NO124540B - - Google Patents
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- NO124540B NO124540B NO1819/68A NO181968A NO124540B NO 124540 B NO124540 B NO 124540B NO 1819/68 A NO1819/68 A NO 1819/68A NO 181968 A NO181968 A NO 181968A NO 124540 B NO124540 B NO 124540B
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- NO
- Norway
- Prior art keywords
- pipecoloxylidide
- butyl
- levo
- tartrate
- dextro
- Prior art date
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- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 69
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 50
- 229940095064 tartrate Drugs 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 13
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 11
- 238000009835 boiling Methods 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- 229960001270 d- tartaric acid Drugs 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 5
- 230000006208 butylation Effects 0.000 claims description 4
- 229960001367 tartaric acid Drugs 0.000 claims description 4
- 239000011975 tartaric acid Substances 0.000 claims description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 3
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 235000002906 tartaric acid Nutrition 0.000 claims description 3
- 238000011081 inoculation Methods 0.000 claims description 2
- 239000000243 solution Substances 0.000 description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 239000002585 base Substances 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 14
- 239000002244 precipitate Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 9
- 238000002844 melting Methods 0.000 description 8
- 230000008018 melting Effects 0.000 description 8
- 229910021529 ammonia Inorganic materials 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 238000003776 cleavage reaction Methods 0.000 description 6
- 230000007017 scission Effects 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N Butyraldehyde Chemical compound CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- -1 dextro-2' Chemical class 0.000 description 4
- 239000003589 local anesthetic agent Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000007790 scraping Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000029142 excretion Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 230000003444 anaesthetic effect Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 150000003840 hydrochlorides Chemical class 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 210000001557 animal structure Anatomy 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000000887 hydrating effect Effects 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229960002409 mepivacaine Drugs 0.000 description 1
- INWLQCZOYSRPNW-UHFFFAOYSA-N mepivacaine Chemical compound CN1CCCCC1C(=O)NC1=C(C)C=CC=C1C INWLQCZOYSRPNW-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Analogifremgangsmåte ved fremstilling av terapeutisk aktivt levo-l-n-butyl-2<1>,6<1->pipecoloxylidid. Analogous method for the production of therapeutically active levo-1-n-butyl-2<1>,6<1->pipecoloxylidide.
Foreliggende oppfinnelse angår en fremgangsmåte ved fremstilling av en ny optisk aktiv levo-form av det kjente langtidsvirkende lokalbedøvelsesmiddel som kjemisk betegnes som 1-n-butyl-2 * ,6•-pipecoloxylidid, og som har formelen: The present invention relates to a method for the production of a new optically active levo form of the known long-acting local anesthetic which is chemically designated as 1-n-butyl-2*,6•-pipecoloxylidide, and which has the formula:
Ved foreliggende fremgangsmåte fremstilles de nye levo-l-n-butyl-2 • ,6•-pipecoloxylididene i krystallinsk form og stort sett frie fra sin optiske antipode. By the present method, the new levo-1-n-butyl-2•,6•-pipecoloxylidides are produced in crystalline form and largely free of their optical antipode.
Ifølge foreliggende oppfinnelse fremstilles levo-l-n-butyl-2',6<*->pipecoloxylidid ved at a) dl-2' ,6*-pipecoloxylidid omsettes med 0,0-dibenzoyl-d-vinsyre for å danne en blanding av de diastereoisomere 0,0-dibenzoyl-d-tartrater, at denne blanding behandles med kokende aceton, at det acetonuoppløselige dextro-2<*>,6'-pipecoloxylidid-salt fraskilles og at levo-2<*>,6<*->pipecoloxylidid-saltet utskilles fra acetonoppløs-ningen for å danne levo-2',6<*->pipecoloxylidid-basen fra det respektive O,0-dibenzoyl-d-tartrat, og at denne base butyleres for å danne levo-l-n-butyl-2' ,6*-pipecoloxylidid, eller b) en aceton- eller 2-propanoloppløsning av dl-1-n-buty1-2 *,6 * - pipecoloxylidid-d-tartrat podes med dextro-1-n-butyl-2 *,6•-pipecoloxylidid-d-tartrat, som er fremstilt ved butylering av dextro-2,6-pipecoloxylid og påfølgende behandling med vinsyre, at det dannede krystallinske dextro-1-n-butyl-2*,6pipecoloxylidid-d-tartrat fraskilles, og at enten acetonoppløsningen inndampes for å få levo-l-n-butyl-2<*>,6<*->pipecoloxylidid-d-tartrat eller at 2-propanolfilt rat et behandles med d-vinsyre, at podning skjer med levo-l-n-butyl-2•,6'-pipecoloxylidid-d-bitartrat, og at det gjen-værende krystallinske levo-l-n-butyl-2<*>,6'-pipecoloxylidid-d-bi-tartrat fraskilles, og videre at levo-l-n-butyl-2*,6 *-pipecoloxylidid-basen fåes fra henholdsvis d-tartratet eller d-bitartratet, According to the present invention, levo-1-n-butyl-2',6<*->pipecoloxylidide is prepared by a) reacting dl-2',6*-pipecoloxylidide with 0,0-dibenzoyl-d-tartaric acid to form a mixture of the diastereoisomeric 0,0-dibenzoyl-d-tartrates, that this mixture is treated with boiling acetone, that the acetone-insoluble dextro-2<*>,6'-pipecoloxylidide salt is separated and that levo-2<*>,6<*-> the pipecoloxylidide salt is separated from the acetone solution to form the levo-2',6<*->pipecoloxylidide base from the respective O,0-dibenzoyl-d-tartrate, and that this base is butylated to form levo-1-n-butyl -2' ,6*-pipecoloxylidide, or b) an acetone or 2-propanol solution of dl-1-n-buty1-2*,6*-pipecoloxylidide-d-tartrate grafted with dextro-1-n-butyl-2 *,6•-pipecoloxylidide-d-tartrate, which is prepared by butylation of dextro-2,6-pipecoloxylide and subsequent treatment with tartaric acid, that it formed crystalline dextro-1-n-butyl-2*,6pipecoloxylidide-d-tartrate are separated, and that either the acetone solution is evaporated to obtain levo-l -n-butyl-2<*>,6<*->pipecoloxylidide-d-tartrate or that the 2-propanol filtrate is treated with d-tartaric acid, that inoculation takes place with levo-1-n-butyl-2•,6'-pipecoloxylidide -d-bitartrate, and that the remaining crystalline levo-l-n-butyl-2<*>,6'-pipecoloxylidide-d-bitartrate is separated, and further that levo-l-n-butyl-2*,6 *- the pipecoloxylidide base is obtained from the d-tartrate or d-bitartrate respectively,
og at den erholdte forbindelse eventuelt overføres til et salt derav på i og for seg kjent vis. and that the compound obtained is optionally transferred to a salt thereof in a manner known per se.
