DK158980B - Analogifremgangsmaade til fremstilling af 2,5-bis-(2,2,2-trifluorethoxy)-n-(2-piperidylmethyl)benzamid eller et farmaceutisk acceptabelt syreadditionssalt deraf - Google Patents

Analogifremgangsmaade til fremstilling af 2,5-bis-(2,2,2-trifluorethoxy)-n-(2-piperidylmethyl)benzamid eller et farmaceutisk acceptabelt syreadditionssalt deraf Download PDF

Info

Publication number
DK158980B
DK158980B DK119675A DK119675A DK158980B DK 158980 B DK158980 B DK 158980B DK 119675 A DK119675 A DK 119675A DK 119675 A DK119675 A DK 119675A DK 158980 B DK158980 B DK 158980B
Authority
DK
Denmark
Prior art keywords
bis
benzamide
piperidylmethyl
acid
acid addition
Prior art date
Application number
DK119675A
Other languages
English (en)
Other versions
DK158980C (da
DK119675A (da
Inventor
Elden Harris Banitt
William Robert Bronn
Original Assignee
Riker Laboratories Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Riker Laboratories Inc filed Critical Riker Laboratories Inc
Publication of DK119675A publication Critical patent/DK119675A/da
Publication of DK158980B publication Critical patent/DK158980B/da
Application granted granted Critical
Publication of DK158980C publication Critical patent/DK158980C/da

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • C07D213/02—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
    • C07D213/04—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
    • 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
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D211/56—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • C07D213/02—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
    • C07D213/04—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
    • C07D213/60—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 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
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pain & Pain Management (AREA)
  • Cardiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pyrrole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

