DK143500B - METHOD OF ANALOGY FOR PREPARING PYRIDINE DERIVATIVES - Google Patents
METHOD OF ANALOGY FOR PREPARING PYRIDINE DERIVATIVES Download PDFInfo
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- C—CHEMISTRY; METALLURGY
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Description
143500143500
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte pyridinderivater med den almene formel IThe present invention relates to an analogous process for the preparation of novel pyridine derivatives of the general formula I
5 0 n ii /—\ 2 l *J-(CH2>„-c-N m -r* i R1 F '- i 2 10 hvor R betegner hydrogen eller methyl, R betegner hydrogen, alkyl med 1-3 carbonatomer, alkyl med 1-3 carbonatomer substitueret med hydroxy, benzyl eller med halogen substitueret benzyl, og n betegner 0 eller 1, eller syreadditionssalte deraf, hvilken fremgangsmåde er ejendommelig ved, at et pyridinderivat med den almene formel II 15 ^ 0 L , ΐ , 11 (CS2>n - C - E~Wherein R represents hydrogen or methyl, R represents hydrogen, alkyl of 1-3 carbon atoms, alkyl of 1-3 carbon atoms substituted with hydroxy, benzyl or halogen substituted benzyl, and n represents 0 or 1, or acid addition salts thereof, characterized in that a pyridine derivative of the general formula II is 15 L 0, 11 (CS 2 > n - C - E ~
KK
20 1 3 hvor R og n har de ovenfor anførte betydninger, og R betegner halogen,Wherein R and n have the above meanings and R represents halogen,
hydroxy, amino eller ligekædet eller forgrenet alkoxy med 1-4 carbonatomer, eller et syreadditionssalt deraf, omsættes med et piperazinderivat 25 med den almene formel IIIhydroxy, amino or straight chain or branched alkoxy of 1-4 carbon atoms, or an acid addition salt thereof, is reacted with a piperazine derivative of the general formula III
h/ \ - RZ IIIh / \ - RZ III
30 o hvor R har den ovenfor anførte betydning, eller med et syreadditionssalt deraf, hvorefter om ønsket, 2 35 a) den resulterende forbindelse med den almene formel I, hvor R er et hydrogenatom, omdannes til en forbindelse med den almene formel I, der som substituenten R har et alkalimetalatom, fortrinsvis ved behandling 2 143500 med et alkalimetal, og den resulterende forbindelse med formlen I, hvor 2 R er et alkalimetalatom, ved behandling med et alkylerings- eller aralkyle- ringsmiddel omdannes til en forbindelse med den almene formel I, hvor 2 R er alkyl med 1-3 carbonatomer, hydroxyalkyl med 1-3 carbon-5 atomer, benzyl eller halogensubstitueret benzyl, eller, om ønsket, b) den vundne forbindelse med den almene formel I omdannes til et syreadditionssalt ved omsætning med en syre, eller, om ønsket, 10 c) det vundne syreadditionssalt af forbindelsen med formlen I omdannes til den frie base med formlen I ved omsætning af saltet med en stærk base.Wherein R is as defined above, or with an acid addition salt thereof, and if desired, a) the resulting compound of general formula I wherein R is a hydrogen atom is converted to a compound of general formula I which as the substituent R has an alkali metal atom, preferably by treatment with an alkali metal, and the resulting compound of formula I wherein 2 R is an alkali metal atom, by treatment with an alkylating or aralkylating agent is converted to a compound of the general formula I wherein 2 R is alkyl of 1-3 carbon atoms, hydroxyalkyl of 1-3 carbon atoms, benzyl or halogen-substituted benzyl, or, if desired, b) the compound of formula I obtained is converted to an acid addition salt by reaction with a acid, or, if desired, c) the obtained acid addition salt of the compound of formula I is converted to the free base of formula I by reacting the salt with a strong base.
De frie baser med den almene formel I kan renses før dannelse af 15 saltene, fortrinsvis ved omkrystaUisation eller vakuumdestillation, men de rå baser med den almene formel I kan også anvendes til saltdannelsen.The free bases of the general formula I can be purified before the salts are formed, preferably by recrystallization or vacuum distillation, but the crude bases of the general formula I can also be used for the salt formation.