Fremgangsmåteproduktene ifølge foreliggende oppfinnelse kan anvendes som et middel som kan utøve langvarig lokalanestetisk virkning på dyreorganer som bestemmes ved hjelp av standardiserte farmakologiske bedømmelsesmetoder ved testforsøk på dyr. i mot-setning til hva som tidligere har vært oppfatningen på dette om-råde, nemlig at de optisk aktive former av mepivacain, dvs. dextro-og levo-l-methyl-2',6<*->pipecoloxylidid, ikke hadde vist seg å ha noen statistisk forskjell i lokalanestetisk virkning eller toksisitet, har de nu fremstilte levo-l-n-butyl-2<*>,6<*->pipecoloxylidener uventet vist seg å være betraktelig lengrevirkende enn dens dextro-isomer og videre påtagelig mindre giftig enn dextro-isomeren og dl-formen, når de administreres subkutant. The method products according to the present invention can be used as an agent that can exert a long-term local anesthetic effect on animal organs which is determined by means of standardized pharmacological assessment methods in test experiments on animals. contrary to what has previously been the opinion in this area, namely that the optically active forms of mepivacaine, i.e. dextro- and levo-l-methyl-2',6<*->pipecoloxylidide, had not shown to have any statistical difference in local anesthetic effect or toxicity, the now produced levo-l-n-butyl-2<*>,6<*->pipecoloxylidenes have unexpectedly proved to be considerably longer-acting than its dextro-isomer and furthermore noticeably less toxic than the dextro isomer and the dl form, when administered subcutaneously.
Levo-l-n-butyl-2* ,6 *-pipecolox-ylididsaltene er anvendbare på mange måter, ikke bare som lokal-bedøvelsesmiddel, men de er også anvendbare i alle former som kjennetegnende eller identifiserende derivater på den frie syre og til adskillelses- eller rénseprosesser. Saltene reagerer dessuten med sterke baser, som ammonium- eller alkalihydroxyder, under dann-else av den frie base, og i overensstemmelse hermed er alle saltene, uavhengig om man tar i betraktning oppløselighet, toksisitet, fysi-kalsk form eller lignende av et bestemt slags salt , anvendbare for formålet ifølge oppfinnelsen, da de er kilder til den frie base. The levo-1-n-butyl-2*,6*-pipecolox-ylidide salts are useful in many ways, not only as local anesthetics, but they are also useful in all forms as characteristic or identifying derivatives of the free acid and for separation or cleaning processes. The salts also react with strong bases, such as ammonium or alkali hydroxides, to form the free base, and accordingly all the salts, regardless of whether one takes into account solubility, toxicity, physical form or the like, are of a certain kind salt, useful for the purpose according to the invention, as they are sources of the free base.
Oppspaltning av dl- 2', 6'- pipecoloxylidid Cleavage of dl-2', 6'- pipecoloxylidide
Det første trinn i denne oppspaltning utføres ved å omsette dl-2',6'-pipecoloxylidid med 0,0-dibenzoyl-d-vinsyre for å danne en blanding av de diastereoisomere saltene, dvs. dext ro-2 ' ,6*-pipe - coloxylidid-0,0-dibenzoyl-d-tartrat og levo-2',6'-pipecoloxylidid-O,0-dibenzoyl-d-tartrat. Denne reaksjon utføres fortrinnsvis ved The first step in this resolution is carried out by reacting dl-2',6'-pipecoloxylidide with 0,0-dibenzoyl-d-tartaric acid to form a mixture of the diastereoisomeric salts, i.e., dextro-2',6*- pipe - coloxylidide-0,0-dibenzoyl-d-tartrate and levo-2',6'-pipecoloxylidide-O,0-dibenzoyl-d-tartrate. This reaction is preferably carried out by
å blande reaksjonskomponentene i et passende oppløsningsmiddel, f.eks. i kokende 95%-ig ethanol og derpå fjerne oppløsningsmidlet. Derefter behandles blandingen med kokende aceton for å oppløse levo-isomersaltet og oppsamle det acetonuoppløselige dextro-2*,6*-pipecoloxylidid-0,0-dibenzoyl-d-tartrat. Det isomere levo-2',6'-pipecoloxylidid-O,0-dibenzoyl-d-tartrat skilles fra acetonoppløsningen ved å fjerne all aceton eller fortrinnsvis endel av den og oppsamle det krystalliserte salt. Behandlingen av de adskilte diastereoisomere salter med en uorganisk base, f.eks. en vandig oppløsning av ammonium- eller alkalihydroxyd, ga henholdsvis dextro-2',6 *-pipecoloxylidid og levo-2<*>,6'-pipecoloxylidid. mixing the reaction components in a suitable solvent, e.g. in boiling 95% ethanol and then remove the solvent. The mixture is then treated with boiling acetone to dissolve the levo-isomer salt and collect the acetone-insoluble dextro-2*,6*-pipecoloxylidide-0,0-dibenzoyl-d-tartrate. The isomeric levo-2',6'-pipecoloxylidide-O,0-dibenzoyl-d-tartrate is separated from the acetone solution by removing all or preferably part of the acetone and collecting the crystallized salt. The treatment of the separated diastereoisomeric salts with an inorganic base, e.g. an aqueous solution of ammonium or alkali hydroxide gave dextro-2',6*-pipecoloxylidide and levo-2<*>,6'-pipecoloxylidide, respectively.
