buffer pH 10) 1q Example 9 ·
Højredrejende 7~(para-fluorbenzylamino)-8-methylnonansyre Trin ARight-turning 7 ~ (para-fluorobenzylamino) -8-methylnonanoic acid Step A
Fra moderluden fra trin C i eksempel g fås der efter inddampning under nedsat tryk, omdannelse af den frie base, 12 tilsætning af 1(-) vinsyre, udvinding af det derved udfældede 1(-) tartrat og omkrystallisation i ethanol 30 g af den venstredrej ende ethylester af 7-amino-8-methylnonan-syre, 1(-) tartrat, forbindelsen smelter ved 100-103°C.From the mother liquor of step C of Example g, after evaporation under reduced pressure, conversion of the free base, 12 addition of 1 (-) tartaric acid, recovery of the thus precipitated 1 (-) tartrate and recrystallization in ethanol are obtained 30 g of the left turn. end ethyl ester of 7-amino-8-methylnonanoic acid, 1 (-) tartrate, the compound melts at 100-103 ° C.
[ c<] 578 = - 20° (C = 1 * vand) 2o [ce]365 - ~ 1*6,6° (C = 1 * vand) 1(-) tartratet omdannes til den frie base. Udbytte 15,1* g.[c <] 578 = - 20 ° (C = 1 * water) 2o [ce] 365 - ~ 1 * 6.6 ° (C = 1 * water) The 1 (-) tartrate is converted to the free base. Yield 15.1 * g.
[a] 578 = - 11*, 5° (C = 1 * ethanol) [α]365 = “ 1*0,6° (C = 1 * ethanol)[α] 578 = - 11 °, 5 ° (C = 1 * ethanol) [α] 365 = "1 * 0.6 ° (C = 1 * ethanol)
25 Trin BStep B
Anvendes den i trin E i eksempel 8 beskrevne fremgangsmåde fås højredrejende ethylester af 7-(p~fluorbenzyl-amino)-8-methylnonansyre i et udbytte på 82 *. Kogepunkt 11*0-11*1 °C/0,08 mm Hg.If the process described in step E of Example 8 is used, the right-turning ethyl ester of 7- (p-fluorobenzylamino) -8-methylnonanoic acid is obtained in a yield of 82 *. Boiling point 11 * 0-11 * 1 ° C / 0.08 mm Hg.
30 [a]578 = + 3’6° (C = 1 * ethanol) [α]^^ = + 16,6° (C = 1 * ethanol)[A] 578 = + 3'6 ° (C = 1 * ethanol) [α] + = 16.6 ° (C = 1 * ethanol)
Trin CStep C
Anvendes fremgangsmåden, der er omtalt i trin F i eksempel 8, fås højredrejende J-(p-fluorbenzylamino )-8-22 methylnonansyre i et udbytte på 90 *. Det smelter ved 91 -99°C.If the procedure described in step F of Example 8 is used, right-turning J- (p-fluorobenzylamino) -8-22 methylnonanoic acid is obtained in a yield of 90 *. It melts at 91 -99 ° C.
[ot] ^55 55 + 1 5,7° (0=1* buffer pH 7) 145080[α] D 55 55 + 1 5.7 ° (0 = 1 * buffer pH 7)
Eksempel 10.Example 10.
dl-9-(para-fluorbenzylamino)-1O-methylundecansyredl-9- (para-fluoro-benzylamino) -1O-methylundecanoic acid
Man amrender den i eksempel 1, trin D, beskrevne • fremgangsmåde, men går ud fra 9-oxo-1O-methylundecansyre 5 og para-fluorbenzylamin, hydrogenerer derefter under tilstedeværelse af en platinkatalysator og får dl~9~(para-fluarbenzylamino)-1O-methylundecansyre. Smeltepunkt 78-82°C efter omkrystallisation i acetonitril.The procedure described in Example 1, step D, is modified, but starting from 9-oxo-10O-methylundecanoic acid 5 and para-fluorobenzylamine, then hydrogenated in the presence of a platinum catalyst and obtained dl ~ 9 ~ (para-fluarobenzylamino) - 1O-methylundecanoic acid. Melting point 78-82 ° C after recrystallization in acetonitrile.
Denne forbindelse er let opløselig i en vandig 10 saltsyreopløsning.This compound is readily soluble in an aqueous 10 hydrochloric acid solution.