33
Hvis der anvendes forbindelser med den almene formel II, hvor R er 20 hydrogen, amino eller alkoxy indeholdende 1-4 carbonatomer, som udgangsmateriale, omsættes disse forbindelser fortrinsvis ved en temperatur mellem 140 og 250°C med forbindelserne med den almene formel III. Omsætningen kan udføres i fraværelse af opløsningsmiddel eller i nærværelse af et opløsningsmiddel med højere kogepunkt, f.eks. ethylenglycol, form-25 amid, dimethylformamid, benzylalkohol eller en eutektisk blanding af diphenyl og diphenylether.If compounds of the general formula II are used, wherein R is 20 hydrogen, amino or alkoxy containing 1-4 carbon atoms as starting material, these compounds are preferably reacted at a temperature between 140 and 250 ° C with the compounds of the general formula III. The reaction may be carried out in the absence of solvent or in the presence of a higher boiling solvent, e.g. ethylene glycol, formamide, dimethylformamide, benzyl alcohol or a eutectic mixture of diphenyl and diphenyl ether.
Hvis der ved fremstillingen af forbindelserne med den almene formel I gås ud fra forbindelser med den almene formel II indeholdende et ha- 3 30 logenatom som substituenten R , udføres omsætningen fortrinsvis ved 0 - 100°C og i fraværelse af et opløsningsmiddel eller i et neutralt opløsningsmiddel, f.eks. ether, dioxan, benzen eller carbontetra-chlorid.In the preparation of the compounds of the general formula I, starting from the compounds of the general formula II containing a halogen atom as the substituent R, the reaction is preferably carried out at 0 - 100 ° C and in the absence of a solvent or in a neutral solvent, e.g. ether, dioxane, benzene or carbon tetrachloride.
35 Udgangsmaterialerne med de almene formler II og III er kendte forbindelser (USA patent nr. 2.415.785; J. Chem. Soc. 1927, 47; 1959, 3634; C.A. 45, 5954/1951/; 47, 617/1953/).The starting materials of general formulas II and III are known compounds (U.S. Patent No. 2,415,785; J. Chem. Soc. 1927, 47; 1959, 3634; CA 45, 5954/1951 /; 47, 617/1953 /) .
3 1435003 143500
De ved fremgangsmåden ifølge den foreliggende opfindelse fremstillede forbindelser har vist sig at være antidepressive midler med betydelig terapeutisk værdi. Forbindelser med lignende struktur er beskrevet i den tekniske litteratur i en enkelt sammenhæng (Pharmacia/Bukarest/10, 5 35, 81/1962/; C.A. 58, 522 11359/1963/). De kendte forbindelser blev fremstillet ved omsætning af N-methyl-piperazin og nicotin- eller iso-nicotinsyrechlorid, og deres cardiovasculære effekt blev undersøgt.The compounds prepared by the process of the present invention have been found to be antidepressants of considerable therapeutic value. Compounds of similar structure are described in the technical literature in a single context (Pharmacia / Bucharest / 10, 35, 81/1962 /; C.A. 58, 522 11359/1963 /). The known compounds were prepared by reaction of N-methyl-piperazine and nicotinic or iso-nicotinic acid chloride and their cardiovascular efficacy was investigated.
Ifølge ansøgernes egne forsøg har disse kendte forbindelser ingen mærkbar antidepressiv effekt.According to the applicants' own experiments, these known compounds have no appreciable antidepressant effect.
1010
Forbindelserne med den almene formel I har ifølge farmakologiske forsøg en stærk tetrabenazin- og reserpin-antagonistisk effekt.The compounds of general formula I have, according to pharmacological tests, a strong tetrabenazine and reserpine antagonistic effect.
Virkningen og toxicitetsdataene for dihydrochlorideme af forbindel-15 serne med den almene formel I er sammenfattet i nedenstående tabel I.The effect and toxicity data of the dihydrochlorides of the compounds of general formula I are summarized in Table I below.
De tilsvarende data for de kendte 5-(Y-dimethylamino-propyliden)-di-benz(a,d)l,4-cycloheptadien (Amitryptilin) med antidepressiv effekt er anført til sammenligning. Forsøgene er udført på mus, og forbindelserne er indgivet oralt.The corresponding data for the known 5- (γ-dimethylamino-propylidene) di-benz (a, d) 1,4-cycloheptadiene (Amitryptiline) with antidepressant effect are given for comparison. The experiments were performed on mice and the compounds were administered orally.