Butylerinq av dextro- og levo- <2>6'- pipecoloxylidid Butylerinq of dextro- and levo- <2>6'-pipecoloxylidide
Denne reaksjon ble utført ved å behandle hver optisk isomer med n-butyraldehyd under katalytisk hydrerende betingelser. Reak-sjonen utføres enklést i et passende oppløsningsmiddel, f.eks. ethanol, under et måtelig hydrogentrykk, f.eks. 1,75 - 35 mm Hg, i nærvær av en passende katalysator, f.eks. palladium på trekull, platinaoxyd eller lignende. Denne katalytiske hydrering utføres fortrinnsvis i et svakt surt medium og frembringes passende ved å anvende en liten mengde eddiksyre. Alternativt kan man utføre butyleringen ved oppvarmning under omrøring av hver optisk isomer med et n-butylhalogenid, f.eks. bromid, i et passende oppløsnings-middel, f.eks. n-butylalkohol eller dimethylformamid i nærvær av et syrebindende middel, f.eks. kaliumcarbonat. This reaction was carried out by treating each optical isomer with n-butyraldehyde under catalytically hydrating conditions. The reaction is simply carried out in a suitable solvent, e.g. ethanol, under a moderate hydrogen pressure, e.g. 1.75 - 35 mm Hg, in the presence of a suitable catalyst, e.g. palladium on charcoal, platinum oxide or the like. This catalytic hydrogenation is preferably carried out in a weakly acidic medium and is conveniently produced by using a small amount of acetic acid. Alternatively, the butylation can be carried out by heating while stirring each optical isomer with an n-butyl halide, e.g. bromide, in a suitable solvent, e.g. n-butyl alcohol or dimethylformamide in the presence of an acid-binding agent, e.g. potassium carbonate.
Oppspaltning av dl- 1- n- butyl- 2', 6'- pipecoloxylidid Cleavage of dl-1-n-butyl-2', 6'- pipecoloxylidide
Denne oppspaltning utføres ved å pode en acetonoppløsning av dl-l-n-butyl-2•,6'-pipecoloxylidid-d-tartrat med dextro-1-n-butyl-2 *,6 *-pipecoloxylidid-d-tartrat ved å omrøre den ved 25°C dannede blanding inneholdende en viskøs feining inntil feiningen hadde satt seg og oppsamle den acetonuoppløselige dextro-1-n-butyl-2',6<*->pipecoloxylidid-d-tartrat og inndampe acetonfiltratet for å få det isomere levo-l-n-butyl-2',6'-pipecoloxylidid-d-tartrat. Isomer-d-tartratet kan renses ved omkrystallisasjon i et passende oppløs-ningsmiddel, f.eks. isopropylalkohol, og kan overtres til de til-svarende isomere baser, som i sin tur lett omdannes til de respektive salter, f.eks. hydroklorider, ved å la dem reagere med den passende syre. This cleavage is carried out by inoculating an acetone solution of dl-1-n-butyl-2•,6'-pipecoloxylidide-d-tartrate with dextro-1-n-butyl-2*,6*-pipecoloxylidide-d-tartrate by stirring it at 25°C formed mixture containing a viscous fine until the fine had settled and collected the acetone-insoluble dextro-1-n-butyl-2',6<*->pipecoloxylidide-d-tartrate and evaporated the acetone filtrate to obtain the isomeric levo- 1-n-Butyl-2',6'-pipecoloxylidide-d-tartrate. The isomer d-tartrate can be purified by recrystallization in a suitable solvent, e.g. isopropyl alcohol, and can be converted into the corresponding isomeric bases, which in turn are easily converted into the respective salts, e.g. hydrochlorides, by allowing them to react with the appropriate acid.
Oppspaltningen av dl-l-n-butyl-2<*>,6<*->pipecoloxylidid utføres ved å pode en varm 2-propanoloppløsning med dl-1-n-butyl-2',6'-pipecoloxylidid-d-tartrat med dextro-l-n-butyl-2'^'-pipecoloxylidid-d-tartrat, hvorpå oppløsningen tillates å avkjøle til værelsetemperatur (25 - 28°C) under tilfeldig omrøring, hvorpå det krystallinske d-base-d-tartrat oppsamles, d-vinsyre tilsettes til filtratet under oppvarmning og omrøring inntil den oppløses, hvorpå den The cleavage of dl-1-n-butyl-2<*>,6<*->pipecoloxylidide is carried out by grafting a warm 2-propanol solution of dl-1-n-butyl-2',6'-pipecoloxylidide-d-tartrate with dextro -l-n-butyl-2'^'-pipecoloxylidide-d-tartrate, whereupon the solution is allowed to cool to room temperature (25 - 28°C) with occasional stirring, whereupon the crystalline d-base-d-tartrate is collected, d-tartaric acid is added to the filtrate while heating and stirring until dissolved, whereupon the
varme oppløsning podes med levo-1-n-butyl-2',6'-pipecoloxylidid-d-ditartrat. Oppløsningen omrøres mens den får avkjøles til værelsetemperatur, det felte krystallinske 1-base-d-ditartrat oppsamles, hvilket i og for seg er anvendbart som et farmasøytisk middel, eller om ønskes behandles denne forbindelse med en uorganisk base, f.eks. ammoniakk, alkalihydroxyd, etc, for å få levo-1-n-butyl-2 *,6'-pipecoloxylidid. Denne base kan derpå overføres til andre farmasøytisk godtagbare salter, f.eks. hydrokloridet. hot solution grafted with levo-1-n-butyl-2',6'-pipecoloxylidide-d-ditartrate. The solution is stirred while it is allowed to cool to room temperature, the precipitated crystalline 1-base-d-ditartrate is collected, which in itself is useful as a pharmaceutical agent, or if desired this compound is treated with an inorganic base, e.g. ammonia, alkali hydroxide, etc., to obtain levo-1-n-butyl-2*,6'-pipecoloxylidide. This base can then be transferred to other pharmaceutically acceptable salts, e.g. the hydrochloride.
Den kjemiske struktur av forbindelsene fremstilt ifølge oppfinnelsen er bestemt ved feiningsmetoden og er bekreftet ved det infrarøde spektrum og ved elementæranalyse. The chemical structure of the compounds produced according to the invention is determined by the fine method and is confirmed by the infrared spectrum and by elemental analysis.
