DK154889B - METHOD OF PRODUCING CEFAZOLINE - Google Patents
METHOD OF PRODUCING CEFAZOLINE Download PDFInfo
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- DK154889B DK154889B DK638172AA DK638172A DK154889B DK 154889 B DK154889 B DK 154889B DK 638172A A DK638172A A DK 638172AA DK 638172 A DK638172 A DK 638172A DK 154889 B DK154889 B DK 154889B
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- DK
- Denmark
- Prior art keywords
- acid
- cefazoline
- reacted
- reaction product
- compound
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
Description
iin
DK 154889 BDK 154889 B
Den foreliggende opfindelse angår en hidtil ukendt fremgangsmåde til fremstilling af cefazolin, 7-[2-(lH-tetrazol-l-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylsyre og farmaceutisk acceptable salte deraf.The present invention relates to a novel process for the preparation of cefazolin, 7- [2- (1H-tetrazol-1-yl) acetamido] -3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl -3-cephem-4-carboxylic acid and pharmaceutically acceptable salts thereof.
5 Cefazolin er et værdifuldt antibiotikum. Det anvendes i vidt omfang ved forebyggelse eller ved behandling af infektioner, og der er derfor et stort behov for fremstillingsprocesser, som i godt udbytte og under anvendelse af de mindst mulige mængder dyre mellemprodukter fører til det ønskede slutprodukt i høj renhed. Denne opgave har 10 imidlertid ikke været løst på tilfredsstillende måde ved de kendte fremgangsmåder. Som beskrevet i tysk offentliggørelsesskrift 20 55 796 fås cefazolin ved, at der ud fra en cephalosporinforbin- —. delse, som i cephem-kernens 7-stilling har en a-aminoadipoylgruppe som substituent og i øvrigt har cefazolins struktur, ved imidchlorid-15 metoden fås mellemproduktet "iminoether", og dette omsættes direkte med acyleringsmiddel. Hertil kræves imidlertid store mængder acyle-ringsmiddel, og cefazolinet har· et lavt smeltepunkt, dvs. det er ikke særlig rent.5 Cefazoline is a valuable antibiotic. It is widely used in the prevention or treatment of infections, and therefore there is a great need for manufacturing processes which, in good yield and using the least possible amounts of expensive intermediates, result in the desired final product in high purity. However, this task has not been satisfactorily solved by the known methods. As described in German publication specification 20 55 796, cefazoline is obtained by starting from a cephalosporin compound. which, in the 7-position of the cephem nucleus, has an α-aminoadipoyl group as a substituent and otherwise has the structure of cefazoline, by the imide chloride method the intermediate "imino ether" is obtained and this is reacted directly with acylating agent. However, large amounts of acylating agent are required for this and the cefazoline has a low melting point, ie. it's not very clean.
Den foreliggende opfindelse angår en fremgangsmåde til fremstilling 20 af cefazolin med formlen N-N sThe present invention relates to a process for the preparation of cefazoline of formula N-N s
I SN—CH,—CONH—j-S N—NI SN-CH, -CONH-j-S N-N
O*»—N J—CH2—S—IgJ—CHjO * - - N Y — CH 2 —S — IgJ — CH 2
COOHCOOH
og farmaceutisk acceptable salte deraf, hvilken fremgangsmåde er ejendommelig ved, at en dyrkningsvæske, der indeholder cephalosporin C, på i og for sig kendt måde behandles med phenylisocyanat, og at acetoxygruppen i 3-stillingen i den derved vundne forbindelse med 25 formlen 2and pharmaceutically acceptable salts thereof, characterized in that a culture liquid containing cephalosporin C is treated in a manner known per se with phenylisocyanate and that the acetoxy group at the 3-position in the compound of formula 2 thus obtained
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HOOC—CH—(CHjh—CONH—j-f S NHOOC — CH— (CHjh — CONH — j-f S N
rr
CO COOHCO COOH
NHNH
6 på i og for sig kendt måde erstattes med en 5-methyl-1,3,4-thiadia-zol-2-ylthio-gruppe, den derved dannede forbindelse omsættes med chlortrimethylsilan i nærværelse af Ν,Ν-dimethylanilin i dichlor-methan, reaktionsproduktet omsættes med phosphorpentachlorid ved fra 5 -40°C til -50°C, det vundne reaktionsprodukt omsættes med methanol og med IH-tetrazol-1-eddikesyre eller et reaktivt derivat deraf ved carboxygruppen, og reaktionsproduktet derefter hydrolyseres.6 is replaced in a manner known per se with a 5-methyl-1,3,4-thiadiazol-2-ylthio group, the resulting compound is reacted with chlorotrimethylsilane in the presence of Ν, Ν-dimethylaniline in dichloromethane , the reaction product is reacted with phosphorus pentachloride at from -40 ° C to -50 ° C, the reaction product obtained is reacted with methanol and with 1 H-tetrazole-1-acetic acid or a reactive derivative thereof at the carboxy group, and the reaction product is then hydrolyzed.