2020
Tabel ITable I
Forbindelse LD5Q ED5Q mg/kg (eksempel nr.) mg/kg Tetrabenazin- Reserpin-antagoni-25 antagoniserende serende effekt effekt 1 eHer 2 3000 22,5 200 30 3 3000 60 >400 4 eller 5 860 25 39 6 3000 17 190 7 3000 15 >400 8 3000 11 200 35 9 3000 18 200 10 700 12,5 12 11 360 30 30 12 680 70 47 4 143500Compound LD5Q ED5Q mg / kg (Example No.) mg / kg Tetrabenazine Reserpine Antagonist Antagonizing Serative Effect Power 1 or 2,000 22.5 200 30 3 3000 60> 400 4 or 5 860 25 39 6 3000 17 190 7 3000 15> 400 8 3000 11 200 35 9 3000 18 200 10 700 12.5 12 11 360 30 30 12 680 70 47 4 143500
Tabel I fortsat 13 435 20 >100 14 1100 23,5 108 5 .........-...................—.......................................Table I continued 13 435 20> 100 14 1100 23.5 108 5 .........-................... — ..... ..................................
Amitryptilin 185 13 65 10 Det terapeutiske indeks (LD^/ED^q) for en del af forbindelserne med den almene formel I er mere fordelagtigt, og det er i nogle tilfælde størrelsesordner højere end for sammenligningsforbindelsen. Desuden har forbindelserne med den almene formel I katalepsiinhiberende, lokal-anæstetiserende og/eller sedativ effekt.Amitryptiline 185 13 65 10 The therapeutic index (LD 2 / ED 2) for some of the compounds of the general formula I is more advantageous and in some cases is higher in magnitude than for the comparative compound. In addition, the compounds of general formula I have catalepsy inhibitory, local-anesthetizing and / or sedative effects.
1515
Forbindelserne med den almene formel I kan som aktiv ingrediens formuleres til farmaceutiske kompositioner sammen med egnede farmaceutiske excipienser.The compounds of general formula I may be formulated as active ingredient for pharmaceutical compositions together with suitable pharmaceutical excipients.
20 Fremgangsmåden ifølge den foreliggende opfindelse belyses nærmere ved nedenstående eksempler:The process of the present invention is further illustrated by the following examples:
Eksempel 1.Example 1.
2525
Fremstilling af N-picolinoyl-piperazin.Preparation of N-picolinoyl-piperazine.
En blanding af 27,4 g (0,2 mol) picolinsyre-metylester (eller af 30,2 g (0,2 mol) picolinsyre-ethylester eller af 35,8 g (0,2 mol) picolinsyre-30 n-butylester) og 51,6 g (0,6 mol) vandfrit piperazin holdes i 25 timer ved 135 - 145°C, hvorefter den overskydende mængde piperazin destilleres af på et oliebad ved 240°C. Remanensen destilleres fraktioneret under et tryk på 0,1 mm Hg. Der fås på denne måde 21 - 23 g (55 -60%) N-picolinoyl-piperazin med smeltepunkt 152 - 155°C (0,01 mm Hg; 35 produktet krystalliseres ved henstand; smeltepunkt 72 - 73°C).A mixture of 27.4 g (0.2 mole) of picolinic acid methyl ester (or of 30.2 g (0.2 mole) of picolic acid ethyl ester or of 35.8 g (0.2 mole) of picolinic acid 30 n-butyl ester ) and 51.6 g (0.6 mol) of anhydrous piperazine are kept for 25 hours at 135 - 145 ° C, after which the excess piperazine is distilled off on an oil bath at 240 ° C. The residue is fractionally distilled under a pressure of 0.1 mm Hg. There are thus obtained 21-23 g (55 -60%) of N-picolinoyl-piperazine with mp 152-155 ° C (0.01 mm Hg; 35 the product is crystallized on standing; mp 72-73 ° C).
5 1435005 143500
Analyse: (molvægt 191,24)Analysis: (molecular weight 191.24)
Beregnet for: N 21,97Calculated for: N, 21.97
Fundet: N 21,65Found: N, 21.65
Det hvide krystallinske N-picolinoyl-piperazin-dihydrochlorid smel= ter efter omkrystallisation af methanol ved 210°C under sønderdeling.The white crystalline N-picolinoyl-piperazine dihydrochloride melts after recrystallization of methanol at 210 ° C with decomposition.
Analyse: (molvægt 264,17)Analysis: (molecular weight 264.17)
Beregnet for: N 15,91 Cl 26,84Calculated for: N 15.91 Cl 26.84
Fundet: N 15,95 Cl 26,36Found: N 15.95 Cl 26.36
Eksempel 2.Example 2.
