DK154899B - ANALOGY PROCEDURE FOR THE PREPARATION OF AROYL-SUBSTITUTED PHENYLEDIC ACETIC ACID DERIVATIVES. - Google Patents
ANALOGY PROCEDURE FOR THE PREPARATION OF AROYL-SUBSTITUTED PHENYLEDIC ACETIC ACID DERIVATIVES. Download PDFInfo
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- DK154899B DK154899B DK572273AA DK572273A DK154899B DK 154899 B DK154899 B DK 154899B DK 572273A A DK572273A A DK 572273AA DK 572273 A DK572273 A DK 572273A DK 154899 B DK154899 B DK 154899B
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- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
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Description
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DK 154 899 BDK 154 899 B
Den foreliggende opfindelse angår en anal ogi fremgangsmåde til fremstilling af hidtil ukendte aroyl-substituerede phenyleddikesyrederivater, som udviser anti-inflammatorisk aktivitet. De omhandlede forbindelser afviger navnlig fra kendte forbindelser ved aroylfunktionens na-5 tur.The present invention relates to an analogue and method of preparing novel aroyl-substituted phenylacetic acid derivatives which exhibit anti-inflammatory activity. The compounds in question differ in particular from known compounds by the nature of the aroyl function.
Den kendte teknik kan eksemplificeres ved hjælp af følgende litteraturhenvisninger:The prior art can be exemplified by the following literature references:
French Spec. Med. Pat. 8,440M Fransk patent nr. 1.589.691 10 French Spec. Med. Pat. 7,956MFrench Spec. With. Pat. 8,440M French Patent No. 1,589,691 French Spec. With. Pat. 7,956M
Chem. Abstr., 71, 91097sChem. Abstr., 71, 91097s
Chem. Abstr., 73, 66268gChem. Abstr., 73, 66268g
Fransk patent nr. 1.516.775 French Spec. Med. Pat. 5,903M 15 Fransk patentskrift nr. 7.956MFrench Patent No. 1,516,775 French Spec. With. Pat. 5,903M French Patent No. 7,956M
Chem. Abstr., 73, 77035e ogChem. Abstr., 73, 77035e and
French Spec. Med. Pat. 6,444M.French Spec. With. Pat. 6,444M.
De ved fremgangsmåden ifølge den foreliggende opfindelse fremstillede hidtil ukendte forbindelser har den almene formel: 20 \ R2 oThe novel compounds prepared by the process of the present invention have the general formula: 20
Loh (i) 25 ArCO''^'"—\ R3 R1 hvori: 30 ArCO betegner en aroyl-substituent, hvis Ar-funktion er valgt blandt 2-thienyl, 5-(Cj-Cg) al kyl-2-thienyl, 5-halo-2-thienyl, 2-naphthyl og 3-pyridyl, hvorhos ArCO-gruppen er i meta- eller para-stilling i forhold til eddikesyrefunktionen, R er valgt blandt hydrogen, halogen og (Cj-Cg) alkyl under den forud-35 sætning, at når R betegner halogen eller (Cj-Cg) al kyl, er ArCo- gruppen i den ovennævnte para-stilling, og under forusætning af at når R betegner halogen, er Ar-gruppen 2-thienyl, 5-(Cj-Cg) al kyl - 2-thienyl- eller 5-halo-2-thienyl,Loh (i) ArCOCO '^ \ R R R1 wherein: ArCO represents an aroyl substituent whose Ar function is selected from 2-thienyl, 5- (C--Cg) alkyl-2-thienyl, 5-halo-2-thienyl, 2-naphthyl and 3-pyridyl wherein the ArCO group is in the meta or para position with respect to the acetic acid function, R is selected from hydrogen, halogen and (C -35 position that when R represents halogen or (C 1 -C 6) alkyl, the ArCo group is in the above para position, and assuming that when R represents halogen, the Ar group is 2-thienyl, 5- ( Cj-Cg alkyl or 2-thienyl or 5-halo-2-thienyl,
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2 R1 er valgt blandt hydrogen, halogen og (Cj-Cg) al kyl under den forudsætning, at når R1 betegner halogen eller (Cj-Cg) alkyl, er ArCO-gruppen i meta-sti11 ingen, og under den forudsætning at når R1 betegner halogen, er Ar 2-thienyl, 5-(Cj-Cg) al kyl-2-thienyl 5 eller 5-halo-2-thienyl, R2 er valgt blandt hydrogen, allyl og (Cj-Cg) alkyl, R3 er valgt blandt hydrogen og (Cj-Cg) al kyl under den forudsætning, at når R3 betegner (Cj-Cg) alkyl, betegner R2 (Cj-Cg) alkyl, eller 10 R2 og R3 betegner tilsammen en alkylen-bro med fra 2 til 5 carbonatomer med undtagelse af 2-(thienoylphenyl)-propionsyre. Sidstnævnte forbindelse må anses for kendt fra beskrivelsen til dansk patentansøgning nr. 4916/73.2 R 1 is selected from hydrogen, halogen and (C 1 -C 6) alkyl, provided that when R 1 represents halogen or (C 1 -C 6) alkyl, the ArCO group is in the meta-state and under the assumption that R 1 represents halogen, Ar is 2-thienyl, 5- (C 1 -C 6) alkyl-2-thienyl 5 or 5-halo-2-thienyl, R 2 is selected from hydrogen, allyl and (C 1 -C 6) alkyl, R 3 is selected of hydrogen and (Cj-Cg) alkyl provided that when R R represents (Cj-Cg) alkyl, R₂ represents (Cj-Cg) alkyl, or R₂ and R3 together represent an alkylene bridge having from 2 to 5 carbon atoms with the exception of 2- (thienoylphenyl) propionic acid. The latter connection must be considered known from the description of Danish patent application no. 4916/73.
Udtrykket "(Cj-Cg) al kyl" anvendes her for at betegne såvel ligekæ-15 dede som forgrenede grupper med fra 1 til 5 carbonatomer, som f.eks. methyl, ethyl, propyl, isopropyl, butyl, pentyl og lignende. Udtrykket "halogen" er generisk for fluor, chlor, brom og iod.The term "(Cj-Cg) alkyl" is used herein to denote both straight and branched groups having from 1 to 5 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyl, pentyl and the like. The term "halogen" is generic for fluorine, chlorine, bromine and iodine.
Fremgangsmåden ifølge opfindelsen er ejendommelig ved det i krav l's kendetegnende del anførte. De para-aroylsubstituerede phenyleddike-20 syrederivater med formlen (I), hvori R3 betegner hydrogen, fremstilles hensigtsmæssigt ved omsætning af en passende arylketon med formlen (II), hvori Ar og R har den ovenfor anførte betydning, og Z betegner en passende fraspaltelig gruppe, fortrinsvis en fluorphenyl-arylketon, med et passende di-lavere alkyl-2-R2 malonat med formlen (III), fortrinsvis 25 di ethyl esteren, i et passende reaktions-inert organisk opløsningsmiddel.The process according to the invention is characterized by the characterizing part of claim 1. The para-aroyl-substituted phenylacetic acid derivatives of formula (I) wherein R 3 represents hydrogen are conveniently prepared by reacting an appropriate aryl ketone of formula (II) wherein Ar and R , preferably a fluorophenyl-aryl ketone, with a suitable di-lower alkyl-2-R2 malonate of formula (III), preferably the di-ethyl ester, in a suitable reaction-inert organic solvent.
Det er fordelagtigt at erstatte det aktive hydrogenatom i 2-stillingen for (III) med alkalimetal, fortrinsvis natrium, ved behandling med en passende base, f.eks. et al kalimetalhydrid, såsom natriumhydrid, inden omsætning med (II). Udtrykket "reaktions-inert organisk opløsningsmid-30 del" anvendes her for at betegne en hvilken som helst organisk væske, der vil opløseliggøre eller dispergere reaktanterne (II) og (III) uden at indvirke på deres indbyrdes reaktion, f.eks. hexamethylphosphoramid, nitromethan, dimethyl sul foxid, dimethyl formamid og lignende. Den således opnåede di ester (IV) hydrolyseres dernæst, fortrinsvis under anvendelse 35 af alkaliske hydrolysebetingelser, f.eks. ved opvarmning af en blanding af (IV) og en alkalimetalhydroxidopløsning, til dannelse af det tilsvarende alkalimetalsalt af den tilsvarende syre og påfølgende syrning af det resulterende salt til dannelse af de ønskede phenyl eddikesyrederiva-It is advantageous to replace the active hydrogen atom at the 2-position of (III) with alkali metal, preferably sodium, by treatment with a suitable base, e.g. et al. potassium metal hydride, such as sodium hydride, before reaction with (II). The term "reaction-inert organic solvent" is used herein to mean any organic liquid which will solubilize or disperse the reactants (II) and (III) without affecting their reaction, e.g. hexamethylphosphoramide, nitromethane, dimethyl sul foxide, dimethyl formamide and the like. The thus obtained ester (IV) is then hydrolyzed, preferably using alkaline hydrolysis conditions, e.g. by heating a mixture of (IV) and an alkali metal hydroxide solution to form the corresponding alkali metal salt of the corresponding acid and subsequent acidification of the resulting salt to form the desired phenyl acetic acid derivatives.
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3 ter (I-a). De ovennævnte omsætninger kan belyses ved hjælp af følgende skematiske diagram: 5 R 2 R 23 ter (I-a). The above reactions can be illustrated by the following schematic diagram: 5 R 2 R 2
Ar-CO-^r~^-Z + H(Na)-i-COOalkyl_^ Ar-CO-^^-i-COOallo loOalkyl COOalkyl 10 (II) (ΠΙ) (IV> R\ 2 15 /kouj 1Ar-CO- ^ r ~ ^ -Z + H (Na) -i-COOalkyl_ ^ Ar-CO - ^^ - i-COOallo10Oalkyl COOalkyl 10 (II) (ΠΙ) (IV> R \ 2 15 / kouj 1
-Ar-CO-r yCH-COOH-Ar-CO-r yCH-COOH
(la) 20 Det har vist sig, at den ovennævnte omsætning mellem (II) og (III) kan danne en blanding af diesteren (IV) og monoesteren (IV-a), hvilken monoester fremkommer ved dekomponering af diesteren: R 9(la) 20 It has been found that the above reaction between (II) and (III) can form a mixture of the diester (IV) and the monoester (IV-a), which monoester is produced by decomposition of the diester: R 9
\~\ R\ ~ \ R
25 Ar-CO-^ y-CH-COOalkyl (IV-a)Ar-CO- γ-CH-COOalkyl (IV-a)
Monoesteren, som kan isoleres ved hjælp af konventionelle midler, f.eks. ved destillation, underkastes dernæst standardester-til-syre-hy- 30 drolyse til dannelse af det ønskede phenyl eddikesyrederivat med formlen (I-a).The monoester which can be isolated by conventional means, e.g. by distillation, then standard ester-to-acid hydrolysis is obtained to form the desired phenyl acetic acid derivative of formula (I-a).
Ifølge opfindelsen kan man endvidere omsætte en forbindelse med den almene formel t, R2Furthermore, according to the invention, a compound of the general formula t, R2 can be reacted
35 ^-COOH35 -COOH
H,I3 R -H, I3 R -
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4 hvori R, R1, R2 og Ra har de foran angivne betydninger, med en forbindelse med formlen ArCO-halogenid, under Friede!-Crafts betingelser til fremstilling af en forbindelse med formlen R ' .2 5 Κλ f4 wherein R, R1, R2 and Ra have the above meanings, having a compound of the formula ArCO halide, under the conditions of Friede! -Craft to prepare a compound of the formula R '.2 5 Κλ f
tf \—C—COOHtf \ -C-COOH
- i3 (I“C)- i3 (I “C)
ArCCV R1 10 hvori Ar, R, R1, R2 og R3 har de foran angivne betydninger, fortrinsvis under anvendelse af carbondisulfid som opløsningsmiddel.ArCCV R110 wherein Ar, R, R1, R2 and R3 have the above meanings, preferably using carbon disulfide as solvent.
Arylketoner med formlen (II) opnås let ved en Friedel-Crafts reaktion mellem en passende aromatisk forbindelse med formlen Ar-H, hvori Ar betegner thienyl, 5-halogen-2-thienyl eller 5-(Cj-C5) alkyl-2-thienyl, 15 og et passende carbonyl halogenid, fortrinsvis chloridet, med formlenAryl ketones of formula (II) are readily obtained by a Friedel-Crafts reaction between a suitable aromatic compound of formula Ar-H wherein Ar represents thienyl, 5-halo-2-thienyl or 5- (C 1 -C 5) alkyl-2-thienyl , And a suitable carbonyl halide, preferably the chloride, of the formula
RR
CI-CO-Qz 20 hvori R og Z har den ovenfor anførte betydning, i nærværelse af en Lewis syre, fortrinsvis et metallisk halogenid, såsom aluminiumchlorid, stan-nichlorid eller lignende, i et passende opløsningsmiddel, der typisk anvendes til en Friedel-Crafts reaktion, f.eks. methylenchlorid, 1,2-di-25 chlorethan, carbondisulfid, nitrobenzen, vandfri benzen (med SnCl^) og lignende. Omvendt kan formel (II)-ketonerne opnås ved en Friedel-Crafts reaktion mellem en passende substitueret benzenforbindelse med formlenWherein R and Z are as defined above, in the presence of a Lewis acid, preferably a metallic halide, such as aluminum chloride, stannous chloride or the like, in a suitable solvent typically used for a Friedel-Crafts reaction, e.g. methylene chloride, 1,2-dichloroethane, carbon disulfide, nitrobenzene, anhydrous benzene (with SnCl 2) and the like. Conversely, the formula (II) ketones can be obtained by a Friedel-Crafts reaction between a suitably substituted benzene compound of the formula
RR
30 ^~Yz hvori R betegner hydrogen eller (C^-Cg) alkyl, og Z har den ovenfor anførte betydning, fortrinsvis fluor, og et passende aryl carbonyl halogenid, fortrinsvis chloridet med formlen Ar-C0-Cl, hvori Ar har den oven-35 for anførte betydning.Wherein R represents hydrogen or (C 1 -C 6) alkyl and Z has the meaning given above, preferably fluorine, and a suitable aryl carbonyl halide, preferably the chloride of formula Ar-CO-Cl, wherein Ar has the above -35 for the meaning indicated.
