DK141819B - Fremgangsmåde til fremstilling af 2,5-disubstituerede benzamider eller syreadditionssalte eller kvaternære ammoniumsalte deraf. - Google Patents
Fremgangsmåde til fremstilling af 2,5-disubstituerede benzamider eller syreadditionssalte eller kvaternære ammoniumsalte deraf. Download PDFInfo
- Publication number
- DK141819B DK141819B DK500374AA DK500374A DK141819B DK 141819 B DK141819 B DK 141819B DK 500374A A DK500374A A DK 500374AA DK 500374 A DK500374 A DK 500374A DK 141819 B DK141819 B DK 141819B
- Authority
- DK
- Denmark
- Prior art keywords
- methoxy
- quaternary ammonium
- acid
- preparing
- acid addition
- Prior art date
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- 239000002253 acid Chemical class 0.000 title claims description 8
- 229940054066 benzamide antipsychotics Drugs 0.000 title claims description 4
- 150000003936 benzamides Chemical class 0.000 title claims description 4
- 150000003242 quaternary ammonium salts Chemical class 0.000 title claims description 4
- 150000003839 salts Chemical class 0.000 title claims description 4
- 238000004519 manufacturing process Methods 0.000 title claims description 3
- -1 C x 2 monoalkylamino Chemical group 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims 1
- 125000003342 alkenyl group Chemical group 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 1
- 125000000623 heterocyclic group Chemical group 0.000 claims 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 14
- 238000000034 method Methods 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- NBFYWQQYIJTQQV-UHFFFAOYSA-N 5-ethylsulfonyl-2-methoxybenzoic acid Chemical compound CCS(=O)(=O)C1=CC=C(OC)C(C(O)=O)=C1 NBFYWQQYIJTQQV-UHFFFAOYSA-N 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000011574 phosphorus Substances 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- SQAILWDRVDGLGY-UHFFFAOYSA-N 2-methoxy-5-sulfamoylbenzoic acid Chemical compound COC1=CC=C(S(N)(=O)=O)C=C1C(O)=O SQAILWDRVDGLGY-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 230000003474 anti-emetic effect Effects 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- TTWJBBZEZQICBI-UHFFFAOYSA-N metoclopramide Chemical compound CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC TTWJBBZEZQICBI-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- VRKXUSCKISXSIH-UHFFFAOYSA-N (1-butylpyrrolidin-2-yl)methanamine Chemical compound CCCCN1CCCC1CN VRKXUSCKISXSIH-UHFFFAOYSA-N 0.000 description 1
- UNRBEYYLYRXYCG-UHFFFAOYSA-N (1-ethylpyrrolidin-2-yl)methanamine Chemical compound CCN1CCCC1CN UNRBEYYLYRXYCG-UHFFFAOYSA-N 0.000 description 1
- JUFKJRCMBLLXNH-UHFFFAOYSA-N (1-methylpyrrolidin-2-yl)methanamine Chemical compound CN1CCCC1CN JUFKJRCMBLLXNH-UHFFFAOYSA-N 0.000 description 1
