NO790647L - PROCEDURE FOR THE PREPARATION OF 2-METHOXYBENZAMIDES - Google Patents
PROCEDURE FOR THE PREPARATION OF 2-METHOXYBENZAMIDESInfo
- Publication number
- NO790647L NO790647L NO790647A NO790647A NO790647L NO 790647 L NO790647 L NO 790647L NO 790647 A NO790647 A NO 790647A NO 790647 A NO790647 A NO 790647A NO 790647 L NO790647 L NO 790647L
- Authority
- NO
- Norway
- Prior art keywords
- mol
- water
- mixture
- ether
- methoxy
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- MNWSGMTUGXNYHJ-UHFFFAOYSA-N 2-methoxybenzamide Chemical class COC1=CC=CC=C1C(N)=O MNWSGMTUGXNYHJ-UHFFFAOYSA-N 0.000 claims description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 17
- 239000007787 solid Substances 0.000 description 16
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 11
- 150000001875 compounds Chemical class 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- -1 1-cyclopropyl-2-nitromethylene pyrrolidine Chemical compound 0.000 description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- 235000019341 magnesium sulphate Nutrition 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 230000009194 climbing Effects 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000000155 melt Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 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
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 150000003951 lactams Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 2
- 150000003235 pyrrolidines Chemical class 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- FWZCSDNSXJJNLH-UHFFFAOYSA-N (1-cyclohexylpyrrolidin-2-yl)methanamine Chemical compound NCC1CCCN1C1CCCCC1 FWZCSDNSXJJNLH-UHFFFAOYSA-N 0.000 description 1
- DXDVIHWHNZVPOK-UHFFFAOYSA-N (1-cyclopropylpyrrolidin-2-yl)methanamine Chemical compound NCC1CCCN1C1CC1 DXDVIHWHNZVPOK-UHFFFAOYSA-N 0.000 description 1
- AICZMNWUKVFBFK-UHFFFAOYSA-N 1-cyclopropylpyrrolidin-2-one Chemical compound O=C1CCCN1C1CC1 AICZMNWUKVFBFK-UHFFFAOYSA-N 0.000 description 1
- RCFGFTLCCWRMTI-UHFFFAOYSA-N 2-methoxy-5-methylsulfonylbenzoyl chloride Chemical compound COC1=CC=C(S(C)(=O)=O)C=C1C(Cl)=O RCFGFTLCCWRMTI-UHFFFAOYSA-N 0.000 description 1
- CDIIZULDSLKBKV-UHFFFAOYSA-N 4-chlorobutanoyl chloride Chemical compound ClCCCC(Cl)=O CDIIZULDSLKBKV-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 1
- 229960004046 apomorphine Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- GSCLMSFRWBPUSK-UHFFFAOYSA-N beta-Butyrolactone Chemical compound CC1CC(=O)O1 GSCLMSFRWBPUSK-UHFFFAOYSA-N 0.000 description 1
- 229920005556 chlorobutyl Polymers 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- AGFOKWXGIWUOLO-UHFFFAOYSA-N dialuminum chloroform oxygen(2-) Chemical compound C(Cl)(Cl)Cl.[O-2].[Al+3].[O-2].[O-2].[Al+3] AGFOKWXGIWUOLO-UHFFFAOYSA-N 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- PZYDAVFRVJXFHS-UHFFFAOYSA-N n-cyclohexyl-2-pyrrolidone Chemical compound O=C1CCCN1C1CCCCC1 PZYDAVFRVJXFHS-UHFFFAOYSA-N 0.000 description 1
- 230000000701 neuroleptic effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 229910052814 silicon oxide Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 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
- C07D207/18—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 one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—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 one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/267—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
-
- 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
- C07D207/18—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 one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—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 one double bond between ring members or between a ring member and a non-ring member 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pain & Pain Management (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
Description
Fremgangsmåte for fremstilling av 2-metoksybenzamider. Process for the production of 2-methoxybenzamides.
Foreliggende oppfinnelse vedrorer en fremgangsmåte for fremstilling av 2-metoksybenzamider, i form av racemater eller enantiomerer, med den generelle formel (I) The present invention relates to a process for the production of 2-methoxybenzamides, in the form of racemates or enantiomers, with the general formula (I)
hvori in which
n er 1, 2, 3 eller 4,n is 1, 2, 3 or 4,
R er et radikal SC^NR^R^ hvori og R2uavhengig av hverandre står for hydrogen eller alkyl, eller et radikal S(°)mR3hvori R^er alkyl og m er 0, 1 eller 2, eller halogen, eller CF^, idet alkylgruppene har 1 til 4 karbonatomer, R is a radical SC^NR^R^ in which and R2 independently of each other stand for hydrogen or alkyl, or a radical S(°)mR3 in which R^ is alkyl and m is 0, 1 or 2, or halogen, or CF^, as the alkyl groups have 1 to 4 carbon atoms,
og addisjonssalter derav med farmasoytisk tålbare syrer,and addition salts thereof with pharmaceutically acceptable acids,
og det særegne ved fremgangsmåten i henhold til oppfinnelsen er at et pyrrolidin, enten racemisk eller optisk aktivt, med den generelle formel (III) and the distinctive feature of the method according to the invention is that a pyrrolidine, either racemic or optically active, with the general formula (III)
hvori n har den ovennevnte betydning, omsettes med en benzosyre eller et funksjonelt derivat derav, halogenid eller alkylester, med formel (II) in which n has the above meaning, is reacted with a benzoic acid or a functional derivative thereof, halide or alkyl ester, of formula (II)
hvori R har den ovennevnte betydning, wherein R has the above meaning,
og erholdte forbindelser med formel (I) overfores eventuelt i sine syreaddisjonssalter. and obtained compounds of formula (I) are optionally transferred into their acid addition salts.