Adskillige af fluorphenylarylketonerne med formlen (Il-a) formodes at være hidtil ukendte. Disse hidtil ukendte ketoner kan betegnes ved hjælp af følgende almene formel:Several of the fluorophenylaryl ketones of formula (II-a) are believed to be novel. These novel ketones can be denoted by the following general formula:
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55
RR
ArCO-^~^-FArCO- ^ ~ ^ -F
5 (Π-a) hvori ArCO betegner en arylcarbonyl-substituent, hvis Ar-funktion er valgt blandt 2-thienyl, 5-chlor-2-thienyl, 5-methyl-2-thienyl og 3-pyri-dyl, R er valgt blandt hydrogen, halogen og (Cj-C5) alkyl under den 10 forudsætning, at når Ar betegner 2-thienyl, betegner R halogen eller (Cj-Cg) alkyl, og under den forudsætning at når R betegner halogen, betegner Ar 2-thienyl, 5-halogen-2-thienyl eller 5-(Cj-Cg) alkyl-2-thie-nyl.5 (Π-a) wherein ArCO represents an arylcarbonyl substituent whose Ar function is selected from 2-thienyl, 5-chloro-2-thienyl, 5-methyl-2-thienyl and 3-pyridyl, R is selected of hydrogen, halogen and (C 1 -C 5) alkyl under the proviso that when Ar represents 2-thienyl, R represents halogen or (C 1 -C 6) alkyl, and provided that when R represents halogen, Ar represents 2-thienyl , 5-halo-2-thienyl or 5- (C 1 -C 6) alkyl-2-thienyl.
Meta- og para-aroylphenyl eddikesyrederivaterne med formlen (I) kan 15 også fremstilles ved konventionel nitril-til-syre hydrolyse af de tilsvarende aroyl-phenylacetonitriler med formlen (VI), f.eks. ved tilbagesvaling af nitrilen med en stærk syre, som f.eks. vandig svovlsyre (20-70%), med koncentreret svovlsyre i nærværelse af iseddikesyre, eller ved basehydrolyse, såsom med kaliumhydroxid i en alkohol.The meta and para-aroylphenyl acetic acid derivatives of formula (I) may also be prepared by conventional nitrile-to-acid hydrolysis of the corresponding aroylphenylacetonitriles of formula (VI), e.g. by refluxing the nitrile with a strong acid, e.g. aqueous sulfuric acid (20-70%), with concentrated sulfuric acid in the presence of glacial acetic acid, or by base hydrolysis such as with potassium hydroxide in an alcohol.
20 R 2 \ r2 . <Q4r<=°°» 25 ArCCl it lR ' ArCC) R1 (VI) (i-c)20 R 2 \ r2. <Q4r <= °° »25 ArCCl it 1R 'ArCC) R1 (VI) (i-c)
Phenylacetonitri ler med formlen (Vl-a), hvori ArCO og R2 har den 30 ovenfor anførte betydning, R og R1 betegner hydrogen eller (Cj-C5) al-kyl, kan fremstilles ved hjælp af følgende reaktionsforløb: En omtrentlig ækvimolær blanding m- eller p-brombenzylal kohol (VII) og 3,4-dihy-dropyran (VIII), hvortil HC1 er blevet tilsat, får lov at reagere i kulden (ca. -10 til 0eC). Den således opnåede 2-(brombenzyloxy)-tetrahydro-35 pyran (IX), der kan isoleres ved hjælp af konventionelle metoder, omdannes dernæst til et Grignard-kompleks ved standardbehandling med magnesium i et egnet opløsningsmiddel, som f.eks. tetrahydrofuran, og Grig-nard-komplekset omsættes med en passende arylnitril med formlen (X), 6Phenylacetonitriles of formula (V1-a) wherein ArCO and R2 are as defined above, R and R1 are hydrogen or (C1-C5) alkyl can be prepared by the following reaction procedure: An approximate equimolar mixture m or p-bromobenzylal alcohol (VII) and 3,4-dihydropyran (VIII) to which HCl has been added are allowed to react in the cold (about -10 to 0 ° C). The 2- (bromobenzyloxy) -tetrahydropyran (IX) thus obtained, which can be isolated by conventional methods, is then converted to a Grignard complex by standard treatment with magnesium in a suitable solvent, e.g. tetrahydrofuran, and the Grig-nard complex is reacted with a suitable aryl nitrile of formula (X), 6
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hvori Ar har den ovenfor anførte betydning, til dannelse af den resulterende keton med formlen (XI)-. Hydroxy-funktionen i den sidstnævnte keton transformeres til en reaktiv ester-funktion (XII) ved behandling med et passende middel, fortrinsvis et chlorerings- eller bromeringsmiddel, så-5 som thioneylchlorid, phosphortribromid og lignende, i et passende opløsningsmiddel, f.eks. aromatiske carbonhydrider, såsom benzen, toluen, xy-len og lignende, ethere, såsom diethylether, dioxan og lignende, og ha-logencarbonhydrider, såsom chloroform og lignende. Den reaktive esterfunktion transformeres igen til en nitril-funktion (Vl-a), f.eks. ved 10 behandling (XII) med natriumcyanid i et egnet opløsningsmiddel, såsom dimethylsulfoxid. Let forhøjede temperaturer (50-60eC) kan anvendes til forøgelse af reaktionshastigheden.wherein Ar is as defined above to form the resulting ketone of formula (XI) -. The hydroxy function of the latter ketone is transformed into a reactive ester function (XII) by treatment with a suitable agent, preferably a chlorinating or brominating agent, such as thioneyl chloride, phosphorus tribromide and the like, in a suitable solvent, e.g. aromatic hydrocarbons such as benzene, toluene, xylene and the like, ethers such as diethyl ether, dioxane and the like, and halogenated hydrocarbons such as chloroform and the like. The reactive ester function is again transformed into a nitrile function (V1-a), e.g. by treatment (XII) with sodium cyanide in a suitable solvent such as dimethyl sulfoxide. Slightly elevated temperatures (50-60 ° C) can be used to increase the reaction rate.
Det ovennævnte reaktionsforløb er belyst i nedenstående reaktionsskema: 15The above reaction procedure is illustrated in the reaction scheme below: 15
Kl·« . o — KK°-0Kl · «. o - KK ° -0
Bf Vi Rl (VII) (VIII) <«> R 2Bf Vi Rl (VII) (VIII) <«> R 2
Mg_^ /Grignard 1 + ArCN ->- ^TVcH-OHMg_ ^ / Grignard 1 + ArCN -> - ^ TVcH-OH
i komplex J Λ==ι/ (X) ArC0 ** (XI) 35in complex J Λ == ι / (X) ArC0 ** (XI) 35
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7 R 2 R 27 R 2 R 2
Va L y NaCN (I <^H-CNVa L y NaCN (I <^ H-CN
halogeneringsmiddel {'y y—C.H-A -x—/ ~ ^ /=( DMSO / \ ,halogenating agent {γ y C. C.H-A-x— / ~ ^ / = (DMSO
ArTO V ArC° Rl (XII) (vi-a)ArTO V ArC ° Rl (XII) (vi-a)
Forbindelser med formlen (VI-c), hvori Ar betegner thienyl, 5-halo-10 gen-2-thienyl, 5-(Cj-Cg) alkyl-2-thienyl, 3-pyridyl og 2-naphthyl, R og R1 betegner hydrogen, halogen, fortrinsvis chlor eller (Cj-Cg) al kyl, kan fremstilles ved monoalkylering af en α-usubstitueret phenylacetoni-tril med formlen (Vl-b). Dette kan opnås ved omsætning (Vl-b) i et vandigt basisk medium, f.eks. i en 50% vandig natriumhydroxidopløsning, med 15 en ækvivalent mængde af et passende al kyl halogenid i nærværelse af et kvaternært ammoniumsalt, fortrinsvis N-benzyltriethylammoniumchlorid.Compounds of formula (VI-c) wherein Ar represents thienyl, 5-halo-10-2-thienyl, 5- (C 1 -C 6) alkyl-2-thienyl, 3-pyridyl and 2-naphthyl, R and R hydrogen, halogen, preferably chlorine or (Cj-Cg) alkyl can be prepared by monoalkylation of an α-unsubstituted phenylacetonitrile of formula (V1-b). This can be achieved by reaction (V1-b) in an aqueous basic medium, e.g. in a 50% aqueous sodium hydroxide solution, with an equivalent amount of an appropriate alkyl halide in the presence of a quaternary ammonium salt, preferably N-benzyltriethylammonium chloride.
? R (C1~C5) alky? R (C1 ~ C5) alkyl
20 fe^°H2CN X'aU<yl 1 50» Na°H . HL-CN20 fe ^ ° H2CN X'aU <yl 1 50 »Na ° H. HL-CN
χΛ=\ phCH_N(El)_+ Cl'χΛ = \ phCH_N (EI) _ + Cl '
Ar«/ Rl 23 ArCO VAr «/ Rl 23 ArCO V
25 (Vl-b) (Vl-c)(V1-b) (V1-c)
Monoalkylering af (Vl-b) kan også udføres ved omsætning (Vl-b) med 30 et al kyl halogenid, i flydende ammoniak, i nærværelse af en ækvivalent mængde natriumamid.Monoalkylation of (V1-b) can also be carried out by reaction (V1-b) with 30 ethanol of halide, in liquid ammonia, in the presence of an equivalent amount of sodium amide.
Monoalkylering opnås også ved omsætning (Vl-b) med et alkylhaloge-nid i nærværelse af et passende metalli seringsmiddel, såsom natriumhy-drid i et egnet polært opløsningsmiddel, forudsat at alkylgruppen ste-35 risk forhindrer dialkylering, som det f.eks. er tilfældet med en forgrenet al kylgruppe, såsom isopropyl, isobutyl og lignende.Monoalkylation is also achieved by reaction (V1-b) with an alkyl halide in the presence of a suitable metallizing agent, such as sodium hydride in a suitable polar solvent, provided that the alkyl group strictly prevents dialkylation, such as e.g. is the case of a branched alkyl group such as isopropyl, isobutyl and the like.
a-di-iCj-Cg) al kylaroylphenylacetonitri ler med formlen (VI-d) fremstilles hensigtsmæssigt ved dialkylering af (Vl-b). Dialkylering kanα-di-CC-Cg) all the kylaroylphenylacetonitriles of formula (VI-d) are conveniently prepared by dialkylation of (V1-b). Dialkylation can
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δ udføres ved omsætning af en phenylacetoni tril med formlen (Vl-b) med et passende al kyl halogenid, fortrinsvis et alkyliodid, i et egnet organisk opløsningsmiddel, såsom f.eks. hexamethylphosphoramid, nitromethan, dimethyl formamid, dimethyl sulfoxid og lignende, i nærværelse af en passen-5 de base, fortrinsvis et metalhydrid, såsom natriumhydrid. Når alkylerin-gen udføres med en passende· mængde af et passende al kylendihalogenid, opnås en cyklisk homolog med formlen (VI-e), hvori (CHg)n betegner en alkylenkæde med fra 2 til 5 carbonatomer.δ is carried out by reacting a phenylacetone tril of formula (V1-b) with a suitable alkyl halide, preferably an alkyl iodide, in a suitable organic solvent, such as e.g. hexamethylphosphoramide, nitromethane, dimethyl formamide, dimethyl sulfoxide and the like, in the presence of a suitable base, preferably a metal hydride such as sodium hydride. When the alkylation gene is carried out with an appropriate amount of an appropriate alkylene dihalide, a cyclic homologue of formula (VI-e) is obtained, wherein (CHg) n represents an alkylene chain having from 2 to 5 carbon atoms.
Alternativt opnås, når en ar-alkylaroylphenylacetonitril alkyleres 10 under lignende betingelser, en α-di al kyl aroyl phenyl acetoni tril (Vl-f), hvori R3 kan være et forskelligt (Cj-Cg) al kyl radi kal.Alternatively, when an aralkylaroylphenylacetonitrile is alkylated under similar conditions, an α-dialkyl aroyl phenyl acetone tril (V1-f) wherein R3 may be a different (C1-C6) alkyl radical.
* RV_ alkyl (C1-C5)* RV_alkyl (C1-C5)
/TWcN Na»· *-alkyl. <C\-i-CN/ TWcN Na »· * alkyl. <C \ -i-CN
ΙΙΜΡΤΛ L , „ ,ΙΙΜΡΤΛ L, „,
ArCcT V Kr CO fel‘WARCcT V Kr CO fel'W
(vi-b) \ NaH (vw)(vi-b) \ NaH (vw)
HMPTA\x- (CH2)n-XHMPTA \ x- (CH2) n-X
* (ayn fA—-c'—CN AxQO R1 (Vl-e) ^ alkyl (Cj^-Cg) ^ alkyl (C-^-Cg)* (ayn fA-c'-CN AxQO R1 (V1-e) ^ alkyl (C
/JUh-CN NaH- X-r3 ^ ^yi_CN/ JUh-CN NaH-X-r3 ^^ yi_CN
HMPTA R 3HMPTA R 3
Ar CO R.1 Ar CO r1 (VI-c) (Vl-f) 35 Aroylbenzylhalogenider med formlen (ΧΙΙ-a), hvori Ar betegner 2- thienyl, 5-halogen-2-thienyl, 5-(Cj-Cg) al kyl-2-thienyl eller 2-naph-thyl, R og R1 betegner hydrogen eller halogen, og R2 betegner hydrogen eller (Cj-Cg) alkyl, kan fremstilles ved bromering af en egnet meta- 9Ar CO R.1 Ar CO r1 (VI-c) (V1-f) Aroylbenzyl halides of formula (ΧΙΙ-a) wherein Ar represents 2-thienyl, 5-halogen-2-thienyl, 5- (C 1 -C 6) all alkyl-2-thienyl or 2-naphthyl, R and R 1 represent hydrogen or halogen, and R 2 represents hydrogen or (C 1 -C 6) alkyl, may be prepared by bromination of a suitable meta-9
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eller para-al kyl phenyl aryl keton med formlen (XIII) med et hensigtsmæssigt bromeringsmiddel, såsom N-bromsuccinimid i et passende reaktionsinert organisk opløsningsmiddel, såsom f.eks. carbontetrachlorid i nærværelse af en peroxid, såsom benzoyl peroxid. Omsætningen udføres for-5 trinsvis ved forhøjede temperaturer.or para-alkyl phenyl aryl ketone of formula (XIII) with a suitable brominating agent such as N-bromosuccinimide in a suitable reaction inert organic solvent such as e.g. carbon tetrachloride in the presence of a peroxide such as benzoyl peroxide. The reaction is preferably carried out at elevated temperatures.
