NO135934B - - Google Patents
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- NO135934B NO135934B NO4669/71A NO466971A NO135934B NO 135934 B NO135934 B NO 135934B NO 4669/71 A NO4669/71 A NO 4669/71A NO 466971 A NO466971 A NO 466971A NO 135934 B NO135934 B NO 135934B
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- 150000001875 compounds Chemical class 0.000 claims description 40
- 239000003589 local anesthetic agent Substances 0.000 claims description 15
- 238000002360 preparation method Methods 0.000 claims description 11
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 230000003287 optical effect Effects 0.000 claims description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- 239000002168 alkylating agent Substances 0.000 claims description 3
- 229940100198 alkylating agent Drugs 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 90
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 47
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 42
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- 150000001408 amides Chemical class 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- 239000000243 solution Substances 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- 239000000203 mixture Substances 0.000 description 18
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 12
- 239000002244 precipitate Substances 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 238000002844 melting Methods 0.000 description 11
- 230000008018 melting Effects 0.000 description 11
- 239000000126 substance Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 239000012259 ether extract Substances 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 229960005015 local anesthetics Drugs 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- 230000007794 irritation Effects 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 206010042674 Swelling Diseases 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 230000007059 acute toxicity Effects 0.000 description 4
- 231100000403 acute toxicity Toxicity 0.000 description 4
- 230000003444 anaesthetic effect Effects 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- -1 iodine ions Chemical class 0.000 description 4
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 230000008961 swelling Effects 0.000 description 4
- BDKLKNJTMLIAFE-UHFFFAOYSA-N 2-(3-fluorophenyl)-1,3-oxazole-4-carbaldehyde Chemical compound FC1=CC=CC(C=2OC=C(C=O)N=2)=C1 BDKLKNJTMLIAFE-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- 229940087562 sodium acetate trihydrate Drugs 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- LEBVLXFERQHONN-UHFFFAOYSA-N 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide Chemical compound CCCCN1CCCCC1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-UHFFFAOYSA-N 0.000 description 2
- UFFBMTHBGFGIHF-UHFFFAOYSA-N 2,6-dimethylaniline Chemical group CC1=CC=CC(C)=C1N UFFBMTHBGFGIHF-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 229960003150 bupivacaine Drugs 0.000 description 2
- SIEYLFHKZGLBNX-UHFFFAOYSA-N bupivacaine hydrochloride (anhydrous) Chemical compound [Cl-].CCCC[NH+]1CCCCC1C(=O)NC1=C(C)C=CC=C1C SIEYLFHKZGLBNX-UHFFFAOYSA-N 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 231100000517 death Toxicity 0.000 description 2
- DENRZWYUOJLTMF-UHFFFAOYSA-N diethyl sulfate Chemical compound CCOS(=O)(=O)OCC DENRZWYUOJLTMF-UHFFFAOYSA-N 0.000 description 2
- 229940008406 diethyl sulfate Drugs 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- AATGHKSFEUVOPF-UHFFFAOYSA-N diethylazanium;bromide Chemical compound [Br-].CC[NH2+]CC AATGHKSFEUVOPF-UHFFFAOYSA-N 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 2
- 150000003840 hydrochlorides Chemical class 0.000 description 2
- 229940106885 marcaine Drugs 0.000 description 2
- INWLQCZOYSRPNW-UHFFFAOYSA-N mepivacaine Chemical compound CN1CCCCC1C(=O)NC1=C(C)C=CC=C1C INWLQCZOYSRPNW-UHFFFAOYSA-N 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- MVFGUOIZUNYYSO-UHFFFAOYSA-N prilocaine Chemical compound CCCNC(C)C(=O)NC1=CC=CC=C1C MVFGUOIZUNYYSO-UHFFFAOYSA-N 0.000 description 2
- OYCGKECKIVYHTN-UHFFFAOYSA-N pyrrocaine Chemical compound CC1=CC=CC(C)=C1NC(=O)CN1CCCC1 OYCGKECKIVYHTN-UHFFFAOYSA-N 0.000 description 2
- 229960001367 tartaric acid Drugs 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 150000003892 tartrate salts Chemical class 0.000 description 2
- 229940072358 xylocaine Drugs 0.000 description 2
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- YAQLSKVCTLCIIE-UHFFFAOYSA-N 2-bromobutyric acid Chemical compound CCC(Br)C(O)=O YAQLSKVCTLCIIE-UHFFFAOYSA-N 0.000 description 1
- CSFUYRGXBNPTSR-UHFFFAOYSA-N 2-bromohexanoyl bromide Chemical compound CCCCC(Br)C(Br)=O CSFUYRGXBNPTSR-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- VTUSIVBDOCDNHS-UHFFFAOYSA-N Etidocaine Chemical compound CCCN(CC)C(CC)C(=O)NC1=C(C)C=CC=C1C VTUSIVBDOCDNHS-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010021118 Hypotonia Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241000786363 Rhampholeon spectrum Species 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000003461 brachial plexus Anatomy 0.000 description 1
- 229940105270 carbocaine Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229940097598 citanest Drugs 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229960001270 d- tartaric acid Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- 230000006203 ethylation Effects 0.000 description 1
- 238000006200 ethylation reaction Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 229960002409 mepivacaine Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 230000036640 muscle relaxation Effects 0.000 description 1
- FFJMLWSZNCJCSZ-UHFFFAOYSA-N n-methylmethanamine;hydrobromide Chemical compound Br.CNC FFJMLWSZNCJCSZ-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229960001807 prilocaine Drugs 0.000 description 1
- 229950000332 pyrrocaine Drugs 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
- C07C53/38—Acyl halides
- C07C53/46—Acyl halides containing halogen outside the carbonyl halide group
- C07C53/50—Acyl halides containing halogen outside the carbonyl halide group of acids containing three or more carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Description
Foreliggende oppfinnelse vedrører The present invention relates to
fremstilling av 2-alkyl-2-alkylamino-2',6'-acetoksylidid-forbindelser med lokalanestetisk aktivitet. preparation of 2-alkyl-2-alkylamino-2',6'-acetoxylidide compounds with local anesthetic activity.
Man kjenner to acylxylidid-lokalanestetika i handelen, nemlig N-n-butylpipecolyl-2,6-xylidid eller bupivacain forhand- Two acylxylidide local anesthetics are commercially available, namely N-n-butylpipecolyl-2,6-xylidide or bupivacaine pre-
let under varemerket "Marcaine" med strukturformelen: look under the trademark "Marcaine" with the structural formula:
og dietylaminoaceto-2,6-xylidid eller CO-dietylamino-2,6-dimetyl-acetanilid eller lidocaire som forhandles under varemerket "Xylocaine" og har strukturformelen and diethylaminoaceto-2,6-xylidide or CO-diethylamino-2,6-dimethylacetanilide or lidocaire which is marketed under the trade name "Xylocaine" and has the structural formula
Mens imidlertid bupivacaine eller "Marcaine" er et lokalanestetikum med langtidsvirkning, er stoffet imidlertid beheftet med den ulempen at det irreterer vevet, og mens lidocaine eller "Xylocaine" ikke irriterer vev, har det den ulempen at det ikke er lokalanestetika med langtidsvirkning. However, while bupivacaine or "Marcaine" is a long-acting local anesthetic, the drug has the disadvantage of irritating tissue, and while lidocaine or "Xylocaine" does not irritate tissue, it has the disadvantage of not being a long-acting local anesthetic.
Andre lokalanestetika som finnes i handelen omfatter ct-propylaminopropiono-2-toluidid eller prilocaine som forhandles under varemerket "Citanest", a-pyrrolidinoaceto-2,6-xylidid eller pyrocaine som forhandles under va-remerkene "Endocaine" og "Dynacaine", og N-metylpipecolyl-2,6-xylidid eller mepivacaine som forhandles under varemerket "Carbocaine". Imidlertid har disse lokalanestetika kortvarig virkning. Other commercially available local anesthetics include ct-propylaminopropiono-2-toluidide or prilocaine sold under the trade name "Citanest", α-pyrrolidinoaceto-2,6-xylidide or pyrocaine sold under the trade names "Endocaine" and "Dynacaine", and N-methylpipecolyl-2,6-xylidide or mepivacaine sold under the trade name "Carbocaine". However, these local anesthetics have a short-term effect.
Det er derfor en hovedhensikt med oppfinnelsen å til-veiebringe stoffer som generelt har de kombinerte egenskaper langvarig lokalanestetisk virkning eller høy lokalanestetisk aktivitet, tilfredsstillende lavt vevsirritasjonsnivå, samt en godtagbar lav akutt toksisitet.' It is therefore a main purpose of the invention to provide substances which generally have the combined properties of long-lasting local anesthetic effect or high local anesthetic activity, a satisfactory low level of tissue irritation, as well as an acceptable low acute toxicity.
..Forbindelsene som fremstilles i henhold til oppfinnelsen, er 2-alkyl-2-a.lkylamino-2 ' , 6 '-acetoksylidid-f orbindelser med lokalanestetisk virkning, med formel: i optisk aktiv eller racemisk form, samt farmasøytisk akseptable salter derav, hvor R<1> betyr etyl, propyl eller butyl, R<2> og R^ ..betyr hver for seg metyl, etyl, propyl eller butyl, eller Ro sammen med R^ kan også bety tetrametylen, idet det samlede antall ..The compounds produced according to the invention, are 2-alkyl-2-alkylamino-2', 6'-acetoxylidide compounds with local anesthetic action, with formula: in optically active or racemic form, as well as pharmaceutically acceptable salts thereof, where R<1> means ethyl, propyl or butyl, R<2> and R^ ..individually mean methyl, ethyl, propyl or butyl, or Ro together with R^ can also mean tetramethylene, the total number being
12 ^ 12 ^
karbonatomer i R , R og R ^ er minst seks. Forbindelsene er altså racemiske stoffer og derfor faller lokalanastetika som d- eller 1- optiske isomere innenfor rammen av formel I. carbon atoms in R , R and R ^ are at least six. The compounds are thus racemic substances and therefore local anesthetics as d- or 1- optical isomers fall within the framework of formula I.