Fremstilling af N-picolinoyl-piperazin.Preparation of N-picolinoyl-piperazine.
En blanding af 8,6 g (0,1 mol) vandfrit piperazin og 12,2 g (0,1 mol) picolinsyreamid koges under tilbagesvaling i 20 timer i et oliebad ved 150 - 160°C, hvorefter blandingen destilleres frak= . . tioneret ved et tryk på 0,1 mm Hg. Derved fås 21 g (55# af det teoretiske) N-picolinoyl-piperazin. Produktet er identisk med det ... produkt, som fremstilles ved fremgangsmåden, som er beskrevet i eksempel 1.A mixture of 8.6 g (0.1 mole) of anhydrous piperazine and 12.2 g (0.1 mole) of picolinic acid amide is refluxed for 20 hours in an oil bath at 150-160 ° C, after which the mixture is distilled off. . ionized at a pressure of 0.1 mm Hg. There is thus obtained 21 g (55 # of theory) of N-picolinoyl-piperazine. The product is identical to the product produced by the method described in Example 1.
Eksempel 3.Example 3
Fremstilling af N-(6-methylpicolinoyl)-N’-methylpiperazin.Preparation of N- (6-methylpicolinoyl) -N'-methylpiperazine.
En blanding af 33,0 g (0,2 mol) 6-methylpicolinsyre-ethylester (eller 38,6 g (0,2 mol) 6-methylpicolinsyre-n-butylester) og 20,0 g (0,2 mol) N-methylpiperazin koges under tilbagesvaling i 20 ti= mer på oliebad ved 170 - 200°C, hvorefter blandingen afdestilleres fraktioneret under et tryk på 0,4 mm Hg. Herved fås 19,5 - 22 g (45 - 50%) lysegult, olieagtigt N-(6-methylpicolinoyl)-N,-methyl= piperazin som hovedprodukt.A mixture of 33.0 g (0.2 mole) of 6-methylpicolic acid ethyl ester (or 38.6 g (0.2 mole) of 6-methylpicolic acid n-butyl ester) and 20.0 g (0.2 mole) of N -Methylpiperazine is refluxed for 20 hours in an oil bath at 170 - 200 ° C, after which the mixture is fractionally distilled off under a pressure of 0.4 mm Hg. This gives 19.5 - 22 g (45 - 50%) of light yellow, oily N - (6-methylpicolinoyl) -N, -methyl = piperazine as the main product.
143500 6143500 6
Analyse^(molvægt 219 >29)Analysis (m / m 219> 29)
Beregnet for: N 19>16Calculated for: N 19> 16
Fundet: N 19>10Found: N 19> 10
Efter omkrystallisation af ethanol smelter det hvide krystallinske N-(6-methylpicolinoyl)-N'-methylpiperazin-dihydrochlorid ved 247 - 248 °C under sønderdeling.After recrystallization from ethanol, the white crystalline N- (6-methylpicolinoyl) -N'-methylpiperazine dihydrochloride melts at 247 - 248 ° C with decomposition.
Analyse:(molvægt 292,22)Analysis: (mole weight 292.22)
Beregnet for: N 14,38 Cl 24,27Calculated for: N 14.38 Cl 24.27
Fundet: N 14,28 Cl 24,57Found: N 14.28 Cl 24.57
Eksempel 4.Example 4
Fremstilling af N—picolinoyl-N'— benzylpiperazin.Preparation of N-picolinoyl-N'-benzylpiperazine.