Pyrrolidinene (III) oppnås på klassisk måte ved å gå ut fra ^-butyrolakton eller tf-klor-butylklorid som omsettes med et amin The pyrrolidines (III) are obtained in the classical way by starting from ^-butyrolactone or t-chlorobutyl chloride which is reacted with an amine
hvori n har den ovennevnte betydning, hvoretter det oppnådde l-cykloalkyl-2-okso-yrrolidin omdannes til l-cykloalkyl-2-nitrometylen-pyrrolidin som hydrogeneres til 2-aminometyl-l-cyklo-alkyl-pyrrolidin. in which n has the above meaning, after which the obtained 1-cycloalkyl-2-oxo-pyrrolidine is converted to 1-cycloalkyl-2-nitromethylene-pyrrolidine which is hydrogenated to 2-aminomethyl-1-cycloalkyl-pyrrolidine.
Kondensasjonsreaksj onen i "henhold til oppfinnelsen kan gjennomfores ved en temperatur fra 0 til 30°C. The condensation reaction according to the invention can be carried out at a temperature from 0 to 30°C.
De oppnådde forbindelser har en innvirkning på sentralnervesystemet. The compounds obtained have an impact on the central nervous system.
De etterfolgende eksempler illustrerer oppfinnelsen.The following examples illustrate the invention.
Analyser og spektra IR og RMN bekrefter strukturen av forbindelsene. . Eksempel 1 N-/0.-cyklopropyl-2-pyrrolidinyl) -mety 17-2-metoksy-5-sulfamoyl-benzamid og dets metansulfonat 1. 3- cyklopropylaminokarbonyl- propylklorid. Analyzes and spectra IR and RMN confirm the structure of the compounds. . Example 1 N-((O.-cyclopropyl-2-pyrrolidinyl)-methyl 17-2-methoxy-5-sulfamoyl-benzamide and its methanesulfonate 1.3-cyclopropylaminocarbonyl-propyl chloride.
I en 2 liters reaktor anbringes 57,1 g (1 mol) destillert cyklopropylamin, 101,2 g (1 mol) trietylamin og 750 ml torr eter. Det avkjoles på et saltblandet isbad ved omtrent -10°C og innfores dråpevis sakte en opplosning av 112 ml (=141 g:l mol) y~klorbutyrylklorid i 150 ml eter idet det sikres at temperaturen ikke overstiger -5°C. Denne tilsetning krever flere timer. Reaksjonsblandingen tillates å bli varmere og settes bort over natten. Det tilsettes 500 ml vann og kloroform i tilstrekkelig mengde for at alt faststoff forsvinner hvoretter det omrores og det vandige fase dekanteres. Den organiske fase vaskes med surt vann og deretter med bikarbonatholdig vann og til slutt med vann og torkes over magnesiumsulfat. Uorganiske bestanddeler frafiltreres og filtratet inndampes til torrhet. Det oppnås et hvitt faststoff. 57.1 g (1 mol) of distilled cyclopropylamine, 101.2 g (1 mol) of triethylamine and 750 ml of dry ether are placed in a 2 liter reactor. It is cooled in a salt-mixed ice bath at approximately -10°C and a solution of 112 ml (=141 g:l mol) y~chlorobutyryl chloride in 150 ml of ether is slowly introduced dropwise, ensuring that the temperature does not exceed -5°C. This addition requires several hours. The reaction mixture is allowed to warm and is set aside overnight. 500 ml of water and chloroform are added in a sufficient amount so that all solids disappear, after which it is stirred and the aqueous phase is decanted. The organic phase is washed with acidic water and then with bicarbonate-containing water and finally with water and dried over magnesium sulfate. Inorganic components are filtered off and the filtrate is evaporated to dryness. A white solid is obtained.
Dette omkrystalliseres fra omtrent 350 ml isopropyleter. This is recrystallized from about 350 ml of isopropyl ether.
Smp.T=69,5 - 71°C.Mp.T=69.5 - 71°C.
2. l- cyklopropyl- 2- okso- pyrrolidin.2. 1-cyclopropyl-2-oxo-pyrrolidine.
I en 2 liters erlenmeyerkolbe anbringes 37 g (0,77 mol) natriumhydrid som vaskes fire ganger med petroleter og overdekkes med 1 1.torr DMSO. Det oppvarmes forsiktig til 50-60°C og oppnås gassutvikling som viser dannelse av dimsyl-ion. 37 g (0.77 mol) of sodium hydride are placed in a 2 liter Erlenmeyer flask, which is washed four times with petroleum ether and covered with 1 1 torr DMSO. It is heated carefully to 50-60°C and gas evolution is achieved which shows the formation of dimsyl ion.