i
DK 158980 B
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af 2,5-bis-(2,2,2-trifluorethoxy)-N-(2-piperidylmethyl)benzamid eller et farmaceutisk acceptabelt syreadditionssalt deraf.
Den omhandlede forbindelse og farmaceutisk acceptable syreadditionssalte deraf er aktive antiarrhytmimidler.
I US patentskrift nr. 3 719 687 er beskrevet visse benz-amider, der er substituerede i den aromatiske ring med I, 1-dihydroperfluoralkoxygrupper. Den omhandlede forbin-10 delse afviger fra de derfra kendte ved, at 1) benzamidonitrogenatomet er bundet gennem en methylen-gruppe til carbonatomet i piperidinringen, 15 2) den omhandlede forbindelse er en sekundær amin, og 3) i den omhandlede forbindelse er der kun et carbonatom, der forbinder benzamidonitrogenatomet til piperidin-ringen. Endvidere har den omhandlede forbindelse et on asymmetrisk carbonatom.
De ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser er mere antiarrhytmisk aktive end de fra US patentskrift nr. 3 719 687 kendte forbindelser. Acetatet af 2,5-bis-(2,2,2-trifluorethoxy)-N-(2-piperidylmethyl)-benzamid har vist sig at have en ED^-værdi på 48 umol/kg i den prøve, der er gengivet af Baritt et al. i J. Med. Chem., 20, 821-826, se tabel III, sidste spalte, forbindelse nr. 33. Prøven er også udført med to af de 30 fra US patentskriftet kendte forbindelser, forbindelserne fra eksempel 43 og 56. Disse forbindelser har ED^Q-værdi-er på 62 umol/kg henholdsvis 79 umol/kg og er således mindre aktive.
35
OK 158980 B
2
Den omhandlede forbindelse kan spaltes i de optisk aktive enantiomere på kendt måde.
Forbindelserne kan anvendes direkte eller i form af et 5 farmaceutisk acceptabelt syreadditionssalt, især som et opløseligt salt af eddikesyre, saltsyre, svovlsyre eller phosphorsyre. Andre salte er kombinationer med hydrogen-bromidsyre, sulfaminsyre, methansulfonsyre, benzensulfon-syre, ethandisulfonsyre, citronsyre, maleinsyre, oxalsy-10 re, ravsyre, æblesyre, fumarsyre og vinsyre.
De omhandlede forbindelsers antiarrhytmivirkning manifesterer sig ved deres evne til at blokere chloroform-induceret ventriculær flimren hos mus ved prøvepro-15 ceduren, beskrevet af J. W. Lawson, J. Pharmacol. Exp. Therap. 160:22-32, 1968.
Ved klinisk praksis vil den omhandlede forbindelse normalt blive indgivet som antiarrhytmimiddel oralt eller 20 ved injektion af et farmaceutisk præparat omfattende den aktive ingrediens i form af den frie base eller et af de sædvanlige terapeutisk acceptable salte, f.eks. acetatet eller hydrochloridet, i kombination med en farmaceutisk acceptabel bærer.
25 Bæreren kan være et fast, halvfast eller flydende fortyndingsmiddel eller en nedsvælgelig kapsel.
Til parenteral indgivelse ved injektion anvendes for-30 trinsvis en vandig opløsning, i reglen en saltvandsopløsning af et vandopløseligt farmaceutisk acceptabelt salt af den aktive forbindelse og eventuelt også et stabiliseringsmiddel og/eller en puffer, f.eks. natriumacetat.
35 Endvidere udviser den omhandlede forbindelse også en lo-kalanæstetisk virkning, f.eks. ved topisk påføring eller ved injektion. Den lokalanæstetiske virkning er observe- ret ved anvendelse af cornealrefleksprøven på kaniner.
Denne prøvemetode er beskrevet af F. P. Luduena og J. O.
Hoppe, J. Pharmocol. Ex. Therap., 104:40, 1952.
3
DK 158980 B