Representative forbindelser omfatter blant andre: 2- dietylamino-2',6'-n-butyrokxylidid som alternativt kan betegnes 2-etyl-2-dietylamino-2',6'-acetoksylidid, med strukturformelen: 2-(N-etyl-n-propylamino)-2',6'-n-butyroksylidid som eventuelt kan kalles 2-etyl-2(N-etyl-n-propylamino)-2',6'-acetoksylidid, med strukturformelen: 2-dietylamino-2',6'-n-valeroksylidid som eventuelt kan betegnes 2-n-propyl-2-dietylamino-2',6'-acetoksylidid med strukturformelen 2-pyrrolidino-2',6f<->n-butyroxylidid som også kan kalles 2-etyl-2-pyrrolidino-2',6'-acetoxylidid, med strukturformelen 2-(N-etyl-n-butylamino)-2',6'-n-butyroxylidid, som også kan kalles 2-etyl-2-(N-etyl-n-butyl-amino)-2',6'-acetoxylidid, med strukturformelen 2-dimetylamino-2',6'-caproylxylidid som alternativt kan kalles 2-n-butyl-2-dimetylamino-2',6'-acetoxylidid, med strukturformelen og 2-pyrrolidino-2',6'-n-valeroxylidid som også kan kalles 2-n-propyl-2-pyrrolidino-2',6'-acetoxylidid, med strukturformelen Representative compounds include, among others: 2-diethylamino-2',6'-n-butyroxylidide which can alternatively be termed 2-ethyl-2-diethylamino-2',6'-acetoxylidide, with the structural formula: 2-(N-ethyl-n-propylamino)-2',6'-n-butyroxylidide which may optionally be called 2-ethyl-2(N-ethyl-n-propylamino)-2',6'-acetoxylidide, with the structural formula : 2-diethylamino-2',6'-n-valeroxylidide which can optionally be designated 2-n-propyl-2-diethylamino-2',6'-acetoxylidide with the structural formula 2-pyrrolidino-2',6f<->n-butyroxylidide which can also be called 2-ethyl-2-pyrrolidino-2',6'-acetoxylidide, with the structural formula 2-(N-ethyl-n-butylamino)-2',6'-n-butyroxylidide, which can also be called 2-ethyl-2-(N-ethyl-n-butyl-amino)-2',6'- acetoxylidide, with the structural formula 2-dimethylamino-2',6'-caproylxylidide which can alternatively be called 2-n-butyl-2-dimethylamino-2',6'-acetoxylidide, with the structural formula and 2-pyrrolidino-2',6'-n-valeroxylidide which can also be called 2-n-propyl-2-pyrrolidino-2',6'-acetoxylidide, with the structural formula
Forbindelsene med formel I fremstilles ifølge oppfinnel- : sen som illustrert ved siste trinn i nedenstående reaksjonsskjerna A The compounds of formula I are prepared according to the invention as illustrated in the last step in reaction core A below
og ved siste to trinn i reaksjonsskjema B. and at the last two steps in reaction scheme B.
12 "5 hvor R , R og R har betydning som ovenfor og X betegner et brom- eller kloratom. Bromatomet i forbindelsen med formel: kan også overføres til jodid før stoffet brukes i trinn 2 ovenfor. 12 "5 where R , R and R have the meaning as above and X denotes a bromine or chlorine atom. The bromine atom in the compound of formula: can also be transferred to iodide before the substance is used in step 2 above.
Jodatomet i nest siste trinn ovenfor kan erstattes med et bromatom. The iodine atom in the penultimate step above can be replaced with a bromine atom.
hvor R 1 , R 2 , RJ ? og X har betydning som ovenfor. I stedet for KJ where R 1 , R 2 , RJ ? and X has meaning as above. Instead of KJ
kan man bruke andre halogeneringsmidler som for eksempel Na J. can you use other halogenating agents such as Na J.
Som alkyleringsmidler kan man for eksempel bruke (CgH^^SO^ eller <C>2<H>5<J>• As alkylating agents, you can for example use (CgH^^SO^ or <C>2<H>5<J>•
De racemiske stoffer kan atskilles i sine d- og 1-optiske isomere ved behandling med 1- og d-vinsyre. The racemic substances can be separated into their d- and 1-optical isomers by treatment with 1- and d-tartaric acid.
Forbindelsene fremstilt i henhold til oppfinnelsen er nyttige som lokalanestetika på kjent måte i vanlige doser. De basiske forbindelser kan brukes på kjent måte i form av oppløsninger av deres farmasøytiske anvendelige salter, for eksempel som hydroklorider, tartrater eller citrater. The compounds prepared according to the invention are useful as local anesthetics in a known manner in usual doses. The basic compounds can be used in a known manner in the form of solutions of their pharmaceutically usable salts, for example as hydrochlorides, tartrates or citrates.
Parenterale oppløsninger kan gis periduralt, subarach-noidalt og ved infiltrering. Oppløsninger, geleer, salver og spray-preparater fremstilt av basene eller deres farmasøytiske anvendelige salter kan gis topisk på slimhinner eller skadet hud, for eksempel oppskrubbet hud. Parenteral solutions can be given epidurally, subarachnoidally and by infiltration. Solutions, gels, ointments and spray preparations prepared from the bases or their pharmaceutically acceptable salts can be applied topically to mucous membranes or damaged skin, for example exfoliated skin.
Forbindelsene kan brukes i konsentrasjoner på 0,25 - 2 % og i doser på 75 - 3^0 mg. Konsentrasjonene og dosene som brakes skal imidlertid ikke innskrenkes til disse områder, men må fast-legges individuelt idet man tar hensyn til faktorer som pasientens alder og kroppsvekt, den kliniske indikasjon og administrasjonsvegen. The compounds can be used in concentrations of 0.25 - 2% and in doses of 75 - 3^0 mg. However, the concentrations and doses that are braked must not be restricted to these areas, but must be determined individually, taking into account factors such as the patient's age and body weight, the clinical indication and the route of administration.
Oppfinnelsen skal i det følgende illustreres ytterligere y.ed eksempler: In the following, the invention will be further illustrated by examples:
Eksempel 1. Example 1.
_ Dette eksempel illustrerer fremstilling av 2-dietylamino-2', 6'-n-butyroxylidid eller a-(dietylamino)-n-butyro-2,6-xylidid. _ This example illustrates the preparation of 2-diethylamino-2', 6'-n-butyroxylidide or α-(diethylamino)-n-butyro-2,6-xylidide.
( q- brom- n- butyryl klorid)- Redestillert thionyl klorid (2,40 mol) ble satt til a-brom-n-smørsyre (1,20 mol) i en liters kolbe påsatt tilbakeløpskjøler og tørrerør. Blandingen ble kokt ved tilbakeløp i 5 timer. Overskudd av thionyl klorid ble avdestillert under bad-temperatur opp til 120°C. Reaksjonsblandingen ble holdt ved 25 -30°C i en time under vannpumpevakuum, hvoretter badtemperaturen langsomt ble øket til 80°C og på dette punkte begynte a-brom-n-butyryl kloridet å destillere av, kokepunkt 48-50°C, utbytte: 1,10 mol (92$). Et produkt som var tilstrekkelig rent for den nedenstående reaksjon ble fremstilt ved å utelate vakuumdestillasjonen og la en strøm av (q-bromo-n-butyryl chloride)- Redistilled thionyl chloride (2.40 mol) was added to α-bromo-n-butyric acid (1.20 mol) in a one liter flask fitted with a reflux condenser and drying tube. The mixture was refluxed for 5 hours. Excess thionyl chloride was distilled off under a bath temperature of up to 120°C. The reaction mixture was kept at 25-30°C for one hour under water pump vacuum, after which the bath temperature was slowly increased to 80°C and at this point the α-bromo-n-butyryl chloride began to distill off, boiling point 48-50°C, yield: 1.10 moles ($92). A product sufficiently pure for the reaction below was prepared by omitting the vacuum distillation and leaving a current off
tørr argon (eller nitrogen) boble gjennom a-brom-n-butyryl kloridet' ved 80 - 100°C i 1,5 - 2 timer etter at hovedmengden av thionyl kloridet var avdestillert. dry argon (or nitrogen) bubble through the α-bromo-n-butyryl chloride' at 80 - 100°C for 1.5 - 2 hours after the bulk of the thionyl chloride had distilled off.
( q- brom- m- butyryl- 2, 6- xylidid) - a-brom-n-butyryl klorid (I.OO5 mol) ble satt til en kald blanding (5-10°C) av 2,6-xylidine (0,92 mol) (q-bromo-m-butyryl-2, 6-xylidine)-α-bromo-n-butyryl chloride (1.005 mol) was added to a cold mixture (5-10°C) of 2,6-xylidine ( 0.92 moles)
og iseddik (814 ml) i en fire liters kolbe, hurtig blandet og raskt tilsatt en kald oppløsning av natrium acetat-trihydrat (315»6 g) i vann (l6l0 ml.). Kolben ble lukket og rystet i 30 minutter. Fellingen ble frafiltrert og vasket flere ganger ved oppslemming i vann for å fjerne eddiksyren så effektivt som mulig. Stoffet ble deretter tørket i luft eller i vakuum, smeltepunkt 198-200°C, utbytte: 0,74 mol (80 %). Beregnet for G^H^BrNO: C 53.3, H 5.97, Br 29.6, funnet: c 53-3, H 5-79, Br 29.7. and glacial acetic acid (814 ml) in a four liter flask, quickly mixed and quickly added a cold solution of sodium acetate trihydrate (315»6 g) in water (1610 ml.). The flask was closed and shaken for 30 minutes. The precipitate was filtered off and washed several times by slurrying in water to remove the acetic acid as effectively as possible. The substance was then dried in air or in vacuum, melting point 198-200°C, yield: 0.74 mol (80%). Calculated for G^H^BrNO: C 53.3, H 5.97, Br 29.6, found: c 53-3, H 5-79, Br 29.7.