- LDGNKUHLPWNXLU-UHFFFAOYSA-N 1-ethyl-2-methylpiperidin-2-amine Chemical compound CC1(N(CCCC1)CC)N LDGNKUHLPWNXLU-UHFFFAOYSA-N 0.000 description 1
- SEYURSMOEWBZSA-UHFFFAOYSA-N 2-(1-ethylpyrrolidin-2-yl)ethanamine Chemical compound CCN1CCCC1CCN SEYURSMOEWBZSA-UHFFFAOYSA-N 0.000 description 1
- IOHPVZBSOKLVMN-UHFFFAOYSA-N 2-(2-phenylethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1CCC1=CC=CC=C1 IOHPVZBSOKLVMN-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- TWDGNKWWKCGFNH-UHFFFAOYSA-N 2-methoxy-5-(methylsulfamoyl)benzoic acid Chemical compound CNS(=O)(=O)C1=CC=C(OC)C(C(O)=O)=C1 TWDGNKWWKCGFNH-UHFFFAOYSA-N 0.000 description 1
- UMFPWTPHSKBHSR-UHFFFAOYSA-N 2-methoxy-5-propylsulfonylbenzoic acid Chemical compound CCCS(=O)(=O)C1=CC=C(OC)C(C(O)=O)=C1 UMFPWTPHSKBHSR-UHFFFAOYSA-N 0.000 description 1
- NWTNGBCWLCHYLQ-UHFFFAOYSA-N 2-methoxy-N-[(1-propylpyrrolidin-2-yl)methyl]-5-propylsulfonylbenzamide Chemical compound C(CC)N1C(CCC1)CNC(C1=C(C=CC(=C1)S(=O)(=O)CCC)OC)=O NWTNGBCWLCHYLQ-UHFFFAOYSA-N 0.000 description 1
- RYDHRSXDITWYMH-UHFFFAOYSA-N 2-methoxy-N-[2-(propylamino)propyl]-5-sulfamoylbenzamide Chemical compound CC(CNC(C1=C(C=CC(=C1)S(N)(=O)=O)OC)=O)NCCC RYDHRSXDITWYMH-UHFFFAOYSA-N 0.000 description 1
- RNKBBUZWXSBLAD-UHFFFAOYSA-N 2-methyl-1-propylpyrrolidin-2-amine Chemical compound CCCN1CCCC1(C)N RNKBBUZWXSBLAD-UHFFFAOYSA-N 0.000 description 1
- CJNRGSHEMCMUOE-UHFFFAOYSA-N 2-piperidin-1-ylethanamine Chemical compound NCCN1CCCCC1 CJNRGSHEMCMUOE-UHFFFAOYSA-N 0.000 description 1
- HJMBACRULXCTRQ-UHFFFAOYSA-N 5-(dimethylsulfamoyl)-2-methoxybenzoic acid Chemical compound COC1=CC=C(S(=O)(=O)N(C)C)C=C1C(O)=O HJMBACRULXCTRQ-UHFFFAOYSA-N 0.000 description 1
- XKOQGSAPHHFILR-UHFFFAOYSA-N 5-(dimethylsulfamoyl)-N-[(1-ethylpyrrolidin-2-yl)methyl]-2-methoxybenzamide Chemical compound C(C)N1C(CCC1)CNC(C1=C(C=CC(=C1)S(N(C)C)(=O)=O)OC)=O XKOQGSAPHHFILR-UHFFFAOYSA-N 0.000 description 1
- WCIDQZOQJOGWRO-UHFFFAOYSA-N 5-(ethylsulfamoyl)-2-methoxybenzoic acid Chemical compound CCNS(=O)(=O)C1=CC=C(OC)C(C(O)=O)=C1 WCIDQZOQJOGWRO-UHFFFAOYSA-N 0.000 description 1
- JTVPZMFULRWINT-UHFFFAOYSA-N N-[2-(diethylamino)ethyl]-2-methoxy-5-methylsulfonylbenzamide Chemical compound CCN(CC)CCNC(=O)C1=CC(S(C)(=O)=O)=CC=C1OC JTVPZMFULRWINT-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- HTGKTSVPJJNEMQ-QMMMGPOBSA-N [(2s)-1-prop-2-enylpyrrolidin-2-yl]methanamine Chemical compound NC[C@@H]1CCCN1CC=C HTGKTSVPJJNEMQ-QMMMGPOBSA-N 0.000 description 1
- MZVQCMJNVPIDEA-UHFFFAOYSA-N [CH2]CN(CC)CC Chemical group [CH2]CN(CC)CC MZVQCMJNVPIDEA-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 239000002111 antiemetic agent Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- DMSZORWOGDLWGN-UHFFFAOYSA-N ctk1a3526 Chemical compound NP(N)(N)=O DMSZORWOGDLWGN-UHFFFAOYSA-N 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 229920001519 homopolymer Polymers 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 229960004503 metoclopramide Drugs 0.000 description 1