? . \R2? . \ R2
Ad, E! NBS , benzoyl-peroxid ^\cH-BrAd, E! NBS, benzoyl peroxide 1 H-Br
ArCC) V CCl4 ArCCf Ri (XIII) (xn-a)ArCC) V CCl4 ArCCf Ri (XIII) (xn-a)
Det vil kunne forstås, at bromiderne med formlen (XII-a) let kan 15 omdannes til de tilsvarende nitriler ved hjælp af konventionelle midler.It will be appreciated that the bromides of formula (XII-a) can easily be converted to the corresponding nitriles by conventional means.
De ovennævnte al kyl phenyl aryl ketoner med formlen (XIII) kan f.eks. fremstilles ved omsætning af et meta- eller para-al kyl benzoyl halogenid (XIV) med en ArH-forbindelse under Friedel-Crafts betingelser: 20 pThe above-mentioned alkyl phenyl aryl ketones of formula (XIII) is prepared by reacting a meta- or para-alkyl benzoyl halide (XIV) with an ArH compound under Friedel-Crafts conditions: 20 p
ArH ♦ <^Vh2-R2 SnC14 JØ-CH2-R2ArH ♦ <^ Vh2-R2 SnC14 JO-CH2-R2
ClCO^V==/ CH2C12 ArCO^v—/ V * 25 (XIV) (χ1»)ClCO2 V == / CH2Cl2 ArCO2 v— / V * 25 (XIV) (χ1 »)
Forbindelserne med formlen (XII-b), hvori R2 har den tidligere anførte betydning, Ar betegner 2-thienyl, 5-halogen-2-thienyl eller 5-30 (Cj-Cg) al kyl-2-thienyl, og X betegner halogen, kan fremstilles ved omsætning af et α-halogenalkyl benzoyl halogenid med formlen (XV) med en ArH-forbindelse under milde Friede!-Crafts betingelser, hvorved acyle-ring af arylforbindel sen sker selektivt.The compounds of formula (XII-b) wherein R 2 is as previously defined, Ar represents 2-thienyl, 5-halogen-2-thienyl or 5-30 (C 1 -C 6) alkyl-2-thienyl, and X represents halogen , can be prepared by reacting an α-haloalkyl benzoyl halide of formula (XV) with an ArH compound under mild Friede-Kraft conditions, whereby acylation of the aryl compound is selective.
R 2 ^ 35 + ArH snci4 ciccf~^ ch2ci2 (XV) (ΧΠ-b) 10R 2 ^ 35 + ArH snci4 ciccf ~ ^ ch2ci2 (XV) (ΧΠ-b) 10
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En anden metode til fremstilling af meta- og para-aroylbenzyl al kohol erne med formlen (ΧΙ-a), hvori Ar, R og R1 har den tidligere anførte betydning, og R2 betegner hydrogen eller (Cj-C5) alkyl, består i en selektiv reduktion af en keton med formlen (XVI) med en ækvivalent mæng-5 de af et egnet hydrogeneringsmiddel, såsom et metalborhydrid, fortrinsvis natriumborhydrid eller natriumcyanoborhydrid i et egnet organisk opløsningsmiddel, f.eks. en lavere alkanol, såsom methanol, ethanol, iso-propanol og lignende, eller med lithiumaluminiumhydrid-t-butoxid, fortrinsvis i en ether, såsom f.eks. diethylether, tetrahydrofuran, dioxan 10 og lignende.Another method for preparing the meta and para-aroylbenzyl all of the alcohols of formula (ΧΙ-a) wherein Ar, R and R har are as previously defined and R₂ is hydrogen or (Cj-C5) alkyl consists of a selectively reducing a ketone of formula (XVI) with an equivalent amount of a suitable hydrogenating agent, such as a metal borohydride, preferably sodium borohydride or sodium cyanoborohydride in a suitable organic solvent, e.g. a lower alkanol such as methanol, ethanol, isopropanol and the like, or with lithium aluminum hydride t-butoxide, preferably in an ether such as e.g. diethyl ether, tetrahydrofuran, dioxane 10 and the like.
R R n y_ o · \ H2R R n y_ o · \ H2
Vii-R 2 hydrogenering _ yTVcH-OHVii-R2 hydrogenation _ yTVcH-OH
15 ArCO^^V opløsningsmiddel ArCO^^K15 ArCO ^^ V solvent ArCO ^^ K
Ri R1 (XVI) (Xl-a) · 20 Forbindelserne med formlen (XVI), hvori Ar har den tidligere anfør te betydning, og R, R1 og R2 betegner hydrogen eller (Cj-Cg) alkyl, kan fremstilles ud fra m- eller p-brombenzylderivater med formlen (XVII), hvis carbonyl-funktion forud" er beskyttet af en egnet beskyttende gruppe, f.eks. ved ketalisering. Den resulterende cykliske acetal el-25 ler ketal med formlen (XVIII) omdannes derpå til et Grignard-kompleks ved standardbehandling med magnesium i et egnet opløsningsmiddel, og dette Grignard-kompleks omsættes med en passende arylnitril.R 1 (XVI) (Xl-a) · The compounds of formula (XVI) wherein Ar is as previously defined and R, R 1 and R 2 represent hydrogen or (C 1 -C 6) alkyl can be prepared from m- or p-bromobenzyl derivatives of formula (XVII), whose carbonyl function is previously "protected by a suitable protecting group, for example, by ketalization. The resulting cyclic acetal or ketal of formula (XVIII) is then converted into a Grignard -complex by standard treatment with magnesium in a suitable solvent, and this Grignard complex is reacted with an appropriate aryl nitrile.
R \ cT""7R \ cT "" 7
30 H0-CH2-CH2-0H ArCNH0-CH2-CH2-OH ArCN
R RR R
(XVII) % (XVIII)(XVII)% (XVIII)
35 R35 R
Mg \~A li -^ Jkj~ 2Mg \ ~ A li - ^ Jkj ~ 2
ArCCf V. 1ArCCf V. 1
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nn
Forbindelserne med formlerne (VI), (XI), (XII) og (XVI) anses for at være hidtil ukendte.The compounds of formulas (VI), (XI), (XII) and (XVI) are considered to be novel.
De α-usubstituerede aroylphenyl eddikesyrer med formlen (I-d) kan også fremstilles ud fra acetophenoner med formlen (XVI-a) ved anvendelse 5 af Willgerodts reaktion.The α-unsubstituted aroylphenyl acetic acids of formula (I-d) can also be prepared from acetophenones of formula (XVI-a) using Willgerodt's reaction.
sp
R /-\ RR / - \ R
\_ O S ; HN O \ S\_ U.S ; HN O \ S
1010
ArCC) ^1 ArCOArCC) ^ 1 ArCO
S ^ (XVI-a)S ^ (XVI-a)
RR
15 fHOHj Jry CHz-COOH15 fHOHj Jry CH 2 -COOH
ArC° \ 1 (I-d) 20ArC ° \ 1 (I-d) 20
Aroylhydratropi nsyrer med formlen (I-e) fremstilles hensigtsmæssigt ved en modificeret Willgerodts reaktion som belyst ved følgende skema: “ « · f 1Aroylhydratropinic acids of formula (I-e) are conveniently prepared by a modified Willgerodts reaction as illustrated by the following scheme: '' · f 1
ArCC> ArC0 30 (XVI-a)ArCC> ArC0 30 (XVI-a)
RR
fHOHj /T\-CH-COOHfHOHj / T \ -CH-COOH
35 ^ (I-e) 1235 (I-e) 12
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En alternativ mode til fremstilling af a-(C^-Cg) al kylaroylphenyl eddikesyrer med formlen (I-f) består i alkylering af de tilsvarende α-usubstituerede aroylphenyleddikesyrer (I-d). Et af de aktiverede a-hydrogenatomer metalliseres først, f.eks. ved behandling af syren med et 5 passende metalliseringsmiddel, såsom natriumamid i flydende ammoniak. Et al kyl halogenid, fortrinsvis et alkyliodid, tilsættes derpå, og den resulterende α-alkylaroylphenyl eddikesyre renses ved hjælp af konventionelle midler.An alternative mode for the preparation of α- (CC-C al) alkylaryloylphenyl acetic acids of formula (I-f) consists in the alkylation of the corresponding α-unsubstituted aroylphenylacetic acids (I-d). One of the activated α-hydrogen atoms is first metallized, e.g. by treating the acid with a suitable metallizing agent such as sodium amide in liquid ammonia. An alkyl halide, preferably an alkyl iodide, is then added and the resulting α-alkylaroylphenyl acetic acid is purified by conventional means.
,Λ R, Λ R
10 R \_10 R \ _
V“5\ NaNH? , X-alk (/ \-CH-COOHV “5 \ NaNH? , X-alk () -CH-COOH
(/. \-Cllz-COOH -1->- X=J L (c -c 1 X-—/ liq. NH3 Ar CO Vlalk(/. \ -Cllz-COOH -1 -> - X = J L (c -c 1 X - / liq. NH3 Ar CO Vlalk
ArC0 (I-f) 15ArCO (I-f) 15
En yderligere metode til fremstillingen af aroylphenyledddikesyrer med formlen (I-f) anføres i den følgende reaktionssekvens. En a-usubsti-tueret phenylacetonitril med formlen (VI-b) carbalkoxyleres først ved 20 kendte metoder, såsom f.eks. med et di-lavere alkylcarbonat eller et lavere alkylchlorformiat i nærværelse af et alkalisk kondenseringsmiddel, såsom natriumamid eller natriumethoxid. Den resulterende forbindelse med formlen (XXII) alkyleres derpå ved konventionelle metoder, såsom f.eks. med et al kyl halogenid i nærværelse af et passende alkalisk kondense-25 ringsmiddel, såsom natrium- eller kaliumethoxid. Det resulterende cyaneddikesyrederivat med formlen (ΧΧϊϊΙ) hydrolyseres og deearboxyleres dernæst ved kendte metoder, såsom f.eks. ved opvarmning (XXIII) med alkali i et passende organisk opløsningsmiddel, såsom ethanol, hvorved den ønskede forbindelse med formlen (I-f') fremkommer. Ovennævnte belyses 30 ved det efterfølgende reaktionsskema:A further method for the preparation of aroylphenylacetic acids of formula (I-f) is given in the following reaction sequence. An α-unsubstituted phenylacetonitrile of formula (VI-b) is first carboxylated by 20 known methods, such as e.g. with a di-lower alkyl carbonate or lower alkyl chloroformate in the presence of an alkaline condensing agent such as sodium amide or sodium ethoxide. The resulting compound of formula (XXII) is then alkylated by conventional methods such as e.g. with an alkyl halide in the presence of a suitable alkaline condensing agent such as sodium or potassium ethoxide. The resulting cyanoacetic acid derivative of formula (ΧΧϊϊΙ) is then hydrolyzed and then deearboxylated by known methods such as e.g. by heating (XXIII) with alkali in a suitable organic solvent such as ethanol to give the desired compound of formula (I-f '). The above is illustrated by the following reaction scheme:
R RR R
alk-O-CO-O-alk /AcH-CNalk-O-CO-O-alk / AcH-CN
' Λ={ Na0Et . cr/^={ ioOalk 35 ArCO 'R i ArCO ^ χ (VI-b) (XXII) ' 13'Λ = {Na0Et. cr / ^ = {ioOalk 35 ArCO 'R in ArCO ^ χ (VI-b) (XXII)' 13
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* R2 X-R2 ; NaOEt U y—C—CN fttOKj 5 -^ /K iooalk -* R2 X-R2; NaOEt U y — C — CN fttOKj 5 - ^ / K iooalk -
ArCO R1 (XXIII)ArCO R1 (XXIII)
RR
10 \.R210 \ .R2
/T^-iH-COOH/ T ^ -Ih-COOH
ArC0 \ΐ 15 Μ'ArC0 \ ΐ 15 Μ '
Alternative metoder kan også benyttes til transformeringen af aroylbenzoylderi vater med formlen (XVI-b) til phenylacetonitri ler med formlen (VI-c). En af disse metoder omfatter omsætning af (XVI-b) med 20 tosyl hydrazin, hvorved der dannes en tosylhydrazon med formlen (XXIV).Alternative methods can also be used for the transformation of aroylbenzoyl derivatives of formula (XVI-b) into phenylacetonitriles of formula (VI-c). One of these methods comprises reacting (XVI-b) with 20 tosyl hydrazine to give a tosylhydrazone of formula (XXIV).