( a-( dietylamino) - n- butyro- 2 , 6- xylidid) - a-brom-n-butyryl-2-,6-xylidid (O.OI48 mol), dietylamin (O.O444 mol), og vannfri benzen (25 ml.) ble oppvarmet ved 100°C i 15 timer i trykkbeholder. Etter avkjøling ble dietylammonium bromid frafiltrert og benzenoppl^s-ningen ekstrahert med tre 25 ml. porsjoner 1 M saltsyre. Syreekstraktet ble vasket med 25 ml. eter og innstilt på pH 10 med 7 M natriumhydroksyd og ekstrahert med fire 25 ml. porsjoner eter. Eterekstraktet ble tørket over vannfri natriumsulfat, filtrert_og eteren avdampet i vakuum, hvoretter man fikk a-(dietylamino)-n-butyro-2,6-xylidid (O.OO499 mol = 33.7 %) som et voksaktig fast stoff. Stoffet ble overført til hydrokloridsaltet med eterisk saltsyre og saltet ble omkrystallisert tre ganger fra en blanding av absolut etanol og eter, smeltepunkt 224,5-226°C (decomp.) - Beregnet for C-^H^CII^O: C 64.3, H 9.11, N 9.37. Funnet: C 64.4, (α-(diethylamino)-n-butyro-2,6-xylidide)-α-bromo-n-butyryl-2-,6-xylidide (O.OI48 mol), diethylamine (O.O444 mol), and anhydrous benzene (25 ml.) was heated at 100°C for 15 hours in a pressure vessel. After cooling, diethylammonium bromide was filtered off and the benzene solution was extracted with three 25 ml. portions of 1 M hydrochloric acid. The acid extract was washed with 25 ml. ether and adjusted to pH 10 with 7 M sodium hydroxide and extracted with four 25 ml. portions of ether. The ether extract was dried over anhydrous sodium sulfate, filtered, and the ether evaporated in vacuo, after which α-(diethylamino)-n-butyro-2,6-xylidide (0.00499 mol = 33.7%) was obtained as a waxy solid. The substance was converted into the hydrochloride salt with ethereal hydrochloric acid and the salt was recrystallized three times from a mixture of absolute ethanol and ether, mp 224.5-226°C (decomp.) - Calculated for C-^H^CII^O: C 64.3, H 9.11, N 9.37. Found: C 64.4,
H 9.12, N 9.39. I.R. (KBr skive, hydroklorid), 3175 (s, NH amid), 2980 og 2938 (skulder) (s, CH^ og CH2), 2577 (s, NH+), 249° (s,NH+), I685 (s, amide I), 1599 (w, Ph), I53O (s, amide II), 1479 (s), - 1232 (s, amide III), 787 (s, Ph, 3 nabo-hydrogen ute av plan) cm"<1>. N.M.R. (CDCl^, base), «1.10_(t, 9H, CH2 -CH^), \ J>0 - 2.10 (m, 2H, CHCH^H^), 2.18 (s, 6H, Ph -CH^), 2.68 (q, 4H, N-CH^CH^) , 3.25 H 9.12, N 9.39. I.R. (KBr disk, hydrochloride), 3175 (s, NH amide), 2980 and 2938 (shoulder) (s, CH^ and CH2), 2577 (s, NH+), 249° (s,NH+), I685 (s, amide I), 1599 (w, Ph), I53O (s, amide II), 1479 (s), - 1232 (s, amide III), 787 (s, Ph, 3 neighbor hydrogen out of plane) cm"<1 >. N.M.R. (CDCl^, base), «1.10_(t, 9H, CH2 -CH^), \ J>0 - 2.10 (m, 2H, CHCH^H^), 2.18 (s, 6H, Ph -CH ^), 2.68 (q, 4H, N-CH^CH^) , 3.25
(t, 1H, C0CH), 6.98 (s, 3H, Ph), 8,73 (s bredt, 1H, NHC0). En gass kromatografisk analyse av forbindelsen viste bare en enkelt topp. (t, 1H, COCH), 6.98 (s, 3H, Ph), 8.73 (s broad, 1H, NHC0). A gas chromatographic analysis of the compound showed only a single peak.
Eksempel 2 Example 2
Dette eksempel illustrerer fremstilling av 2-(N-etyl-n-propylamino)-2',6'-butyroxylidid eller o(- (N-etyl-n-propylamino)-n-butyro-2,6-xylidid. This example illustrates the preparation of 2-(N-ethyl-n-propylamino)-2',6'-butyroxylidide or o(-(N-ethyl-n-propylamino)-n-butyro-2,6-xylidide.
IfH - brom- n- butyryl- 2 , 6- xylidid) Denne forbindelsen ble fremstilt som beskrevet i eksempel 1. IfH - bromo-n-butyryl-2, 6-xylidide) This compound was prepared as described in example 1.
( op. jod- n- butyry 1- 2 , 6- xylidid) - dj-brom-n-butyryl-2 ,6-xylidid (224,7 g> O.832 mol), pulverisert kaliumjodid (I9I.2 g = 1.15 mol) og vannfri metanol (1200 ml) ble blandet i en 3 liters kolbe forsynt med til-bakeløpskjøler, mekanisk røring og varmekappe. Etter tilbakeløps-koking i 3 timer ble blandingen avkjølt i 30 minutter under fortsatt røring, overført under røring til et begerglass inneholdende 2,5 liter destillert vann og hensatt 1 time. Fellingen ble frafiltrert og presset så tørr som mulig. Deretter ble fellingen fyllt tilbake på begerglasset og omhyggelig utrørt med ca. 1.5 liter destillert vann og filtrert på nytt. Man gjentok fremgangsmåten inntil filtratet var fritt for brom- og jod-ioner. Fellingen ble tørket i luft og/eller i exsiccator. Utbytte: 243 g, smeltepunkt 220-222°C (decomp.). ( op. iodo-n- butyry 1- 2 , 6- xylidide) - dj-bromo-n-butyryl-2 , 6-xylidide (224.7 g> O.832 mol), powdered potassium iodide (I9I.2 g = 1.15 mol) and anhydrous methanol (1200 ml) were mixed in a 3 liter flask fitted with a reflux condenser, mechanical stirring and heating jacket. After refluxing for 3 hours, the mixture was cooled for 30 minutes with continued stirring, transferred while stirring to a beaker containing 2.5 liters of distilled water and left for 1 hour. The precipitate was filtered off and pressed as dry as possible. The precipitate was then filled back into the beaker and carefully stirred with approx. 1.5 liters of distilled water and filtered again. The procedure was repeated until the filtrate was free of bromine and iodine ions. The precipitate was dried in air and/or in a desiccator. Yield: 243 g, melting point 220-222°C (decomp.).
Det fremstilte preparat var nesten fargeløst. Omkrystallisasjon fra 95$ etanol ga et produkt med smeltepunkt 223.5°^ under dekomponering. The prepared preparation was almost colourless. Recrystallization from 95% ethanol gave a product m.p. 223.5°^ during decomposition.
Det-ukrystalliserte produktet inneholder endel bromfor-bindelse, men var tilstrekkelig rent- for det følgende trinn. The uncrystallized product contains some bromine compound, but was sufficiently pure for the following step.
( of-( n- propylamino) - n- butyro- 2 , 6- xylidid) (of-(n-propylamino)-n-butyro-2,6-xylidide)
Metode a n-propylamin (67.9 g = 1*15 mol) og of-jod-n-butyryl-2,6-xylidid (121-5 g = O.383 mol) ble blandet med vannfri benzen (1220 ml.) i en kolbe forsynt med tilbakeløpskjøler, mekanisk rører og varmekappe og kokt ved tilbakeløp i 8 timer. Den lysegule oppløs-ningen ble filtrert fra en gul felling som ble vasket omhyggelig Method a n-propylamine (67.9 g = 1*15 mol) and of-iodo-n-butyryl-2,6-xylidide (121-5 g = 0.383 mol) were mixed with anhydrous benzene (1220 ml.) in a flask fitted with a reflux condenser, mechanical stirrer and heating jacket and boiled at reflux for 8 hours. The light yellow solution was filtered from a yellow precipitate which was washed carefully
■med eter. Fellingen (ingen C=0 bånd i I.R. spekteret) ble kastet. Filtratet og vaskeoppløsningen ble slått sammen og inndampet til ■with ether. The precipitate (no C=0 band in the I.R. spectrum) was discarded. The filtrate and washing solution were combined and evaporated
et gult residum (143-4 g)• a yellow residue (143-4 g)•
Residuet ble behandlet med 380 ml 1 M saltsyre. Et uoppløselig faststoff ble frafiltrert og vasket med eter. Det sure filtratet ble ekstrahert med eter og et ytterligere bunnfall ble frafiltrert og kombinert med det tidligere oppnådde uoppløselige faststoff. Den samlede vekt av de faste utfellinger var 156,2 g (I) . Det sure filtratet (II) ble vasket med ytte"rligere 4 porsjoner eter. Den faste fraksjon I ble kokt under tilbakeløp med vannfri benzen, filtrert og vasket med varm benzen og eter. De samlede benzen- og eterekstrakter fra disse operasjoner inneholdt 6.8 g residum og ble kastet. Den faste fraksjon I og den sure oppløsning II ble slått sammen og behandlet med 7 M NaOH og den derved frigjorte base ekstrahert med eter. Etter tørking over vannfritt natriumsulfat ble eterekstraktet filtrert og inndampet og ga 93 g av et delvis stivnet brunrødt residum. The residue was treated with 380 ml of 1 M hydrochloric acid. An insoluble solid was filtered off and washed with ether. The acidic filtrate was extracted with ether and a further precipitate was filtered off and combined with the previously obtained insoluble solid. The total weight of the solid precipitates was 156.2 g (I). The acidic filtrate (II) was washed with a further 4 portions of ether. The solid fraction I was refluxed with anhydrous benzene, filtered and washed with hot benzene and ether. The combined benzene and ether extracts from these operations contained 6.8 g of residue and was discarded. The solid fraction I and the acidic solution II were combined and treated with 7 M NaOH and the base liberated thereby extracted with ether. After drying over anhydrous sodium sulfate, the ether extract was filtered and evaporated to give 93 g of a partially solidified brown-red residue.