5 Fremgangsmåden ifølge opfindelsen er ejendommelig ved det i kravets kendetegnende del anførte.
Ved fremgangsmåden b) udføres reaktionen i et inert opløsningsmiddel, såsom benzen, ethylenglycoldimethylether, 10 toluen eller diethylether. Når Z er chlor, anvendes fortrinsvis en syreacceptor, f.eks. en tertiær amin. Når Z betegner en 1,1-dihydroperfluoralkoxygruppe, udføres reaktionen i reglen ved at opvarme reaktanterne under tilbagesvaling uden opløsningsmiddel eller i et inert op-15 løsningsmiddel, såsom ethylenglycoldimethylether, efterfulgt af isolation af produktet.
Ved fremgangsmåden a) (1) anvendes reaktionsbetingelser, der minder om betingelserne i den ovenfor beskrevne 1-20 trinsmetode, afhængigt af hvorvidt z betegner chlor eller 1,1-dihydroperfluoralkoxy. Der reduceres derpå (2) selektivt katalytisk til den tilsvarende piperidin med formlen I. Den foretrukne katalysator ved den katalytiske reduktion er platinoxid. Reduktionen gennemføres i reglen un-25 der sure betingelser, f.eks. i eddikesyre som opløsningsmiddel i nærvær af hydrogenchlorid.
Forbindelserne med formel II kan bekvemt fremstilles ud fra de tilsvarende syrer, dvs. forbindelser med formlen 30 II, hvori Z er OH, og disse syrer er kendte, f.eks. fra US patentskrift nr. 3 655 728. Forbindelserne, hvori Z betegner chlor, kan fremstilles ved tilbagesvaling af syrerne med et overskud af thionylchlorid, i nærvær af en ringe mængde dimethylformamid. Overskuddet af thionyl-35 chlorid fjernes derpå ved destillation. Forbindelserne med formlen II, hvori Z betegner 1,1-dihydroperfluoralkoxygruppe, er beskrevet i US patentskrift nr. 3 655 728 og
.DK 158980 B
4 kan fremstilles ved omsætning af hydroxy- og polyhydroxy-aromatiske syrer med alkyleringsmidler med formlen V CF3S020CH2Rf 5 i nærvær af natriumbicarbonat, kaliumbicarbonat eller andre metalbicrbonater i et inert opløsningsmiddel, såsom acetone. Den resulterende 1,1-dihydroperfluoralkylester kan hydrolyseres til den frie syre (forbindelser med 10 formlen II, hvori Z betegner OH).
Forbindelserne med formlerne III og IIIA er generelt kendte eller kan let fremstilles på kendt måde. Således kan forbindelsen III fremstilles ud fra den tilsvarende 15 forbindelse IIIA ved katalytisk reduktion. Yderligere kan forbindelserne III og IIIA fremstilles ved reduktion af de tilsvarende oximer, der igen kan fremstilles ud fra de tilsvarende aldehyder ved omsætning med hydroxylamin-hydrochlorid.
20
Opfindelsen forklares nærmere ved hjælp af nedenstående eksempler.
EKSEMPEL 1 25
En opløsning af 0,20 mol (21,6 g ) 2-aminomethylpyridin i 200 ml ethylenglycoldimethylether behandledes dråbevis i 40 minutter med 0,10 mol (40 g) 2,2,2-trifluorethyl-2,5-bis(2,2,2-trifluorethoxy)benzoat, og den resulterende 30 blanding omrørtes ved ca. 25 °C i ca. 60 timer, opvarmedes og holdtes ved tilbagesvalingstemperaturen i ca. 1 time. Derpå inddampedes blandingen til tørhed, triturere-des med vand, og det dannede produkt filtreredes. Det faste stof skylledes grundigt med vand, tørredes i en ovn 35 under vakuum og rekrystalliseredes fra en 5:3 blanding af cyclohexan og carbontetrachlorid efter behandling med affarvende aktivt kul. Efter omhyggelig tørring opnåedes
DK 158980 B
5 2.5- bis-(2,2,2-trifluorethoxy)-N-(2-piperidylmethyl)benz-amid, som et fast hvidt stof, smp. 102-104 °C.