Når.gassutviklingen er avsluttet avkjoles reaksjonsblandingen i isblandet vann og man innforer dråpevis tilstrekkelig hurtig en opplosning av 118,5 g (0,733 mol) av det foregående klorerte amid i 300 ml DMSO hvoretter blandingen settes bort over natten ved vanlig temperatur. Det omrores i 10 timer og blandingen settes bort ytterligere en natt. Blandingen uthelles deretter på.2 kg is, tilsettes salt til metning og ekstraheres med kloroform tre ganger. When the evolution of gas has ended, the reaction mixture is cooled in ice-cold water and a solution of 118.5 g (0.733 mol) of the preceding chlorinated amide in 300 ml of DMSO is introduced dropwise and sufficiently quickly, after which the mixture is left overnight at ordinary temperature. It is stirred for 10 hours and the mixture is set aside for a further night. The mixture is then poured onto 2 kg of ice, salt is added to saturation and extracted with chloroform three times.
Ekstraktens vaskes fire ganger med omtrent 120 ml vann ogThe extract is washed four times with approximately 120 ml of water and
deretter 2 ganger med saltholdig vann og torkes til slutt over magnesiumsulfat. Etter filtrering avdampes løsningsmiddel under vakuum og resten destilleres med en liten adiabatisk kolonne under redusert trykk. Etter to forlopsfraksjoner inneholdende hovedsakelig DMSO (Kp13: 75-112°C) oppnås produktet: Kp13= 112-114°C. then 2 times with saline water and finally dried over magnesium sulphate. After filtration, the solvent is evaporated under vacuum and the residue is distilled with a small adiabatic column under reduced pressure. After two preliminary fractions containing mainly DMSO (Kp13: 75-112°C), the product is obtained: Kp13= 112-114°C.
3. l- cyklopropyl- 2- nitrometylengpyrrolidin.3. 1-cyclopropyl-2-nitromethylene pyrrolidine.
I en 500 ml erlenmeyerkolbe anbringes 35,05 g (0,28 mol) av det foregående laktam og 35,32 g (0,28 mol) dimetylsulfat hvoretter blandingen oppvarmes ved 60°C i 4 timer. Det avkjoles på is og tilsettes dråpevis en losning av natriummetylat (fremstilt fra 6,44 g (0,28 gat) natrium i 80 ml metanol) hvoretter det oppvarmes ved 50°C i ^ time. Man avkjoles på nytt til 0°C og tilsetter dråpevis 25,64 g (0,42 mol) nitrométan. Blandingen settes bort i 12 timer ved vanlig temperatur og oppvarmes ved 50°C i 5 timer. Blandingen settes på nytt bort over natten. Metanol avdampes til torrhet og resten opptas mellom kloroform og vann, omrystes, dekanteres og den vandige fase ekstraheres på nytt to ganger med kloroform. Kloroformekstraktene vaskes med vann og torkes deretter over magnesiumsulfat, filtreres og inndampes til torrhet. Det oppnås et gult fast stoff som er litt gummiaktig og som opptas i isopropyleter, omrores, In a 500 ml Erlenmeyer flask, 35.05 g (0.28 mol) of the preceding lactam and 35.32 g (0.28 mol) dimethyl sulfate are placed, after which the mixture is heated at 60° C. for 4 hours. It is cooled on ice and a solution of sodium methylate (prepared from 6.44 g (0.28 gat) of sodium in 80 ml of methanol) is added dropwise, after which it is heated at 50°C for ½ hour. It is cooled again to 0°C and 25.64 g (0.42 mol) nitromethane is added dropwise. The mixture is set aside for 12 hours at ordinary temperature and heated at 50°C for 5 hours. The mixture is again put away overnight. Methanol is evaporated to dryness and the residue is taken up between chloroform and water, shaken, decanted and the aqueous phase is extracted again twice with chloroform. The chloroform extracts are washed with water and then dried over magnesium sulphate, filtered and evaporated to dryness. A slightly gummy yellow solid is obtained which is taken up in isopropyl ether, stirred,
avkjoles og avsuges på filter hvorved det oppnås gule krystaller. cooled and suctioned off on a filter whereby yellow crystals are obtained.
Disse omkrystalliseres fra isopropyleter med en liten mengde isopropylalkohol i varmen, avkjoles og et gult faststoff oppnås. These are recrystallized from isopropyl ether with a small amount of isopropyl alcohol in the heat, cooled and a yellow solid is obtained.
Smp.T= 115,5 - 116,5°C. Mp.T= 115.5 - 116.5°C.
4. l- cyklopropyl- 2- aminometyl- pyrrolidin.4. 1-cyclopropyl-2-aminomethyl-pyrrolidine.
I et hydrogeneringsapparat anbringes 18,5 g (0,11 mol) av det foregående pyrrolidin, metanol og raney-nikkel hvoretter det innfores hydrogen under vanlig trykk ved omgivelsenes temperatur. Tilstrekkelig hurtig tilfores 9,5 1 hydrogen hvoretter absorbsjonen avbrytes. Blandingen omrores i 1 time hvoretter katalysatoren frafiltreres, renses med metanol flere ganger og filtratene inndampes til torrhet. Det oppnås en rodbrun olje som destilleres under redusert trykk. Det oppnås en ufarvet olje. 18.5 g (0.11 mol) of the preceding pyrrolidine, methanol and Raney nickel are placed in a hydrogenation apparatus, after which hydrogen is introduced under normal pressure at ambient temperature. Sufficiently quickly, 9.5 1 of hydrogen are supplied, after which the absorption is interrupted. The mixture is stirred for 1 hour, after which the catalyst is filtered off, cleaned with methanol several times and the filtrates are evaporated to dryness. A red-brown oil is obtained which is distilled under reduced pressure. A colorless oil is obtained.
nD<21>= 1,4825. Kp'l3= 78°c-5. N-/"(l-cyklopropyl-2-pyrrolidinyl )-metyl7-2-metoksy-5-sulfamoyl-benzamid. nD<21>= 1.4825. Kp'13 = 78°c-5. N-(1-cyclopropyl-2-pyrrolidinyl)-methyl-7-2-methoxy-5-sulfamoyl-benzamide.