Denne rest ble oppløst i 80 ml eter i en skilletrakt og innstilt i likevekt med 200 ml fosfatbuffer ved en pH på 7.3. Idet man holdt pH på 7-3 ble bufferoppløsningen ekstrahert tre ganger til med 80 porsjoner eter. This residue was dissolved in 80 ml of ether in a separatory funnel and adjusted to equilibrium with 200 ml of phosphate buffer at a pH of 7.3. Keeping the pH at 7-3, the buffer solution was extracted three more times with 80 portions of ether.
Eterekstraktene ga 79,2 g av en base som hovedsakelig inneholdt den ønskede forbindelse og som var tilstrekkelig ren for neste trinn. The ether extracts gave 79.2 g of a base containing essentially the desired compound and sufficiently pure for the next step.
Fra bufferoppløsningen kunne man få 6.3 g av en olje ved å øke pH til 11 og ekstrahere med eter. Denne fraksjonen inneholdt hovedsakelig den (3-substituerte isomer og ble kastet. From the buffer solution, 6.3 g of an oil could be obtained by raising the pH to 11 and extracting with ether. This fraction contained mainly the (3-substituted isomer) and was discarded.
Metode b q( -brom-n-butyryl-2,6-xylidid (63.1 millimol), n-propylamin (254 millimol), natriumiodid (63.I millimol), og absolutt etanol (l80 ml) ble kokt ved tilbakeløp i 6,5 timer. Alkoholen ble fordampet i vakuum og residuet blandet med 0.5 M HC1 (200 ml). Sus-pensjonen ble vasket med to 100 ml porsjoner av eter, pH innstilt til 11 med 7 M NaOH og blandingen ekstrahert tre ganger med 100 ml porsjoner av eter. Etter tørking over vannfritt natriumsulfat ble eteren fordampet idet det etterlot en rest av aminet. Utbytte: 51.0 millimol (8l %). Hydrokloridhydratet ble utvunnet av basen med eterisk saltsyre og tilsetning av vann. Omkrystallisert fra etanol/eter smeltet stoffet ved 199-199.5°C. Beregnet for basen (<C>15H24N20) : C 72,5' H N 11>3- Funnet: C 72.5» H 9-81, Method b q( -bromo-n-butyryl-2,6-xylidide (63.1 mmol), n-propylamine (254 mmol), sodium iodide (63.1 mmol), and absolute ethanol (180 mL) were refluxed for 6, 5 h. The alcohol was evaporated in vacuo and the residue mixed with 0.5 M HCl (200 mL). The suspension was washed with two 100 mL portions of ether, pH adjusted to 11 with 7 M NaOH, and the mixture extracted three times with 100 mL portions of ether. After drying over anhydrous sodium sulfate, the ether was evaporated leaving a residue of the amine. Yield: 51.0 mmol (8l%). The hydrochloride hydrate was recovered from the base with ethereal hydrochloric acid and addition of water. Recrystallized from ethanol/ether, the substance melted at 199 -199.5° C. Calculated for the base (<C>15H24N20) : C 72.5' H N 11>3- Found: C 72.5» H 9-81,
N 11.2. N 11.2.
( Of-( N- etyl- n- propylamino) - n- butyro- 2, 6- xylidid) ( Of-( N- ethyl- n- propylamino)- n- butyro- 2, 6-xylidide)
of-(n-propylamino)-n-butyro-2,6-xylidid (0.243 mol) og frisk destillert dietylsulfat (1.0 mol) ble blandet i en kolbe forsynt med til-bakeløpskjøler, tørkerør og rører. Blandingen ble,, omrørt i 5 timer ved 90°C. Etter avkjøling ble vann (110 ml) tilsatt under omrøring i 15 minutter fulgt av 4 M HC1 (110 ml). Oppløsningen ble vasket med eter (3 x 100 ml) og gjort alkalisk med 7 M NaOH til pH 10-11. Den frigjorte basen ble opptatt i eter (3 x 100 ml), ekstraktene of-(n-propylamino)-n-butyro-2,6-xylidide (0.243 mol) and freshly distilled diethyl sulfate (1.0 mol) were mixed in a flask fitted with a reflux condenser, drying tube and stirrer. The mixture was stirred for 5 hours at 90°C. After cooling, water (110 mL) was added with stirring for 15 minutes followed by 4 M HCl (110 mL). The solution was washed with ether (3 x 100 mL) and basified with 7 M NaOH to pH 10-11. The liberated base was taken up in ether (3 x 100 ml), the extracts
ble tørket over natriumsulfat, filtrert og inndampet. Residuet ble oppløst i absolutt eter (200 ml) og hydrokloridet fremstilt ved tilsetning av eterisk hydrogenklorid. Bunnfallet ble filtrert, vasket med eter og omkrystallisert to ganger fra absolutt etanol/eter og fra isopropanol/isopropyleter, smeltepunkt 203-203.5°C, utbytte: 0.126 mol (52 %) . Beregnet for C-^H^CIN^: C 65.3, H 9-34, was dried over sodium sulfate, filtered and evaporated. The residue was dissolved in absolute ether (200 ml) and the hydrochloride prepared by addition of ethereal hydrogen chloride. The precipitate was filtered, washed with ether and recrystallized twice from absolute ethanol/ether and from isopropanol/isopropyl ether, melting point 203-203.5°C, yield: 0.126 mol (52%). Calculated for C-^H^CIN^: C 65.3, H 9-34,
Cl II.3. Funnet: C 65.2, H 9.29, Cl 11.3. I.R. (KBr skive hydroklorid))J 3175 (s, amid NH), 2970 og 2940 (s, CH^ og CHg), 2580 Cl II.3. Found: C 65.2, H 9.29, Cl 11.3. I.R. (KBr disk hydrochloride))J 3175 (s, amide NH), 2970 and 2940 (s, CH^ and CHg), 2580
(s, NH<+>), 2505 (s, NH<+>), l680 (s, amid I), 1595 (w, Ph), 1531 (s, NH<+>), 2505 (s, NH<+>), 1680 (s, amide I), 1595 (w, Ph), 1531
Cs, amid II), 1474 (s), 1227 (s, amid III), 778 (s, Ph, 3 nabo-hydrogener ut av plan) cm"<1.> N.M.R. (CDCl^, base)£ I.06 (t,CH2CH^), 1.26 (t, CH2CH„) (9H for de to tripletter), I-58 - 2.48 (m, 4H, CH2CH3), 2.53 (s, 6H, PhCH^), 2.82 - 3.3O (m, 4H, NCH2), 3.72 Cs, amide II), 1474 (s), 1227 (s, amide III), 778 (s, Ph, 3 neighboring hydrogens out of plane) cm"<1.> N.M.R. (CDCl^, base)£ I.06 (t,CH2CH^), 1.26 (t, CH2CH„) (9H for the two triplets), I-58 - 2.48 (m, 4H, CH2CH3), 2.53 (s, 6H, PhCH^), 2.82 - 3.3O ( m, 4H, NCH 2 ), 3.72
(t, 1H, C0CH), 7.98 (s, 3H, Ph). Gass kromatografisk analyse viste en enkelt topp. (t, 1H, COCH), 7.98 (s, 3H, Ph). Gas chromatographic analysis showed a single peak.
Eksempel Example
Den racemiske forbindelse fra eksempel 2 ble oppdelt i The racemic compound from Example 2 was resolved into
d- og -^-optiske isomere på følgende måte: d- and -^-optical isomers as follows:
Racematet av of-(N-etyl-n-propylamino)-n-butyro-2,6-xylidid-basen (9,73 <g>> °-3519 mo1) ble oppløst i en blanding av ^-vinsyre (5-28 g, O.3519 mol) og 19«5 ml vann ved forsiktig oppvarming. Etter filtrering ble oppløsningen avkjølt og hensatt ved 4°C. Krystallene som dannet seg ble filtrert fra kaldt. Moderluten ble konsentrert til omtrent halve volumet og man fikk en ytterligere utfelling. De samlede faste stoffer (I) ble omkrystallisert flere ganger fra vann til man oppnådde konstant optisk rotasjon, (o() D^5= -8.3°. Moderluten ble innstilt alkalisk med 7 M natriumhydroksyd og ekstrahert med eter. Eteren ble avdampet og 3.18 g (O.OII5 mol) gjenværende base ble utvunnet, og forbindelsen oppløst i en oppløsning av ^-vinsyre (1.73 S» 0.0115 mol) i 6.4 nil vann under oppvarming. Fra den kalde oppløsning (4°C) fikk man krystaller (II) som ble omkrystallisert gjentatte ganger fra vann til konstant rotasjon, The racemate of -(N-ethyl-n-propylamino)-n-butyro-2,6-xylidide base (9.73 <g>> °-3519 mo1) was dissolved in a mixture of ^-tartaric acid (5- 28 g, O.3519 mol) and 19«5 ml of water by gentle heating. After filtration, the solution was cooled and stored at 4°C. The crystals that formed were filtered from cold. The mother liquor was concentrated to approximately half the volume and a further precipitate was obtained. The combined solids (I) were recrystallized several times from water until constant optical rotation was obtained, (o() D^5= -8.3°. The mother liquor was made alkaline with 7 M sodium hydroxide and extracted with ether. The ether was evaporated and 3.18 g (O.OII5 mol) of residual base was recovered, and the compound dissolved in a solution of ^-tartaric acid (1.73 S» 0.0115 mol) in 6.4 nil of water under heating. From the cold solution (4°C) crystals (II ) which was recrystallized repeatedly from water to constant rotation,
(a) D = +8.6°. Basen ble frigjort fra de to tartrater med natrium hydroksyd i vann. Basene fra (I) og (II) hadde spesifikke rotasjoner på +34»1° °g -32«8°, respektivt. Rotasjonen for deres hydroklorider var +6.2° og -6.2°, respektivt, etter omkrystallisasjon fra absolute etanol - eter. Deres smeltepunkter var identiske, l84-l85°C. (a) D = +8.6°. The base was liberated from the two tartrates with sodium hydroxide in water. The bases from (I) and (II) had specific rotations of +34»1° °g -32«8°, respectively. The rotation for their hydrochlorides was +6.2° and -6.2°, respectively, after recrystallization from absolute ethanol - ether. Their melting points were identical, 184-185°C.