En blanding af 15>95 g (0,1 mol) picolinsyre-hydrochlorid og 17,6 g (0,1 mol) N-benzylpiperazin holdes i et apparatur i 5 timer ved 160 - 170°C. Den vundne N-picolinoyl-N' -benzylpiperazin-monohy= drochlorid opløses i 200 ml varmt absolut ethanol, og opløsningen syrnes ved 50 - 70°C med absolut ethanol mættet med hydrogenchlorid. Opløsningens pH-værdi 'undersøges med indikatorpapir. Blandingen holdes i nogle timer i køleskab, hvorefter de udskilte krystaller frafiltreres, vaskes to gange med hver gang 20 ml ethanol og tørres. På denne måde fås 20,5 g (58fo) N-picolinoyl-N'-benzylpipe= razin-dihydrochlorid, som smelter ved 214 - 215°C under sønderde= ling. Efter omkrystallisation af absolut ethanol hæves sønderdelings= punktet til 216 - 217°C.A mixture of 15> 95 g (0.1 mole) of picolinic acid hydrochloride and 17.6 g (0.1 mole) of N-benzylpiperazine is kept in an apparatus for 5 hours at 160 - 170 ° C. The obtained N-picolinoyl-N '-benzylpiperazine monohydrochloride is dissolved in 200 ml of warm absolute ethanol and the solution is acidified at 50-70 ° C with absolute ethanol saturated with hydrogen chloride. The pH of the solution is examined with indicator paper. The mixture is kept in the refrigerator for a few hours, after which the separated crystals are filtered off, washed twice with 20 ml of ethanol each time and dried. In this way, 20.5 g (58fo) of N-picolinoyl-N'-benzylpipe = dihydrochloride is obtained, which melts at 214 - 215 ° C with decomposition. After recrystallization from absolute ethanol, the decomposition point is raised to 216 - 217 ° C.
Analys e: (Molvægt 354,29).Analyze: (Molecular Weight 354.29).
7 1435007 143500
Beregnet for: N 11,86 Cl 20,01 Fundet: N 11,91 Cl 19,70.Calculated for: N 11.86 Cl 20.01 Found: N 11.91 Cl 19.70.
N-Picolinoyl-N'-benzylpiperazin-maleatet (C^yH^N^O.C^H^O^) smelter ved 169 - 170°C, medens N-picolinoyl-N'-benzylpiperazin-fumaratet ^17H19^3^'smelter ved 165°C.The N-picolinoyl-N'-benzylpiperazine maleate (C ^ yHHN ^O ^H HO ^) melts at 169-170 ° C, while the N-picolinoyl-N'-benzylpiperazine fumarate ^ 17H19 ^3 ^ 'melts at 165 ° C.
Eksempel 5.Example 5
Fremstilling af N-picolinoyl-N'-benzylpiperazin.Preparation of N-picolinoyl-N'-benzylpiperazine.
Til en varm opløsning af 19,1 g (0,1 mol) N-pioolinoyl-piperazin (fremstillet som beskrevet i eksempel 1) i 150 ml absolut dioxan sættes 2,3 g metallisk natriumpulver portionsvis i løbet af 1 time lander omrøring. Blandingen lades henstå ved stuetemperatur 1 dag.To a warm solution of 19.1 g (0.1 mole) of N-pioolinoyl-piperazine (prepared as described in Example 1) in 150 ml of absolute dioxane, 2.3 g of metallic sodium powder are added portionwise over 1 hour of stirring. The mixture is allowed to stand at room temperature for 1 day.
I løbet af 1 time’ tildryppes 0,1 mol benzylchlorid til det resul= terende N-picolinoyl-piperazin-natrium under ydre afkøling med vand, hvorefter blandingen opvarmes til kogning. Det udskilte natriumchlorid frafiltreres, opløsningsmidlet afdestilleres, og remanensen destilleres fraktioneret under vakuum. På denne måde fås 18,2 g (65$) N-picolinoyl-N'-benzylpiperazin med smeltepunkt 218 - 220°C/0,1 mm Hg. Produktet er identisk med det ifølge eksempel 4 fremstillede.Over 1 hour, 0.1 mole of benzyl chloride is added dropwise to the resulting N-picolinoyl-piperazine sodium under external cooling with water and the mixture is heated to boiling. The separated sodium chloride is filtered off, the solvent is distilled off and the residue is fractionally distilled under vacuum. In this way 18.2 g (65 $) of N-picolinoyl-N'-benzylpiperazine are obtained, mp 218 - 220 ° C / 0.1 mm Hg. The product is identical to that of Example 4.
Eksempler 6-12.Examples 6-12.
De i tabel II anførte forbindelser, hvor n = 0, er fremstillet som beskrevet i de ovenstående eksempler.The compounds listed in Table II, where n = 0, are prepared as described in the above examples.
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9 1435009 143500
Fremstilling af N-(pyridyl-2-acetyl)-N’-methylpiperazin.Preparation of N- (pyridyl-2-acetyl) -N'-methylpiperazine.