Dette produkt omdannedes til hydrochloridet ved omsætning 5 i diethylether med en opløsning af hydrogenchloridgas i diethylether. Omkrystallisation af produktet f:ra en blanding af isopropanol og diethylether efter behandling med af farvende aktivt kul gav et rent hvidt salt, smp. 190-193 °C.
10
Det følgende eksempel illustrerer reduktionen af mellemproduktet med formlen IV til dannelse af forbindelsen med formlen I.
15 EKSEMPEL 2
En opløsning af 40,8 g (0,01 mol) N-(2-pyridylmethyl)- 2.5- bis(2,2,2-trifluorethoxy)benzamid i 600 ml eddikesyre blev under ^ sat til en pasta af 0,4 g platinoxid i 20 eddikesyre og hydrogeneret på et Parr-apparat. Efter optagelse af den teoretiske mængde hydrogen blev blandingen filtreret til fjernelse af katalysatoren, og filtratet blev genfiltreret med tilsat supercell. Inddampning af filtratet under vakuum efterlod en viskos sirup, som 25 størknede ved triturering med isopropylether. Det faste stof blev samlet ved sugningsfiltrering og opløst i varm isopropanol. Udkrystallisering blev indledt ved tilsætning af isopropylether til uklarhedspunktet. Det rensede produkt, N-(2-piperidylmethyl)-2,5-bis(2,2,2-trifluor- 30 ethoxy)benzamid-acetat blev samlet som et hvidt kornet fast stof, smp. 145-147 °C, udbyttet 35,8 g (76%). Denne reduktion kan også udføres i ethanol under anvendelse af foruddannet hydrochlorid af pyridylmethylbenzamid-ud-gangsmaterialet.
35 6
DK 158980 B
EKSEMPEL 3
Under en nitrogenatmosfære behandledes 0,249 mol (28,4 g) 2-aminomethylpiperidin i 25 minutter med 0,0249 (10,0 g) 5 2,2,2-trifluorethyl-2,5-bis-(2,2,2-trifluorethoxy)benzo- at. Efter tre timer tilsattes 50 ml benzen, og der omrør-tes i ca. 40 timer ved 45 °C. Blandingen koncentreredes derpå under vakuum. Remanensen størknede efter afkøling, vanddampdestilleredes og separeredes ved filtrering og 10 ekstraheredes med dichlormethan, udvaskedes med mættet natriumchloridopløsning, hvorpå det organiske lag blev tørret over vandfri magnesiumsulfat. Magnesiumsulfat fjernedes ved filtrering, og der tilsattes 4 ml 8,4 N hy-drogenchlorid i isopropanol til dichlormethanopløsningen 15 under omrøring. Efter to timer afkøledes blandingen til ca. 0 °C, og det rå produkt opsamledes ved filtrering, udvaskedes med diethylether og tørredes i en vakuumovn.
Efter behandling med affarvende aktivt kul og krystallisation fra en blanding af lige dele isopropanol og etha- 20 nol opnåedes produktet 2,5-bis-(2,2,2-trifluorethoxy)-N-(2-piperidylmethyl)benzamid-hydrochiorid, smp. 228-229 °C.
EKSEMPEL 4 25 10 ml isopropanol anvendtes til at opløse 0,005 mol (2,07 g) 2,5-bis(2,2,2-trifluorethoxy)-N-(2-piperidylmethyl)- benzamid, og der tilsattes 1 ækvivalent eddikesyre opløst i 1 ml isopropanol. Ved afkøling opnåedes et fast stof, 30 der separeredes fra ved filtrering. Produktet omkrystalliseredes fra isopropanol til dannelse af acetatet, smp. 145-147 °C.
Analogt med eksempel 4 fremstilledes en række farmaceu-35 tisk acceptable salte af forbindelsen 2,5-bis-(2,2,2-trifluorethoxy)-N-(2-piperidylmethyl)benzamid.
Deres opløselighed og data fremgår af nedenstående tabel
DK 158980 B
7 1.
iMBE L I
5 Opløselighed
Eks. Syre i varmt vand smp., °C
5 H2S04 >2% 100 6 H3P04 >5% 210 10 7 CH = CH >5% 122-124
I I
HOOC COOH
8 CH3S03H >10% 115-121 9 HCOOH >10% 171-172 15 10 uopl. ----- 11 CH3(CH2)14C00H uopl. ----- 12 ch3ch2cooh >10% ----- 20 13 CHoCHoC00H > 5% I Z /
COOH
25 30 35