De racemiske stoffer fra eksemplene 1 og 4-8 kan atskilles i deres d- og 1- optiske isomere etter en fremgangsmåte som tilsvarer den beskrevne i eksempel 3«The racemic substances from examples 1 and 4-8 can be separated into their d- and 1- optical isomers by a method corresponding to that described in example 3"
Eksempel 4»Example 4»
Eksemplet viser fremstilling av 2-dietylamino-2',6'-n-valeroxylidid. The example shows the preparation of 2-diethylamino-2',6'-n-valeroxylidide.
2- brom- 2', 6', n, valeroxylidid - I en 2 liters kolbe blandet man 2,6-xylidine (O.347 mol) og iseddik (3IO ml). Blandingen ble avkjølt til 12°C og 2-brom-n-valeryl klorid (O.349 mol) tilsatt raskt. Etter hurtig blanding tilsatte man umiddelbart en forhåndsavkjølt opp-løsning (5°C) av natrium acetat - trihydrat (85 g) i vann (340 ml), og blandingen ble rystet i ca. 30 minutter. Det faste stoffet ble filtrert fra og vasket omhyggelig og gjentatte ganger med vann til filtratet var fritt for bromidioner. Etter tørking i desiccator over et kalium hydroksyd - flak smeltet det faste stoff (O.345 mol) ved l8g-190.5oC. Etter omkrystallisasjon fra 95 % etanol var smeltepunktet for de fargeløse krystaller I9O-I9O.5°C. Utbytte: .65-78 %. Beregnet for C^H^BrNO: C 54,9, H 6.38, Br 28.1. Funnet: C 54.9, 2-bromo-2', 6', n, valeroxylidide - 2,6-xylidine (0.347 mol) and glacial acetic acid (310 ml) were mixed in a 2 liter flask. The mixture was cooled to 12°C and 2-bromo-n-valeryl chloride (0.349 mol) added rapidly. After rapid mixing, a pre-cooled solution (5°C) of sodium acetate trihydrate (85 g) in water (340 ml) was immediately added, and the mixture was shaken for approx. 30 minutes. The solid was filtered off and washed carefully and repeatedly with water until the filtrate was free of bromide ions. After drying in a desiccator over a potassium hydroxide flake, the solid (0.345 mol) melted at 18g-190.5oC. After recrystallization from 95% ethanol, the melting point of the colorless crystals was 190-190.5°C. Yield: .65-78%. Calculated for C^H^BrNO: C 54.9, H 6.38, Br 28.1. Found: C 54.9,
H 6.33, Br 28.2. H 6.33, Br 28.2.
2- dietylamino- 2T, 6'- n- valeroxylidid - En blanding av 2-brom-2',6'-n-valeroxylidid (O.I76 mol), dietylamin (O.528 mol), og benzen (125 mD ble anbragt i en trykkbeholder og oppvarmet til 100°C i 35 timer. Etter avkjøling ble det mørkebrune innhold filtrert og det faste stoffet (23.2 g dietylammonium bromid) vasket grundig med benzen. Filtratet ble ekstrahert med 4 N saltsyre (3x50 ml), syreekstraktet vasket med eter (3x50 ml), og innstilt basisk med 7H natriumhydroksyd under kjøling og røring og i nærvær av eter (100 ml). Etter t<q >ytterligere ekstraksjoner med eter (2x50 ml), ble de samlede 2-diethylamino-2T,6'-n-valeroxylidide - A mixture of 2-bromo-2',6'-n-valeroxylidide (0.176 mol), diethylamine (0.528 mol), and benzene (125 mD was placed in a pressure vessel and heated to 100°C for 35 hours. After cooling, the dark brown contents were filtered and the solid (23.2 g diethylammonium bromide) washed thoroughly with benzene. The filtrate was extracted with 4 N hydrochloric acid (3x50 ml), the acid extract washed with ether (3x50 mL), and basified with 7H sodium hydroxide with cooling and stirring and in the presence of ether (100 mL). After t<q >further extractions with ether (2x50 mL), the combined
eterekstrakter tørket (Na2S0^) og eteren avdampet hvilket ga en rest som veiet 16.5 g. Hydrokloridet ble fremstilt fra residuet ved oppløsning i eter og tilsetning av eterisk saltsyre. Hydrokloridet ble omkrystallisert fra absolute etanol: eter (3:5) to ganger, smeltepunkt 205-206°C. Beregnet for C-^H^ClNgO: C 65.3, ether extracts dried (Na 2 SO 4 ) and the ether evaporated giving a residue weighing 16.5 g. The hydrochloride was prepared from the residue by dissolution in ether and addition of ethereal hydrochloric acid. The hydrochloride was recrystallized from absolute ethanol:ether (3:5) twice, mp 205-206°C. Calculated for C-^H^ClNgO: C 65.3,
H 9.34, N 8.95. Funnet: C 65.2, H 9.49, N 9.15. Man fikk bare en distinkt topp ved gasskromatografering av saltet. I.r. (KBr skive, hydrokloridet): 317O (mw, NH amide),2968 og 293O (m,CH^ og CH2), 256O (m, NH<+>), 1677 (s, amide I), I593 (w, Ph, 1528 (s, amide II), 1472 og 1433 (ms), 1230 (mw, amide-III), 775 (m, 3 nabo-Ph-hydro-gener ute av plan). H 9.34, N 8.95. Found: C 65.2, H 9.49, N 9.15. Only a distinct peak was obtained by gas chromatography of the salt. i.r. (KBr disk, the hydrochloride): 317O (mw, NH amide), 2968 and 293O (m, CH^ and CH2), 256O (m, NH<+>), 1677 (s, amide I), I593 (w, Ph , 1528 (s, amide II), 1472 and 1433 (ms), 1230 (mw, amide-III), 775 (m, 3 neighboring Ph-hydro genes out of plan).
Eksempel 5»Example 5»
Dette eksempel viser fremstilling av 2-pyrrolidino-2', 6'-n-butyroxylidid. This example shows the preparation of 2-pyrrolidino-2', 6'-n-butyroxylidide.
2- pyrrolidiono- 2', 6'- n- butyroxylidid - En blanding av 2-brom-2',6'-butyroxylidid (O.O463 mol), pyrrolidine (0,13 g mol) og benzen 2- pyrrolidiono- 2', 6'- n- butyroxylidide - A mixture of 2-bromo-2',6'-butyroxylidide (0.0463 mol), pyrrolidine (0.13 g mol) and benzene
(100 ml) ble kokt ved tilbakeløp i 21 timer. Oppløsningsmiddel og overskudd av pyrrolidine ble avdampet i vakuum og etterlot en delvis fast rest som ble oppløst i 1 N saltsyre (125 ml). Syre-oppløsningen ble vasket med eter (2x50 ml), hvoretter den ble innstilt alkalisk med 7 N natriumhydroksyd og ekstrahert med eter (3x50 ml). Eterekstraktet ble tørket (Na2S0^) og oppløsningsmidlet inndampet i vakuum. Hydrokloridet ble fremstilt ved oppløsning av residuet i eter og tilsetning av en tilstrekkelig mengde gassformig saltsyre, utbytte O.O414 mol. Etter to omkrystallisas3oner fra 95 % etanol: etyl acetat (1:1) smeltet de fargeløse krystaller ved 238-240°C. Beregnet for C^H^^OCl: C 64.7, H 8.49, Cl 11.9. Funnet: C 64.9, H 8.59, Cl 12.1. I.r (KBr skiver, hydroklorid): 3450 (m, bredt), 3175 (ms, amide NH), 2965 og 2927 (ms, CHo og CH2), 2670, 263O, og 2600 (ms), 2475 (mw, NH<+>), l680 (s, amide I), 1529 (w, Ph), 1525 (s, amide II), I469 (ms), 1227 U, amide III), 781 (ms, 3 nabo^Ph-hydrogenatomer ute av plan). (100 ml) was refluxed for 21 hrs. Solvent and excess pyrrolidine were evaporated in vacuo leaving a partially solid residue which was dissolved in 1 N hydrochloric acid (125 mL). The acid solution was washed with ether (2x50 mL), then made alkaline with 7 N sodium hydroxide and extracted with ether (3x50 mL). The ether extract was dried (Na 2 SO 4 ) and the solvent was evaporated in vacuo. The hydrochloride was prepared by dissolving the residue in ether and adding a sufficient quantity of gaseous hydrochloric acid, yield 0.0414 moles. After two recrystallizations from 95% ethanol:ethyl acetate (1:1) the colorless crystals melted at 238-240°C. Calculated for C^H^^OCl: C 64.7, H 8.49, Cl 11.9. Found: C 64.9, H 8.59, Cl 12.1. I.r (KBr discs, hydrochloride): 3450 (m, broad), 3175 (ms, amide NH), 2965 and 2927 (ms, CHo and CH2), 2670, 263O, and 2600 (ms), 2475 (mw, NH< +>), l680 (s, amide I), 1529 (w, Ph), 1525 (s, amide II), I469 (ms), 1227 U, amide III), 781 (ms, 3 neighboring ^Ph hydrogen atoms out of plan).
Eksempel 6. Example 6.
Dette eksempel illustrerer fremstilling av 2-(N-etyl-n-butylamino)-2',6'-n-butyroxylidid. This example illustrates the preparation of 2-(N-ethyl-n-butylamino)-2',6'-n-butyroxylidide.