A. Oppspaltning av dl- 2', 6'- pipecoloxylidid A. Cleavage of dl-2', 6'- pipecoloxylidide
1. Utskilling av dextro-2•,6<*->pipecoloxylidid-0,0-dibenzoyl-d- tartrat og overføring til dextro- 2', 6'- pipecoloxylidid 1. Separation of dextro-2•,6<*->pipecoloxylidide-0,0-dibenzoyl-d-tartrate and transfer to dextro-2', 6'- pipecoloxylidide
En blanding av 15 g dl-2',6'-pipecoloxylidid (sm.p. 116 - ll8°C) og 11,9 g O,0-dibenzoyl-d-vinsyre ble suspendert i 400 ml kokende 95%-ig ethanol og ga derved et uoppløselig voksiignende faststoff, som ikke kunne gjøres krystallinsk ved kokning i adskillige timer. Hele blandingen ble derved befridd for ethanolen under vakuuminndampning under omrøring. Residuet ble suspendert i 250 ml kokende aceton inntil det ble krystallinsk, idet den faste del ble oppsamlet ved 25°C hvorved man fikk en 20 g fraksjon med smeltepunkt l6o - 175°C. (Acetonoppløsningen ble spart for å gjen-vinne levoisomeren, se eksempel A-2 nedenfor.) Den faste fraksjon på 20 g ble suspendert i 500 ml kokende absolutt ethanol og ble filtrert varm fra en liten uoppløselig rest. Filtratet ble holdt ved 25°C i 1 time under leilighetsvis omrøring og skrapning av begerets vegger, hvorved man fikk 4,5 g krystallinsk dextro-2<*>,6<*->pipecoloxylidid-0,0-benzoyl-d-tartrat med smeltepunkt 189 - 190°C. Dette diastereoisomere salt ble hydrolysert til dextro-basen ved å oppløse denne i 20 ml vann og gjøre oppløsningen basisk med 28%-ig ammoniakk og ekst raksjon med ether. Etherekstraktet ble inndampet for å fjerne etheren og resten ble krystallisert fra 10 ml isopropylalkohol, hvilket ga 0,5 g dextro-2•,6'-pipecoloxylidid med smeltepunkt 131 - 132°C. Denne dextro-base ble oppløst i IO ml isopropylalkohol og behandlet med 0,20 ml konsentrert saltsyre, hvorefter det hele ble avkjølt til 5°C samtidig som skrapningen påskyndet krystallisasjonen. Oppløsningen ble oppsamlet og vasket med isopropylalkohol og ether og ga derved 0,55 g dextro-2',6'-pipecoloxylidid-hydroklorid, smeltepunkt 305°C og [a]j^ (1% i H20) = +41,4°. 2. Utskillelse av levo-2• ,6*-pipecoloxylidid-0,0-dibenzoyl-d-tartrat og overføring til levo- 2', 6'- pipecoloxylidid Den ovennevnte acetonoppløsning ble inndampet til 75 ml, avkjølt og skrapet for å bevirke krystallisering. Det dannede bunn-fall ble oppsamlet, hvilket ga 2,4 g levo-2•,6•-pipecoloxylidid-O,0-dibenzoyl-d-tartrat med smeltepunkt ca. 250°C. En del av dette salt ble hydrolysert til levo-basen med 28%-ig ammoniakk som be-skrevet ovenfor, og levo-basen ble krystallisert fra isopropylalkohol og ga derved levo-2*,6'-pipecoloxylidid, sm.p. 131 - 132°c, som ved tilsetning av den ovennevnte d-base ble senket til 120°C. A mixture of 15 g of dl-2',6'-pipecoloxylidide (m.p. 116 - 118°C) and 11.9 g of O,0-dibenzoyl-d-tartaric acid was suspended in 400 ml of boiling 95% ethanol and thereby gave an insoluble waxy solid, which could not be made crystalline by boiling for several hours. The entire mixture was thereby freed from the ethanol under vacuum evaporation with stirring. The residue was suspended in 250 ml of boiling acetone until it became crystalline, the solid part being collected at 25°C, whereby a 20 g fraction with melting point 160 - 175°C was obtained. (The acetone solution was saved to recover the levoisomer, see Example A-2 below.) The 20 g solid fraction was suspended in 500 mL boiling absolute ethanol and filtered hot from a small insoluble residue. The filtrate was kept at 25°C for 1 hour with occasional stirring and scraping of the walls of the beaker, whereby 4.5 g of crystalline dextro-2<*>,6<*->pipecoloxylidide-0,0-benzoyl-d-tartrate was obtained with melting point 189 - 190°C. This diastereoisomeric salt was hydrolyzed to the dextro base by dissolving this in 20 ml of water and basing the solution with 28% ammonia and extracting with ether. The ether extract was evaporated to remove the ether and the residue was crystallized from 10 ml of isopropyl alcohol to give 0.5 g of dextro-2•,6'-pipecoloxylidide m.p. 131-132°C. This dextro base was dissolved in 10 ml of isopropyl alcohol and treated with 0.20 ml of concentrated hydrochloric acid, after which the whole was cooled to 5°C while the scraping accelerated the crystallization. The solution was collected and washed with isopropyl alcohol and ether to give 0.55 g of dextro-2',6'-pipecoloxylidide hydrochloride, mp 305°C and [a]j^ (1% in H 2 O) = +41.4° . 2. Separation of levo-2•,6*-pipecoloxylidide-0,0-dibenzoyl-d-tartrate and transfer to levo-2',6'-pipecoloxylidide The above acetone solution was evaporated to 75 ml, cooled and scraped to effect crystallization. The formed precipitate was collected, which gave 2.4 g of levo-2•,6•-pipecoloxylidide-O,0-dibenzoyl-d-tartrate with a melting point of approx. 250°C. A portion of this salt was hydrolyzed to the levo base with 28% ammonia as described above, and the levo base was crystallized from isopropyl alcohol to give levo-2*,6'-pipecoloxylidide, m.p. 131 - 132°C, which was lowered to 120°C by addition of the above-mentioned d-base.