Claims (1)

15 H <0 og (2) isolerer forbindelsen I, hvorefter en ved frem-20 gangsmåde a) eller b) fremstillet forbindelse I om ønsket omsættes med en syre til dannelse af et farmaceutisk acceptabelt syreadditionssalt, eventuelt efterfulgt af overføring i en anden isomer form deraf, herunder blandinger, på i og for sig kendt måde. 25 30 35
DK119675A 1974-04-01 1975-03-21 Analogifremgangsmaade til fremstilling af 2,5-bis-(2,2,2-trifluorethoxy)-n-(2-piperidylmethyl)benzamid eller et farmaceutisk acceptabelt syreadditionssalt deraf DK158980C (da)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US45709974 1974-04-01
US457099A US3900481A (en) 1974-04-01 1974-04-01 Derivatives of pyrrolidine and piperidine

Publications (3)

Publication Number Publication Date
DK119675A DK119675A (da) 1975-10-02
DK158980B true DK158980B (da) 1990-08-13
DK158980C DK158980C (da) 1991-01-07

Family

ID=23815433

Family Applications (1)

Application Number Title Priority Date Filing Date
DK119675A DK158980C (da) 1974-04-01 1975-03-21 Analogifremgangsmaade til fremstilling af 2,5-bis-(2,2,2-trifluorethoxy)-n-(2-piperidylmethyl)benzamid eller et farmaceutisk acceptabelt syreadditionssalt deraf

Country Status (22)

Country Link
US (1) US3900481A (da)
JP (2) JPS5827268B2 (da)
AR (1) AR210990A1 (da)
BE (1) BE827354A (da)
CA (1) CA1054602A (da)
CH (1) CH618425A5 (da)
CS (1) CS209846B2 (da)
DE (1) DE2513916C2 (da)
DK (1) DK158980C (da)
ES (1) ES435870A1 (da)
FR (1) FR2265366B1 (da)
GB (1) GB1508015A (da)
HU (1) HU169762B (da)
IE (1) IE41224B1 (da)
IL (1) IL46967A (da)
NL (1) NL186633C (da)
NO (1) NO144262C (da)
OA (1) OA04912A (da)
PL (1) PL95576B1 (da)
SE (1) SE391336B (da)
SU (1) SU668599A3 (da)
ZA (1) ZA751040B (da)