- BYONKIGBXOVRHV-UHFFFAOYSA-N n-[(1-ethylpyrrolidin-2-yl)methyl]-2-methoxy-5-(methylsulfamoyl)benzamide Chemical compound CCN1CCCC1CNC(=O)C1=CC(S(=O)(=O)NC)=CC=C1OC BYONKIGBXOVRHV-UHFFFAOYSA-N 0.000 description 1
- IJOVAPIWJRMZTB-UHFFFAOYSA-N n-[(1-ethylpyrrolidin-2-yl)methyl]-5-(ethylsulfamoyl)-2-methoxybenzamide Chemical compound CCNS(=O)(=O)C1=CC=C(OC)C(C(=O)NCC2N(CCC2)CC)=C1 IJOVAPIWJRMZTB-UHFFFAOYSA-N 0.000 description 1
- IGOWMQPOGQYFFM-UHFFFAOYSA-N n-[(1-ethylpyrrolidin-2-yl)methyl]-5-ethylsulfonyl-2-methoxybenzamide;hydron;chloride Chemical compound [Cl-].CC[NH+]1CCCC1CNC(=O)C1=CC(S(=O)(=O)CC)=CC=C1OC IGOWMQPOGQYFFM-UHFFFAOYSA-N 0.000 description 1
- CHKWHTPECBLEBR-UHFFFAOYSA-N n-methyl-n'-propylethane-1,2-diamine Chemical compound CCCNCCNC CHKWHTPECBLEBR-UHFFFAOYSA-N 0.000 description 1
- 239000003176 neuroleptic agent Substances 0.000 description 1
- 230000000701 neuroleptic effect Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- BGRJTUBHPOOWDU-UHFFFAOYSA-N sulpiride Chemical compound CCN1CCCC1CNC(=O)C1=CC(S(N)(=O)=O)=CC=C1OC BGRJTUBHPOOWDU-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Indole Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Description
(11) FREMLÆGGELSESSKRIFT 1 *4· 1 8 1 9 C 07 C 143/78 DANMARK (ευ int ci.3 c 07 c 147/107 UMmVIMm\ C 07 D 227/04 te 07 O 295/12 (21) Antegning nr. 5003/74 (22) Indlever« den 24. Ββρ. T9?4 (23) Lebedag 24. ββρ. 1974 (44) Antegningen fremlagt og fremlæggelsestkriftet offentliggjort den 23. jun. 1980
DIREKTORATET FOR
PATENT-OG VAREMÆRKEVÆSENET (30) Prioritet begteret fra den
25· sep. 1973, 7334436, PR
(71) SOCIETE D'ETUDES SCIENTIFIQUES ET INDUSTRIELT,S DE L' ILE-DE-FRANCE, 46, boulevard de Latour-Maubourg, 75 Paris 7e, PR.
(72) Opfinder: Ger ard Bulteau, 5, avenue Albert Bartholome, 75015 Paris, PR: Jacques Acher, 32, route de Salnt-Vraln, 91769 Ittevllle, PR: Jean-Claude Monler, 7, rue Tlre-Barbe, 91510 Lardy, PR.
(74) Fuldmægtig under tagent behandling:
Ingeniørfirmaet Hoftnan-Bang & Bout ard.
(54) Fremgangsmåde til fremstilling af 2,5-disubstituerede benzamider eller syreadditionssalte eller kvaternsare ammoniumsalte deraf.
Den foreliggende opfindelse angår en særlig fremgangsmåde til fremstilling af 2,5-disubstituerede benzamider med den i krav l's indledning anførte almene formel eller syreadditionssalte eller kvatemære ammoniumsalte deraf.
De omhandlede forbindelser har nyttige farmakologiske virkninger, f.eks. antiemetiske, neuroleptiske og lokalanæstetiske virkninger·.