Den fremkomne tosylhydrazon omsættes derpå med hydrocyansyre eller med et egnet metalcyanid i nærværelse af en passende syre, såsom eddikesyre, i et passende opløsningsmiddel, såsom methanol. Dekomponeringen af (XXV), som giver den ønskede phenylacetonitri1, kan udføres ved dekompo-25 nering med base eller ved opvarmning (XXV) i et bad af decal in. Ovennævnte reaktionssekvens belyses ved følgende reaktionsskema: R ? alkyl (C -Cg)The resulting tosylhydrazone is then reacted with hydrocyanic acid or with a suitable metal cyanide in the presence of a suitable acid, such as acetic acid, in a suitable solvent such as methanol. The decomposition of (XXV) which gives the desired phenylacetonitrile can be carried out by decomposition with base or by heating (XXV) in a bath of decal in. The above reaction sequence is illustrated by the following reaction scheme: R? alkyl (C-Cg)
Aro/\l ArCOAro / \ l ArCO
(XVI-b) ' (XXIV) 35(XVI-b) '(XXIV) 35
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14 ? alkyl- (C-^-C^) HCN I dekomponering _(f \VC—NH-NH-Ts -^14? alkyl (C --C C) HCN In decomposition _ (f \ VC-NH-NH-Ts -
KrCQ> NrIKrCQ> Nr
5 * alkyl (Crc5) (XXV) /KL-cn5 * alkyl (Crc5) (XXV) / KL-cn
ArCO^ \l 10 (VI-c)ArCO ^ 10 (VI-c)
En yderligere metode består i behandling (XVI-b) med methylcarba-zat, hvorefter den resulterende methoxycarbonylhydrazon omsættes med 15 hydrocyansyre til dannelse af det tilsvarende hydrazid med formlen (XXVII). Hydrazidet oxideres derefter, f.eks. med brom, og den resulterende diazen med formlen (XXVIII) dekomponeres, f.eks. ved anvendelse af natriummethoxid i methanol, hvorved den ønskede phenylacetonitril opnås: R o 20 //Vli , H-N-NH-H-OMe alkyl·—^^A further method consists of treatment (XVI-b) with methylcarbazate, after which the resulting methoxycarbonylhydrazone is reacted with hydrocyanic acid to give the corresponding hydrazide of formula (XXVII). The hydrazide is then oxidized, e.g. with bromine and the resulting diazene of formula (XXVIII) decomposed, e.g. using sodium methoxide in methanol to give the desired phenylacetonitrile: R o 20 // Vli, H-N-NH-H-OMe alkyl · - ^^
ArCOT χ (XVI-b) 25 alkyl( c -C )ArCOT χ (XVI-b) alkyl (c-C)
Ki=N.NH-CO-OMe «04 ^Ki = N.NH-CO-OMe «04 ^
ArCCfA-l 30 RArCCfA-1 R
(XXVI) 35 Y alkyl (C!-C5) \-C-NH-NH-CO-0Me Br2 V__ / i -y(XXVI) Y alkyl (C1-C5) \ -C-NH-NH-CO-Ome Br2 V__ / i-y
\ -iCN\ -iCN
Ar COAr CO
(XXVII) 15(XXVII) 15
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^ alkylCc^-cy \_ ^Cl“C5^ 5 ^r\^-N=N-co-°Me NaQMe j ('Γ^Η-ΟΝ^ alkylCc ^ -cy \ _ ^ Cl “C5 ^ 5 ^ r \ ^ - N = N-co- ° Me NaQMe j ('Γ ^ Η-ΟΝ
ArCO^^T ArCc/S^ (XXVIII) (VI-c) 10ArCO ^^ T ArCc / S ^ (XXVIII) (VI-c) 10
Ved en anden metode omsættes en forbindelse med formlen (XVI-b) med tosylmethyl i socyanid i nærværelse af en passende mængde natriumethoxid i et egnet opløsningsmiddel, såsom dimethoxyethan, hvorved de ønskede forbindelser med formlen (XV-c) opnås:In another method, a compound of formula (XVI-b) is reacted with tosylmethyl in socyanide in the presence of a suitable amount of sodium ethoxide in a suitable solvent such as dimethoxyethane to give the desired compounds of formula (XV-c):
15 R15 R
(OpC^alkyl + H3C-Q)-S02.CH2-N=C(OpC ^ alkyl + H HC-Q) -SO₂CH₂-N = C
ArC r1 20 (XVI-b) alkyl (ci -C^)ArC R1 (XVI-b) alkyl (C1 -C4)
EtONa )r\ LEtONa) r \ L
-> (O \yCH-CN-> (O \ yCH-CN
(CH.OCH )_ yX=< 25 3 2 2 Arccy (VI-c)(CH.OCH) _ yX = <25 3 2 2 Arccy (VI-c)
Som følge af, at der findes asymmetrisk a-carbatom i de omhandlede forbindelser (I), er det indlysende, at de kan eksistere i form af stereokemiske isomerer (enantiomorfe). Ved standardresolutions-metoder kan 30 de tilsvarende (-) eller (+) former af de ønskede forbindelser fås. Sådanne farmakologisk aktive enantiomorfes fremstilling falder selvsagt inden for opfindelsens rammer.Due to the existence of asymmetric α-carb atom in the compounds of the present invention (I), it is obvious that they may exist in the form of stereochemical isomers (enantiomorphs). By standard resolution methods, the corresponding (-) or (+) forms of the desired compounds can be obtained. The preparation of such pharmacologically active enantiomorphs, of course, falls within the scope of the invention.
De omhandlede forbindelser (I) besidder værdifulde anti-inflammatoriske egenskaber, hvilket er påvist ved deres aktivitet ved den HOAc-in-35 ducerede reflektionsprøve og/eller ved mycobacterium-butyricum-prøven.The compounds of the present invention (I) possess valuable anti-inflammatory properties, as evidenced by their activity in the HOAc-induced reflection sample and / or in the mycobacterium-butyricum sample.
Ved disse prøver har de omhandlede forbindelser vist sig at være kraftige antagonister på eddikesyre-induceret forvridning i rotter og/eller på mycobacterium-butyricum-induceret arthritis i rotter.In these tests, the compounds of this invention have been shown to be potent antagonists on acetic acid-induced distortion in rats and / or on mycobacterium-butyricum-induced arthritis in rats.
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Ifølge den eddikesyre-inducerede reflektionsprøve suites hun-Wi-star-rotter (legemsvægt 100±5 g) natten over og injiceres intraperito-nealt med 0,5 ml af en 1% eddikesyreopløsning. Rotter med mindst 10 reflekt i oner inden for de første 10 minutter efter eddikesyreinjektionen 5 udvælges og behandles 5 minutter senere med en oral dosis af forbindelsen, som skal undersøges, eller med bæreren (kontrol). Antallet af re-flektioner, dvs. den bagudretttede forlængelse af baglemmerne, tælles i en 15 minutters forsøgsperiode 45-60 minutter efter den orale behandling. Mindst tre rotter anvendes for hvert dosisniveau, som undersøges.According to the acetic acid-induced reflection sample, female Wi-Star rats (body weight 100 ± 5 g) were sued overnight and injected intraperitoneally with 0.5 ml of a 1% acetic acid solution. Rats with at least 10 reflex in ones within the first 10 minutes after the acetic acid injection 5 are selected and treated 5 minutes later with an oral dose of the compound to be examined or with the vehicle (control). The number of reflections, ie. the posterior extension of the hind limbs, is counted for a 15 minute trial period 45-60 minutes after oral treatment. At least three rats are used for each dose level tested.
10 En signifikant lægemiddel virkning siges at foreligge, såfremt antallet af talte reflekti oner under 15 minutters forsøgsperioden er færre end 15, eftersom dette er signifikant (P <0,05) forskelligt fra kontrollerne.A significant drug effect is said to exist if the number of reflected reflections during the 15-minute experimental period is less than 15, since this is significantly (P <0.05) different from the controls.
De nedenfor anførte data viser den laveste effektive orale dosis 15 udtrykt som ED5Q (mg/kg) for den foretrukne forbindelse A, p-(2-the-noyl)-α-methylphenyl eddikesyre, sammenlignet med den tilsvarende phenyl-forbindelse B, p-benzoyl-α-methylphenyl eddikesyre, beregnet på alt-el-ler-ingen basis ved færre end 15 reflektioner pr. dyr pr. forsøgsperiode. Under disse eksperimentelle betingelser viser det sig, at den først-20 nævnte forbindelse er 16 gange mere aktiv end den sidstnævnte forbindelse.The data set forth below shows the lowest effective oral dose expressed as ED5Q (mg / kg) for the preferred compound A, p- (2-theoyl) -α-methylphenyl acetic acid, as compared to the corresponding phenyl compound B, p -benzoyl-α-methylphenyl acetic acid, calculated on an all-or-none basis at less than 15 reflections per animals per trial period. Under these experimental conditions, the first-mentioned compound is found to be 16 times more active than the latter.
Forbindelse Oral ED50 (mg/kg) Styrkeforhold 25 A 0,08 (?) B 1,25 1/16Compound Oral ED50 (mg / kg) Strength 25 A 0.08 (?) B 1.25 1/16
Ifølge den mycobacterium-butyricum-inducerede arthritis-prøve injiceres han-Wistar-rotter (legemsvægt 235+15 g) intradermalt i haleroden 30 med 0,05 ml af en oliesuspension af mycobacterium butyricum. Pote- og total di ametrene på baglemmerne måles på injektionsdagen og to uger senere. Rotter med etableret arthritis, dvs. signifikant forøgelse i pote-og total di ametre, anvendes til afprøvning af lægemidlerne. Grupper af tre individuelt indburede dyr modtager prøveforbindelsen blandet med 35 pulveriseret foder i forskellige koncentrationer i løbet af 14 efter hinanden følgende dage. Efter denne behandlingsperiode måles diametrene på baglemmerne igen, og virkningen af behandlingen vurderes ved sammenligning af den endelige opsvulmningsgrad hos behandlede dyr med den, der 17According to the mycobacterium-butyricum-induced arthritis test, male Wistar rats (body weight 235 + 15 g) are injected intradermally into the tail root 30 with 0.05 ml of an oil suspension of mycobacterium butyricum. The paw and total diameters of the hind limbs are measured on the day of injection and two weeks later. Rats with established arthritis, ie. significant increase in paw and total diameters is used for drug testing. Groups of three individually housed animals receive the test compound mixed with 35 powdered feed at various concentrations over 14 consecutive days. After this treatment period, the diameters of the hind limbs are again measured and the effect of the treatment is assessed by comparing the final swelling rate of treated animals with that of the animals.
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forekommer hos ubehandlede kontroldyr. Den laveste effektive dosis er den dosis, hvor en signifikant opsvulmningsformindskelse kan iagttages i forhold til ubehandlede kontrol dyr.occurs in untreated control animals. The lowest effective dose is the dose at which a significant swelling decrease can be observed relative to untreated control animals.
De nedenfor gengivne data viser den laveste effektive dosis for den 5 foretrukne forbindelse A igen sammenlignet med den tilsvarende phenyl-forbindelse B. Under disse forsøgsbetingelser viser det sig, at den førstnævnte forbindelse er en kraftig antagonist mod mycobacterium buty-ricum-induceret arthritis i rotter, idet den er mindst 16 gange mere effektiv end den sidstnævnte forbindelse.The data presented below show the lowest effective dose of the preferred compound A again compared to the corresponding phenyl compound B. Under these test conditions, the former compound is found to be a potent antagonist for mycobacterium butyricum-induced arthritis in rats. , being at least 16 times more effective than the latter compound.
1010
Forbindelse Laveste effektive dosis Styrkeforhold A 0,63 ® B 10,0 1/16 15 I den efterfølgende tabel er anført data for andre forbindelser med formi en (I).Compound Lowest effective dose Strength ratio A 0.63 ® B 10.0 1/16 15 The following table lists data for other compounds of formula (I).
20 25 30 3520 25 30 35
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VvfJ- -VvfJ- -
Ar CO Å3 10Ar CO Å3 10
ArCO R R* R^ R^ Reflektions- Mycobac- prøve på rot-, bactericum ter, EDg0 i prøve 15 mg/kg effektiv dosis i mg/kg 20 j3-(2-thenoyl) Cl H Me H 1,25 1,25 £-(3-pyridylcarbonyl) HH Me H 2,5 2,5 £-(5-Me-2-thenoyl) HH Me H 1,25 5,0 £-(2-naphtoyl) Η H Me H 1,25 10, m-(2-thenoyl) Η H Me H 1,25 25 £-(2-thenoyl) Η H Me H 0,31 fi-(2-thenoyl) Η H Me H 0,63 £-(2-thenoyl) Η H Et H 0,63 fi-(2-thenoyl) Η H ally! H 1,25 10, fi-(2-thenoyl) (+) Η H Me H 0,31 <2,5 30 j)-(2-thenoyl) (-) Η H Me H 5,0 £-(thenoyl) Me H Me H 5,0 10, j)-(thenoyl) HH Me Me 0,31 <10, fi-(5-chlor-2-thenoyl) Η H Me H 0,63 5,0 m-(2-thenoyl) H Me Η H 10, 1,25 35 _, ___ArCO RR * R ^ R ^ Reflection Mycobac Sample on Root, Bacterial, EDg0 Sample 15 mg / kg Effective Dose in mg / kg 20 µl (2-thenoyl) Cl H Me H 1.25 £ - (3-pyridylcarbonyl) HH Me H 2.5 2.5 £ - (5-Me-2-thenoyl) HH Me H 1.25 5.0 £ - (2-naphthyl) Η H Me H 1.25 10, m- (2-thenoyl) Η H Me H 1.25 £ - (2-thenoyl) Η H Me H 0.31 fi- (2-thenoyl) Η H Me H 0.63 £ - (2- thenoyl) Η H It H 0.63 fi- (2-thenoyl) Η H ally! H 1.25 10, fi- (2-thenoyl) (+) Η H Me H 0.31 <2.5 30 j) - (2-thenoyl) (-) Η H Me H 5.0 £ - (thenoyl ) Me H Me H 5.0 10, j) - (thenoyl) HH Me Me 0.31 <10, fi- (5-Chloro-2-thenoyl) Η H Me H 0.63 5.0 m- (2 -thenoyl) H Me Η H 10, 1.25 _, ___
Som tidligere påvist med anti-inflammatoriske midler viste forbin-, , , - η _ c-fn at inhibere blodplade-aggregering.As previously demonstrated with anti-inflammatory agents, dressing, η-c-fn was shown to inhibit platelet aggregation.
delserne med formlen (I) s19 athe equations of formula (I) s19 a
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Fremgangsmåden ifølge opfindelsen belyses nærmere i de følgende eksempler, hvor alle dele er vægtdele, medmindre andet er anført.The process according to the invention is illustrated in more detail in the following examples, where all parts are parts by weight, unless otherwise stated.