Denne fremgangsmåde forløber via et hidtil ukendt mellemprodukt med formlenThis process proceeds via a novel intermediate of the formula
SS
HOOC—CH—(CHjb—CONH—i-/ \ N—NHOOC — CH— (CHjb — CONH — i- / \ N — N
NH —NJ-CH>—S—%s' CHjNH-NO-CH> -S-% s' CH 2
CO COOHCO COOH
^h « 10 Dette fås ved, at en dyrkningsvæske, der indeholder cephalosporin C, behandles med phenylisocyanat, og at acetoxygruppen i 3-stillingen i den derved vundne forbindelse, som nævnt ovenfor, erstattes med en 5-methyl-l,3,4-thiadiazol-2-ylthio-gruppe. Det ovennævnte hidtil ukendte mellemprodukt adskiller sig fra den i tysk offentliggørelses-15 skrift nr. 20 55 796 anvendte tilsvarende a-aminoadipoylforbindelse ikke bare ved sin kemiske struktur, men også ved, at de to forbindelser har endog forskellige fysisk-kemiske egenskaber, hvilket resulterer i forskellige fremgangsmådebetingelser. Således kan fx den nævnte kendte forbindelse ikke ekstraheres med et organisk opløs-20 ningsmiddel. Derimod lader det ifølge opfindelsen hidtil ukendte 3This is obtained by treating a culture liquid containing cephalosporin C with phenyl isocyanate and replacing the acetoxy group at the 3-position of the thus obtained compound, as mentioned above, with a 5-methyl-1,3,4 thiadiazol-2-ylthio group. The aforementioned novel intermediate differs from the corresponding α-aminoadipoyl compound used in German Publication No. 15 55 796 not only by its chemical structure, but also by the fact that the two compounds even have different physicochemical properties, resulting in in various process conditions. Thus, for example, the aforementioned known compound cannot be extracted with an organic solvent. In contrast, according to the invention, the novel 3 leaves
DK 154889 BDK 154889 B
mellemprodukt sig let ekstrahere med et organisk opløsningsmiddel.intermediate easily extract with an organic solvent.
Herved fås fremgangsmådetekniske fordele og for fagmanden ikke forudsigelige virkninger, nemlig et fortræffeligt udbytte af slutproduktet cefazolin i høj renhed under anvendelse af ringe mængder af den til 5 acylering nødvendige kostbare lH-tetrazol-l-eddikesyre.This gives the process technical advantages and unpredictable effects for those of ordinary skill in the art, namely a superior yield of the high purity cefazoline, using low amounts of the expensive 1 H-tetrazole-1-acetic acid required for acylation.