Lignende forbindelser er f.eks. beskrevet i norsk fremlæggelsesskrift nr. 119.533, norsk patentskrift nr. 108.018 og tysk fremlæggelsesskrift nr. 1.233.877. I disse skrifter anvendes en totrinsproces, idet benzoesyren omdannes til et reaktivt derivat, der omsættes med en passende amin. Oftest anvendes syrechloridet, 2 141819 hvis fremstilling er tidkrævende og fortrinsvis involverer SOC^, der er ubehagelig at arbejde med. Specielt for norsk fremlæggelsesskrift nr. 119-533 gælder det, at man i andet trin må anvende meget lange reaktionstider på op til 24 timer.
Fra beskrivelsen til dansk patentansøgning nr. 5179/72 er det kendt, at fremstille en af de omhandlede forbindelser i et trin ved omsætning af benzoesyren med et phosphoramid. Udbyttet er dog kun 28,5%.
Formålet med den foreliggende opfindelse er at angive en simpel ettrinsmetode, der muliggør fremstilling af de omhandlede forbindelser i gode udbytter. Dette opnås ved fremgangsmåden ifølge opfindelsen, der er ejendommelig ved det i krav l's kendetegnende del anførte.
Omsætningen mellem benzoesyrederivatet og aminen udføres som anført i krav 1’s kendetegnende del i nærvær af 4-methyl-2-chlor- 1,3,2-dioxophosphorinan. Denne forbindelse kan fremstilles som anført i Houben-Weyl, Methoden der Organischen Chemie, Volume 12/2, side 49.
En fremgangsmåde, der umiddelbart synes at have store lighedspunkter med den omhandlede, er beskrevet i beskrivelsen til japansk patentansøgning nr. 71.24405, jævnfør Chemical Abstracts 78, 124313 j. (1973).
Nævnte skrift beskriver fremstillingen af den konkrete forbindelse N-(β-diethylaminoethyl)-2-methoxy-4-amino-5-chlor-benzamid (også kendt som metoclopramid), der imidlertid ikke er omfattet af nærværende opfindelse.
Nærværende opfindelse angår derimod forbindelser, der kun er 2,5-substituerede, og hvor 5-substituenten ikke kan være chlor, men derimod gruppen XSO^, hvor X har de i kravet nærmere angivne betydninger, hvoriblandt heller ikke findes chlor eller andre halogener.
I skriftet beskrives en kondensation i nærværelse af fire alternative kondensationsmidler, hvoriblandt de tre phosphorholdige forbindelser alle indeholder oxygen bundet homøopolart til semi- 3 141819 polart til phosphor, og herunder er specielt nævnt forbindelsen 2-chlor-4-methyl-l,3,2-dioxaphosphoran-2-oxid.
Til forskel herfra anvendes ved fremgangsmåden ifølge opfindelsen den ikke oxiderede 2-chlor-4-methyl-l,3,2-dioxophosphorinan. Det kunne ikke forventes, at denne forbindelse også ville være virksom ved en kondensation af den omhandlede art under anvendelse af anderledes substituerede syrer som udgangsmaterialer, idet fagmanden måtte forvente, at virksomheden var betinget af tilstedeværelsen af separat binding mellem phosphor og oxygen, og derfor ikke a priori ville anse den ikke-oxiderede phosphoran for havende de samme egenskaber som kondensationsmiddel som den oxiderede phosphoran.
Fremgangsmåden ifølge opfindelsen illustreres nærmere ved nedenstående eksempler, der angår de i krav 2-4 omtalte foretrukne forbindelser, hvor specielt forbindelsen fremstillet ifølge krav 2 og 4 udviser stor aktivitet, mens forbindelsen franstillet ifølge krav 3 er den mindst toxiske.
EKSEMPEL 1 N-(l-ethyl-2-pyrro lidinylmethyl) - 2-me tho xy-3-sulf ^ido benzaini d 2,31 g (0,01 mol) 2-methoxy-5-sulfamoylbenzoesyre, 3,22 g (0,025 mol) N-ethyl-2-aminomethylpyrrolidin og 50 ml dioxan anbringes i en 100 ml rundbundet kolbe forsynet med omrører og tilbagesvaler forsynet med calciumchloridrør.