I en 250 ml erlenmeyerkolbe anbringes 6,03 g (0,043 mol) av det ovennevnte pyrrolidin sammen med 5,95 g (0,043 mol) kaliumkarbonat i aceton (ca. 120 ml). Blandingen avkjoles til mellom 0 og 5°C og det tilsettes dråpevis en losning av 10,73 g In a 250 ml Erlenmeyer flask, place 6.03 g (0.043 mol) of the above-mentioned pyrrolidine together with 5.95 g (0.043 mol) of potassium carbonate in acetone (approx. 120 ml). The mixture is cooled to between 0 and 5°C and a solution of 10.73 g is added dropwise
(0,043 mol) av 2-metoksy-5-sulfamoyl-benzosyre i omtrent 100 ml aceton. Blandingen blir varmere og omrores i 2 timer ved 20°C. Aceton avdampes til torrhet (T<30°C) og den faste rest opptas mellom vann og eter, omrores og faststoffet avsuges på filter hvoretter det vaskes omhyggelig med vann og eter. Det oppnås et hvitbeige faststoff. (0.043 mol) of 2-methoxy-5-sulfamoyl-benzoic acid in about 100 ml of acetone. The mixture becomes warmer and is stirred for 2 hours at 20°C. Acetone is evaporated to dryness (T<30°C) and the solid residue is taken up between water and ether, stirred and the solid is sucked off on a filter after which it is washed carefully with water and ether. A white-beige solid is obtained.
Det omkrystalliseres fra en blanding metanol/etanol (50/50), filtreres noe vanskelig i varmen hvoretter det omkrystalliseres, avsuges på filter, vaskes og det hvite faststoff torkes. It is recrystallized from a mixture of methanol/ethanol (50/50), filtered somewhat difficult in the heat, after which it is recrystallized, suction filtered, washed and the white solid dried.
Smp.T= 172 - 172,5°C (spalting).Mp.T= 172 - 172.5°C (decomposition).
6. Metansulfonat.6. Methanesulfonate.
I litt metanol anbringes i suspensjon 5,3 g (0,015 mol) av den foregående base og det tilsettes 1,44 g (0,015 mol) metansulfonsyre. Alt loses. Losningsmidlet avdampes til torrhet og den gummiaktige rest opptas i kokende aceton og dette forer til krystallisering av et fint hvitt faststoff som omrores, avkjoles og avsuges på filter. Ved omkrystallisering fra etanol oppnås et fint hvitt pulver. 5.3 g (0.015 mol) of the preceding base are suspended in a little methanol and 1.44 g (0.015 mol) methanesulfonic acid is added. Everything is unloaded. The solvent is evaporated to dryness and the gummy residue is taken up in boiling acetone and this leads to the crystallization of a fine white solid which is stirred, cooled and filtered off. Upon recrystallization from ethanol, a fine white powder is obtained.
Smp.T = 178 - 180°C (spalting).Mp.T = 178 - 180°C (decomposition).
Eksempel 2 N-/Tl-cykloheksyl-2-pyrrolidinyl)-metyl7-2-metoksy-5-sulfamoyl-benzamid og dets metansulfonat. Example 2 N-((1-cyclohexyl-2-pyrrolidinyl)-methyl-7-2-methoxy-5-sulfamoyl-benzamide and its methanesulfonate.
1. l- cykloheksyl- 2- okso- pyrrolidin.1. 1-cyclohexyl-2-oxo-pyrrolidine.
I en 500 ml trykkbombe innfores 86,1 g (1 mol) ^-butyrolakton, 105 g (1,058 mol) cykloheksylamin og noen krystaller av hydrokinon. 86.1 g (1 mol) of β-butyrolactone, 105 g (1.058 mol) of cyclohexylamine and some crystals of hydroquinone are introduced into a 500 ml pressure bomb.
Det fores en nitrogenstrom gjennom roret og deretter lukkes dette, oppvarmes til 330°C i 10 timer, og det oppnås en olje som destilleres. Kokepunkt = 120°C (0,5 mmHg). A stream of nitrogen is fed through the rudder and then this is closed, heated to 330°C for 10 hours, and an oil is obtained which is distilled. Boiling point = 120°C (0.5 mmHg).
2. l- cykloheksyl- 2- nitrometylen- pyrrolidin.2. 1-cyclohexyl-2-nitromethylene-pyrrolidine.
I en 500 ml erlenmeyerkolbe innfores 66,9 g (0,4 mol) av det foregående laktam og 50,44 g (0,4 mol) metylsulfat. Det oppvarmes i 2 timer ved 60°C og avkjoles med et isbad og det innfores dråpevis natriummetylat fremstilt ved å gå ut fra 9,2 g 66.9 g (0.4 mol) of the preceding lactam and 50.44 g (0.4 mol) methyl sulfate are introduced into a 500 ml Erlenmeyer flask. It is heated for 2 hours at 60°C and cooled with an ice bath and sodium methylate prepared by starting from 9.2 g is introduced dropwise
(0,4 mol) Na. i 150 ml metanol. Det omrores i 1 time ved omgivelsenes temperatur hvoretter det avkjoles og tilsettes dråpevis 36,6 g (0,6 mol) nitrometan. I lopet av noen minutter utfelles et gult faststoff og omroringen fortsetter i 2 timer. (0.4 mol) of Na. in 150 ml of methanol. It is stirred for 1 hour at ambient temperature, after which it is cooled and 36.6 g (0.6 mol) of nitromethane are added dropwise. In the course of a few minutes, a yellow solid precipitates and stirring is continued for 2 hours.