Eksempel 1 5 Til en omrørt blanding af 25,25 dele thiophen, 58,1 dele 2-chlor-4-fluorbenzoylchlorid og 200 dele vandfri benzen sættes dråbevis 78,16 dele stannichlorid (rygende) ved stuetemperatur (let exotermisk reaktion: Temperaturen holdes i 3 timer på 25eC). Reaktionsblandingen hældes på en blanding af knust is og koncentreret saltsyreopløsning. Det hele omrøres 10 i nogle få minutter, og lagene adskilles. Det organiske lag fortyndes med 80 dele toluen, udvaskes først med 200 dele natriumhydroxidopløsning 5% og derefter med 200 dele vand, tørres og. inddampes. Remanensen destilleres og giver som udbytte 2-chlor-4-fluor-phenyl-2-thienylketon, kogepunkt 129-130°C ved et tryk på 0,5 mm.Example 1 To a stirred mixture of 25.25 parts of thiophene, 58.1 parts of 2-chloro-4-fluorobenzoyl chloride and 200 parts of anhydrous benzene is added dropwise 78.16 parts of stannous chloride (smoking) at room temperature (slightly exothermic reaction: The temperature is kept at 3 hours at 25 ° C). The reaction mixture is poured onto a mixture of crushed ice and concentrated hydrochloric acid solution. The whole is stirred for a few minutes and the layers are separated. The organic layer is diluted with 80 parts of toluene, washed first with 200 parts of sodium hydroxide solution 5% and then with 200 parts of water, dried and dried. evaporated. The residue is distilled to yield 2-chloro-4-fluoro-phenyl-2-thienyl ketone, boiling point 129-130 ° C at a pressure of 0.5 mm.
1515
Eksempel 2Example 2
Til en omrørt blanding af 29,5 dele 2-methylthiophen, 39,65 dele p-fluorbenzoylchlorid og 280 dele methylenchlorid sættes portionsvis 40 dele aluminiumchlorid, mens temperaturen holdes på 20eC (vandbad).To a stirred mixture of 29.5 parts of 2-methylthiophene, 39.65 parts of p-fluorobenzoyl chloride and 280 parts of methylene chloride, 40 parts of aluminum chloride are added portionwise while keeping the temperature at 20 ° C (water bath).
20 Derefter fortsættes omrøringen i 4 timer ved stuetemperatur. Reaktionsblandingen hældes under kraftig omrøring på knust is og 50 dele og 50 dele saltsyre. Lagene adskilles, og den vandige fase udvaskes med chloroform. De organiske lag tørres og inddampes. Remanensen optages i benzen, der inddampes igen. Remanensen størkner ved tri turering i petrole-25 umsether. Det faste produkt frafiltreres og udkrystalliseres fra ethanol ved -20°C og giver som udbytte p-fluorphenyl-5-methyl-2-thienylketon, smp. 68°C.Then stirring is continued for 4 hours at room temperature. The reaction mixture is poured with vigorous stirring on crushed ice and 50 parts and 50 parts hydrochloric acid. The layers are separated and the aqueous phase is washed out with chloroform. The organic layers are dried and evaporated. The residue is taken up in benzene which is evaporated again. The residue solidifies by trituration in petroleum ether. The solid product is filtered off and crystallized from ethanol at -20 ° C to yield p-fluorophenyl-5-methyl-2-thienyl ketone, m.p. 68 ° C.
Eksempel 3 30 Til en omrørt blanding af 29,2 dele 2-thenoylchlorid, 22 dele m-fluortoluen og 200 dele methylenchlorid sættes portionsvis 37,4 dele aluminiumchlorid (exotermisk reaktion: Temperaturen stiger til 30°C).Example 3 To a stirred mixture of 29.2 parts of 2-thenoyl chloride, 22 parts of m-fluorotoluene and 200 parts of methylene chloride is added portionwise 37.4 parts of aluminum chloride (exothermic reaction: the temperature rises to 30 ° C).
Derefter fortsættes omrøringen i 3 timer ved tilbagesvalingstemperatur. Reaktionsblandingen hældes under omrøring på knust is. Produktet ekstra-35 heres med methylenchlorid. Det organiske lag udvaskes først med natrium-hydrogencarbonatopløsning og derefter med vand, tørres og inddampes. Remanensen destilleres to gange og giver som udbytte 4-fluor-o-tolyl-2-thienylketon, kogepunkt !05-106eC ved et tryk på 0,2 mm.Then stirring is continued for 3 hours at reflux temperature. The reaction mixture is poured with stirring on crushed ice. The product is extracted with methylene chloride. The organic layer is washed out first with sodium hydrogen carbonate solution and then with water, dried and evaporated. The residue is twice distilled to yield 4-fluoro-o-tolyl-2-thienyl ketone, boiling point 05-106 ° C at a pressure of 0.2 mm.
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Eksempel 4Example 4
Til en omrørt og afkølet (isbad) blanding af 88 dele nicotinoyl-chlorid,hydrochlorid i 400 dele fluorbenzen sættes portionsvis 165 dele aluminiumchlorid ved en temperatur mellem 5 og 10°C. Derefter fjernes 5 kølebadet, og blandingen omrøres og tilbagesvales i 6 timer. Reaktions-blandingen henstår natten over ved stuetemperatur og hældes derefter på en blanding af knust is og saltsyre. Efter afkøling adskilles lagene.To a stirred and cooled (ice bath) mixture of 88 parts of nicotinoyl chloride, hydrochloride in 400 parts of fluorobenzene, 165 parts of aluminum chloride are added portionwise at a temperature between 5 and 10 ° C. Then, the cooling bath is removed and the mixture is stirred and refluxed for 6 hours. The reaction mixture is left at room temperature overnight and then poured onto a mixture of crushed ice and hydrochloric acid. After cooling, the layers are separated.
Den vandige fase ekstraheres tre gange med ether. De forenede organiske lag kastes bort, og den vandige fase al kali seres med en 40% natriumhy-10 droxidopløsning. Produktet ekstraheres adskillige gange med choroform. Ekstrakterne udvaskes to gange med vand, tørres og inddampes. Remanensen opløses i ether. Opløsningen frafiltreres uopløseligt materiale, og filtratet får lov at udkrystallisere ved fortynding med petroleumsether ved -20°C og giver p-f 1 uorpheny1-3-pyridy1 keton, smp. 74,5eC.The aqueous phase is extracted three times with ether. The combined organic layers are discarded and the aqueous phase is alkalized with a 40% sodium hydroxide solution. The product is extracted several times with choroform. The extracts are washed twice with water, dried and evaporated. The residue is dissolved in ether. The solution is filtered off insoluble material and the filtrate is allowed to crystallize by dilution with petroleum ether at -20 ° C to give p-f 1 uorphenyl-3-pyridyl ketone, m.p. 74,5eC.
1515
Eksempel 5 9,6 dele natriumhydriddispersion 55% suspenderes tre gange i vandfri benzen, som hver gang dekanteres. Derpå tilsættes der først 200 dele hexamethylphosphoramid og derpå dråbevis 34,8 dele diethyl-2-methylmalo-20 nat. Blandingen opvarmes forsigtigt, hvorefter en kraftig reaktion finder sted. Når reaktionen ophører, afkøles blandingen, og 41,2 dele p-fluorphenyl-2-thienylketon tilsættes. Det hele opvarmes til 100°C og omrøres ved denne temperatur i 10 timer. Reaktionsblandingen fortyndes med 400 dele benzen, udvaskes to gange, tørres og inddampes. Den olieagtige 25 remanens destilleres og giver som udbytte di ethyl-2-methyl-2-[p-(2-the-noyl)-phenyl]-malonat, kogepunkt 205-210'C ved et tryk på 0,4 mm.Example 5 9.6 parts of sodium hydride dispersion 55% are suspended three times in anhydrous benzene, which is decanted each time. Then 200 parts of hexamethylphosphoramide are first added and then 34.8 parts of diethyl-2-methylmalonate dropwise dropwise. The mixture is gently heated, after which a vigorous reaction takes place. When the reaction ceases, the mixture is cooled and 41.2 parts of p-fluorophenyl-2-thienyl ketone are added. The whole is heated to 100 ° C and stirred at this temperature for 10 hours. The reaction mixture is diluted with 400 parts of benzene, washed twice, dried and evaporated. The oily residue is distilled to yield di ethyl 2-methyl-2- [p- (2-theoyl) phenyl] malonate, boiling point 205-210 ° C at a pressure of 0.4 mm.
Ved gentagelse af fremgangsmåden ifølge eksempel 5 og erstatning af p-fluorpheny!-2-thienylketon med en hensigtsmæssig mængde af en egnet p-fluorphenylarylketon og erstatning af diethyl-2-methylmalonat med en 30 ækvivalent mængde af et egnet diethylmalonat opnås følgende forbindelser:By repeating the procedure of Example 5 and replacing p-fluorophenyl-2-thienyl ketone with an appropriate amount of a suitable p-fluorophenylaryl ketone and replacing diethyl-2-methyl malonate with an equivalent amount of a suitable diethyl malonate, the following compounds are obtained:
Di ethyl-2-methyl-2-[4-(2-thenoyl)-m-tolyl]-malonat, kogepunkt 186-193eC ved et tryk på 0,2 mm.Di ethyl 2-methyl-2- [4- (2-thenoyl) -m-tolyl] malonate, bp 186-193 ° C at a pressure of 0.2 mm.
Di ethyl-2-[3-chlor-4-(2-thenoyl)-phenyl]-2-methylmalonat, 35 kogepunkt 225-235°C ved et tryk på 0,6-0,8 mm.Di ethyl 2- [3-chloro-4- (2-thenoyl) phenyl] -2-methylmalonate, bp 225-235 ° C at a pressure of 0.6-0.8 mm.
Di ethyl-2-methyl-2-[p-(5-methyl-2-thenoyl)-phenyl]-mal onat, kogepunkt 235-240°C ved et tryk på 1 mm.Di ethyl 2-methyl-2- [p- (5-methyl-2-thenoyl) -phenyl] -malate, boiling point 235-240 ° C at a pressure of 1 mm.
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Diethyl-2-ethyl-2-[p-(2-thenoyl)-phenyl]-malonat, kogepunkt 175-199°C ved et tryk på 0,1 mm.Diethyl 2-ethyl-2- [p- (2-thenoyl) phenyl] malonate, bp 175-199 ° C at a pressure of 0.1 mm.
Di ethyl-2-allyl-2-[p-(2-thenoyl)-phenyl]-mal onat, kogepunkt 215-220°C ved et tryk på 0,2 mm.Di ethyl 2-allyl-2- [p- (2-thenoyl) -phenyl] -malate, boiling point 215-220 ° C at a pressure of 0.2 mm.
55
Eksempel 6Example 6
En blanding af 30,3 dele diethyl-2-methyl-2-[p-thenoyl)-phenyl]-ma-lonat og 200 dele natriumhydroxidopløsning 5% omrøres og tilbagesvales i 6 timer. Reaktionsblandingen får lov at afkøle under omrøring. Det hele 10 filtreres, og den vandige fase fraskilles. Sidstnævnte udvaskes med benzen, syrnes med koncentreret saltsyreopløsning og omrøres i 15 minutter. Produktet ekstraheres med choroform. Ekstrakten udvaskes med vand, tørres, filtreres og inddampes. Den olieagtige remanens tritureres to gange i petroleumsether. Det faste produkt frafilteres og udkrystalliseres to 15 gange fra acetonitril: Først ved -20eC og derpå ved 0°C og giver som udbytte p-(2-thenoyl)-hydratropinsyre, smp. 124,3*0, også kaldet p-(2-thenoyl )-a-methylphenyleddi kesyre.A mixture of 30.3 parts of diethyl-2-methyl-2- [p-thenoyl) phenyl] malonate and 200 parts of sodium hydroxide solution 5% is stirred and refluxed for 6 hours. The reaction mixture is allowed to cool while stirring. The entire 10 is filtered and the aqueous phase is separated. The latter is washed with benzene, acidified with concentrated hydrochloric acid solution and stirred for 15 minutes. The product is extracted with choroform. The extract is washed with water, dried, filtered and evaporated. The oily residue is triturated twice in petroleum ether. The solid product is filtered off and crystallized two times by acetonitrile: first at -20 ° C and then at 0 ° C to yield p- (2-thenoyl) -hydratropic acid, m.p. 124.3 * 0, also called p- (2-thenoyl) -α-methylphenylacetic acid.
Ved gentagelse af fremgangsmåden ifølge eksempel 6 og erstatning af diethyl-2-methyl-2-[p-(2-thenoyl)-phenyl]-malonat med en ækvivalent 20 mængde af et egnet diethylaroylphenylmalonat opnås følgende forbindelser:By repeating the procedure of Example 6 and replacing diethyl-2-methyl-2- [p- (2-thenoyl) phenyl] malonate with an equivalent amount of a suitable diethylaroylphenylmalonate, the following compounds are obtained:
3-chlor-4-(2-thenoyl)-hydratropinsyre, smp. 82,5°C p-(5-methyl-2-thenoyl)-hydratropinsyre, smp. 93,7eC p-(2-naphthoyl)-hydratropinsyre, smp. 149,7°C 25 2-[p-(2-thenoyl)-phenyl]-smørsyre, smp. 122,8°C3-chloro-4- (2-thenoyl) -hydratropic acid, m.p. 82.5 ° C β- (5-methyl-2-thenoyl) -hydratropic acid, m.p. 93.7 ° C p- (2-naphthoyl) hydratropic acid, m.p. 149.7 ° C 2- [p- (2-thenoyl) -phenyl] -butyric acid, m.p. 122.8 ° C
2- [p-(2-thenoyl)-phenyl]-4-pentensyre, smp. 117,1°C2- [p- (2-thenoyl) -phenyl] -4-pentenoic acid, m.p. 117.1 ° C
3- methyl-4-(2-thenoyl)-hydratropinsyre, smp. 100,2°C3-methyl-4- (2-thenoyl) -hydratropic acid, m.p. 100.2 ° C
Eksempel 7 30 60 dele diethyl-2-methyl-2-[p-3-pyridylcarbonyl)-phenyl]-malonat (remanens af tidligere reaktion) destilleres og giver som udbytte ca.EXAMPLE 7 60 parts of diethyl-2-methyl-2- [p-3-pyridylcarbonyl) phenyl] malonate (residue of previous reaction) are distilled to yield approximately
20,3 dele ethyl-p-(3-pyridylcarbonyl)-hydratropat, også betegnet ethyl-p-(3-pyridylcarbonyl)-a-methylphenylacetat, kogepunkt 235-244°C ved et tryk på over 3 mm.20.3 parts of ethyl p- (3-pyridylcarbonyl) hydrate propate, also called ethyl p- (3-pyridylcarbonyl) -a-methylphenyl acetate, boiling point 235-244 ° C at a pressure exceeding 3 mm.