Blandingen omrøres i 30 minutter. Der dannes en gullig gummi, hvorpå der tilsættes 1,7 g (0,11 mol) 4-methyl-2-chlor-l,3,2-dioxophospho-rinan, og blandingen opvarmes i 5 timer under tilbagesvaling. Der afkøles og opløsningsmidlet afdampes under vacuum. Remanensen opløses i 30 ml vand,og der tilsættes 10 ml ammoniak. En ringe mængde bundfald filtreres fra. Filtratet opvarmes til kogning, hvorpå det får lov til at krystallisere ved afkøling. Der filtreres, og det dannede produkt udvaskes med vand og tørres i en ovn ved 50° C.
Der opnås 2 g (udbytte 5990 N-(l-ethyl-2-pyrrolidinylmethyl)-2-meth-oxy-5-sulfamoylbenzamid (smp.: 179° C).
4 141819
Ud fra samme syre, men ved anvendelse af N-methyl-2-aminomethyl-pyrrolidin fås analogt N- (l-methyl-2-pyrrolidinylmeth.yl) -2-methoxy- 5-sulfamidobenzamid, (smp: 210-212°C). Ud fra N-propyl-2-amino-methylpyrrolidin, fås N-(l-propyl-2-pyrrolidinylmethyl)-2-methoxy- 5-sulfamidobenzamid, (smp: 169-171°C). Ud fra N-butyl-2-aminomethyl-pyrrolidin fås N-(l-butyl-2-pyrrolidinylmethyl)-2-methoxy-5-sulf-amidobenzamid, smp: = 129-130°C. Ud fra N-allyl-2-aminomethyl-pyrrolidin fås N- (l-allyl-2-pyrrolidinylmethyl) -2-methoxy-5-sulf-amidobenzamid smp: 151-152° C.
Ud fra samme amin, men ved anvendelse af 2-methoxy-5-methylsulfamoyl-benzoesyre, fås analogt N-(l-ethyl-2-pyrrolidinylmethyl)-2-methoxy- 5-methylsulf amoylbenzamid smp: = 143-145°C.
Ud fra 2-methoxy-5-ethylsulfamoylbenzoesyre fås analogt N-(l-ethyl-2-pyrrolidinylmethyl)-2-methoxy-5-eth.ylsulf amoylbenzamid, smp: = 127-128°C.
Ud fra 2-methoxy-5-dimethylsulfamoylbenzoesyre, fås analogt N-(l-ethyl-2-pyrrolidinylmethyl)-2-methoxy-5-dimethylsulf amoylbenzamid, smp: = 90°C.
EKSEMPEL 2 iizlÉiÉiiiXilSiiiSSiiZillå^methox^^S-meth^lsulfonylbenzamid 2,3 g (0,01 mol) 2-methoxy-5-methylsulfonylbenzoesyre, 2,9 g (0,025 mol) N,N-dietfaylethylendiamin og 40 ml dioxan anbringes i en 100 ml rundbundet kolbe forsynet med omrører og tilbagesvaler.
Blandingen opvarmes i 30 minutter ved omgivelsestemperaturen, hvorpå der tilsættes 1,7 g (0,011 mol) 4-methyl-2-chlor-l,3,2-dioxophospho- rinan. Blandingen opvarmes i 5 timer under tilbagesvaling efterfulgt af afkøling. Opløsningsmidlet afdampes under vacuum, hvorpå der tilsættes 40 ml vand til remanensen, og produktet udfældes ved at gøre opløsningen basisk med natriumhydroxid. Den henstår til krystallisation efterfulgt af filtrering og udvaskning med vand. Krystallerne tørres i en ovn ved 50° C.
Der opnås 2,6 g (udbytte 79%) N-(diethylaminoethyl)-2-methoxy-5-methyl-sulfonylbenzamid (smp.: 117° C).
5 141819
Ud fra samme amin, men ved anvendelse af 2-methoxy-5-allylsulfonyl-benzoesyre, fås analogt N-(diethylaminoethyl)-2-methoxy-5-ållyl-sulfonylbenzamid, som ved behandling med saltsyre overføres i hydrochloridet, smp: 143-14-5°C.