B. Butylering av dextro- og levo- 26'- pipecoloxylidid B. Butylation of dextro- and levo-26'- pipecoloxylidide
1. Dextro- isomer 1. Dextro isomer
En oppløsning av 0,46 g dextro-2',6'-pipecoloxylidid i lOO ml ethylalkohol tilsatt 5 ml eddiksyre og 2 ml n-butyraldehyd ble rystet under 14,4 mm Hg hydrogentrykk med 2 g 10%-ig palladium-på-trekull i 5 timer for å oppta det beregnede hydrogen. Fra denne oppløsning ble dextro-basen gjenvunnet ved inndampning, behandling av feiningen med fortynnet vandig natriumhydroxydoppløsning og ekstraksjon med ether. Den faste dextro-base som var igjen efter at etheren var fordampet, utgjorde 0,3 9- Denne ble oppløst i IO ml aceton og behandlet med 0,1 g d-vinsyre og ga derved 0,3 g krystallinsk dextro-1-n-butyl-2', 6'-pipecoloxylidid-d-tartrat, sm.p. 175 - 180°C. 2. levo- l- n- butyl- 2', 6'- pipecoloxylidid ble fremstilt ifølge fremgangsmåten i eksempel B-l under anvendelse av levo-2<*>,6'-pipecoloxylidid istedenfor dextro-isomeren. A solution of 0.46 g of dextro-2',6'-pipecoloxylidide in 100 ml of ethyl alcohol added with 5 ml of acetic acid and 2 ml of n-butyraldehyde was shaken under 14.4 mm Hg hydrogen pressure with 2 g of 10% palladium-on- charcoal for 5 hours to absorb the calculated hydrogen. From this solution the dextro base was recovered by evaporation, treatment of the filtrate with dilute aqueous sodium hydroxide solution and extraction with ether. The solid dextro-base that remained after the ether had evaporated amounted to 0.3 9- This was dissolved in 10 ml of acetone and treated with 0.1 g of d-tartaric acid, thereby giving 0.3 g of crystalline dextro-1-n -butyl-2', 6'-pipecoloxylidide-d-tartrate, m.p. 175 - 180°C. 2. levo-1-n-butyl-2',6'-pipecoloxylidide was prepared according to the procedure in Example B-1 using levo-2<*>,6'-pipecoloxylidide instead of the dextro isomer.
C. Oppspaltning av dl- 1- n- butyl- 2', 6'- pipecoloxylidid fra aceton C. Cleavage of dl-1-n-butyl-2',6'-pipecoloxylidide from acetone
1. Fraskillelse av dextro- l- n- butyl- 2', 6'- pipecoloxylidid 1. Separation of dextro-l-n-butyl-2', 6'- pipecoloxylidide
En oppløsning inneholdende 45 9 dl-l-n-butyl-2•,6'-pipecoloxylidid og 23 g d-vinsyre i 1500 ml aceton ble podet med noen krystaller dextro-l-n-butyl-2',6<*->pipecoloxylidid-d-tartrat (fremstilt ifølge eksempel B-l). En viskøs felning utskiltes, og den erholdte blanding ble omrørt ved 25°C inntil felningen gradvis satte seg. Det bunnfelte materiale ble oppsamlet og oppslemmet i 100 ml kokende aceton. Blandingen ble avkjølt og filtrert og ga derved en A solution containing 45 9 dl-l-n-butyl-2•,6'-pipecoloxylidide and 23 g of d-tartaric acid in 1500 ml of acetone was seeded with some crystals of dextro-l-n-butyl-2',6<*->pipecoloxylidide-d -tartrate (prepared according to example B-1). A viscous precipitate separated, and the resulting mixture was stirred at 25°C until the precipitate gradually settled. The precipitated material was collected and slurried in 100 ml of boiling acetone. The mixture was cooled and filtered to give a
krystallinsk fraksjon på 25 g med smeltepunkt 110 - l6o°C. Dette materiale ble oppløst i 150 ml kokende isopropylalkohol, og oppløs-ningen fikk krystallisere langsomt i løpet av noen timer ved 25°C. Det utskilte materiale ble oppsamlet og vasket med isopropylalkohol og derpå med aceton, hvorved man fikk 10,2 g dextro-l-n-butyl-2•,6'-pipecoloxylidid-d-tartrat med smeltepunkt l8l - l83°c. Dette dextro-tartrat salt ble hydrolysert til sin base ved å oppløse saltet i 100 ml vann og behandle oppløsningen med 5 ml 28%-ig ammoniakk. Basen ble ekstrahert med ether (i porsjoner på 3 x 50 ml) og etheren avdestillert i vakuum, hvorved man fikk igjen 7,6 g crystalline fraction of 25 g with melting point 110 - 16o°C. This material was dissolved in 150 ml of boiling isopropyl alcohol, and the solution was allowed to crystallize slowly over a few hours at 25°C. The separated material was collected and washed with isopropyl alcohol and then with acetone, whereby 10.2 g of dextro-1-n-butyl-2•,6'-pipecoloxylidide-d-tartrate with a melting point of 181 - 183°C was obtained. This dextro-tartrate salt was hydrolyzed to its base by dissolving the salt in 100 ml of water and treating the solution with 5 ml of 28% ammonia. The base was extracted with ether (in portions of 3 x 50 ml) and the ether distilled off in vacuo, whereby 7.6 g were recovered
dextro-l-n-butyl-2•,6*-pipecoloxylidid med smeltepunkt 110°C. Denne base ble oppløst i l5o ml isopropylalkohol, og oppløsningen ble tilsatt 2,5 ml konsentrert saltsyre. Oppløsningsmidlet ble avdestillert i vakuum, og den krystallinske rest ble omkrystallisert i 35 ml iso- dextro-1-n-butyl-2•,6*-pipecoloxylidide with melting point 110°C. This base was dissolved in 150 ml of isopropyl alcohol, and 2.5 ml of concentrated hydrochloric acid was added to the solution. The solvent was distilled off in vacuo, and the crystalline residue was recrystallized in 35 ml of iso-
propylalkohol, hvorved man fikk 7,0 g dextro-1-butyl-26<*->pipecoloxylidid-hydroklorid med sm.p. 258°C; [a]^5 (<2>% vekt/vol. <v>ann)= +12,7°. Et blandet smeltepunkt med dl-l-n-butyl-2•,6<*->pipecoloxylidid -hydroklorid ble 2Z+2 - 248°C. propyl alcohol, whereby 7.0 g of dextro-1-butyl-26<*->pipecoloxylidide hydrochloride with m.p. 258°C; [a]^5 (<2>% wt/vol. <v>ann)= +12.7°. A mixed melting point with dl-1-n-butyl-2•,6<*->pipecoloxylidide hydrochloride was 2Z+2 - 248°C.