35 En blanding af 10 dele ethyl-p-(3-pyridylcarbonyl)-hydratropat og 50 dele natriumhydroxidopløsning 4% omrøres og tilbagesvales i 6 timer.A mixture of 10 parts of ethyl p- (3-pyridylcarbonyl) hydrate propate and 50 parts of sodium hydroxide solution 4% is stirred and refluxed for 6 hours.
Raktionsblandingen henstår natten over ved stuetemperatur. Det hele ekstraheres med ether. Det organiske lag kastes bort, og den vandige fa-The reaction mixture is allowed to stand overnight at room temperature. It is all extracted with ether. The organic layer is discarded and the aqueous phase
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22 se syrnes med saltsyreopløsning. Det bundfældede produkt frafiltreres, udvaskes med ether og suspenderes i acetone. Suspensionen syrnes med et overskud af 2-propanol, som forud er mættet med luftformig hydrogenchlo-rid. Saltet udvaskes med acetone og tørres og giver som udbytte p-(3-py-5 ridylcarbonyl)-hydratropinsyre,hydrochlorid. smp. 210eC, også betegnet p-(3-pyridylcarbonyl)-α-methylphenyleddi kesyre,hydrochlorid.22 acidified with hydrochloric acid solution. The precipitated product is filtered off, washed with ether and suspended in acetone. The suspension is acidified with an excess of 2-propanol, which is previously saturated with gaseous hydrogen chloride. The salt is washed out with acetone and dried to yield p- (3-pyridylcarbonyl) -hydratropic acid, hydrochloride. mp. 210 ° C, also called p- (3-pyridylcarbonyl) -α-methylphenylacetic acid, hydrochloride.
Eksempel 8Example 8
En blanding af 269 dele p-brom-a-methylbenzyl al kohol og 225 dele 10 2H-3,4-dihydropyran omrøres og afkøles til 0*C. Derpå tilsættes dråbevis 10 dråber koncentreret saltsyreopløsning, og det hele omrøres på et isbad (stuetemperatur nås). Efter omrøring i 24 timer hældes reaktionsblandingen på 1200 dele ether. Den organiske fase udvaskes to gange med en natriumhydrogencarbonatopløsning og to gange med vand, tørres og 15 filtreres og inddampes. Remanensen destilleres og giver som udbytte 2-(p-brom-a-methylbenzyloxy)-tetrahydropyran, kogepunkt 165-177°C ved et tryp på 20 mm.A mixture of 269 parts of p-bromo-α-methylbenzylalcohol and 225 parts of 10H-3,4-dihydropyran is stirred and cooled to 0 ° C. Then 10 drops of concentrated hydrochloric acid solution are added dropwise and the whole is stirred in an ice bath (room temperature is reached). After stirring for 24 hours, the reaction mixture is poured onto 1200 parts of ether. The organic phase is washed twice with a sodium bicarbonate solution and twice with water, dried and filtered and evaporated. The residue is distilled to yield 2- (p-bromo-α-methylbenzyloxy) -tetrahydropyran, boiling point 165-177 ° C at a trough of 20 mm.
Ved gentagelse af fremgangsmåden ifølge eksempel 8 og ved erstatning af p-brom-a-methylbenzyl al kohol med en ækvivalent mængde af m-brom-20 α-methylbenzenal kohol opnås forbindelsen 2-(m-brom-a-methyl benzyloxy)-tetrahydropyran, kogepunkt 168-169eC ved et tryk på 12 mm.By repeating the procedure of Example 8 and replacing p-bromo-α-methylbenzylalcohol with an equivalent amount of m-bromo-20α-methylbenzenalalcohol, the compound 2- (m-bromo-α-methylbenzyloxy) -tetrahydropyran is obtained. , boiling point 168-169eC at a pressure of 12 mm.
Eksempel 9Example 9
Til et omrørt og til bagesvalet Grignard-kompleks, forud fremstillet 25 ud fra 2,4 dele magnesium og 31,3 dele 2-(m-brom-a-methylbenzyloxy)-te-trahydropyran i 70 dele tetrahydrofuran, sættes dråbevis en opløsning af 10,9 dele 2-thiophencarbonitril i 20 dele tetrahydrofuran. Derefter fortsættes omrøringen under tilbagesvaling i 3 timer. Reaktionsblandingen afkøles til ca. 15eC og behandles med 50 dele af en mættet ammoni-30 umchloridopløsning. Det hele ekstraheres med vand og ether. Den organiske fase udvaskes grundigt med vand, tørres og syrnes med saltsyre i 2-propanol. Det bundfældede produkt frafiltreres og opløses i 100 dele vand og 50 dele koncentreret saltsyreopløsning. Opløsningen omrøres med trækul, filtreres, og filtratet omrøres derefter ved tilbagesvalingstem-35 peratur i 10 minutter, hvorefter produktet fraskilles som en olie. Efter afkøling ekstraheres produktet med ether. Sidstnævnte udvaskes med vand, tørres og inddampes og giver som udbytte a-hydroxy-a-methyl-m-tolyl-2-thienylketon som en remanens.To a stirred and refluxed Grignard complex, previously prepared from 2.4 parts of magnesium and 31.3 parts of 2- (m-bromo-a-methylbenzyloxy) -tetrahydropyran in 70 parts of tetrahydrofuran, is added dropwise a solution of 10.9 parts of 2-thiophenecarbonitrile in 20 parts of tetrahydrofuran. Then, stirring is continued under reflux for 3 hours. The reaction mixture is cooled to ca. 15 ° C and treated with 50 parts of a saturated ammonium chloride solution. It is all extracted with water and ether. The organic phase is thoroughly washed with water, dried and acidified with hydrochloric acid in 2-propanol. The precipitated product is filtered off and dissolved in 100 parts of water and 50 parts of concentrated hydrochloric acid solution. The solution is stirred with charcoal, filtered, and the filtrate is then stirred at reflux temperature for 10 minutes, after which the product is separated as an oil. After cooling, the product is extracted with ether. The latter is washed with water, dried and evaporated to yield a-hydroxy-α-methyl-m-tolyl-2-thienyl ketone as a residue.
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23 Når fremgangsmåden ifølge eksempel 9 gentages bortset dra, at 2-(m-brom-a-methylbenzyloxy)-tetrahydropyran erstattes med en ækvivalent mængde af en egnet meta- eller para-brombenzyloxytetrahydropyran opnås følgende forbindelse: 5 a-hydroxy-p-tolyl-2-thienylketon, kogepunkt 180-190°C ved et tryk på 0,2 mm.When the procedure of Example 9 is repeated except that 2- (m-bromo-α-methylbenzyloxy) -tetrahydropyran is replaced by an equivalent amount of a suitable meta- or para-bromobenzyloxy-tetrahydropyran, the following compound is obtained: 5 α-hydroxy-p-tolyl -2-thienyl ketone, boiling point 180-190 ° C at a pressure of 0.2 mm.
Eksempel 10Example 10
Til et omrørt og tilbagesvalet Grignard-kompleks, forud fremstillet 10 ud fra 7,3 dele magnesium, 52,6 dele methyliodid i 160 dele ether, sættes dråbevis en opløsning af 19,6 dele 3'-brom-2'-methylbenzonitril i 40 dele ether. Derefter fortsættes omrøringen under tilbagesvaling i 20 timer. Reaktionsblandingen afkøles til 0°C og hældes under kraftig omrøring på 500 dele is-vand. Den etheriske fase fraskilles, tørres og ind-15 dampes. Remanensen koges i 60 dele 6N saltsyreopløsning i 10 minutter.To a stirred and refluxed Grignard complex, pre-prepared from 7.3 parts of magnesium, 52.6 parts of methyl iodide in 160 parts of ether, is added dropwise a solution of 19.6 parts of 3'-bromo-2'-methylbenzonitrile in 40 parts. parts ether. Then, stirring is continued under reflux for 20 hours. The reaction mixture is cooled to 0 ° C and poured with vigorous stirring on 500 parts of ice-water. The etheric phase is separated, dried and evaporated. The residue is boiled in 60 parts of 6N hydrochloric acid solution for 10 minutes.
Den fraskilte olie ekstraheres med ether. Ekstrakten udvaskes med vand, tørres og inddampes. Remanensen destilleres og giver som udbytte 3'-brom-2'-methylacetophenon, kogepunkt 125-128eC ved 10 mm.The separated oil is extracted with ether. The extract is washed with water, dried and evaporated. The residue is distilled to yield 3'-bromo-2'-methylacetophenone, boiling point 125-128 ° C at 10 mm.
En blanding af 100 dele 3'-brom-2'-methylacetophenon, 30 dele ethy-20 lenglycol, 320 dele vandfri toluen og 2 dele p-toluensulfonsyre omrøres og tilbagesvales i 4 timer med vandseparator. En anden fraktion af 30 dele ethylenglycol tilsættes, og omrøringen under tilbagesvaling fortsættes i 18 timer. Reaktionsblandingen afkøles og omrøres i 30 minutter med 5 dele natriumcarbonat, tørres og inddampes. Remanensen destilleres 25 to gange og giver som udbytte 2-(3-brom-o-tolyl)-2-methyl-l,3-dioxolan, kogepunkt 148-150eC ved et tryk på 12 mm.A mixture of 100 parts of 3'-bromo-2'-methylacetophenone, 30 parts of ethylene glycol, 320 parts of anhydrous toluene and 2 parts of p-toluenesulfonic acid is stirred and refluxed for 4 hours with water separator. Another fraction of 30 parts of ethylene glycol is added and stirring under reflux is continued for 18 hours. The reaction mixture is cooled and stirred for 30 minutes with 5 parts of sodium carbonate, dried and evaporated. The residue is distilled twice and yields 2- (3-bromo-o-tolyl) -2-methyl-1,3-dioxolane, boiling point 148-150 ° C at a pressure of 12 mm.
Til et omrørt og tilbagesvalet Grignard-kompleks, forud fremstillet ud fra 72 dele 2-(3-brom-o-tolyl)-2-methyl-l,3-dioxolan, 6,8 dele magnesium og 180 dele tør tetrahydrofuran, sættes dråbevis en opløsning af 30 30,6 dele 2-thenonitril i 90 dele tør tetrahydrofuran. Derefter fortsættes omrøringen under tilbagesvaling i 2 timer. Reaktionsblandingen omrøres natten over ved stuetemperatur. Efter afkøling til 0°C dekomponeres blandingen ved tilsætning af 200 dele af en mættet ammoniumchloridopløs-ning, medens temperaturen holdes under 20°C. Produktet ekstraheres med 35 1200 dele ether. Ekstrakten udvaskes tre gange med 300 dele vand, og efter mætning af etherfasen med luftformig hydrogenchlorid fraskilles ke-timin-forbindelsen som en olie. Etheren dekanteres, og olien omrøres og tilbagesvales i 3 timer i 500 dele 6N saltsyreopløsning. Efter afkølingTo a stirred and refluxed Grignard complex, previously prepared from 72 parts of 2- (3-bromo-o-tolyl) -2-methyl-1,3-dioxolane, 6.8 parts of magnesium and 180 parts of dry tetrahydrofuran, is added dropwise a solution of 30.6 parts of 2-thenonitrile in 90 parts of dry tetrahydrofuran. Then, stirring is continued under reflux for 2 hours. The reaction mixture is stirred overnight at room temperature. After cooling to 0 ° C, the mixture is decomposed by adding 200 parts of a saturated ammonium chloride solution while keeping the temperature below 20 ° C. The product is extracted with 35 1200 parts ether. The extract is washed three times with 300 parts of water and after saturation of the ether phase with gaseous hydrogen chloride, the cotimine compound is separated as an oil. The ether is decanted and the oil is stirred and refluxed for 3 hours in 500 parts of 6N hydrochloric acid solution. After cooling
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24 ekstraheres produktet med chloroform (2 x 225 dele). Ekstrakten tørres og inddampes, remanensen destilleres to gange og giver som udbytte 2'-methyl-3'-(2-thenoyl)-acetophenon, kogepunkt 185-190eC ved et tryk på 0,4 mm.24, the product is extracted with chloroform (2 x 225 parts). The extract is dried and evaporated, the residue distilled twice to yield 2'-methyl-3 '- (2-thenoyl) -acetophenone, bp 185-190eC at a pressure of 0.4 mm.
5 En blanding af 14,7 dele 2'-methyl-3'-(2-thenoyl)-acetophenon og 40 dele methanol omrøres under afkøling på et isbad. Derpå tilsættes der på én gang 0,6 dele natriumborhydrid. Reaktionsblandingen omrøres natten over ved stuetemperatur, og 50 dele vand tilsættes. Methanol et inddampes, og produktet ekstraheres med ether. Ekstrakten udvaskes to gange 10 med vand, tørres og inddampes i vakuum og giver som udbytte 3-(l-hydro-xyethyl)-o-tolyl-thienyl keton som en remanens.A mixture of 14.7 parts of 2'-methyl-3 '- (2-thenoyl) -acetophenone and 40 parts of methanol is stirred while cooling on an ice bath. Then 0.6 parts of sodium borohydride are added at once. The reaction mixture is stirred overnight at room temperature and 50 parts of water are added. The methanol is evaporated and the product is extracted with ether. The extract is washed twice with water, dried and evaporated in vacuo to yield 3- (1-hydroxyethyl) o-tolyl-thienyl ketone as a residue.