Vann tilsettes hvoretter det gule faststoff frafiltreres, vaskes med vann og deretter med eter, det opploses i kloroform, torkes over magnesiumsulfat og inndampes. Det oppnås et faststoff som omkrystalliseres fra en blanding isopropyleter/etylacetat. Water is added, after which the yellow solid is filtered off, washed with water and then with ether, it is dissolved in chloroform, dried over magnesium sulphate and evaporated. A solid is obtained which is recrystallized from an isopropyl ether/ethyl acetate mixture.
Smp. = 14.9 - 149, 5°C. Temp. = 14.9 - 149.5°C.
3. l- cykloheksvl- 2- aminometvl- pvrrolidin.3. 1-cyclohexyl-2-aminomethyl-pyrrolidine.
Ved omgivelsenes temperatur og atmosfæretrykk hydrogeneres 21 gAt ambient temperature and atmospheric pressure, 21 g are hydrogenated
(0,1 mol) av den ovennevnte forbindelse med raney-nikkel som katalysator, i metanol. Etter at den teoretiske mengde hydrogen er absorbert frafiltreres katalysatoren og den alkoholiske losning inndampes. (0.1 mole) of the above compound with Raney nickel as catalyst, in methanol. After the theoretical amount of hydrogen has been absorbed, the catalyst is filtered off and the alcoholic solution is evaporated.
Det resterende olje destilleres.The remaining oil is distilled.
Kp.2Q= 142°C.Kp.2Q= 142°C.
4. N/"(l-cykloheksyl-2-pyrrolidinyl )-metyl/-2-metoksy-5-sulfamoyl- benzamid. 4. N/(1-Cyclohexyl-2-pyrrolidinyl)-methyl/-2-methoxy-5-sulfamoyl-benzamide.
I en erlenmeyerkolbe innfores 9 g (0,0493 mol) av aminet og 12,2 g . 9 g (0.0493 mol) of the amine and 12.2 g of .
(0,047 mol), av etylesteren av 2-metoksy-5-sulfamoyl-benzosyre og 50 ml vann. (0.047 mole), of the ethyl ester of 2-methoxy-5-sulfamoyl-benzoic acid and 50 ml of water.
Det oppvarmes under tilbakelop i 5 timer. Det avkjoles og blandingen utrives mellom vann og eter, og det hvite faststoff frafiltrerés og opploses i kloroform, torkes over magnesium- It is heated under reflux for 5 hours. It is cooled and the mixture is triturated between water and ether, and the white solid is filtered off and dissolved in chloroform, dried over magnesium
sulfat og oppløsningen inndampes. Det oppnås et faststoff som omkrystalliseres fra isopropanol. sulfate and the solution is evaporated. A solid is obtained which is recrystallized from isopropanol.
Smp. = 194 - 194,5°C. Temp. = 194 - 194.5°C.
5. Metansulfonat.5. Methanesulfonate.
I en rundkolbe innfores 11,1 g (0,028 mol) av basen i metanol og 2,69 g (0,028 mol) metansulfonsyre i metanol. 11.1 g (0.028 mol) of the base in methanol and 2.69 g (0.028 mol) of methanesulfonic acid in methanol are introduced into a round flask.
Det inndampes til torrhet og den resterende olje behandles med isopropylalkohol. It is evaporated to dryness and the remaining oil is treated with isopropyl alcohol.
Saltet krystalliserer og frafiltreres og omkrystalliseres fraThe salt crystallizes and is filtered off and recrystallized from
en blanding etylalkohol/metylalkohol.a mixture of ethyl alcohol/methyl alcohol.
Smp. = 196 - 197°C. Temp. = 196 - 197°C.
Eksempel 3 N-/"(l-cyklopropyl-2-pyrrolidinyl )-mety^J7-2-metoksy-5-metyltio-benzamid og dets hydroklorid. Example 3 N-[(1-cyclopropyl-2-pyrrolidinyl)-methyl]-2-methoxy-5-methylthiobenzamide and its hydrochloride.