Beregnet analyse: <C>^<gH>^I^O.HC1: N 8,62; Cl 10,9<2.>Calculated analysis: <C>^<gH>^I^O.HCl: N 8.62; Cl 10.9<2.>
Funnet: N 8,71; Cl 10,92. Found: N 8.71; Cl 10.92.
2. Utskillelse av levo- l- n- butyl- 2', 6'- pipecoloxylidid 2. Excretion of levo-l-n-butyl-2', 6'- pipecoloxylidide
Flere av de ovennevnte væsker i eksempel C-l, dvs. aceton-reaksjonsmediet, isopropylalkohol-omkrystalliseringsmediet og aceton-vaskevæsken ble forenet og inndampet i vakuum og ga derved en rest som utgjordes hovedsakelig av levo-1-n-butyl-2',6<*->pipecoloxylidid-d-tartrat . Når denne rest ble oppløst i 200 ml vann og gjort alkalisk med overskudd av 28%-ig ammoniakk, utskiltes der et materiale som ble oppsamlet, tørret og ga et utbytte på 12 g levo-l-n-butyl-2 ',6"-pipecoloxylidid. Denne base ble oppløst med 6,2 g 1-vinsyre i 300 ml aceton. Krystallisering ble fremkalt ved hjelp av skrapning. Efter henstand i adskillige timer ved 25°C ble den krystallinske felning oppsamlet og renset ved først å oppslemmes i 300 ml aceton og derpå ved omkrystallisering fra 60 ml isopropylalkohol, hvilket ga et utbytte på 8,2 g levo-l-n-butyl-2<*>,6<*->pipecoloxylidid-l-tartrat, sm.p. l83°C. Dette 1-tartrat ble hydrolysert som i eksempel C-l angitt for d-base-d-tartrat ved oppløs-ning i lOO ml vann og behandling av oppløsningen med 5 ml 28%-ig ammoniakk, hvorved man fikk et utbytte på 5 9 levo-1-n-butyl-2',6<*->pipecoloxylidid med smeltepunkt 137 - 138°C efter krystalli-sasjon fra ether. Forbindelsen ble overført til sitt hydroklorid ved oppløsning i isopropylalkohol med påfølgende behandling med et lite overskudd av konsentrert saltsyre. Efter avkjøling av denne oppløsning ble den holdt ved 5°C i noen timer, hvorved man fikk et utbytte av krystallinsk felning som ble oppsamlet i en mengde av 5,3 gQlevo-l-n-butyl-2•,6'-pipecoloxylidid-hydroklorid, sm.p. 258°C [a]p<5> (2% vekt/vol.) Several of the above-mentioned liquids in Example C-1, i.e. the acetone reaction medium, the isopropyl alcohol recrystallization medium and the acetone washing liquid were combined and evaporated in vacuo, thereby giving a residue consisting mainly of levo-1-n-butyl-2',6< *->pipecoloxylidide-d-tartrate . When this residue was dissolved in 200 ml of water and made alkaline with an excess of 28% ammonia, a material was separated which was collected, dried and gave a yield of 12 g of levo-1-n-butyl-2',6"-pipecoloxylidide . This base was dissolved with 6.2 g of 1-tartaric acid in 300 ml of acetone. Crystallization was induced by scraping. After standing for several hours at 25°C, the crystalline precipitate was collected and purified by first suspending in 300 ml of acetone and then by recrystallization from 60 ml of isopropyl alcohol, which gave a yield of 8.2 g of levo-l-n-butyl-2<*>,6<*->pipecoloxylidide-l-tartrate, m.p. 183° C. This 1 -tartrate was hydrolysed as in example C-1 indicated for d-base-d-tartrate by dissolving in 100 ml of water and treating the solution with 5 ml of 28% ammonia, whereby a yield of 59 levo-1- n-butyl-2',6<*->pipecoloxylidide with melting point 137 - 138°C after crystallization from ether.The compound was transferred to its hydrochloride by dissolving in isopropyl alcohol with following treatment with a small excess of concentrated hydrochloric acid. After cooling this solution, it was kept at 5°C for a few hours, whereby a yield of crystalline precipitate was obtained which was collected in an amount of 5.3 g Qlevo-1-n-butyl-2•,6'-pipecoloxylidide hydrochloride, sm.p. 258°C [a]p<5> (2% wt/vol.)
Beregnet analyse: C^gHggNgO.HC1: N 8,62; Cl IO,92. Calculated analysis: C 2 gHggNgO.HCl: N 8.62; Cl 10,92.
Funnet: N 8,72; Cl IO,96. Found: N 8.72; Cl 10.96.
D. Adskillelse av dl- 1- n- butyl- 2', 6'- pipecoloxylididi 2- propanol D. Separation of dl-1-n-butyl-2',6'-pipecoloxylididi 2-propanol
L. Utskillelse av dextro- 1- n- butyl- 2', 6'- pipecoloxylidid L. Excretion of dextro-1-n-butyl-2', 6'- pipecoloxylidide
En oppløsning inneholdende 410 g dl-l-n-butyl-2•,6<*->pipecoloxylidid og 110 g d-vinsyre i 2 liter varm 2-propanol ble podet med noen krystaller av dextro-1-n-butyl-2',6'-pipecoloxylidid-d - tartrat ved ca. 50°C, og tillatt å avkjøle til værelsetemperatur under leilighetsvis omrøring. Den dannede krystallinske felning ble oppsamlet, vasket med litt 2-propanol og tørret ved 70°C, hvorved man fikk et utbytte på 200 g dextro-l-n-butyl-2•,6'-pipecoloxylidid-d-tartrat , sm.p. 182 - l84°C. A solution containing 410 g of dl-1-n-butyl-2•,6<*->pipecoloxylidide and 110 g of d-tartaric acid in 2 liters of hot 2-propanol was seeded with some crystals of dextro-1-n-butyl-2', 6'-pipecoloxylidide-d -tartrate at approx. 50°C, and allowed to cool to room temperature with occasional stirring. The formed crystalline precipitate was collected, washed with a little 2-propanol and dried at 70°C, whereby a yield of 200 g of dextro-1-n-butyl-2•,6'-pipecoloxylidide-d-tartrate was obtained, m.p. 182 - 184°C.