Analyse: ^H^FNOg = 323,51 C % Η % I %Analysis: HH ^FNOg = 323.51 C% Η% I%
Beregnet: 70,5¾ 9,3¾ ^33Calculated: 70.5¾ 9.3¾ ^ 33
Fundet: 70,61 9,08 U,U0 15 Udgangsmaterialet 9-oxo-1O-methylundecansyre er fremstillet efter den fremgangsmåde, der er beskrevet af S. Akiya, Journal Phar. Soc. Jap. 76, ^01-2 (1956).Found: 70.61 9.08 U, U0 15 The starting material 9-oxo-10O-methylundecanoic acid is prepared according to the procedure described by S. Akiya, Journal Phar. Soc. Jap. 76, 01-2 (1956).
Eksempel 11.Example 11.
dl-8-parafluorbenzylamino-9-methyldecansyre 20 Man anvender den fremgangsmåde, der er beskrevet i eksempel 1, trin D, men går ud fra 8-oxo-9-methyldecansyre og para-fluorbenzylamin og får dl-8-(para-fluorbenzylamino)-9-methyldecansyre.dl-8-parafluorobenzylamino-9-methyldecanoic acid The procedure described in Example 1 is used in step D, but starting from 8-oxo-9-methyldecanoic acid and para-fluorobenzylamine, and dl-8- (para-fluorobenzylamino) is obtained. ) -9-methyl decanoic acid.
Det smelter efter omkrystallisation i acetonitril , 25 ved 110-11U°C.It melts after recrystallization in acetonitrile, at 110-11U ° C.
Analyse: C18H28FF02 = 309^3 C % Η % N %Analysis: C18H28FF02 = 309 ^ 3 C% Η% N%
Beregnet: 69,87 9,12 ^53Calculated: 69.87 9.12 ^ 53
Fundet: 70,38 8,90 ^80 30 Udgangsmaterialet 8-oxo-9-methyldecansyre er frem stillet efter en fremgangsmåde, der er beskrevet af S. Akiya, Journal Pharm. Soc. Jap. 76, ^01-2 (1956).Found: 70.38 8.90 ^ 80 The starting material 8-oxo-9-methyldecanoic acid is prepared according to a method described by S. Akiya, Journal Pharm. Soc. Jap. 76, 01-2 (1956).
Terapeutiske undersøgelser af de efter fremgangsmåden ifølge opfindelsen fremstillede forbindelser.Therapeutic studies on the compounds of the present invention.
35 a) akut toxicitetA) acute toxicity
Forbindelserne fremstillede efter fremgangsmåden i-følge opfindelsen er blevet undersøgte for akut toxicitet # ' 15 145080 ved tab af mus af stammen C.C. som vejede ca 20 g. Stigende doser blev indgivet ad intraperitoneal vej eller oralt.The compounds prepared according to the method of the invention have been tested for acute toxicity # 145080 in the loss of mice of the strain C.C. weighing approximately 20 g. Increasing doses were administered by intraperitoneal route or orally.
Dyrene blev holdt under opsyn i 8 dage, og dødsfaldene, hvis der var nogle, blev talt. Gennemsnits dødelig doeis 5 li>5o beregnet efter Wilcox og Lichtfields fremgangs- ‘ måde. Ved intraperitoneal indgift var LD^-området fra 50 til 200 mg/kg og ved oral indgift fra 100 til 300 mg/kg, hovedsageligt fra 100 til 200 mg/kg. Resultaterne af disse forsøg er vist i den efterfølgende tabel.The animals were kept under surveillance for 8 days and the deaths, if any, were counted. Average lethal doeis 5 li> 5o calculated according to Wilcox and Lichtfield's manner. For intraperitoneal administration, the LD 2 range was from 50 to 200 mg / kg and for oral administration from 100 to 300 mg / kg, mainly from 100 to 200 mg / kg. The results of these experiments are shown in the following table.
10 b) virkninger på det centrale nervesystem hos mus.B) effects on the central nervous system of mice.