Eksempel 11Example 11
Til en omrørt og afkølet opløsning af 43,7 dele p-(l-hydroxyethyl)-15 phenyl-2-thienyl keton i 180 dele tør benzen sættes dråbevis 16 dele thionylchlorid. Derefter fortsættes omrøringen natten over ved stuetemperatur. Reaktionsblandingen inddampes. Remanensen optages i toluen, der inddampes en gang mere. Den sidstnævnte remanens destilleres, og destillatet udkrystalliseres fra ethanol ved stuetemperatur og giver som ud-20 bytte p-(l-chlorethyl)-phenyl-2-thienylketon, smp. 60eC.To a stirred and cooled solution of 43.7 parts of p- (1-hydroxyethyl) -phenyl-2-thienyl ketone in 180 parts of dry benzene is added dropwise 16 parts of thionyl chloride. Then stirring is continued overnight at room temperature. The reaction mixture is evaporated. The residue is taken up in toluene which is evaporated once more. The latter residue is distilled and the distillate is crystallized from ethanol at room temperature to yield p- (1-chloroethyl) -phenyl-2-thienyl ketone, m.p. 60EC.
Ved gentagelse af fremgangsmåden ifølge eksempel 11 og erstatning af p-(l-hydroxyethyl)-phenyl-2-thienylketon med en ækvivalent mængde af en egnet aroylbenzyl al kohol opnås følgende forbindelser: a-chlor-a-methyl-m-tolyl-2-thienylketon, kogepunkt 168-178eC ved et 25 tryk på 0,7 mm.By repeating the procedure of Example 11 and replacing p- (1-hydroxyethyl) -phenyl-2-thienyl ketone with an equivalent amount of a suitable aroylbenzylalcohol, the following compounds are obtained: α-chloro-α-methyl-m-tolyl-2 -thienyl ketone, boiling point 168-178 ° C at a pressure of 0.7 mm.
Eksempel 12Example 12
Til en omrørt og afkølet (0°C) blanding af 4,2 dele thiophen, 13 dele stannichlorid og 40 dele methylenchlorid sættes dråbevis en opløs-30 ning af 11,7 dele p-(brommethyl)-benzoylchlorid i 16 dele methylenchlo-rid (exotermisk reaktion med udvikling af luftformig hydrogenchlorid).To a stirred and cooled (0 ° C) mixture of 4.2 parts of thiophene, 13 parts of stannous chloride and 40 parts of methylene chloride is added dropwise a solution of 11.7 parts of p- (bromomethyl) benzoyl chloride in 16 parts of methylene chloride. (exothermic reaction with evolution of gaseous hydrogen chloride).
Efter omrøring i 2 1/2 time hældes reaktionsblandingen på en blanding af 20 dele saltsyreopløsning og 100 dele knust is. Produktet ekstraheres med methylenchlorid. Den organiske fase udvaskes med alkalisk vand, tør-35 res og inddampes. Den faste remanens tritureres med varm petroleums-ether. Produktet frafiltreres og udkrystalliseres fra ethanol og giver som udbytte a-brom-p-tolyl-2-thienylketon, smp. 85,6T (dekomponer!ng).After stirring for 2 1/2 hours, the reaction mixture is poured onto a mixture of 20 parts hydrochloric acid solution and 100 parts crushed ice. The product is extracted with methylene chloride. The organic phase is washed with alkaline water, dried and evaporated. The solid residue is triturated with hot petroleum ether. The product is filtered off and crystallized from ethanol to yield α-bromo-p-tolyl-2-thienyl ketone, m.p. 85.6T (decomposition).
2525
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Eksempel 13Example 13
Til en omrørt blanding af 26,7 dele p-ethylbenzoylchlorid og 13,3 dele thiophen i 80 dele methylenchlorid sættes 41,1 dele stannichlorid i 40 dele methylenchlorid ved 30eC. Derefter fortsættes omrøringen i 5 3 1/2 time ved tilbagesvalingstemperatur. Reaktionsblandingen hældes på en blanding af knust is og saltsyre. Lagene adskilles, og den vandige fase ekstraheres med methylenchlorid. De forenede organiske faser udvaskes med vand, tørres, filtreres og inddampes. Remanensen inddampes en gang mere fra benzen. Sidstnævnte remanens destilleres og giver som ud-10 bytte p-ethylphenyl-2-thienylketon, kogepunkt 200-205°C ved et tryk på 12 mm.To a stirred mixture of 26.7 parts of p-ethylbenzoyl chloride and 13.3 parts of thiophene in 80 parts of methylene chloride, 41.1 parts of stannous chloride are added in 40 parts of methylene chloride at 30 ° C. Then stirring is continued for 5 3 1/2 hours at reflux temperature. The reaction mixture is poured onto a mixture of crushed ice and hydrochloric acid. The layers are separated and the aqueous phase is extracted with methylene chloride. The combined organic phases are washed with water, dried, filtered and evaporated. The residue is evaporated once more from benzene. The latter residue is distilled off to yield p-ethylphenyl-2-thienyl ketone, boiling point 200-205 ° C at a pressure of 12 mm.
Ved gentagelse af fremgangsmåden ifølge eksempel 13 og erstatning af p-ethylbenzoylchlorid med en ækvivalent mængde 2-chlor-m-toluoylchlo-rid opnås følgende forbindelse: 15 2-chlor-m-tolyl-e-thienylketon, kogepunkt 197-199°C ved et tryk på 12 mm.By repeating the procedure of Example 13 and replacing p-ethylbenzoyl chloride with an equivalent amount of 2-chloro-m-toluoyl chloride, the following compound is obtained: 2-chloro-m-tolyl-e-thienyl ketone, bp 197-199 ° C a pressure of 12 mm.
Eksempel 14Example 14
En blanding af 23,5 dele p-ethylphenyl-2-thienylketon, 19,5 dele N-20 bromsuccinimid, 220 dele carbontetrachlorid, 1,1 dele benzoyl peroxid og en dråbe toluen omrøres og tilbagesvales i 2 timer. Det bundfældede suc-cinimid frafiltreres, og carbontetrachlorid-filtratet tørres og inddampes. Den olieagtige remanens størkner ved afkøling. Det faste produkt opløses i 2-propanol, og produktet får lov at udkrystallisere. Det fra-25 filtreres og tørres i vakuum og giver som udbytte a-brom-a-methyl-p-to-lyl-thienylketon, smp. 71,leC.A mixture of 23.5 parts of p-ethylphenyl-2-thienyl ketone, 19.5 parts of N-20 bromosuccinimide, 220 parts of carbon tetrachloride, 1.1 parts of benzoyl peroxide and a drop of toluene is stirred and refluxed for 2 hours. The precipitated succinimide is filtered off and the carbon tetrachloride filtrate is dried and evaporated. The oily residue solidifies upon cooling. The solid product is dissolved in 2-propanol and the product is allowed to crystallize. It is filtered and dried in vacuo to yield a-bromo-a-methyl-p-to-lyl-thienyl ketone, m.p. 71, LEC.
Eksempel 15Example 15
En blanding af 26 dele 5-chlor-2-thienyl-p-ethylphenylketon, 350 30 dele carbontetrachlorid, 1 del benzoyl peroxid og 18,5 dele N-bromsucci-nimid omrøres og tilbagesvales. Når reaktionen er ophørt, frafiltreres det dannede bundfald, og carbontetrachloridfasen tørres og inddampes. Remanensen størkner ved afkøling på is. Det faste produkt udkrystalliseres fra 2-propanol (aktivt kul) og giver som udbytte efter tørring i va-35 kuum a-brom-a-methyl-p-tolyl-5-chlor-2-thienylketon, smp. 69,4°C.A mixture of 26 parts of 5-chloro-2-thienyl-p-ethylphenyl ketone, 350 parts of carbon tetrachloride, 1 part of benzoyl peroxide and 18.5 parts of N-bromosuccinimide is stirred and refluxed. When the reaction has ceased, the precipitate formed is filtered off and the carbon tetrachloride phase is dried and evaporated. The residue solidifies upon cooling on ice. The solid product is crystallized from 2-propanol (activated carbon) to yield as a vacuum after drying in vacuo α-bromo-α-methyl-p-tolyl-5-chloro-2-thienyl ketone, m.p. 69.4 ° C.
Eksempel 16Example 16
En blanding af 9,9 dele a-brom-a-methyl-p-tolyl-5-chlor-2-thienyl-A mixture of 9.9 parts of α-bromo-α-methyl-p-tolyl-5-chloro-2-thienyl
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26 keton, 1,96 dele natriumcyanid, 12 dele vand og 48 dele dioxan omrøres i 17 timer under opvarmning ved 90eC. Reaktionsblandingen inddampes, og 36 dele vand sættes til remanensen. Produktet ekstraheres med ether. Ekstrakten tørres og inddampes. Remanensen renses ved søjlekromatografi 5 over silicagel under anvendelse af chloroform som elueringsmiddel. Den rene fraktion opsamles, og elueringsmidlet afdampes. Remanensen triture-res i n-hexan og giver som udbytte p-(5-chlor-2-thenoyl)-hydratroponi-tril, smp. 90eC.26 ketone, 1.96 parts sodium cyanide, 12 parts water and 48 parts dioxane are stirred for 17 hours under heating at 90 ° C. The reaction mixture is evaporated and 36 parts of water are added to the residue. The product is extracted with ether. The extract is dried and evaporated. The residue is purified by column chromatography over silica gel using chloroform as eluant. The pure fraction is collected and the eluent is evaporated. The residue is triturated in n-hexane to yield p- (5-chloro-2-thenoyl) -hydratroponitrile, m.p. 90eC.
10 Eksempel 17Example 17
En blanding af 7,3 dele p-(2-thenoyl)-hydratroponitril, 18 dele svovlsyre, 10 dele vand og 10 dele eddikesyre omrøres og tilbagesvales i 2 timer. Reaktionsblandingen hældes på knust is, og produktet ekstraheres med ether. Det organiske lag udvaskes med fortyndet natriumhydro-15 xidopløsning. Den vandige fase syrnes med saltsyreopløsning, og produktet ekstraheres med ether. Det organiske lag tørres, omrøres med aktivt kul, filtreres og inddampes i vakuum. Remanensen størkner ved triture-ring i petroleumsether. Det faste produkt frafiltreres og udkrystalli seres fra acetonitril og giver som udbytte p-(2-thenoyl)-hydratropinsyre, 20 smp. 121,1°C.A mixture of 7.3 parts of β- (2-thenoyl) -hydratroponitrile, 18 parts of sulfuric acid, 10 parts of water and 10 parts of acetic acid is stirred and refluxed for 2 hours. The reaction mixture is poured onto crushed ice and the product is extracted with ether. The organic layer is washed out with dilute sodium hydroxide solution. The aqueous phase is acidified with hydrochloric acid solution and the product is extracted with ether. The organic layer is dried, stirred with activated charcoal, filtered and evaporated in vacuo. The residue solidifies by trituration in petroleum ether. The solid product is filtered off and crystallized from acetonitrile to yield p- (2-thenoyl) -hydratropic acid, 20 m.p. 121.1 ° C.
Ved gentagelse af fremgangsmåden ifølge eksempel 17 og erstatning af p-(2-thenoyl)-hydratroponitril med en ækvivalent mængde af en egnet aroylphenylacetonitril opnås følgende forbindelser:By repeating the procedure of Example 17 and replacing p- (2-thenoyl) -hydratroponitrile with an equivalent amount of a suitable aroylphenylacetonitrile, the following compounds are obtained:
p-(5-chlor-2-thenoyl)-hydratropinsyre, smp. 137,4eC 25 2-[p-(2-thenoyl)-phenyl]-eddikesyre, smp. 126-129eCp- (5-chloro-2-thenoyl) -hydratropic acid, m.p. 137.4 ° C 2- [p- (2-thenoyl) -phenyl] -acetic acid, m.p. 126-129eC
a-methyl-p-(2-thenoyl)-hydratropinsyre, smp. 138,8eCα-methyl-β- (2-thenoyl) -hydratropic acid, m.p. 138,8eC
2-[2-chlor-3-(2-thenoyl)-phenyl]-eddikesyre, smp. 112,2eC.2- [2-Chloro-3- (2-thenoyl) -phenyl] -acetic acid, m.p. 112,2eC.
Eksempel 18 30 En blanding af 6 dele 2-methyl-3-(2-thenoyl)-hydratroponitril, 2,7 dele kaliumhydroxid, 28 dele ethanol og 3,5 dele vand omrøres og tilbagesvales i 44 timer. Reaktionsblandingen inddampes. Remanensen optages i vand og udvaskes to gange med 80 dele ether. Den vandige fase syrnes med koncentreret saltsyreopløsning. Det fraskilte olieagtige produkt ekstra-35 heres med ether. Sidstnævnte tørres og inddampes. Den olieagtige remanens størkner ved triturering i petroleumsether. Produktet udkrystalliseres fra acetonitril ved -20eC og giver som udbytte en første fraktion af 2-methyl-3-(2-thenoyl)-hydratropinsyre, smp. 118,7°C. Moderluden ind-Example 18 A mixture of 6 parts of 2-methyl-3- (2-thenoyl) hydratroponitrile, 2.7 parts of potassium hydroxide, 28 parts of ethanol and 3.5 parts of water is stirred and refluxed for 44 hours. The reaction mixture is evaporated. The residue is taken up in water and washed twice with 80 parts of ether. The aqueous phase is acidified with concentrated hydrochloric acid solution. The separated oily product is extracted with ether. The latter is dried and evaporated. The oily residue solidifies by trituration in petroleum ether. The product is crystallized from acetonitrile at -20 ° C to yield a first fraction of 2-methyl-3- (2-thenoyl) hydratropic acid, m.p. 118.7 ° C. The mother liquor
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27 dampes. Remanensen størkner ved tri turering i petroleumsether og giver som udbytte en anden fraktion af 2-methyl-3-(2-thenoyl)-hydratropinsyre, smp. 100°C.27 steamed. The residue solidifies by trituration in petroleum ether to yield a second fraction of 2-methyl-3- (2-thenoyl) -hydratropic acid, m.p. 100 ° C.