Families Citing this family (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4197243A (en) * 1975-04-02 1980-04-08 Yamanouchi Pharmaceutical Co., Ltd. N-1-Benzyl-3-pyrrolidinyl-4-dimethylamino benzamide derivatives
GB1520584A (en) * 1975-04-02 1978-08-09 Yamanouchi Pharma Co Ltd 2 - alkoxy - 5 substituted benzamide derivatives and their use in pharmaceutical compositions
US4093734A (en) * 1975-11-03 1978-06-06 Boehringer Ingelheim Gmbh Amino-benzoic acid amides
US4071524A (en) * 1976-11-08 1978-01-31 Riker Laboratories, Inc. Derivatives of urea
US4097481A (en) * 1976-11-08 1978-06-27 Riker Laboratories, Inc. Tertiary amide derivatives of pyrrolidine and piperidine
US4617396A (en) * 1979-03-19 1986-10-14 Riker Laboratories, Inc. Process for the preparation of derivatives of piperidine
US4642384A (en) * 1979-03-19 1987-02-10 Riker Laboratories, Inc. Process for the preparation of derivatives of pyrrolidine and piperidine
US4684733A (en) * 1979-03-19 1987-08-04 Riker Laboratories, Inc. Process for the preparation of intermediates of derivatives of pyrrolidine and piperidine
ZA801565B (en) * 1979-03-19 1981-05-27 Riker Laboratories Inc Process for the preparation of 2,5-bis(2,2,2-trifluoroethoxy)-n-(2-piperidylmethyl)benzamide
GB2097000B (en) 1979-03-19 1983-11-30 Riker Laboratories Inc Process for the preparation of 1,4-bis(2,2,2-trifluoroethoxy) benzene
US4339587A (en) * 1981-06-08 1982-07-13 Riker Laboratories, Inc. 5-Benzyloxy or 5-hydroxy-2-(2,2,2-trifluoroethoxy)-N-(2-pyridylmethyl)benzamide
US4452983A (en) * 1981-06-08 1984-06-05 Riker Laboratories, Inc. Phenolic derivative
US4390716A (en) * 1981-06-08 1983-06-28 Riker Laboratories, Inc. Phenolic derivative
JPS5970666A (ja) * 1982-10-15 1984-04-21 Kyowa Hakko Kogyo Co Ltd １，４−ジヒドロピリジン誘導体
US4497954A (en) * 1983-11-15 1985-02-05 Riker Laboratories, Inc. Cyclopentanone derivatives
US4496734A (en) * 1983-11-15 1985-01-29 Riker Laboratories, Inc. Metabolite
US4555573A (en) * 1983-11-15 1985-11-26 Riker Laboratories, Inc. Certain 6-benzamidomethyl-2(1H)-pyridone derivatives
US4599434A (en) * 1983-11-15 1986-07-08 Riker Laboratories, Inc. Cyclopentanone derivatives
US4656285A (en) * 1983-11-15 1987-04-07 Riker Laboratories, Inc. Compound 2-acetamidomethyl-6-methoxy-pyridine
DE3786037T2 (de) * 1986-04-25 1993-11-25 Abbott Lab Tracer zur Benutzung in immunologischen Fluoreszenz-Polarisationsverfahren zum Nachweis von Flecainid.
US5336622A (en) * 1986-04-25 1994-08-09 Abbott Laboratories Tracers for use in flecainide fluorescence polarization immunoassay
NZ219913A (en) * 1986-04-25 1990-08-28 Riker Laboratories Inc Various flecainide derivatives and antibodies raised thereto
US4952574A (en) * 1988-09-26 1990-08-28 Riker Laboratories, Inc. Antiarrhythmic substituted N-(2-piperidylmethyl)benzamides
US4938966A (en) * 1988-11-30 1990-07-03 Riker Laboratories, Inc. Controlled release flecainide acetate formulation
US5254569A (en) * 1991-01-14 1993-10-19 The Du Pont Merck Pharmaceutical Company (Amidomethyl)nitrogen heterocyclic analgesics
IL121288A (en) * 1997-07-11 2000-10-31 Finetech Ltd Process and a novel intermediate for the preparation of flecainide
ITMI20011772A1 (it) * 2001-08-10 2003-02-10 A M S A Anonima Materie Sint E Processo per la preparazione della 2,5-bis-(2,2,2-trifluoroetossi)-n-(2-piperidilmetil)-benzamide(flecainide)
EP1500651A1 (en) * 2003-07-25 2005-01-26 Bayer CropScience S.A. N-[2-(2-Pyridinyl)ethyl]benzamide compounds and their use as fungicides
US7196197B2 (en) * 2003-09-17 2007-03-27 Apotex Pharmachem Inc. Process for the preparation of Flecainide, its pharmaceutically acceptable salts and important intermediates thereof
EP1918280A1 (en) * 2006-11-06 2008-05-07 "Joint Stock Company Grindeks" Process for the preparation of 2,5-bis-(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)-benzamide and salts thereof
EP2446903B1 (en) 2006-11-20 2019-10-09 President and Fellows of Harvard College Compositions for treating itch
JP4946482B2 (ja) 2007-02-08 2012-06-06 船井電機株式会社 緩衝用梱包材及びｔｖ受像機の緩衝用梱包材
US20120172429A1 (en) 2009-07-10 2012-07-05 Woolf Clifford J Permanently charged sodium and calcium channel blockers as anti- inflammatory agents
US11021443B2 (en) 2015-08-03 2021-06-01 President And Fellows Of Harvard College Charged ion channel blockers and methods for use
US10786485B1 (en) 2019-03-11 2020-09-29 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
JP7692834B2 (ja) 2019-03-11 2025-06-16 ノシオン セラピューティクス，インコーポレイテッド 荷電したイオンチャンネル遮断薬および使用方法
CA3129111A1 (en) 2019-03-11 2020-09-17 Bridget M. Cole Charged ion channel blockers and methods for use
MA55320A (fr) 2019-03-11 2022-01-19 Nocion Therapeutics Inc Bloqueurs de canaux ioniques substitués par un ester et méthodes d'utilisation
US10780083B1 (en) 2019-03-11 2020-09-22 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US10933055B1 (en) 2019-11-06 2021-03-02 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
CN114828845A (zh) 2019-11-06 2022-07-29 诺西恩医疗公司 带电的离子通道阻滞剂及其使用方法
EP4118070A4 (en) 2020-03-11 2024-04-10 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
US12162851B2 (en) 2020-03-11 2024-12-10 Nocion Therapeutics, Inc. Charged ion channel blockers and methods for use
WO2024132080A1 (en) 2022-12-22 2024-06-27 Colonis Pharma Ltd Liquid pharmaceutical composition containing flecainide and process for the preparaton thereof