2. Utskillelse av levo- l- n- butyl- 2', 6'- pipecoloxylidid 2. Excretion of levo-l-n-butyl-2', 6'- pipecoloxylidide
Til filtratet fra eksempel D-l ble tilsatt 60 g d-vinsyre, og blandingen ble oppvarmet under omrøring inntil all vinsyre var opp-løst. Oppløsningen fikk avkjøles til ca. 40°C, ble podet med et par krystaller levo-l-n-butyl-2',6'-pipecoloxylidid-d-bitartrat og tillatt å avkjøle til værelsetemperatur. Den dannede krystallinske felning ble vasket med 2-propanol og tørret i vakuum ved 70°C, hvorved man fikk et utbytte på 400 g levo-l-n-butyl-2<*>,6<*->pipecoloxylidid-d-bitartrat , sm.p. 110 - 115°C. Disse 400 g levo-l-n-butyl-2 *,6'-pipecoloxylidid-d-bitartrat ble oppløst i 2 liter vann og oppløsningen gjort basisk ved gradvis tilsetning av 28%-ig ammoniakk under kraftig omrøring. Den dannede felning ble oppsamlet og vasket meget omhyggelig med vann og derefter med n-hexan, tørret ved 6o°C og omkrystallisert fra 2-propanol (ca. 1 liter), hvilket ga et utbytte på nesten 120 g nesten rent produkt, som ble omkrystallisert nok en gang fra isopropylacetat, hvilket ga 109 9 levo-l-n-butyl-2 ',6'-pipecoloxylidid, sm.p. 135 - 137°C. Til en oppløs-ning av 145 g levo-l-n-butyl-2',6'-pipecoloxylidid i 1200 ml 2-propanol ble tilsatt 43 ml konsentrert saltsyre, og blandingen ble avkjølt til 5°C. Den dannede krystallinske felning ble oppsamlet og tørret ved 70°C i vakuum og ga derved et utbytte på 116 g levo-l-n-butyl-2 * ,6' -pipecoloxylidid-hydroklor id, sm.p. 255 - 257°C. 60 g of d-tartaric acid was added to the filtrate from example D-1, and the mixture was heated with stirring until all the tartaric acid had dissolved. The solution was allowed to cool to approx. 40°C, was seeded with a few crystals of levo-1-n-butyl-2',6'-pipecoloxylidide-d-bitartrate and allowed to cool to room temperature. The formed crystalline precipitate was washed with 2-propanol and dried in vacuum at 70°C, whereby a yield of 400 g of levo-1-n-butyl-2<*>,6<*->pipecoloxylidide-d-bitartrate was obtained, sm .p. 110 - 115°C. These 400 g of levo-1-n-butyl-2*,6'-pipecoloxylidide-d-bitartrate were dissolved in 2 liters of water and the solution made basic by gradual addition of 28% ammonia with vigorous stirring. The resulting precipitate was collected and washed very carefully with water and then with n-hexane, dried at 6o°C and recrystallized from 2-propanol (ca. 1 liter), yielding nearly 120 g of almost pure product, which was recrystallized once more from isopropyl acetate, yielding 109 9 levo-1-n-butyl-2',6'-pipecoloxylidide, m.p. 135 - 137°C. To a solution of 145 g of levo-1-n-butyl-2',6'-pipecoloxylidide in 1200 ml of 2-propanol was added 43 ml of concentrated hydrochloric acid, and the mixture was cooled to 5°C. The crystalline precipitate formed was collected and dried at 70°C in vacuo, thereby yielding 116 g of levo-1-n-butyl-2*,6'-pipecoloxylidide hydrochloride, m.p. 255 - 257°C.
Ved konsentrering og avkjøling av morluten fikk man et ytter-ligere utbytte på 31,5 g av det nevnte hydroklorid med sm.p. 255 - 258°C. By concentrating and cooling the mother liquor, a further yield of 31.5 g of the aforementioned hydrochloride with m.p. 255 - 258°C.
Ovennevnte krystallinske levo-1-n-butyl-2• ,6'-pipecoloxylidid-d-bitartrat som ble anvendt som podningsmiddel, ble fremstilt som følger: 0,288 g levo-1-n-butyl-2',6•-pipecoloxylidid (fremstilt ifølge eksempel C-2) ble oppløst med 0,15 g d-vinsyre i 5 1 2-propanol under oppvarmning. Efter avkjøling av oppløsningen og skrapning av glassbegerets vegger med en glasstav utskiltes en krystallinsk felning. Felningen ble oppsamlet og tørret med 2- The above-mentioned crystalline levo-1-n-butyl-2•,6'-pipecoloxylidide-d-bitartrate used as grafting agent was prepared as follows: 0.288 g of levo-1-n-butyl-2',6•-pipecoloxylidide ( prepared according to example C-2) was dissolved with 0.15 g of d-tartaric acid in 5 1 of 2-propanol while heating. After cooling the solution and scraping the walls of the beaker with a glass rod, a crystalline precipitate is secreted. The droppings were collected and dried with 2-
propanol og ether og tørret ved 6o°C, hvilket ga et utbytte på propanol and ether and dried at 6o°C, which gave a yield of
0,2 g levo-l-n-butyl-2',6'-pipecoloxylidid-d-bitartrat, sm.p. 114 - ii7°c. 0.2 g levo-1-n-butyl-2',6'-pipecoloxylidide-d-bitartrate, m.p. 114 - ii7°c.
De tidligere nevnte levo-1-n-butyl-2',6<*->pipecoloxylidid og dextro-l-butyl-2',6'-pipecoloxylidid i form av de respektive hydroklorider ble prøvet med intradermal injeksjon på marsvin for å be-stemme den fremkalte bedøvnings varighet. To forsøk ble utført, hvorved 10 dyr pr. dose ble anvendt. På hvert dyr oppsto et ødem med levo-isomeren (0,25%, vekt/vol.) og andre ødem med dextro-isomeren (0,25%, vekt/vol.). Ved et forsøk tilsattes adrenalin (1:200.000 vekt/vol.) til begge oppløsninger. Resultatene som er angitt nedenfor, viser at bedøvelsen med levo-»isomeren varer ca. 45% lengre. I tabellen betegner "dextro" dextro-l-n-butyl-2 *,6'-pipecoloxylidid-hydroklorid og "levo" levo-1-n-butyl-2',6'-pipecoloxylidid-hydroklorid. The previously mentioned levo-1-n-butyl-2',6<*->pipecoloxylidide and dextro-l-butyl-2',6'-pipecoloxylidide in the form of the respective hydrochlorides were tested by intradermal injection on guinea pigs in order to - adjust the duration of the induced anesthesia. Two experiments were carried out, whereby 10 animals per dose was used. In each animal, one edema occurred with the levo isomer (0.25%, w/v) and another edema with the dextro isomer (0.25%, w/v). In one experiment, adrenaline (1:200,000 weight/vol.) was added to both solutions. The results given below show that the anesthesia with the levo-isomer lasts approx. 45% longer. In the table, "dextro" denotes dextro-1-n-butyl-2*,6'-pipecoloxylidide hydrochloride and "levo" levo-1-n-butyl-2',6'-pipecoloxylidide hydrochloride.