En blanding af 50,2 g (0,2 mol) pyridyl-2-eddikesyre-methylester (eller 58 g (0,2 mol) pyridyl-2-eddikesyre-n-butylester) og 20 g (0,2 mol) N-methylpiperazin koges under tilbagesvaling i 10 timer på et oliebad ved 180 - 200°C, hvorefter blandingen afdestilleres fraktioneret under et tryk på 0,2 mm Hg. På denne måde fås 22 - 24 g (50 - 55$) lysegult, olieagtigt N-(pyridyl-2-acetyl)-N,-methylpi= perazin.A mixture of 50.2 g (0.2 mole) of pyridyl-2-acetic acid methyl ester (or 58 g (0.2 mole) of pyridyl-2-acetic acid n-butyl ester) and 20 g (0.2 mole) of N -Methylpiperazine is refluxed for 10 hours on an oil bath at 180 - 200 ° C, after which the mixture is distilled off fractionally under a pressure of 0.2 mm Hg. In this way, 22-24 g (50-55 $) of light yellow, oily N- (pyridyl-2-acetyl) -N, methylpiperazine are obtained.
Analyse: (Molvægt 219,29).Analysis: (Molecular Weight 219.29).
Beregnet for: N 19,16Calculated for: N 19.16
Fundet: N 19,19.Found: N 19.19.
Dihydrochloridet af N-(pyridyl-2-acetyl)-N'-methylpiperazin smel= ter efter omkrystallisation af 96$'s ethanol ved 176 - 177°C.The dihydrochloride of N- (pyridyl-2-acetyl) -N'-methylpiperazine melts after recrystallization of 96 $ ethanol at 176 - 177 ° C.
Analyse: (Molvægt 292,22).Analysis: (Molecular Weight 292.22).
Beregnet for: N 14,38 Cl 24,27Calculated for: N 14.38 Cl 24.27
Fundet: N 14,25 Cl 25,98.Found: N 14.25 Cl 25.98.
Eksempel 14.Example 14.
Fremstilling af N-(pyridyl-2-acetyl)-N,-benzylpiperazin.Preparation of N- (pyridyl-2-acetyl) -N, -benzylpiperazine.
Til en opløsning af 17,6 g (0,1 mol) N-benzylpiperazin sættes 19,25 g (0,1 mol) pyridyl-2-acetylchlorid-hydrochlorid portions= vis under omrøring ved 5 - 10°C i løbet af 50 - 60 minutter. Reak= tionsblandingen koges i 1 time, hvorefter den afkøles og indstilles på alkalisk reaktion ved tilsætning af en opløsning af 10 g natrium= hydroxid i 60 ml vand. Benzenfasen indeholdende det ønskede pro= dukt fraskilles, hvorefter benzenet afdestilleres, og remanensen destilleres fraktioneret under vakuum. På denne måde fås 12,7 g (43$) grønligt gult, olieagtigt N-(pyridyl-2-acetyl)-N*-benzyl= piperazin med kogepunkt 222 - 225°C/3 mm Hg.To a solution of 17.6 g (0.1 mole) of N-benzylpiperazine is added 19.25 g (0.1 mole) of pyridyl-2-acetyl chloride-hydrochloride portions = stirred at 5 - 10 ° C over 50 - 60 minutes. The reaction mixture is boiled for 1 hour, then cooled and adjusted to alkaline reaction by adding a solution of 10 g of sodium = hydroxide in 60 ml of water. The benzene phase containing the desired product is separated, the benzene is distilled off and the residue is fractionally distilled under vacuum. In this way, 12.7 g ($ 43) of greenish yellow oily N- (pyridyl-2-acetyl) -N * -benzyl = piperazine having a boiling point of 222 - 225 ° C / 3 mm Hg is obtained.