5 Eksempel 19Example 19
En blanding af 14,7 dele 2'-methyl-3'-(2-thenoyl)-acetophenon, 4,3 dele svovl og 33 dele morpholin omrøres og tilbagesvales i 3 timer. Reaktionsblandingen afkøles, fortyndes og rystes først to gange med fortyndet saltsyreopløsning og derefter to gange med vand. Det organiske 10 lag tørres og inddampes. Den olieagtige remanens koges i en blanding af 200 dele iseddikesyre og 150 dele 50% svovlsyreopløsning i 2 timer. Efter afkøling hældes blandingen på 700 dele is-vand, og produktet ekstra-heres to gange med ether. De forenede ekstrakter udvaskes med vand, tørres, omrøres med aktivt kul, filtreres og inddampes. Remanensen optages 15 i 200 dele vand, alkaliseres med fortyndet natriumhydroxidopløsning og udvaskes to gange med ether. Den vandige fase syrnes med koncentreret saltsyreopløsning, og produktet ekstraheres to gange med ether. Ekstrakterne tørres og inddampes. Remanensen renses ved søjlekromatografi over silicagel under anvendelse af en blanding af chloroform og 5% methanol 20 som elueringsmiddel. De rene fraktioner opsamles, og elueringsmidlet af-dampes. Remanensen opløses i ether, og opløsningen omrøres med aktivt kul. Sidstnævnte frafiltreres, og filtratet inddampes. Remanensen udkrystalliseres fra acetonitril ved -20eC og giver som udbytte 2-[3-(2-thenoyl)-o-tolyl]-eddikesyre, smp. 136*C.A mixture of 14.7 parts of 2'-methyl-3 '- (2-thenoyl) acetophenone, 4.3 parts of sulfur and 33 parts of morpholine is stirred and refluxed for 3 hours. The reaction mixture is cooled, diluted and shaken first twice with dilute hydrochloric acid solution and then twice with water. The organic layer is dried and evaporated. The oily residue is boiled in a mixture of 200 parts glacial acetic acid and 150 parts 50% sulfuric acid solution for 2 hours. After cooling, the mixture is poured into 700 parts of ice-water and the product is extracted twice with ether. The combined extracts are washed with water, dried, stirred with activated charcoal, filtered and evaporated. The residue is taken up in 200 parts of water, alkalized with dilute sodium hydroxide solution and washed twice with ether. The aqueous phase is acidified with concentrated hydrochloric acid solution and the product is extracted twice with ether. The extracts are dried and evaporated. The residue is purified by column chromatography over silica gel using a mixture of chloroform and 5% methanol 20 as eluent. The pure fractions are collected and the eluent is evaporated. The residue is dissolved in ether and the solution is stirred with activated charcoal. The latter is filtered off and the filtrate is evaporated. The residue is crystallized from acetonitrile at -20 ° C to yield 2- [3- (2-thenoyl) -o-tolyl] -acetic acid, m.p. 136 * C.
2525
Eksempel 20Example 20
Til 400 dele flydende ammoniak sættes spor af ferrichlorid og 3 dele natrium. Blandingen omrøres i 30 minutter, hvorefter 14,8 dele 2-[p-(2-thenoyl)-phenyl]-eddikesyre tilsættes langsomt i løbet af 30 minut-30 ter, og blandingen omrøres i yderligere 45 minutter. 13,6 dele methylio-did tilsættes dråbevis, og reaktionsblandingen omrøres i 2 1/2 time.Traces of ferric chloride and 3 parts of sodium are added to 400 parts of liquid ammonia. The mixture is stirred for 30 minutes, then 14.8 parts of 2- [p- (2-thenoyl) -phenyl] -acetic acid are added slowly over 30 minutes and the mixture is stirred for an additional 45 minutes. 13.6 parts of methyl iodide are added dropwise and the reaction mixture is stirred for 2 1/2 hours.
Derpå tilsættes 400 dele diethylether, og blandingen omrøres natten over. Ammoniak afdampes, og den resulterende opløsning syrnes med fortyndet saltsyre. Det etheriske lag adskilles og ekstraheres med 10% na-35 triumhydroxidopiøsning. Ekstrakten udvaskes med ether, syrnes og ekstraheres med ether. Den etheriske opløsning tørres over natriumsulfat, og etheren afdampes i vakuum. Remanensen tritureres i petroleumsether, frafiltreres og udkrystalliseres to gange fra acetonitril, først ved -20°CThen 400 parts of diethyl ether are added and the mixture is stirred overnight. The ammonia is evaporated and the resulting solution is acidified with dilute hydrochloric acid. The etheric layer is separated and extracted with 10% sodium hydroxide solution. The extract is washed with ether, acidified and extracted with ether. The ethereal solution is dried over sodium sulfate and the ether is evaporated in vacuo. The residue is triturated in petroleum ether, filtered and crystallized twice from acetonitrile, first at -20 ° C.
DK 154899 BDK 154899 B
28 og derefter ved 0eC og giver som udbytte p-(2-thenoy1)-hydratropinsyre med smp. som i eksempel 6.28 and then at 0 ° C to yield β- (2-thenoy1) -hydratropic acid with m.p. as in Example 6.
Eksempel 21 5 Til en omrørt blanding af 20 dele p-(thenoyl)-hydratropinsyre og 9,3 dele (-)-a-methylbenzylamin i 200 dele ethanol sættes 50 dele vand.Example 21 To a stirred mixture of 20 parts of p- (thenoyl) -hydratropic acid and 9.3 parts of (-) - α-methylbenzylamine in 200 parts of ethanol, 50 parts of water are added.
Det udfældede salt frafiltreres og udkrystalliseres fra en blanding af ethanol og vand (10 : 2 efter volumen) og giver den rå saltform. Den fraktion omkrystalliseres adskillige gange til konstant rotation fra en 10 blanding af ethanol og vand (10 : 2 efter volumen) og giver som udbytte (-)-p-(2-thenoyl)-hydratropinsyre-a-methylbenzylamin, smp. 170,5eC.The precipitated salt is filtered off and crystallized from a mixture of ethanol and water (10: 2 by volume) to give the crude salt form. The fraction is recrystallized several times for constant rotation from a mixture of ethanol and water (10: 2 by volume) to yield (-) - p- (2-thenoyl) -hydratropic acid α-methylbenzylamine, m.p. 170,5eC.
[e] (1,98% MeOH) = -13,74°.[e] (1.98% MeOH) = -13.74 °.
1,5 dele (-)-p-(2-thenoyl)-hydratropinsyre-a-methylbenzylamin suspenderes i vand og syrnes med saltsyre. Produktet ekstraheres med 15 ether. Det organiske lag udvaskes med vand, tørres og inddampes. Den olieagtige remanens størkner ved triturering i petroleumsether. Det størknede produkt frafiltreres og tørres i vakuum ved 50eC og giver som udbytte (+)-p-(2-thenoyl)-hydratropinsyre.1.5 parts of (-) - p- (2-thenoyl) -hydratropic acid α-methylbenzylamine are suspended in water and acidified with hydrochloric acid. The product is extracted with 15 ether. The organic layer is washed with water, dried and evaporated. The oily residue solidifies by trituration in petroleum ether. The solidified product is filtered off and dried in vacuo at 50 ° C to yield (+) - p- (2-thenoyl) hydratropic acid.
[ot] (1% i MeOH) = +44,5°.[ot] (1% in MeOH) = + 44.5 °.
2020
Eksempel 22Example 22
Til en omrørt blanding af 30 dele p-(2-thenoyl)-hydratropinsyre og 14 dele (+)-α-methylbenzylamin i 200 dele ethanol sættes 50 dele vand.To a stirred mixture of 30 parts of p- (2-thenoyl) -hydratropic acid and 14 parts of (+) - α-methylbenzylamine in 200 parts of ethanol is added 50 parts of water.
Det udfældede salt frafiltreres og udkrystalliseres fra en blanding af 25 ethanol og vand (10 : 2 efter volumen) til dannelse af den rå saltform.The precipitated salt is filtered off and crystallized from a mixture of ethanol and water (10: 2 by volume) to give the crude salt form.
Denne fraktion udkrystalliseres adskillige gange til konstant rotation fra en blanding af ethanol og vand (10 : 2 efter volumen) og giver som udbytte (+)-p-(2-thenoyl)-hydratropinsyre-a-methylbenzylamin, smp.This fraction is crystallized several times for constant rotation from a mixture of ethanol and water (10: 2 by volume) to yield (+) - p- (2-thenoyl) -hydratropic acid α-methylbenzylamine, m.p.
171,1.171.1.
30 [tt] (2,02% MeOh) = + 13,55°.[Tt] (2.02% MeOh) = + 13.55 °.
1 del (+)-p-(2-thenoyl)-hydratropinsyre-a-methylbenzylamin suspenderes i vand og syrnes med saltsyre. Produktet ekstraheres med ether.1 part (+) - p- (2-thenoyl) -hydratropic acid α-methylbenzylamine is suspended in water and acidified with hydrochloric acid. The product is extracted with ether.
Det organiske lag udvaskes med vand, tørres, filtreres og inddampes i vakuum. Den olieagtige remanens størkner ved triturering i petroleums-35 ether. Det størknede produkt frafilteres og tørres i vakuum ved 50°C og giver som udbytte (-)-p-(2-thenoyl)-hydratropinsyre.The organic layer is washed with water, dried, filtered and evaporated in vacuo. The oily residue solidifies by trituration in petroleum ether. The solidified product is filtered off and dried in vacuo at 50 ° C to yield (-) - p- (2-thenoyl) hydratropic acid.
[a] (1% MeOH) = -45,6°.[α] (1% MeOH) = -45.6 °.
Claims (2)
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US30007972A | 1972-10-24 | 1972-10-24 | |
| US30007972 | 1972-10-24 | ||
| US39587773A | 1973-09-10 | 1973-09-10 | |
| US39587773 | 1973-09-10 |
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| DK154899C DK154899C (en) | 1989-05-29 |
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| JP (2) | JPS5940811B2 (en) |
| AT (1) | AT333269B (en) |
| BE (1) | BE806389A (en) |
| BG (1) | BG25209A3 (en) |
| CA (1) | CA1007643A (en) |
| CH (1) | CH597219A5 (en) |
| CS (1) | CS183719B2 (en) |
| DD (1) | DD110044A5 (en) |
| DE (1) | DE2353357C2 (en) |
| DK (1) | DK154899C (en) |
| ES (1) | ES419871A1 (en) |
| FI (1) | FI66369C (en) |
| FR (1) | FR2203635B1 (en) |
| GB (1) | GB1446239A (en) |
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| IE (1) | IE38402B1 (en) |
| IL (1) | IL43570A (en) |
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| PH (1) | PH12124A (en) |
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|---|---|---|---|---|
| IT1036466B (en) * | 1975-07-08 | 1979-10-30 | Sigurta Farmaceutici Spa | PROCESS FOR THE PREPARATION OF DERIVATIVES OF ALPHA PHENYLPROPIONIC ACID |
| FR2374033A1 (en) * | 1976-12-16 | 1978-07-13 | Rhone Poulenc Ind | Thienothienylcarbonyl-phenyl-alkanoic acids - for use as analgesics, antipyretics, antithrombotics and antiinflammatory agents |
| FR2345148A1 (en) * | 1976-03-24 | 1977-10-21 | Lipha | NEW SUBSTITUTE PROPIONIC ACID, PREPARATION AND APPLICATION |
| GB1569404A (en) * | 1977-04-22 | 1980-06-11 | Soc D Etudes Prod Chimique | (2-isopropyl-4-(2'-theonyl)-5-methyl) phenoxy acetic acid |
| JPS5538339A (en) * | 1978-09-12 | 1980-03-17 | Taiyo Yakuhin Kogyo Kk | Preparation of 2- 4-(2-thienylcarbonyl)phenyl propionic acid |
| GB2030131B (en) * | 1978-09-12 | 1982-12-22 | Taiyo Pharma Ind | Process for producing 2-(4-(2-thienyl-carbonyl) phenyl) propionic acid |
| JPS5538340A (en) * | 1978-09-12 | 1980-03-17 | Taiyo Yakuhin Kogyo Kk | Preparation of 2- 4-(2-thienylcarbonyl)phenyl propionic acid |
| JPS5825675B2 (en) * | 1979-02-02 | 1983-05-28 | 財団法人相模中央化学研究所 | ketal derivative |
| JPS5823873B2 (en) * | 1979-02-02 | 1983-05-18 | 財団法人相模中央化学研究所 | Method for producing substituted phenylacetic acid derivatives |
| ES479300A1 (en) * | 1979-04-04 | 1979-07-01 | Cusi Lab | An alpha-methyl-4(2'-thienyl-carbonyl)phenyl acetic acid derivative, process for its preparation and its pharmaceutical use. |
| EP0046337A3 (en) * | 1980-08-20 | 1982-09-15 | Imperial Chemical Industries Plc | Triazole compounds, a process for preparing them, their use as plant and pharmaceutical fungicides and as plant growth regulators and compositions containing them |
| CA2023954C (en) * | 1989-10-17 | 1999-05-04 | Hiroyuki Nohira | Process for the optical resolution of 2-(3-benzoyl) phenylpropionic acid |
| JP6290947B2 (en) * | 2016-02-05 | 2018-03-07 | テックフィールズ バイオケム カンパニー リミテッド | Positively charged water-soluble prodrugs of aryl- and heteroarylpropionic acids with very fast skin permeability |
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| FR2113760A1 (en) * | 1970-11-10 | 1972-06-30 | Roussel Uclaf | 5-Arylcarbonyl-3(or 4)-methylthien-2-yl alkanoic acids and esters - with antiinflammatory and analgesic activity |
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1973
- 1973-10-17 CA CA183,576A patent/CA1007643A/en not_active Expired
- 1973-10-18 PH PH15118A patent/PH12124A/en unknown
- 1973-10-19 FR FR7337487A patent/FR2203635B1/fr not_active Expired
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- 1973-10-23 JP JP48118585A patent/JPS5940811B2/en not_active Expired
- 1973-10-23 FI FI3278/73A patent/FI66369C/en active
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- 1973-10-24 AT AT900773A patent/AT333269B/en not_active IP Right Cessation
- 1973-10-24 DD DD174327A patent/DD110044A5/xx unknown
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- 1973-10-24 NL NLAANVRAGE7314629,A patent/NL179583C/en not_active IP Right Cessation
- 1973-10-24 BG BG024830A patent/BG25209A3/en unknown
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- 1973-10-24 GB GB4958073A patent/GB1446239A/en not_active Expired
- 1973-11-05 IL IL43570A patent/IL43570A/en unknown
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| FR7956M (en) * | 1967-07-31 | 1970-05-25 |
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