Ud fra 2-methoxy-5-ethylsulfonylbenzoesyre og piperidinoethylamin, fås analogt N-(piperidinoethyl)-2-methoxy-5-ethylsulfonylbenzamid, smp: 178-180°C.
Ud fra 2-methoxy-5-sulfamoylbenzoesyre og methylpropylaminoethyl-amin, fås analogt N-(methylpropylaminoethyl)-2-methoxy-5-sulfam0yl-benzamld, smp: 173°C.
EKSEMPEL 3 N-(l-eth^l-2-£yrrolldinyMeth^l^-2-m^^o3^^j-ethjls2^fonylbenzamid 2,44 g (0,01 mol) 2-methoxy-5-ethylsulfonylbenzoesyre, 3,22 g (0,025 mol) N-ethyl-2-aminoethylpyrrolidin og 50 ml dioxan anbringes i en 100 ml rundbundet kolbe forsynet med omrører og tilbagesvaler, hvorpå der er anbragt et calciumchloridrør.
Blandingen opvarmes i 30 minutter ved omgivelsestemperaturen, hvorpå der tilsættes 1,7 g (0,011 mol) 4-methyl-2-chlor-l,3,2-dioxo-phosphorinan. Blandingen opvarmes i 5 timer under tilbagesvaling efterfulgt af afkøling. Opløsningsmidlet afdampes under vacuum, hvorpå der tilsættes 50 ml vand til remanensen, og opløsningen gøres basisk med natriumhydroxid. Opløsningen extraheres tre gange med 25 ml methylenchlorid, og den organiske opløsning tørres over magnesiumsulfat og filtreres, hvorpå opløsningsmidlet afdampes under vacuum. Remanensen opløses i acetone, og opløsningen gøres sur med saltsyre. Opløsningen henstår til krystallisation i en køler, efterfulgt af filtrering og tørring i en ved 50° C. Produktet omkrystalliseres fra en minimal mængde ethanol. Der opnås 2,5 (udbytte 61%) N-(l-ethyl-2-pyrrolidinylmethyl)-2-methoxy-5-ethylsulfo-nylbenzamid, hydrochlorid (smp.: 190° C).
Ud fra 2-methoxy-5-propylsulfonylbenzoesyre og N-propyl-2-amino-ethylpyrrolidin, opnås analogt N-(l-propyl-2-pyrrolidinylmethyl)-2-methoxy-5-propylsulfonylbenzamid i form af hydrochloridet, smp: 145-147°C.
6 1418 T9
Ud fra 2-methoxy-5-ethylsulfonylbenzoesyre og N-ethyl-2-amino-methylpiperidin, opnås analogt N-(l-ethyl-2-piperidylmethyl)-2-methoxy- 5-ethyl sulf onylbenz amid, som ved behandling med phosphor-syre overføres i phosphatet, smp: 186-187°C.
Pharmacologiske undersøgelser:
De omhandlede forbindelser udviser en betydelig antiemetisk virkning, som illustreret i nedenstående tabel, der angiver ED^q ved subcutan indgivelse. Endvidere er anført LD^q, der som det ses ligger betydeligt over de terapeutisk virksomme doser.