På grund af reaktiviteten hos ureidogruppen i det hidtil ukendte mellemprodukt skulle der i acyleringstrinet forventes sidereaktioner (jfr. Sandler-Karo, Organic Functional Group Preparations, bind II, 1971, side 169). Det viser sig imidlertid overraskende, at det hidtil 10 ukendte mellemprodukt ved en one-pot-fremgangsmåde med endog lidt acyleringsmiddel giver omtrent det samme udbytte som fremgangsmåden i tysk offentliggørelsesskrift nr. 20 55 796, hvorved der fås et renere slutprodukt.Due to the reactivity of the ureido group in the novel intermediate, side reactions were expected in the acylation step (cf. Sandler-Karo, Organic Functional Group Preparations, Vol. II, 1971, p. 169). However, it is surprising that the novel intermediate by a one-pot process with even a little acylating agent yields about the same yield as the process of German Publication No. 20 55 796, thereby obtaining a cleaner final product.
Behandlingen af en dyrkningsvæske, der indeholder cephalosporin C, 15 udføres på i og for sig kendt måde, og den resulterende forbindelse underkastes på i og for sig kendt måde en reaktion, ved hvilken der sker udskiftning i 3-stillingen, hvorved det hidtil ukendte mellemprodukt fås (jfr. de tyske offentliggørelsesskrifter nr. 1.933.187 og 1.953.861).The treatment of a culture liquid containing cephalosporin C is carried out in a manner known per se, and the resulting compound is subjected in a manner known per se to a reaction in which the 3-position exchange occurs, whereby the novel intermediate available (cf. German Publication Nos. 1,933,187 and 1,953,861).
20 Som eksempler på salte af cefazolin kan fx angives et salt af et alkalimetal, fx natrium og kalium, og en tertiær organisk base, fx trimethylamin, triethylamin, N-methylpiperazin, Ν,Ν-dimethylanilin og pyridin. Reaktionstemperaturen ved silyleringen er fortrinsvis mellem stuetemperatur og 40°C, men er ikke begrænset dertil, og omsætningen 25 kan også udføres tinder afkøling. Silyleringsmidlet anvendes fortrinsvis i en mængde på 2 eller flere mol pr. mol af det hidtil ukendte mellemprodukt.Examples of salts of cefazoline may be mentioned, for example, a salt of an alkali metal, for example, sodium and potassium, and a tertiary organic base, for example trimethylamine, triethylamine, N-methylpiperazine, Ν, Ν-dimethylaniline and pyridine. The reaction temperature of the silylation is preferably between room temperature and 40 ° C, but is not limited thereto, and the reaction 25 can also be carried out with cooling. The silylating agent is preferably used in an amount of 2 or more moles per ml. moles of the novel intermediate.
Som eksempler på iminohalogeneringsmidler, som anvendes i iminohalo-generingstrinnet, kan fortrinsvis angives phosphortrichlorid, phos-30 phorpentachlorid, phosphortribromid, phosphorpentabromid, phosphor-oxychlorid, thionylchlorid og phosgen. Reaktionstemperaturen ved iminohalogeneringen er ikke begrænset, men omsætningen udføres sædvanligvis under afkøling.As examples of imino halogenating agents used in the imino halogenation step, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride, and phosgene may be preferred. The reaction temperature of the imino halogenation is not limited, but the reaction is usually carried out under cooling.
DK 154889BDK 154889B
44
Temperaturen ved iminoetherificeringen er ikke begrænset, og omsætningen udføres sædvanligvis under afkøling eller ved forhøjet temperatur.The temperature of the imino etherification is not limited and the reaction is usually carried out under cooling or at elevated temperature.