2- n- butylamino- 2', 6'- butyroxylidid - En blanding av 2-jod-2',6'- 2- n- butylamino- 2', 6'- butyroxylidide - A mixture of 2-iodo-2',6'-
butyroxylidid (O.O315 mol), n-butylamin (0.0945 m°D °S vannfri benzen (100 ml) ble kokt ved tilbakeløp i 5 timer. Etter avkjøling ble benzenet og overskudd av n-butylamin inndampet i vakuum. Residuet ble tatt opp i IN saltsyre, vasket med eter(3*25 ml), filtrert, innstilt alkalisk til pH 9 med 7 E natriumhydroksyd og ekstrahert med eter (4x25 ml). Eterekstraktet ble tørket (Na2S0^) og eteren inndampet i vakuum til en fargeløs olje (0,0153 mol). butyroxylidide (0.0315 mol), n-butylamine (0.0945 m°D °S anhydrous benzene (100 ml) was refluxed for 5 hours. After cooling, the benzene and excess n-butylamine were evaporated in vacuo. The residue was taken up in 1N hydrochloric acid, washed with ether (3*25 mL), filtered, made alkaline to pH 9 with 7 U sodium hydroxide, and extracted with ether (4x25 mL). The ether extract was dried (Na 2 SO 4 ) and the ether evaporated in vacuo to a colorless oil (0.0153 mol).
(Denne oljen er tilstrekkelig ren for etyleringstrinnet beskrevet nedenfor). Man fremstilte et hydroklorid fra oljebasen i vannfri eter ved tilsetning av eterisk saltsyreoppløsning. Det dannede produktet kunne man bare med vanskelighet krystallisere fra en rekke oppløsningsmidler. Ved oppløsning i vann dannet det seg krystaller ved henstand. Det dannede hydroklorid hydratet ble omkrystallisert fra vandig etyl acetat, smeltepunkt 92>95°C' Beregnet for C-j^H^Cl^O . H20: H20 5.7I. Funnet: 5.73 (Karl Fischer) En prøve ble tørket i høyvakuum ved forhøyet temperatur. Beregnet for Cl6H27ClN20: C 64.3, H 9.11, Cl 11.9. Funnet: C 64.1, H 9.26, (This oil is sufficiently pure for the ethylation step described below). A hydrochloride was prepared from the oil base in anhydrous ether by adding ethereal hydrochloric acid solution. The product formed could only be crystallized with difficulty from a variety of solvents. When dissolved in water, crystals formed on standing. The hydrochloride hydrate formed was recrystallized from aqueous ethyl acetate, melting point 92>95°C' Calculated for C-j^H^Cl^O . H 2 O: H 2 O 5.7 I. Found: 5.73 (Karl Fischer) A sample was dried in a high vacuum at an elevated temperature. Calculated for Cl6H27ClN20: C 64.3, H 9.11, Cl 11.9. Found: C 64.1, H 9.26,
Cl 11.8. Clause 11.8.
2-( N- etyl- n- butylamino)- 2*, 6*- n- butyroxylidid - En blanding av 2-n-butylamino-2',6'-butyroxylidid (den oljeaktige ikke rensede base (O.OI53 mol) nevnt ovenfor) og dietyl sulfat (O.O996 mol) 2-( N- ethyl- n- butylamino)- 2*, 6*- n- butyroxylidide - A mixture of 2-n-butylamino-2',6'-butyroxylidide (the oily crude base (O.OI53 mol) mentioned above) and diethyl sulfate (O.O996 mol)
ble oppvarmet ved ^ 0°C i 5 timer. Etter avkjøling ble den klare ravfargede oppløsning blandet med 10 ml vann, rørt i 15 minutter og blandet med 10 ml 4 N saltsyre. Syreoppløsningen ble vasket med eter og fasene ble separert fullstendig, idet øvre etersjiktet hver gang ble kastet. pH ble innstilt på 11 med 7 N natriumhydroksyd og den separerte base opptatt i eter (4 x 30 ml). Etter tørking (Na2S0^) ble eteren avdampet og man fikk en rest som utgjorde den rå base (O.O395 mol). Hydrokloridet ble fremstilt ved å oppløse residuet i vannfri eter og innføre eterisk saltsyre. Omkrystalli-sas jon fra abs. alkohol: Eter, ga fargeløse krystaller, med smeltepunkt 202.5-204.5°C. Beregnet for C-^H^CIN^: C 66.1, H 9.56, was heated at ^ 0°C for 5 hours. After cooling, the clear amber solution was mixed with 10 ml of water, stirred for 15 minutes and mixed with 10 ml of 4 N hydrochloric acid. The acid solution was washed with ether and the phases were separated completely, the upper ether layer being discarded each time. The pH was adjusted to 11 with 7 N sodium hydroxide and the separated base taken up in ether (4 x 30 mL). After drying (Na2S0^), the ether was evaporated and a residue was obtained which constituted the crude base (0.0395 mol). The hydrochloride was prepared by dissolving the residue in anhydrous ether and introducing ethereal hydrochloric acid. Recrystallization from abs. alcohol: Ether, gave colorless crystals, m.p. 202.5-204.5°C. Calculated for C-^H^CIN^: C 66.1, H 9.56,
Cl 10.8. Funnet: C 66.1, H 9.71, Cl 11.1. I.R. (KBr skive, hydroklorid) : 316O (ms, amide NH), 296O (s) og 2890 (msMCH^ og CHg), 2615-2595 (m, bredt), 2505 (m, NH<+>), l680 (s, amide I), 1594 Clause 10.8. Found: C 66.1, H 9.71, Cl 11.1. I.R. (KBr disk, hydrochloride) : 316O (ms, amide NH), 296O (s) and 2890 (msMCH^ and CHg), 2615-2595 (m, broad), 2505 (m, NH<+>), 1680 (s , amide I), 1594
(w, Ph), 1530 (s, amide II), 147° (s), 1228 (m, amide III), 781 (w, Ph), 1530 (s, amide II), 147° (s), 1228 (m, amide III), 781
(m, 3 nabo-Ph-hydrogenatomer ute av plan). (m, 3 neighboring Ph hydrogen atoms out of plane).
Eksempel 7«Example 7«
Dette eksempel illustrerer fremstilling av 2-dimetylamino-2',6'-caproylxylidid. This example illustrates the preparation of 2-dimethylamino-2',6'-caproylxylidide.
2- brom- 2', 6'- caproylxylidid - En blanding av 2,6-xylidine (0.125 mol) og iseddik (115 ml) ble avkjølt til 10°C i en 1 liters flaske og 2-bromcaproyl bromid (O.I36 mol) tilsatt og blandet hurtig. Så raskt som mulig ble dette fulgt av en kald oppløsning (50°C) natrium acetat trihydrat (45 g) i vann (190 ml). Blandingen ble rystet i 45 minutter og filtrert. Fellingen ble vasket grundig og gjentatte ganger med vann til den var fri for bromidioner. Deretter ble den tørket i desiccator over kaliumhydroksyd flak og omkrystallisert fra metanol: vann (ca. 15=D to ganger, smeltepunkt l67-l69°C. Utbytte 67 %. Dette stoffet var tilstrekkelig rent for påfølgende reaksjon. Den rene forbindelse (ennå en omkrystallisasjon) hadde 2-bromo-2',6'-caproylxylidide - A mixture of 2,6-xylidine (0.125 mol) and glacial acetic acid (115 ml) was cooled to 10°C in a 1 liter flask and 2-bromocaproyl bromide (O.I36 mol) added and mixed rapidly. As quickly as possible this was followed by a cold solution (50°C) of sodium acetate trihydrate (45 g) in water (190 ml). The mixture was shaken for 45 minutes and filtered. The precipitate was washed thoroughly and repeatedly with water until it was free of bromide ions. It was then dried in a desiccator over potassium hydroxide flakes and recrystallized from methanol:water (ca. 15=D twice, melting point 167-169°C. Yield 67%. This substance was sufficiently pure for subsequent reaction. The pure compound (still a recrystallization) had
et smeltepunkt på l68.5-l69°C. Beregnet for C-^H^BrNO: C 56.4, a melting point of l68.5-l69°C. Calculated for C-^H^BrNO: C 56.4,
H 6.76, Br 26.8. Funnet: C 56.2, H 6,40, Br 25.9. H 6.76, W 26.8. Found: C 56.2, H 6.40, Br 25.9.
2- dimetylamino- 2', 6'- caproylxylidid - En blanding av 2-brom-2',6 caproylxylidid (0.119 mol), dimetylamine (O.356 mol) og benzen (177 ml) ble oppvarmet i en trykkbeholder i 22 timer ved 100°C. Etter avkjøling ble reaksjonsblandingen filtrert. Vekten av utfelt dimetylammonium bromid tydet på at 97 f° av bromforbindelsen hadde reagert. Filtratet ble ekstrahert med 4 N saltsyre (1x50+2x25 ml), syreoppløsningen innstilt alkalisk til pH 11 med 7 N natriumhydroksyd og ekstrahert med eter (3x50 ml). De samlede eterekstrakter ble tørket (Na2S0^) og inndampet i vakuum. Av residuet fremstilte man hydrokloridet med eterisk saltsyre. Dette ble omkrystallisert fra abs. alkohol: Eter (1:8) to ganger, og ga fargeløse krystaller (0.0992 mol) som smeltet ved 193.5-194.5°C. Beregnet for <C>l6<H>27C1N20:C 64«3» H 9.10, N 9.37, <C>l II.9. Funnet: C 64.2, H 9.04, N 9.52, Cl 12.0. I.r. (KBr skive, hydroklorid):3l85 (m, amide NH), 2950 og 2920 (ms-m, CH^ og CH2), 245O (ms, NH+), 1682 (s, amide I), 1591 (w, Ph), I53O (s, amide II), 1470 (s), 1236 (mw, amide III), 776 (m, 3 nabo-Ph-hydrogenatomer ute av plan). 2-dimethylamino-2',6'-caproylxylidide - A mixture of 2-bromo-2',6 caproylxylidide (0.119 mol), dimethylamine (0.356 mol) and benzene (177 ml) was heated in a pressure vessel for 22 hours at 100°C. After cooling, the reaction mixture was filtered. The weight of precipitated dimethylammonium bromide indicated that 97% of the bromine compound had reacted. The filtrate was extracted with 4 N hydrochloric acid (1x50+2x25 ml), the acid solution made alkaline to pH 11 with 7 N sodium hydroxide and extracted with ether (3x50 ml). The combined ether extracts were dried (Na 2 SO 4 ) and evaporated in vacuo. The hydrochloride was prepared from the residue with ethereal hydrochloric acid. This was recrystallized from abs. alcohol:ether (1:8) twice, giving colorless crystals (0.0992 mol) melting at 193.5-194.5°C. Calculated for <C>l6<H>27C1N20:C 64«3» H 9.10, N 9.37, <C>l II.9. Found: C 64.2, H 9.04, N 9.52, Cl 12.0. i.r. (KBr disk, hydrochloride):3l85 (m, amide NH), 2950 and 2920 (ms-m, CH^ and CH2), 245O (ms, NH+), 1682 (s, amide I), 1591 (w, Ph) , I53O (s, amide II), 1470 (s), 1236 (mw, amide III), 776 (m, 3 neighboring Ph hydrogen atoms out of plane).