n mg/kg yug/kg l-ethyl-2-pyrrolidinyl i NEL, 44 4,8 l-methyl-2-pyrrolidimyl 1 NH2 67 15 l-propyl-2-pyrrolidinyl 1 NH2 52 -4,1 l-butyl-2-pyrrolidinyl l NH2 70 19 l-allyl-2-pyrrolidinyl 1 NHL, 91 2,7 l-ethyl-2-pyrrolidinyl 1 99>7 1,8 l-ethyl-2-piperidinyl l C2H^ 110,5 16,5 l-ethyl-2-pyrrolidinyl l CH2CH=CH2 92 3,8 diethylamino 2 CH^ 135 24 l-propyl-2-pyrrolidinyl 1 C3H7 66 4,1 l-ethyl-2-pyrrolidinyl 1 -N-(CH^)2 90,3 3,8
Claims (2)
- 7 141819. Patentkrav :
- 1. Fremgangsmåde til fremstilling af 2,5-disubstituerede benz-amider med den almene formel: C0NH(CH2)nA —OCH, (1) D X02S-V> hvori A betegner en mono- eller di-C-^ alkylaminogruppe, en piperidinogruppe, eller en heterocyclisk gruppe med den almene formel: tf®2)a R hvori R betegner en alkyl- eller alkenylgruppe med indtil 5 carbon-atomer, og m er 1 eller 2, n er 1 eller 2, og X betegner amino, Cx 2monoalkylamino, dimethylamino, alkyl eller allyl, eller syreadditionssalte eller kvateraære ammoniumsalte deraf, kendetegnet ved, at man behandler en 2,5-disubstitueret benzoesyre med formlen COOH Λτ"? (II) hvori X har den ovenfor anførte betydning, med en amin med formlen H2N(CH2)nA (111)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7334436 | 1973-09-25 | ||
| FR7334436A FR2244760B1 (da) | 1973-09-25 | 1973-09-25 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK500374A DK500374A (da) | 1975-05-26 |
| DK141819B true DK141819B (da) | 1980-06-23 |
| DK141819C DK141819C (da) | 1980-11-10 |
Family
ID=9125563
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK500374AA DK141819B (da) | 1973-09-25 | 1974-09-24 | Fremgangsmåde til fremstilling af 2,5-disubstituerede benzamider eller syreadditionssalte eller kvaternære ammoniumsalte deraf. |
Country Status (35)
| Country | Link |
|---|---|
| US (1) | US3975434A (da) |
| JP (1) | JPS5721197B2 (da) |
| AR (1) | AR206610A1 (da) |
| AT (1) | AT338234B (da) |
| BE (1) | BE820197A (da) |
| BG (1) | BG25512A3 (da) |
| CA (1) | CA1050034A (da) |
| CH (1) | CH603569A5 (da) |
| CS (1) | CS176283B2 (da) |
| DD (1) | DD116610A5 (da) |
| DE (1) | DE2442885A1 (da) |
| DK (1) | DK141819B (da) |
| EG (1) | EG11473A (da) |
| ES (1) | ES430329A1 (da) |
| FI (1) | FI59086C (da) |
| FR (1) | FR2244760B1 (da) |
| GB (1) | GB1461185A (da) |
| HK (1) | HK23682A (da) |
| HU (1) | HU168564B (da) |
| IE (1) | IE40032B1 (da) |
| IL (1) | IL45720A (da) |
| LU (1) | LU70971A1 (da) |
| MC (1) | MC1035A1 (da) |
| MW (1) | MW3874A1 (da) |
| NL (1) | NL7412421A (da) |
| NO (1) | NO139920C (da) |
| OA (1) | OA04784A (da) |
| PH (1) | PH11709A (da) |
| PL (1) | PL94114B1 (da) |
| RO (1) | RO64488A (da) |
| SE (1) | SE406585B (da) |
| SU (1) | SU555847A3 (da) |
| YU (1) | YU39309B (da) |
| ZA (1) | ZA746035B (da) |
| ZM (1) | ZM14574A1 (da) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4189495A (en) * | 1974-09-17 | 1980-02-19 | Synthelabo | 2-Methoxy-benzamide derivatives |
| US4172143A (en) * | 1974-12-18 | 1979-10-23 | Synthelabo | 2-Methoxy-benzamide derivatives |
| US4158060A (en) * | 1974-12-18 | 1979-06-12 | Synthelabo | 2-Methoxy-benzamide derivatives |
| FR2305176A1 (fr) * | 1975-03-28 | 1976-10-22 | Ile De France | Nouveau medicament a base de n-(diethylaminoethyl) 2-methoxy-5-methyl-sulfonyl benzamide |