Reaktive derivater på carboxygruppen i lH-tetrazol-l-eddikesyre eller 5 et salt deraf kan fx. være et syrehalogenid, syreanhydrid, aktiveret amid eller en aktiveret ester. Som eksempler på særlig egnede forbindelser kan fx angives et syrechlorid, et syreazid, et blandet syreanhydrid af syrer udvalgt blandt dialkylphosphorsyrer, phenylphosphor-syrer, diphenylphosphorsyrer, dibenzylphosphorsyrer, halogenerede 10 phosphorsyrer, dialkylphosphorsyrling, svovlsyrling, thiosvovlsyre, svovlsyre, alkylkulsyrer, aliphatiske carboxylsyrer, fx pivalinsyre, pentansyre, isopentansyre, 2-ethylsmørsyre eller trichloreddikesyre, og aromatiske carboxylsyrer, fx benzoesyre, eller et symmetrisk syreanhydrid.Reactive derivatives of the carboxy group in 1H-tetrazole-1-acetic acid or a salt thereof may e.g. be an acid halide, acid anhydride, activated amide or an activated ester. As examples of particularly suitable compounds may be mentioned, for example, an acid chloride, an acid azide, a mixed acid anhydride of acids selected from dialkylphosphoric acids, phenylphosphoric acids, diphenylphosphoric acids, dibenzylphosphoric acids, halogenated phosphoric acids, dialkylphosphoric acid acid, sulfuric acid acid, sulfuric acid acid, sulfuric acid pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid or trichloroacetic acid, and aromatic carboxylic acids, for example benzoic acid, or a symmetrical acid anhydride.
15 Ved acyleringsomsætningen kan der tilsættes et kondensationsmiddel.15 A condensing agent may be added to the acylation reaction.
Som eksempler på egnede kondensationsmidler kan fx angives N,N'-dicyclohexylcarbodiimid, N- cyclohexyl -N' -morpholinoethylcarbodiimid, N-cyclohexyl-N' -(4-diethylaminocyclohexyl)carbodiimid, N,N' -diethyl-carbodiimid, N,N' -diisopropylcarbodiimid, N-ethyl-N'-(3-dimethylami-20 nopropyl) carbodiimid, N,N' -carbonyldi- (2-methylimidazol) , pentameth- ylenketen-N-cyclohexylimin, diphenylketen-N-cyclohexylimin, alkoxy-ace ty lener, 1-alkoxy-1-chlorethylener, trialkylphosphiter, ethyl-polyphosphat, isopropylpolyphosphat, phosphoroxychlorid, phosphor-trichlorid, thionylchlorid, oxalylchlorid, triphenylphosphin, 2-25 ethyl-7-hydroxybenzisoxazoliumsalt, intramolekylært 2-ethyl-5-(m- * sulfophenyl)isoxazoliumhydroxidsalt og (chlormethylen)dimethylam-moniumchlorid.Examples of suitable condensing agents may be mentioned, for example, N, N'-dicyclohexylcarbodiimide, N-cyclohexyl -N '-morpholinoethylcarbodiimide, N-cyclohexyl-N' - (4-diethylaminocyclohexyl) carbodiimide, N, N'-dieth '-diisopropylcarbodiimide, N-ethyl-N' - (3-dimethylaminopropyl) carbodiimide, N, N '-carbonyldi- (2-methylimidazole), pentamethylene-ketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, Acetylene, 1-alkoxy-1-chloroethylenes, trialkyl phosphites, ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride, triphenylphosphine, 2-25 ethyl-7-hydroxybenzisoxazolium salt, intramethyl - * sulfophenyl) isoxazolium hydroxide salt and (chloromethylene) dimethylammonium chloride.
Ved acyleringsomsætningen kan der tilsættes en organisk base såsom en trialkylamin, en Ν,Ν-dialkylbenzylamin eller pyridin. Reakt ions tempe-30 raturen ved acyleringstrinet er ikke begrænset, og omsætningen udføres sædvanligvis mellem stuetemperatur og forhøjet temperatur. Ved denne omsætning kan den reaktionsblanding, som er dannet i det forudgående trin, anvendes som den er, men reaktionsblandingen kan også anvendes efter at den til fjernelse af ikke-omsat iminohalogeneririgs-35 middel og iminoetherificeringsmiddel er inddampet tinder reduceret 5In the acylation reaction, an organic base such as a trialkylamine, a Ν, dial-dialkylbenzylamine or pyridine may be added. The reaction temperature at the acylation step is not limited and the reaction is usually carried out between room temperature and elevated temperature. In this reaction, the reaction mixture formed in the preceding step can be used as is, but the reaction mixture can also be used after the tinnitus has been evaporated to remove the unreacted imino halogen enrichment agent and imino etherifier.