/n= 1, m= 0, R3 = CH^//n= 1, m= 0, R3 = CH^/
1 en slipt erlenmeyerkolbe, avkjolt på isbad og anbragt under en r hitrogenstrom, innfores 6,6 g (0,047 mol) N-/"(l-cyklopropyl-2-pyrrol.idinyl)-metyl/amin og 6,5 g (0,047 mol) kaliumkarbonat i 100 ml aceton. Blandingen avkjoles til 1-2°C og tilfores dråpevis en losning av 10,2 g (0,047 mol) 2-metoksy-5-metyltié-benzoylklorid i aceton. Blandingen settes bort i 2 timer ved vanlig temperatur, losningsmidlet avdampes til torrhet og resten opptas i vann og kloroform.• Den organiske fase separeres, vaskes med vann og torkes over magnesiumsulfat. Etter filtrering og destillasjon opptas den viskose rest i eter, behandles med aktivt karbon og filtreres gjennom "Hyflo-supercel" for å fjerne en harpiksaktig gummi. 6.6 g (0.047 mol) of N-(1-cyclopropyl-2-pyrroleidinyl)-methylamine and 6.5 g (0.047 mol) of potassium carbonate in 100 ml of acetone. The mixture is cooled to 1-2°C and a solution of 10.2 g (0.047 mol) of 2-methoxy-5-methylthié-benzoyl chloride in acetone is added dropwise. The mixture is set aside for 2 hours at normal temperature, the solvent is evaporated to dryness and the residue is taken up in water and chloroform.• The organic phase is separated, washed with water and dried over magnesium sulfate. After filtration and distillation, the viscous residue is taken up in ether, treated with activated carbon and filtered through "Hyflo-supercell " to remove a resinous gum.
Etter avdamping av losningsmidlet blir det tilbake en blekgul olje som elueres over en torket kolonne med aluminiumoksyd (1700 g, TSC) ved hjelp av kloroform. Ved fraksjonering oppnås en blekgul olje som gir en enhetlig kromatografisk prove After evaporation of the solvent, a pale yellow oil remains which is eluted over a dried column of alumina (1700 g, TSC) using chloroform. Fractionation yields a pale yellow oil which gives a uniform chromatographic sample
(siiisiumoksyd-aceton og aluminiumoksyd-kloroform) og som spaltes, hvis man prover å destillere den. (silica-acetone and aluminum oxide-chloroform) and which splits if you try to distill it.
Denne olje omdannes til hydroklorid ved reaksjon mellom basen og saltsyre i eter. Hydrokloridet av n-/ll-cyklopropyl-2-pyrrolidinyl)-mdyi7-2-metoksy-5-metyltio-benzamid smelter ved 165 - 166°C. This oil is converted into hydrochloride by reaction between the base and hydrochloric acid in ether. The hydrochloride of n-(11-cyclopropyl-2-pyrrolidinyl)-mdyyl-2-methoxy-5-methylthiobenzamide melts at 165-166°C.
Eksempel 4 N-/ll-cyklopentyl-2-pyirolidinyl) -metyl/*- 5-me tyl ti o-2-metoksy-benzamid og dets hydroklorid. Example 4 N-(11-Cyclopentyl-2-pyrirolidinyl)-methyl (*-5-methyl thio-2-methoxy-benzamide and its hydrochloride).
/n=3, m=0, R3=C2H&7/n=3, m=0, R3=C2H&7
I en erlenmeyerkolbe, avkjolt på isbad og anbragt under nitrogenstrom, innfores 5,84 g (0,0346 mol) N-/"(l-cyklopentyl-2-pyrrolidinyD-metyl,/amin og 4,8 g (0,0346 mol) kaliumkarbonat i aceton. Det tilsettes dråpevis til denne blanding 8 g (0,0346 mol) 5-etyltio-2-metoksy-benzoyl i aceton. Kolben får anta omgivelsenes temperatur og omrores i 2 timer. In an Erlenmeyer flask, cooled in an ice bath and placed under a stream of nitrogen, introduce 5.84 g (0.0346 mol) N-/"(1-cyclopentyl-2-pyrrolidinyD-methyl,/amine and 4.8 g (0.0346 mol ) potassium carbonate in acetone. To this mixture is added dropwise 8 g (0.0346 mol) of 5-ethylthio-2-methoxy-benzoyl in acetone. The flask is allowed to assume ambient temperature and stirred for 2 hours.
Etter avdamping av losningsmidlet opptas resten i vann og eter, den organiske fase ekstraheres i surt miljo og gjores alkalisk og ekstraheres med eter. Etter torking over magnesiumsulfat avdampes eter og det oppnås en olje som renses ved å sendes gjennom en kolonne av silisiumoksyd ved eluering med aceton. After evaporation of the solvent, the residue is taken up in water and ether, the organic phase is extracted in an acidic environment and made alkaline and extracted with ether. After drying over magnesium sulfate, ether is evaporated and an oil is obtained which is purified by passing through a column of silicon oxide by elution with acetone.
Ved behandling av denne base med saltsyre i eter fremstilles N-/~(l-cyklopentyl-2-pyrrolidinyl)-metyl/-5-etyltio-2-metoksy-benzamid-hydroklorid som smelter ved 126,5 - 127,5°C. By treating this base with hydrochloric acid in ether, N-/~(1-cyclopentyl-2-pyrrolidinyl)-methyl/-5-ethylthio-2-methoxy-benzamide hydrochloride is produced which melts at 126.5 - 127.5°C .
Eksempel 5 N-/"(l-cyklopropyl-2-pyrrolidinyl )-metyl7-2-metoksy-5-metyl-sulfonyl-benxamid og dets hydroklorid. Example 5 N-(1-cyclopropyl-2-pyrrolidinyl)-methyl-7-2-methoxy-5-methyl-sulfonyl-benxamide and its hydrochloride.