| US4093734A (en) * | 1975-11-03 | 1978-06-06 | Boehringer Ingelheim Gmbh | Amino-benzoic acid amides |
| FR2415099A1 (fr) * | 1978-01-20 | 1979-08-17 | Ile De France | Nouveaux derives de 4-amino-5-alkylsulfonyl ortho-anisamides, leurs procedes de preparation et leur application comme psychotropes |
| FR2489327B1 (fr) * | 1980-08-28 | 1984-05-18 | Ile De France | N (1 allyl 2 pyrrolidinyl methyl) 2 methoxy 4 amino 5 methylsulfa moyl benzamide, son procede de preparation et son application comme medicament |
| IT1207506B (it) * | 1985-10-15 | 1989-05-25 | Montedipe Spa | Processo per il recupero dello iodio dallo ioduro sodico. |
| GB8926512D0 (en) * | 1989-11-23 | 1990-01-10 | Pfizer Ltd | Therapeutic agents |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB884206A (en) * | 1957-06-17 | 1961-12-06 | Du Pont | 4-alkoxymetanilamides and compositions containing them |
-
1973
- 1973-09-25 FR FR7334436A patent/FR2244760B1/fr not_active Expired
-
1974
- 1974-01-01 AR AR255683A patent/AR206610A1/es active
- 1974-09-04 HU HUSO1127A patent/HU168564B/hu not_active IP Right Cessation
- 1974-09-07 DE DE2442885A patent/DE2442885A1/de not_active Withdrawn
- 1974-09-12 AT AT736374A patent/AT338234B/de not_active IP Right Cessation
- 1974-09-18 EG EG407/74A patent/EG11473A/xx active
- 1974-09-19 GB GB4091374A patent/GB1461185A/en not_active Expired
- 1974-09-19 BG BG027732A patent/BG25512A3/xx unknown
- 1974-09-19 CS CS6458A patent/CS176283B2/cs unknown
- 1974-09-19 FI FI2743/74A patent/FI59086C/fi active
- 1974-09-19 NL NL7412421A patent/NL7412421A/xx unknown
- 1974-09-20 IE IE1947/74A patent/IE40032B1/xx unknown
- 1974-09-20 JP JP10944874A patent/JPS5721197B2/ja not_active Expired
- 1974-09-20 RO RO7480034A patent/RO64488A/ro unknown
- 1974-09-23 LU LU70971A patent/LU70971A1/xx unknown
- 1974-09-23 NO NO743416A patent/NO139920C/no unknown
- 1974-09-23 BE BE1006195A patent/BE820197A/xx not_active IP Right Cessation
- 1974-09-23 YU YU2563/74A patent/YU39309B/xx unknown
- 1974-09-23 OA OA55304A patent/OA04784A/xx unknown
- 1974-09-23 US US05/508,536 patent/US3975434A/en not_active Expired - Lifetime
- 1974-09-23 DD DD181246A patent/DD116610A5/xx unknown
- 1974-09-24 ES ES430329A patent/ES430329A1/es not_active Expired
- 1974-09-24 SE SE7411976A patent/SE406585B/xx not_active IP Right Cessation
- 1974-09-24 ZM ZM145/74A patent/ZM14574A1/xx unknown
- 1974-09-24 SU SU2062926A patent/SU555847A3/ru active
- 1974-09-24 CA CA209,913A patent/CA1050034A/en not_active Expired
- 1974-09-24 MW MW38/74*UA patent/MW3874A1/xx unknown
- 1974-09-24 MC MC1124A patent/MC1035A1/fr unknown
- 1974-09-24 CH CH1288474A patent/CH603569A5/xx not_active IP Right Cessation
- 1974-09-24 DK DK500374AA patent/DK141819B/da not_active IP Right Cessation
- 1974-09-24 ZA ZA00746035A patent/ZA746035B/xx unknown
- 1974-09-24 IL IL45720A patent/IL45720A/xx unknown
- 1974-09-25 PL PL1974174328A patent/PL94114B1/pl unknown
-
1977
- 1977-03-28 PH PH19597A patent/PH11709A/en unknown
-
1982
- 1982-06-03 HK HK236/82A patent/HK23682A/xx unknown
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| Date | Code | Title | Description |
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| PBP | Patent lapsed |