Eksempel 8. Example 8.
Dette eksempel illustrerer fremstilling av 2-pyrrolidino- This example illustrates the preparation of 2-pyrrolidino-
2',6'-n-valeroxylidid. 2',6'-n-valeroxylidide.
2-. jod- 2' ^'- n- valeroxylidid - En blanding av 2-brom-2',6'-n-valeroxylidid (0.137 mol), kaliumjodid (0.274 mol) og tørr metanol (375 ml) ble kokt ved tilbakeløp under røring i 3 timer. Etter kjøling tilsatte man 1 liter vann til den gulfargede reaksjons-blanding og hensatte denne under røring i 15 minutter. Fellingen ble filtrert fra, vasket gjentatte ganger med vann, til filtratet var fritt for halogenidioner og tørket. Etter omkrystallisasjon fra 95 % etanol smeltet stoffet ved 196.5-<1>97.5°C, utbytte .0.105 mol, og produktet var tilstrekkelig rent for det neste syntesetrinn. En ny krystallisasjon bragte smeltepunktet opp til 197-198°C. Beregnet for C-^H-lqJNO: C 47.1, H 5.48, J 38.3. Funnet: C 47-3, H 5.36, 2-. iodo- 2' ^'- n- valeroxylidide - A mixture of 2-bromo-2',6'-n-valeroxylidide (0.137 mol), potassium iodide (0.274 mol) and dry methanol (375 ml) was refluxed with stirring for 3 hours. After cooling, 1 liter of water was added to the yellow-coloured reaction mixture and this was allowed to stand with stirring for 15 minutes. The precipitate was filtered off, washed repeatedly with water until the filtrate was free of halide ions and dried. After recrystallization from 95% ethanol, the substance melted at 196.5-<1>97.5°C, yield .0.105 mol, and the product was sufficiently pure for the next synthesis step. A new crystallization brought the melting point up to 197-198°C. Calculated for C-3H-lqJNO: C 47.1, H 5.48, J 38.3. Found: C 47-3, H 5.36,
J 38.2. J 38.2.
2- pyrrolidino- 2', 6'- n- valeroxylidid - En blanding av 2-jod-2',6'-n-valeroxylidid (0.0754 mol), pyrrolidine (0.226 mol) og benzen (65 ml) ble oppvarmet i en trykkbeholder i 24 timer ved 100°C. Etter av-kjøling ble benzenet og overskudd av pyrrolidine inndampet i vakuum. Residuet ble utrørt med vann (150 ml) i 30 minutter og filtrert. Til filtratet satte man 7 N natriumhydroksyd (til pH 11) under røring og etter 30 minutter ble den faste basen filtrert fra, vasket grundig og gjentatté ganger med vann og tørket i vakuum. Den rå basen (14 g) ble omkrystallisert fra vandig etanol til konstant smeltepunkt (126-127.5°C), utbytte 4*9 g« Fra moderluten fikk man ytterligere 2.7 g. Totalt utbytte: 37 %. Beregnet for C-^<HggNgO:> C 74.4, 2-pyrrolidino-2',6'-n-valeroxylidide - A mixture of 2-iodo-2',6'-n-valeroxylidide (0.0754 mol), pyrrolidine (0.226 mol) and benzene (65 mL) was heated in a pressure vessel for 24 hours at 100°C. After cooling, the benzene and excess pyrrolidine were evaporated in vacuo. The residue was stirred with water (150 ml) for 30 minutes and filtered. 7 N sodium hydroxide (to pH 11) was added to the filtrate with stirring and after 30 minutes the solid base was filtered off, washed thoroughly and repeatedly with water and dried in a vacuum. The crude base (14 g) was recrystallized from aqueous ethanol to a constant melting point (126-127.5°C), yield 4*9 g« From the mother liquor a further 2.7 g was obtained. Total yield: 37%. Calculated for C-^<HggNgO:> C 74.4,
H 9.55, N 10.2. Funnet: C 74.1, H 9.66, N 10.4. Ir. (KBr skive, base): 3210 (s, NH amide), 2933 (s), 2915 (ms) (CH^ og CHg), 1645 H 9.55, N 10.2. Found: C 74.1, H 9.66, N 10.4. Ir. (KBr disc, base): 3210 (s, NH amide), 2933 (s), 2915 (ms) (CH^ and CHg), 1645
(s, amide I), 1593 (w, Ph), 1529 (s, amide II), 1478 og I465 (ms), 770 (s, 3 nabo-Ph-hydrogenatomer ute av plan). (s, amide I), 1593 (w, Ph), 1529 (s, amide II), 1478 and I465 (ms), 770 (s, 3 neighboring Ph hydrogen atoms out of plane).
Eksempel 9»Example 9»
Dette eksempel illustrerer farmasøytiske, preparater. Oppløsningen inneholdende 0. <2>5. 0* 50. 0. 75 og 1. 0 % 2-( N- etylpropylamino)- 2', 6'- butyroxylidid This example illustrates pharmaceutical preparations. The solution containing 0. <2>5. 0* 50. 0. 75 and 1. 0% 2-( N- ethylpropylamino)- 2', 6'- butyroxylidide
hydroklorid uten tilsatt vasoconstrictor. pH 3. 5- 4. 5. hydrochloride without added vasoconstrictor. pH 3.5- 4.5.
Den aktive ingrediens i oppløsningen ovenfor kan erstattes med 2-dietylamino-2',6'-n-valeroxylidid-hydroklorid. The active ingredient in the above solution can be replaced with 2-diethylamino-2',6'-n-valeroxylidide hydrochloride.
Eksempel 10. Example 10.
Eksempelet illustrerer farmasøytiske preparater. Oppløsninger inneholdende 0. 25, 0. 50. 0. 75 og 1. 0 f° 2,-( N- etyl- propylamino) - 2 ', 6'- butyroxylidid hydroklorid med epinephrine 1:200, 000. pH 3. 5- 4. 5 The example illustrates pharmaceutical preparations. Solutions containing 0.25, 0.50, 0.75 and 1.0 f° 2,-(N-ethyl-propylamino)-2',6'- butyroxylidide hydrochloride with epinephrine 1:200,000. pH 3.5 - 4. 5
Tabellene I til V inneholder sammenlignende data som viser virketiden eller varigheten for en rekke av disse lokal-anestetiske forbindelser, tabell VI inneholder sammenligningsdata vedrørende vevsirritasjonen for en rekke av lokalanestetika-forbindelsene, tabellene VII og VIII inneholder sammenligningsdata vedrørende den akutte toksisitet for flere av ovenstående lokalanestetika, mens tabellene IX til XI inneholder data fra kliniske prøver med forbindelsen B på mennesker. Tables I to V contain comparative data showing the time of action or duration for a number of these local anesthetic compounds, table VI contains comparative data regarding the tissue irritation for a number of the local anesthetic compounds, tables VII and VIII contain comparative data regarding the acute toxicity of several of the above local anesthetics, while Tables IX to XI contain data from human clinical trials with compound B.
Irritasjonsangivelser som er oppført i tabell VI måles Irritation indications listed in Table VI are measured
på følgende måte: in the following way:
Man fremkaller hevelser eller filipenser på de barberte ryggene hos albino kaniner ved intradermal injeksjon av vandige opp-løsninger av forbindelsene. 24 timer senere bedømmes hver hevelse: Nærvær og graden av erythema, nærvær og grad av ødem og nærvær eller fravær av nevrotisk vev i hevelsen. Graderingen foretas etter en tilfeldig numerisk skala og man finner en midlere "irritasjonsindeks" for alle hevelser ved en gitt konsentrasjon. Swellings or filipenses are induced on the shaved backs of albino rabbits by intradermal injection of aqueous solutions of the compounds. 24 hours later, each swelling is assessed: Presence and degree of erythema, presence and degree of edema and presence or absence of neurotic tissue in the swelling. Grading is done according to a random numerical scale and an average "irritation index" is found for all swellings at a given concentration.
Forsøksmetoden som anvendes for bestemmelse av akutt toksisitet oppført i tabellene VII og VIII er som følger: Man an-vender seksuelt voksne hann- eller hunndyr. Dyrene deles i grupper på 10 og gis en dose av aktiv oppløsning eller bæremedium. Etter hver dose observeres dyrene etter bestemte mellomrom for å finne åpenbare virkninger og eventuelle dødsfall. Overlevende dyr anbringes i grupper etter doseringsnivå og undersøkes en gang daglig i løpet av undersøkelsestiden for å finne eventuelle forsinkede dødsfall. The test method used for determining acute toxicity listed in tables VII and VIII is as follows: Sexually mature male or female animals are used. The animals are divided into groups of 10 and given a dose of active solution or carrier medium. After each dose, the animals are observed at certain intervals to find obvious effects and possible deaths. Surviving animals are placed in groups by dosage level and examined once daily during the study period to detect any delayed deaths.