/n=l, m=2, R3=CH37/n=1, m=2, R3=CH37
I en erlenmeyerkolbe opploses 5,33 g (0,038 mol) N-/Tl-cykloQ propyl-2-pyrrolidinyl)-metyi7amin i 100 ml vannfri aceton og tilsettes 5,25 g (0,038 mol) kaliumkarbonat. Denne suspensjon avkjoles ved omtrent 2°C og tilsettes dråpevis en losning av 9,45 g (0,038 mol) 2-metoksy-5-metyl-sulfonyl-benzoyl-klorid i 200 ml aceton, hele tiden under omroring. Isbadet fjernes og blandingen får anta vanlig temperatur i lopet av 2 timer under omroring. Losningsmidlet avdampes til torrhet og resten opptas i vann og kloroform. Den organiske fase vaskes med vann, deretter med saltholdig vann og torkes til slutt over magnesiumsulfat. In an Erlenmeyer flask, 5.33 g (0.038 mol) of N-((T1-cyclo(propyl-2-pyrrolidinyl)-methylamine) are dissolved in 100 ml of anhydrous acetone and 5.25 g (0.038 mol) of potassium carbonate are added. This suspension is cooled at approximately 2°C and a solution of 9.45 g (0.038 mol) of 2-methoxy-5-methyl-sulfonyl-benzoyl chloride in 200 ml of acetone is added dropwise, all the while stirring. The ice bath is removed and the mixture is allowed to reach normal temperature over the course of 2 hours while stirring. The solvent is evaporated to dryness and the residue is taken up in water and chloroform. The organic phase is washed with water, then with saline water and finally dried over magnesium sulphate.
Etter filtrering og avdamping av losningsmidlet blir tilbakeAfter filtration and evaporation the solvent remains
en brun olje som dekket under etylacetat omdannes til et rod-aktig faststoff som avsuges på filter, vaskes og torkes. a brown oil which is covered under ethyl acetate is converted into a root-like solid which is sucked off on a filter, washed and dried.
Smp. = 140 - 141°C. Temp. = 140 - 141°C.
Etter omkrystallisering fra isopropylalkohol er N-/"(l-cyklopropyl-2-pyrrolidinyl)-metyl7-2-metoksy-5-metylsulfonyl-benzamid et hvitt faststoff som smelter ved 140,5 - 141,5°C. After recrystallization from isopropyl alcohol, N-(1-cyclopropyl-2-pyrrolidinyl)-methyl7-2-methoxy-5-methylsulfonyl-benzamide is a white solid melting at 140.5 - 141.5°C.
Hydrokloridet, fremstilt ved reaksjon mellom ovennevnte base og saltsyre i aceton, metanol og etanol, smelter ved 165 - 166°C. The hydrochloride, prepared by reaction between the above-mentioned base and hydrochloric acid in acetone, methanol and ethanol, melts at 165 - 166°C.
I den etterfølgende tabell I er anfort forbindelse (I) fremstilt ved lignende metoder. In the following Table I, the indicated compound (I) is prepared by similar methods.
Enantiomerene av forbindelsene (I) oppnås enten ved spalting eller ved stereospesifikk syntese. De fremstilte forbindelser ble underkastet farmakologisk provning med hensyn til innvirkning på sentralnervesystemet. The enantiomers of the compounds (I) are obtained either by cleavage or by stereospecific synthesis. The compounds produced were subjected to pharmacological testing with regard to the effect on the central nervous system.
Akutt giftighet ble bestemt i hanmus, swiss CD1, med middelvekt 20 g, ved tilforsel i.p. Acute toxicity was determined in male mice, swiss CD1, with an average weight of 20 g, by i.p.
Den nevroleptiske aktivitet ble bestemt ved antagonisme overfor "klatring" ("climbing", "redressement") innfort ved apomorfin i mus i henhold til artikkelen av Gouret C, J. Pharmacol. The neuroleptic activity was determined by antagonism to "climbing" ("climbing", "redressement") induced by apomorphine in mice according to the article by Gouret C, J. Pharmacol.
(Paris) 4, 341 (1973). (Paris) 4, 341 (1973).
LD 50 utgjor 60 til 1000 mg/kg tilfort i.p.LD 50 amounts to 60 to 1000 mg/kg administered i.p.
ED 50 ved klatreproven varierer fra 0,3 til 1 mg/kg ved tilforsel i.p. og er 0,5 mg/kg, 0,6 mg/kg og 0,3 mg/kg for henholdsvis forbindelsene 4, 10 og 14. ED 50 in the climbing test varies from 0.3 to 1 mg/kg when administered i.p. and are 0.5 mg/kg, 0.6 mg/kg and 0.3 mg/kg for compounds 4, 10 and 14, respectively.
Forbindelsene kan anvendes for behandling av forskjellige psykosymatiske forstyrrelser og psykiske lidelser (depressive tilstander og psykoser). The compounds can be used for the treatment of various psychosymatic disorders and mental disorders (depressive states and psychoses).
Forbindelsene kan anvendes som sådanne eller i form av deres salter som aktive bestanddeler i forbindelse med alle vanlige tilsetningsmidler for oral, endorektal eller parenteral tilforsel. The compounds can be used as such or in the form of their salts as active ingredients in connection with all common additives for oral, endorectal or parenteral administration.
Total daglig dose kan utgjore 5 til 300 mg. Total daily dose can amount to 5 to 300 mg.