Levo-1-n-butyl-2',6'-pipecoloxylidid viste seg også å ha betraktelig lavere toksisitet når det ble prøvet subkutant på mus enn dextro-isomeren og den racemiske form. Levo-1-n-butyl-2',6'-pipecoloxylidide was also shown to have significantly lower toxicity when tested subcutaneously in mice than the dextro-isomer and the racemic form.
LD tjQ-ver di ene i mg/kg viste seg å være som følger: LD tjQ-ver di ene in mg/kg was found to be as follows:
Dødeligheten pr. dose var: Mortality per dose was:
Claims (1)
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Application Number | Priority Date | Filing Date | Title |
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US63927767A | 1967-05-18 | 1967-05-18 |
Publications (1)
Publication Number | Publication Date |
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NO124540B true NO124540B (en) | 1972-05-02 |
Family
ID=24563449
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Application Number | Title | Priority Date | Filing Date |
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NO1819/68A NO124540B (en) | 1967-05-18 | 1968-05-10 |
Country Status (13)
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AT (2) | AT284843B (en) |
BE (1) | BE715188A (en) |
CH (1) | CH498834A (en) |
DE (1) | DE1770408C3 (en) |
DK (1) | DK129234B (en) |
ES (1) | ES354352A1 (en) |
FI (1) | FI50333C (en) |
FR (2) | FR1583872A (en) |
GB (1) | GB1180712A (en) |
IL (1) | IL29958A (en) |
NL (1) | NL6806995A (en) |
NO (1) | NO124540B (en) |
SE (1) | SE341404B (en) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
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ATE40994T1 (en) * | 1983-08-01 | 1989-03-15 | Astra Laekemedel Ab | L-N-N-PROPYLPIPECOLIC-2,6-XYLIDIDE AND ITS PRODUCTION. |
SE451840B (en) * | 1986-01-03 | 1987-11-02 | Astra Laekemedel Ab | OPTICALLY PURE MONOHYDRATED OF S - (-) - 1-PROPYL-2 ', 6'-PIPECOLOXYLIDE HYDROCHLORIDE, SET TO PREPARE THIS AND PHARMACEUTICAL PREPARATIONS FOR LOCAL ANCHORING |
DK0788480T3 (en) * | 1994-10-25 | 2003-09-29 | Darwin Discovery Ltd | Crystallization of levobupivacaine and analogues thereof |
SE9501808D0 (en) * | 1995-05-16 | 1995-05-16 | Astra Ab | New process |
KR100844336B1 (en) * | 2007-01-16 | 2008-07-07 | 하나제약 주식회사 | New synthetic method of levobupivacaine and its hydrochloride |
WO2014009964A1 (en) * | 2012-07-11 | 2014-01-16 | Neon Laboratories Limited | Process for enantiomeric enrichment of 2 ', 6 ' - pipecoloxylidide |
CN105315196A (en) * | 2015-11-28 | 2016-02-10 | 山东齐都药业有限公司 | High-purity levobupivacaine hydrochloride refining method |
CN109896992A (en) * | 2017-12-08 | 2019-06-18 | 武汉软件工程职业学院 | Prepare the method and its application of ionic liquid |
-
1968
- 1968-05-02 SE SE05905/68A patent/SE341404B/xx unknown
- 1968-05-07 IL IL29958A patent/IL29958A/en unknown
- 1968-05-10 GB GB22420/68A patent/GB1180712A/en not_active Expired
- 1968-05-10 NO NO1819/68A patent/NO124540B/no unknown
- 1968-05-14 DE DE1770408A patent/DE1770408C3/en not_active Expired
- 1968-05-15 BE BE715188D patent/BE715188A/xx unknown
- 1968-05-16 DK DK226968AA patent/DK129234B/en unknown
- 1968-05-16 ES ES354352A patent/ES354352A1/en not_active Expired
- 1968-05-17 FR FR1583872D patent/FR1583872A/fr not_active Expired
- 1968-05-17 FI FI681394A patent/FI50333C/en active
- 1968-05-17 AT AT475368A patent/AT284843B/en not_active IP Right Cessation
- 1968-05-17 NL NL6806995A patent/NL6806995A/xx unknown
- 1968-05-17 AT AT1097469A patent/AT286298B/en not_active IP Right Cessation
- 1968-05-17 CH CH733568A patent/CH498834A/en not_active IP Right Cessation
- 1968-08-16 FR FR163282A patent/FR8160M/fr not_active Expired
Also Published As
Publication number | Publication date |
---|---|
GB1180712A (en) | 1970-02-11 |
AT284843B (en) | 1970-09-25 |
DE1770408B2 (en) | 1974-04-11 |
FI50333B (en) | 1975-10-31 |
NL6806995A (en) | 1968-11-19 |
DK129234B (en) | 1974-09-16 |
DE1770408A1 (en) | 1971-10-21 |
FR1583872A (en) | 1969-12-05 |
BE715188A (en) | 1968-09-30 |
SE341404B (en) | 1971-12-27 |
IL29958A (en) | 1971-04-28 |
FI50333C (en) | 1976-02-10 |
DK129234C (en) | 1975-02-03 |
ES354352A1 (en) | 1969-11-01 |
AT286298B (en) | 1970-12-10 |
IL29958A0 (en) | 1968-07-25 |
DE1770408C3 (en) | 1974-11-07 |
CH498834A (en) | 1970-11-15 |
FR8160M (en) | 1970-08-24 |
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