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HUEE1907A HU162396B (en) | 1971-03-31 | 1971-03-31 | |
| HUEE001907 | 1971-03-31 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DK143500B true DK143500B (en) | 1981-08-31 |
| DK143500C DK143500C (en) | 1982-01-18 |
Family
ID=10995361
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK154272A DK143500C (en) | 1971-03-31 | 1972-03-29 | METHOD OF ANALOGUE FOR PREPARING PYRIDINE DERIVATIVES |
Country Status (20)
| Country | Link |
|---|---|
| JP (1) | JPS5144957B1 (en) |
| AT (1) | AT316549B (en) |
| AU (1) | AU464287B2 (en) |
| BE (1) | BE781494A (en) |
| CA (1) | CA1024147A (en) |
| CH (1) | CH574438A5 (en) |
| CS (1) | CS166043B2 (en) |
| DK (1) | DK143500C (en) |
| ES (1) | ES401342A1 (en) |
| FI (1) | FI54709C (en) |
| FR (1) | FR2132136B1 (en) |
| GB (1) | GB1378964A (en) |
| HU (1) | HU162396B (en) |
| IL (1) | IL39058A (en) |
| NL (1) | NL164853C (en) |
| PL (1) | PL94559B1 (en) |
| SE (1) | SE396219B (en) |
| SU (1) | SU512712A3 (en) |
| YU (1) | YU35015B (en) |
| ZA (1) | ZA721972B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20040012851A (en) | 2001-05-22 | 2004-02-11 | 뉴로젠 코포레이션 | Melanin concentrating hormone receptor ligands: substituted 1-benzyl-4-aryl piperazine analogues |
| US7253168B2 (en) | 2004-04-07 | 2007-08-07 | Neurogen Corporation | Substituted 1-benzyl-4-substituted piperazine analogues |
| KR101372941B1 (en) * | 2006-05-30 | 2014-03-14 | 얀센 파마슈티카 엔.브이. | Substituted pyridyl amide compounds as modulators of the histamine h3 receptor |
-
1971
- 1971-03-31 HU HUEE1907A patent/HU162396B/hu unknown
-
1972
- 1972-03-22 ZA ZA721972A patent/ZA721972B/en unknown
- 1972-03-22 FI FI795/72A patent/FI54709C/en active
- 1972-03-22 IL IL39058A patent/IL39058A/en unknown
- 1972-03-28 FR FR7210851A patent/FR2132136B1/fr not_active Expired
- 1972-03-28 PL PL1972154378A patent/PL94559B1/en unknown
- 1972-03-29 SE SE7204168A patent/SE396219B/en unknown
- 1972-03-29 GB GB1488772A patent/GB1378964A/en not_active Expired
- 1972-03-29 YU YU848/72A patent/YU35015B/en unknown
- 1972-03-29 DK DK154272A patent/DK143500C/en not_active IP Right Cessation
- 1972-03-29 AU AU40515/72A patent/AU464287B2/en not_active Expired
- 1972-03-29 ES ES401342A patent/ES401342A1/en not_active Expired
- 1972-03-30 NL NL7204296.A patent/NL164853C/en not_active IP Right Cessation
- 1972-03-30 BE BE781494A patent/BE781494A/en not_active IP Right Cessation
- 1972-03-30 CH CH478072A patent/CH574438A5/xx not_active IP Right Cessation
- 1972-03-30 SU SU1766171A patent/SU512712A3/en active
- 1972-03-30 CA CA138,620A patent/CA1024147A/en not_active Expired
- 1972-03-31 CS CS2183A patent/CS166043B2/cs unknown
- 1972-03-31 JP JP47031839A patent/JPS5144957B1/ja active Pending
- 1972-03-31 AT AT284872A patent/AT316549B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| CS166043B2 (en) | 1976-01-29 |
| IL39058A (en) | 1975-07-28 |
| GB1378964A (en) | 1975-01-02 |
| ES401342A1 (en) | 1975-02-16 |
| AU464287B2 (en) | 1975-08-05 |
| FI54709C (en) | 1979-02-12 |
| HU162396B (en) | 1973-02-28 |
| ZA721972B (en) | 1973-01-31 |
| JPS5144957B1 (en) | 1976-12-01 |
| BE781494A (en) | 1972-07-17 |
| YU84872A (en) | 1979-12-31 |
| NL164853B (en) | 1980-09-15 |
| AT316549B (en) | 1974-07-10 |
| SU512712A3 (en) | 1976-04-30 |
| FR2132136A1 (en) | 1972-11-17 |
| FI54709B (en) | 1978-10-31 |
| DE2215545B2 (en) | 1975-07-31 |
| CA1024147A (en) | 1978-01-10 |
| DE2215545A1 (en) | 1972-10-12 |
| SE396219B (en) | 1977-09-12 |
| CH574438A5 (en) | 1976-04-15 |
| FR2132136B1 (en) | 1975-04-25 |
| AU4051572A (en) | 1974-03-07 |
| IL39058A0 (en) | 1972-05-30 |
| DK143500C (en) | 1982-01-18 |
| NL7204296A (en) | 1972-10-03 |
| YU35015B (en) | 1980-06-30 |
| NL164853C (en) | 1981-02-16 |
| PL94559B1 (en) | 1977-08-31 |
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Legal Events
| Date | Code | Title | Description |
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| PUP | Patent expired |