Claims (1)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR7805579A FR2418225A1 (en) | 1978-02-27 | 1978-02-27 | N-1-Cycloalkyl-2-pyrrolidinyl-methyl 2-methoxy-benzamide derivs. - for treating psychoses and depressive states, prepd. by reaction of 1-cycloalkyl-2-aminomethyl-pyrrolidine with methoxy-benzoic acid deriv. |
FR7900259A FR2445829A2 (en) | 1978-02-27 | 1979-01-05 | METHOXY-2 BENZAMIDES AND THEIR THERAPEUTIC APPLICATION |
Publications (1)
Publication Number | Publication Date |
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NO790647L true NO790647L (en) | 1979-08-28 |
Family
ID=26220462
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO790647A NO790647L (en) | 1978-02-27 | 1979-02-26 | PROCEDURE FOR THE PREPARATION OF 2-METHOXYBENZAMIDES |
Country Status (18)
Country | Link |
---|---|
JP (1) | JPS54135765A (en) |
AU (1) | AU521027B2 (en) |
BE (1) | BE874489A (en) |
DE (1) | DE2907378A1 (en) |
DK (1) | DK82179A (en) |
ES (1) | ES478072A1 (en) |
FI (1) | FI790657A (en) |
FR (1) | FR2445829A2 (en) |
GB (1) | GB2016467A (en) |
GR (1) | GR66972B (en) |
IL (1) | IL56738A0 (en) |
IT (1) | IT1113417B (en) |
LU (1) | LU80975A1 (en) |
NL (1) | NL7901473A (en) |
NO (1) | NO790647L (en) |
NZ (1) | NZ189770A (en) |
PT (1) | PT69289A (en) |
SE (1) | SE7901707L (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0320630A1 (en) * | 1987-11-19 | 1989-06-21 | The Vanderbilt University | Enantiometric iodobenzamides |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH584688A5 (en) * | 1972-06-23 | 1977-02-15 | Delmar Chem | |
FR2294698A1 (en) * | 1974-12-18 | 1976-07-16 | Synthelabo | NEW DERIVATIVES OF 2-METHOXY BENZAMIDES SUBSTITUTE, THEIR SALTS, THEIR PREPARATION AND THE MEDICINAL PRODUCTS CONTAINING THEM |
FR2393794A2 (en) * | 1977-06-06 | 1979-01-05 | Synthelabo | Therapeutic 2-methoxy benzamido methyl heterocycle(s) prepn. - from 2-methoxy benzoic ester(s) and amino methyl heterocycle(s) |
JPS52106863A (en) * | 1976-03-03 | 1977-09-07 | Teikoku Hormone Mfg Co Ltd | Synthesis of substituted benzamides |
FR2360572A1 (en) * | 1976-08-05 | 1978-03-03 | Synthelabo | Optically active (2)-amino-methyl-(1)-substd. pyrrolidine derivs. - intermediates for benzoylamino-methyl-pyrrolidine pharmaceuticals |
JPS5365875A (en) * | 1976-11-24 | 1978-06-12 | Teijin Ltd | Preparation of benzenesulfone amide derivs. |
-
1979
- 1979-01-05 FR FR7900259A patent/FR2445829A2/en active Granted
- 1979-02-26 DE DE19792907378 patent/DE2907378A1/en not_active Withdrawn
- 1979-02-26 PT PT69289A patent/PT69289A/en unknown
- 1979-02-26 NO NO790647A patent/NO790647L/en unknown
- 1979-02-26 SE SE7901707A patent/SE7901707L/en not_active Application Discontinuation
- 1979-02-26 IL IL56738A patent/IL56738A0/en unknown
- 1979-02-26 JP JP2247779A patent/JPS54135765A/en active Pending
- 1979-02-26 DK DK82179A patent/DK82179A/en not_active Application Discontinuation
- 1979-02-26 IT IT20541/79A patent/IT1113417B/en active
- 1979-02-26 AU AU44603/79A patent/AU521027B2/en not_active Expired - Fee Related
- 1979-02-26 NZ NZ189770A patent/NZ189770A/en unknown
- 1979-02-26 ES ES478072A patent/ES478072A1/en not_active Expired
- 1979-02-26 NL NL7901473A patent/NL7901473A/en not_active Application Discontinuation
- 1979-02-27 BE BE0/193729A patent/BE874489A/en unknown
- 1979-02-27 GR GR58491A patent/GR66972B/el unknown
- 1979-02-27 LU LU80975A patent/LU80975A1/en unknown
- 1979-02-27 FI FI790657A patent/FI790657A/en not_active Application Discontinuation
- 1979-02-27 GB GB7906952A patent/GB2016467A/en not_active Withdrawn
Also Published As
Publication number | Publication date |
---|---|
ES478072A1 (en) | 1979-07-01 |
FI790657A (en) | 1979-08-28 |
AU4460379A (en) | 1979-09-06 |
IL56738A0 (en) | 1979-05-31 |
IT1113417B (en) | 1986-01-20 |
AU521027B2 (en) | 1982-03-11 |
SE7901707L (en) | 1979-08-28 |
PT69289A (en) | 1979-03-01 |
FR2445829A2 (en) | 1980-08-01 |
JPS54135765A (en) | 1979-10-22 |
GB2016467A (en) | 1979-09-26 |
LU80975A1 (en) | 1980-09-24 |
NZ189770A (en) | 1980-11-14 |
FR2445829B2 (en) | 1982-09-10 |
NL7901473A (en) | 1979-08-29 |
BE874489A (en) | 1979-08-27 |
DE2907378A1 (en) | 1979-09-06 |
DK82179A (en) | 1979-08-28 |
IT7920541A0 (en) | 1979-02-26 |
GR66972B (en) | 1981-05-15 |
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