Den første aktive dosis fremkalder sædvanligvis en let nedsættelse af motiliteten og deh muskulære tonus hos dyrene. Stigende doser fremkalser konvulsioner, mydriasis, tremor og forøgelse af respirationsfrekvensen. Der er in-15 gen toxiske symptomer, ingen depressionstilstand eller hyper exeitabilitet.The first active dose usually induces a slight decrease in motility and de muscular tone of the animals. Increasing doses induce convulsions, mydriasis, tremors, and increase respiratory rate. There are no toxic symptoms, no depression or hyper exertability.
c) aktiveringsvirkning på de somaesthetiske baner (våd hunderysteprøve)c) activation effect on the somaesthetic pathways (wet dog shake test)
Forbindelserne blev undersøgte på han-rotter, der 20 vejede ca 150 g. Hvert hold rotter fik intraperitonealt en dosis af en forbindelse fremstillet ifølge opfindelsen, dog fik et hold kun opløsningsmidlet. Antallet af de derved frembragte rystelser blev bestemt på hvert hold for 5 min, i 30 min efter injektionen, og angiver summen af alle 25 de individuelle rystelser hos holdet.The compounds were tested on male rats weighing approximately 150 g. Each team of rats received a dose of a compound of the invention, but one team received only the solvent. The number of shakes thus produced was determined on each team for 5 min, for 30 min after injection, indicating the sum of all the 25 individual shakes of the team.
De opnåede resultater er proportionale med de indsprøjtede doser, og resultaterne er angivet i den efterfølgende tabel.The results obtained are proportional to the injected doses and the results are given in the following table.
145080 16145080 16
TabelTable
Forbindelse Toxicitet (LD ) Aktiveringsvirkning på ifølge eksem- (mg/kg) 5 de somaesthetiske baner pel i.p. p.o. dosis (mg/kg) antal i.p. rystelser ~ I is 2 200-^00 25 tø 50 129 3 99 - 3 2tø - 30 25 U8 50 121 1* >, 200 50 100 5 170 - 10 277 - 60 ^ 25,0 169Compound Toxicity (LD) Activation effect on, according to eczema (mg / kg), the somaesthetic pathways pel i.p. p.o. dose (mg / kg) number of i.p. shakes ~ I ice 2 200- ^ 00 25 th 50 129 3 99 - 3 2 th - 30 25 U8 50 121 1 *>, 200 50 100 5 170 - 10 277 - 60 ^ 25,0 169
£ S£ S
50 107 7 5°-,0° 50 8 250 ,0 37 50 78 9 67 96 10 69 25 102 10 200 25 37 50 78 11 200 25 38 50 151 d) hæmning af aggressivitet.50 107 7 5 ° -, 0 ° 50 8 250, 0 37 50 78 9 67 96 10 69 25 102 10 200 25 37 50 78 11 200 25 38 50 151 d) inhibition of aggressiveness.
Denne undersøgelse blev foretaget under anvendelse af den fremgangsmåde, hvor man isolerer en enkelt mus (af C.D. stammen) i et bur eller en hanrotte (af Long Evans stam-5 men) efter at have fået fjernet lugtekolberne og efter den fremgangsmåde, der er beskrevet af L. Valzelli, Agressive Behaviour, 1969 side 70-76, Excerpta Medica Foundation (Amsterdam) og af P. Karli, M. Vergnes og F. Didiergeorges Agressive Behaviour, 1969, side tø~55· 17 145080This study was performed using the method of isolating a single mouse (of the CD strain) in a cage or male rat (of the Long Evans strain) after removing the odor flasks and following the procedure described. by L. Valzelli, Aggressive Behavior, 1969 pages 70-76, Excerpta Medica Foundation (Amsterdam) and by P. Karli, M. Vergnes and F. Didiergeorges Aggressive Behavior, 1969, page th ~ 55 · 17 145080
Forbindelserne fremstillede efter fremgangsmåden ifølge opfindelsen nedsætter i doser fra 10 til 50 mg/kg givet intraperitonealt antallet af slagsmål hos mus med 20 til if5 % og nedsætter antallet af aggressivitetsmærker.The compounds prepared according to the method of the invention decrease in doses from 10 to 50 mg / kg given intraperitoneally the number of fights in mice by 20 to if5% and decrease the number of aggression marks.
5 Hos rotter nedsætter doser på fra 6,25'fil 50 mg/kg givet intraperitonealt progressivt antallet af aggressive dyr fra ca 100 % (kontrol) til ca ^0 % af dyrene.5 In rats, doses of 6.25 µl 50 mg / kg given intraperitoneally progressively reduce the number of aggressive animals from about 100% (control) to about ^ 0% of animals.
Den hæmmende virkning på slagsmål hos mus og den høje procentiske nedsættelse af aggressiviteten hos behand-10 lede rotter er ikke ledsaget af bivirkninger som hyperaktivitet eller depression hos de behandlede dyr.The inhibitory effect on fighting in mice and the high percentage reduction in aggressiveness in treated rats are not accompanied by side effects such as hyperactivity or depression in the treated animals.