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR6209M (da) * 1967-04-03 1968-07-29
US3719687A (en) * 1970-07-22 1973-03-06 Riker Laboratories Inc N-(2-dialkylaminoalkylene)amides of 1,1-dihydroperfluoroalkoxy-substituted aryl acids and salts thereof
US3655728A (en) * 1970-07-22 1972-04-11 Riker Laboratories Inc N-(2 - dialkylaminoalkylene)-esters of fluoroalkoxy-substituted aryl carboxylic acid and salts thereof

Also Published As

Publication number Publication date
NL186633B (nl) 1990-08-16
ES435870A1 (es) 1976-12-16
US3900481A (en) 1975-08-19
IL46967A0 (en) 1975-05-22
BE827354A (fr) 1975-09-29
JPS5865268A (ja) 1983-04-18
HU169762B (da) 1977-02-28
DK158980C (da) 1991-01-07
JPS5827268B2 (ja) 1983-06-08
CH618425A5 (da) 1980-07-31
NO144262B (no) 1981-04-21
JPS50137975A (da) 1975-11-01
DK119675A (da) 1975-10-02
DE2513916A1 (de) 1975-10-09
NO750976L (da) 1975-10-02
FR2265366B1 (da) 1980-01-11
SE7503262L (da) 1975-10-02
IE41224L (en) 1975-10-01
CS209846B2 (en) 1981-12-31
IL46967A (en) 1978-09-29
NO144262C (no) 1981-07-29
JPS5858347B2 (ja) 1983-12-24
GB1508015A (en) 1978-04-19
SE391336B (sv) 1977-02-14
NL186633C (nl) 1991-01-16
OA04912A (fr) 1980-10-31
AU7957875A (en) 1976-09-30
PL95576B1 (pl) 1977-10-31
ZA751040B (en) 1976-01-28
SU668599A3 (ru) 1979-06-15
CA1054602A (en) 1979-05-15
DE2513916C2 (de) 1982-12-23
FR2265366A1 (da) 1975-10-24
AR210990A1 (es) 1977-10-14
IE41224B1 (en) 1979-11-21
NL7503389A (nl) 1975-10-03

Similar Documents

Publication Publication Date Title
DK158980B (da) Analogifremgangsmaade til fremstilling af 2,5-bis-(2,2,2-trifluorethoxy)-n-(2-piperidylmethyl)benzamid eller et farmaceutisk acceptabelt syreadditionssalt deraf
JPS6058750B2 (ja) Ｎ−（１−ベンジルピロリジニル−２−メチル）置換ベンズアミド誘導体またはその塩類の製造法
SU508199A3 (ru) Способ получени производных морфолина
DE2847621A1 (de) Phthalazin-derivate, verfahren zu ihrer herstellung und solche derivate enthaltende arzneimittel
US3103516A (en) J-tertiaryaminq-lower alkyl-jb-meta-
DK158658B (da) Analogifremgangsmaade til fremstilling af 9-aminoalkylfluorener eller farmaceutisk acceptable salte deraf
IE42978B1 (en) Triaryl alkyl azabicyclo compounds
JPS5845423B2 (ja) 新規アミノプロパノ−ル・誘導体の製法
DK145574B (da) Analogifremgangsmaade til fremstilling af substituerede cyclopropylalkylaminer eller syreadditionssalte deraf
NO151387B (no) Innstillingsinnretning for en elektronisk digitalindikator
US3201406A (en) Pyridylcoumarins
JP3901239B2 (ja) アリールアルカン誘導体
Norton et al. The Synthesis of Some Substituted 8-Aminoquinolines1
US4013670A (en) Derivatives of pyrrolidine and piperidine
KR880001715B1 (ko) 1-푸릴-3,4-디하이드로이소퀴놀린의 제조방법
US3378592A (en) Process for the production of 3, 4-dihydroxybenzyloxyaminehydrobromide
US2778829A (en) New 5:6-dihydro-benzo (c) cinnoline derivatives and a process for their preparation
US2650230A (en) Xanthene-9-carboxylic acid esters of nuclearly alkylated 4-piperidinols and salts thereof
CH657848A5 (de) 3,3-dialkyl- und 3,3-alkylen-indolinderivate, verfahren zu ihrer herstellung und pharmazeutische praeparate sie enthaltend.
CN119019328B (zh) 一类含异羟肟酸片段的喹啉衍生物及其制备方法和应用
US3423415A (en) 4 - (n - (3,3 - diphenyl - propyl) - amino) - 1-methyl-3-phenyl-piperidine and intermediates thereto
JPS6348265B2 (da)
JPS62178585A (ja) １−〔３−（２−ヒドロキシ−３−アルキルアミノプロポキシ）−２−チエニル〕−３−フエニル−１−プロパノン及びそれらの酸付加塩並びにそれらの製造法及びそれらを含む薬学的組成物
US3072667A (en) Alkylated derivatives of 4, 4&#39;-bis(4-piperidinols)
JPS6344737B2 (da)