Man beregner LD^q og 95 $ Fieller-sannsynlighetsgrenser (eller 95 % approksimasjonsgrenser) etter minste kvadraters metode (Minimum Logit Chi Square Method) Berkson J.Am.Stat.Assoc. 48:565 One calculates LD^q and 95 $ Fieller probability limits (or 95% approximation limits) according to the least squares method (Minimum Logit Chi Square Method) Berkson J.Am.Stat.Assoc. 48:565
(<1>953). Man har gjennomført kirurgiske operasjoner på pasienter som har mottatt forbindelse B enten epiduralt (Tabell IX), intracostalt (Tabell X), eller i brachial plexus-regionen (Tabell XI). Særlig skal det fremheves de overraskende korte påsettingstider, den tilfredsstillende dybde og varighet av bedøvelsen og det fullstendige fravær av systemiske og lokale sidevirkninger. En uventet gunstig virkning av muskelavslappingen kunne iakttas, hvilket lettet de kirurgiske inngrep, f.eks. ved underlivsoperasjoner. (<1>953). Surgical operations have been carried out on patients who have received compound B either epidurally (Table IX), intracostally (Table X), or in the brachial plexus region (Table XI). In particular, the surprisingly short application times, the satisfactory depth and duration of anesthesia and the complete absence of systemic and local side effects must be emphasized. An unexpected beneficial effect of the muscle relaxation could be observed, which facilitated the surgical interventions, e.g. during abdominal operations.
De sammenlignende data som er oppført i tabellene I-VIII viser at de racemiske forbindelser', fremstilt i henhold til oppfinnelsen vanligvis har betraktelig lengere virketid, særlig ved konsentrasjoner på 1 % eller 2 %, enn de sammenlignede homologe forbindelser Y og Z, og samtidig har de tilfredsstillende lav vevsirritasjon og tilfredsstillende lav akutt toksisitet. The comparative data listed in Tables I-VIII show that the racemic compounds' produced according to the invention usually have a considerably longer duration of action, especially at concentrations of 1% or 2%, than the compared homologous compounds Y and Z, and at the same time they have satisfactorily low tissue irritation and satisfactorily low acute toxicity.
Claims (2)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10077770A | 1970-12-22 | 1970-12-22 | |
| US00164022A US3812147A (en) | 1970-12-22 | 1971-07-19 | Acylxylidide local anaesthetics |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NO135934B true NO135934B (en) | 1977-03-21 |
| NO135934C NO135934C (en) | 1977-06-29 |
Family
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| NO4669/71A NO135934C (en) | 1970-12-22 | 1971-12-17 |
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| US (1) | US3812147A (en) |
| JP (1) | JPS5644063B1 (en) |
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| AU (1) | AU468489B2 (en) |
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| CA (1) | CA943966A (en) |
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| DK (1) | DK139814B (en) |
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| HU (1) | HU163373B (en) |
| IE (1) | IE35909B1 (en) |
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| NO (1) | NO135934C (en) |
| PL (1) | PL83097B1 (en) |
| SE (1) | SE393374B (en) |
| SU (1) | SU419023A3 (en) |
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| US4237068A (en) * | 1971-07-28 | 1980-12-02 | Astra Pharmaceutical Products, Inc. | Primary aminoacylanilides |
| US3957996A (en) * | 1971-12-08 | 1976-05-18 | Astra Pharmaceutical Products, Inc. | Pharmaceutical local anesthetic compositions |
| US3966934A (en) * | 1971-12-08 | 1976-06-29 | Astra Pharmaceutical Products, Inc. | Synergistic local anesthetic compositions |
| US3975443A (en) * | 1972-06-06 | 1976-08-17 | Allen & Hanburys Limited | 1-(3,4-dichlorobenzamidomethyl)-cyclohexyldimethylamine |
| JPS598269B2 (en) * | 1975-08-22 | 1984-02-23 | 萬有製薬株式会社 | Omega - aminoalkanesane arylamide |
| JPS57176939A (en) * | 1981-04-03 | 1982-10-30 | Goodrich Co B F | Improved synthesis of hindered amine stabilizer for high polymer materials |
| US4891058A (en) * | 1988-07-18 | 1990-01-02 | Ici Americas Inc. | 1-alkyl-3-aryl imidazolidine-2,4-diones and herbicidal use |
| SE8900685D0 (en) * | 1989-02-28 | 1989-02-28 | Astra Ab | NEW COMPOUNDS |
| US5153226A (en) * | 1989-08-31 | 1992-10-06 | Warner-Lambert Company | Acat inhibitors for treating hypocholesterolemia |
| ES2402789T3 (en) | 2006-11-20 | 2013-05-08 | President And Fellows Of Harvard College | Methods, compositions and kits to treat pain and pruritus |
| EP2451944A4 (en) | 2009-07-10 | 2012-11-28 | Harvard College | Permanently charged sodium and calcium channel blockers as anti-inflammatory agents |
| MX2018001447A (en) | 2015-08-03 | 2019-02-21 | Harvard College | Charged ion channel blockers and methods for use. |
| JP2022527690A (en) | 2019-03-11 | 2022-06-03 | ノシオン セラピューティクス，インコーポレイテッド | Charged ion channel blockers and usage |
| US10780083B1 (en) | 2019-03-11 | 2020-09-22 | Nocion Therapeutics, Inc. | Charged ion channel blockers and methods for use |
| BR112021017809A2 (en) | 2019-03-11 | 2021-11-23 | Nocion Therapeutics Inc | Ester-substituted 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 |
| US10934263B2 (en) | 2019-03-11 | 2021-03-02 | Nocion Therapeutics, Inc. | Charged ion channel blockers and methods for use |
| JP2023500890A (en) | 2019-11-06 | 2023-01-11 | ノシオン セラピューティクス，インコーポレイテッド | Charged ion channel blockers and methods of use |
| AU2020380118A1 (en) | 2019-11-06 | 2022-05-19 | Nocion Therapeutics, Inc. | Charged ion channel blockers and methods for use |
| JP2023517604A (en) | 2020-03-11 | 2023-04-26 | ノシオン セラピューティクス，インコーポレイテッド | Charged ion channel blockers and methods of use |
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| GB1124837A (en) * | 1966-06-03 | 1968-08-21 | Wyeth John & Brother Ltd | Substituted anilides |
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- 1971-12-07 SE SE7115656A patent/SE393374B/en unknown
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- 1971-12-15 SU SU1726195A patent/SU419023A3/en active
- 1971-12-16 HU HUAA690A patent/HU163373B/hu unknown
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- 1971-12-18 IT IT54845/71A patent/IT1066334B/en active
- 1971-12-20 AT AT1089671A patent/AT319205B/en not_active IP Right Cessation
- 1971-12-20 IE IE1609/71A patent/IE35909B1/en unknown
- 1971-12-20 AU AU37099/71A patent/AU468489B2/en not_active Expired
- 1971-12-21 CA CA130,662A patent/CA943966A/en not_active Expired
- 1971-12-21 BR BR8466/71A patent/BR7108466D0/en unknown
- 1971-12-21 DD DD159785A patent/DD99779A5/xx unknown
- 1971-12-21 AR AR239721A patent/AR193840A1/en active
- 1971-12-21 ES ES398210A patent/ES398210A1/en not_active Expired
- 1971-12-21 FR FR7145983A patent/FR2118985B1/fr not_active Expired
- 1971-12-21 PL PL1971152331A patent/PL83097B1/pl unknown
- 1971-12-21 GB GB5937771A patent/GB1369259A/en not_active Expired
- 1971-12-22 JP JP10453571A patent/JPS5644063B1/ja active Pending
- 1971-12-22 NL NLAANVRAGE7117644,A patent/NL172149C/en not_active IP Right Cessation
- 1971-12-22 FI FI3658/71A patent/FI55027C/en active
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- 1982-10-26 NL NL8204126A patent/NL8204126A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| CA943966A (en) | 1974-03-19 |
| GB1369259A (en) | 1974-10-23 |
| NL172149B (en) | 1983-02-16 |
| AU468489B2 (en) | 1976-01-15 |
| IE35909L (en) | 1972-06-22 |
| SE393374B (en) | 1977-05-09 |
| AR193840A1 (en) | 1973-05-31 |
| SU419023A3 (en) | 1974-03-05 |
| DE2162744C3 (en) | 1982-04-15 |
| FR2118985B1 (en) | 1975-12-26 |
| AU3709971A (en) | 1973-06-28 |
| NL172149C (en) | 1983-07-18 |
| ES425626A1 (en) | 1976-06-16 |
| NO135934C (en) | 1977-06-29 |
| IT1066334B (en) | 1985-03-04 |
| NL7117644A (en) | 1972-06-26 |
| ES398210A1 (en) | 1975-03-16 |
| BE776656A (en) | 1972-06-14 |
| NL8204126A (en) | 1983-02-01 |
| DK139814B (en) | 1979-04-23 |
| FI55027C (en) | 1979-05-10 |
| FR2118985A1 (en) | 1972-08-04 |
| BR7108466D0 (en) | 1973-06-14 |
| DD99779A5 (en) | 1973-08-20 |
| JPS5644063B1 (en) | 1981-10-16 |
| DE2162744B2 (en) | 1981-07-02 |
| IE35909B1 (en) | 1976-06-23 |
| FI55027B (en) | 1979-01-31 |
| HU163373B (en) | 1973-08-28 |
| PL83097B1 (en) | 1975-12-31 |
| US3812147A (en) | 1974-05-21 |
| DE2162744A1 (en) | 1972-07-06 |
| AT319205B (en) | 1974-12-10 |
| DK139814C (en) | 1979-10-01 |
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