Claims (2)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB3944374A GB1472627A (en) | 1974-09-10 | 1974-09-10 | Benzylaminoalkanoic acids process for their preparation and pharmaceutical compositions containing them |
| GB3944374 | 1974-09-10 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK396175A DK396175A (en) | 1976-03-11 |
| DK145080B true DK145080B (en) | 1982-08-23 |
| DK145080C DK145080C (en) | 1983-01-24 |
Family
ID=10409574
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK396175A DK145080C (en) | 1974-09-10 | 1975-09-04 | METHOD OF ANALOGUE FOR THE PREPARATION OF BENZYLAMINOALKANIC ACIDS OR SALTS OR OPTICALLY ACTIVE ISOMERS THEREOF |
Country Status (14)
| Country | Link |
|---|---|
| JP (1) | JPS5645905B2 (en) |
| BE (1) | BE833238A (en) |
| CA (1) | CA1063619A (en) |
| CH (1) | CH608784A5 (en) |
| DE (1) | DE2540334C2 (en) |
| DK (1) | DK145080C (en) |
| ES (1) | ES440831A1 (en) |
| FR (1) | FR2284322A1 (en) |
| GB (1) | GB1472627A (en) |
| NL (1) | NL166253C (en) |
| PH (1) | PH16279A (en) |
| SE (1) | SE420917B (en) |
| SU (1) | SU660588A3 (en) |
| ZA (1) | ZA755777B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1545291A (en) * | 1976-03-11 | 1979-05-10 | Science Union & Cie | Benzylamino-alkanamides process for their preparation and pharmaceutical compositions containing them |
| CA1137775A (en) * | 1978-09-01 | 1982-12-21 | Andrew J. Welebir | Formulation comprising 1-triacontanol and its use as plant growth regulator |
| CN112920042A (en) * | 2021-01-27 | 2021-06-08 | 北京岳达生物科技有限公司 | Method for preparing alkane carboxylic acid by increasing alkane carbon chain |
-
1974
- 1974-09-10 GB GB3944374A patent/GB1472627A/en not_active Expired
-
1975
- 1975-09-01 SU SU752167228A patent/SU660588A3/en active
- 1975-09-04 DK DK396175A patent/DK145080C/en active
- 1975-09-09 SE SE7510024A patent/SE420917B/en not_active IP Right Cessation
- 1975-09-09 NL NL7510588.A patent/NL166253C/en not_active IP Right Cessation
- 1975-09-09 JP JP10942475A patent/JPS5645905B2/ja not_active Expired
- 1975-09-09 BE BE159885A patent/BE833238A/en not_active IP Right Cessation
- 1975-09-09 CA CA235,367A patent/CA1063619A/en not_active Expired
- 1975-09-09 FR FR7527536A patent/FR2284322A1/en active Granted
- 1975-09-09 ES ES440831A patent/ES440831A1/en not_active Expired
- 1975-09-10 ZA ZA00755777A patent/ZA755777B/en unknown
- 1975-09-10 CH CH7511709A patent/CH608784A5/en not_active IP Right Cessation
- 1975-09-10 DE DE2540334A patent/DE2540334C2/en not_active Expired
-
1980
- 1980-06-11 PH PH24126A patent/PH16279A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ZA755777B (en) | 1976-08-25 |
| ES440831A1 (en) | 1977-03-01 |
| BE833238A (en) | 1976-03-09 |
| SU660588A3 (en) | 1979-04-30 |
| NL7510588A (en) | 1976-03-12 |
| AU8464875A (en) | 1977-03-17 |
| NL166253C (en) | 1981-07-15 |
| CA1063619A (en) | 1979-10-02 |
| DE2540334A1 (en) | 1976-03-25 |
| JPS5645905B2 (en) | 1981-10-29 |
| GB1472627A (en) | 1977-05-04 |
| PH16279A (en) | 1983-08-26 |
| DK396175A (en) | 1976-03-11 |
| SE7510024L (en) | 1976-03-11 |
| FR2284322B1 (en) | 1978-07-28 |
| DK145080C (en) | 1983-01-24 |
| CH608784A5 (en) | 1979-01-31 |
| JPS5159826A (en) | 1976-05-25 |
| FR2284322A1 (en) | 1976-04-09 |
| DE2540334C2 (en) | 1983-03-10 |
| NL166253B (en) | 1981-02-16 |
| SE420917B (en) | 1981-11-09 |
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