DK 154889 BDK 154889 B
tryk. Når reaktionsblandingen anvendes direkte, foretrækkes det først at opvarme blandingen for at lade ikke-omsat iminohalogeneringsmiddel reagere med ikke-omsat iminoetherificeringsmiddel eller at tilsætte fx dimethylformamid i en mængde, som er tilstrækkelig til at elimi-5 nere ikke-omsat iminohalogeneringsmiddel.pressure. When the reaction mixture is used directly, it is first preferred to heat the mixture to react unreacted imino halogenating agent with unreacted imino etherifying agent or to add, for example, dimethylformamide in an amount sufficient to eliminate unreacted imino halogenating agent.
Hydrolyse af den ved det ovenfor angivne acyleringstrin dannede forbindelse kan let udføres ved at hælde reaktionsblandingen indeholdende reaktionsproduktet i vand, men det er også muligt først at tilsætte en base, fx et alkalimetalhydrogencarbonat eller en trialkyl-10 amin, eller en syre, fx fortyndet saltsyre eller eddikesyre, til vandet. Det på denne måde fremstillede cefazolin kan let isoleres på sædvanlig måde.Hydrolysis of the compound formed at the above acylation step can be easily carried out by pouring the reaction mixture containing the reaction product into water, but it is also possible to first add a base, for example an alkali metal hydrogen carbonate or a trialkylamine, or an acid, for example dilute hydrochloric acid. or acetic acid, to the water. The cefazoline thus prepared can be readily isolated in the usual manner.
Fremgangsmåden ifølge opfindelsen belyses nærmere ved følgende eksempel: 15 EKSEMPEL 1 1,52 g 7-[5-(N-phenylcarbamoylamino)adipinamido]-3-(5-methyl-l,3,4-thiazidazol-2-yl)thiomethyl-3-cephem-4-carboxylsyre sættes til 20 ml dichlormethan, der tilsættes 1,5 ml N,N-dimethylanilinoog 2 ml chlor-trimethylsilan, og blandingen opvarmes under tilbagesvåling i 1 time.The process of the invention is further illustrated by the following example: EXAMPLE 1 1.52 g of 7- [5- (N-phenylcarbamoylamino) adipinamido] -3- (5-methyl-1,3,4-thiazidazol-2-yl) thiomethyl 3-cephem-4-carboxylic acid is added to 20 ml of dichloromethane, 1.5 ml of N, N-dimethylanilino and 2 ml of chloro-trimethylsilane are added and the mixture is heated under reflux for 1 hour.
20 Efter afkøling til mellem -40 og -50°C sættes 1,1 g phosphorpenta-chlorid til blandingen, og den omrøres ved den samme temperatur i 2 timer. Der tilsættes 0,1 ml Ν,Ν-dimethylanilin og 8 ml aabsolut methanol,, og blandingen omrøres ved en temperatur mellem -40 og -50°C i 30 minutter og yderligere ved stuetemperatur i 30 minutter. Reak-25 tionsblandingen destilleres under reduceret tryk for at fjerne opløsningsmidlet. Den resulterende remanens suspenderes i 30 ml dichlormethan, og der tilsættes 2,5 ml triethylamin. Til blandingen sættes på én gang et blandet syrearihydrid, som er fremstillet uid fra 0,96 g IH-tetrazol-1-eddikesyre og 0,97 g pivalinsyre på sædvanlig måde 30 under isafkøling med koncentreret saltsyre og ekstraheres med ethyl-acetat. Til ekstrakten sættes en mættet vandig natriumtyydrogencar-bonatopløsning, og den vandige fase fraskilles. Til denwandige fase sættes ethylacetat, blandingen syrnes med koncentreret ssal tsyre, ogAfter cooling to between -40 and -50 ° C, 1.1 g of phosphorus pentachloride is added to the mixture and stirred at the same temperature for 2 hours. 0.1 ml of Ν, Ν-dimethylaniline and 8 ml of absolute methanol, are added and the mixture is stirred at a temperature between -40 and -50 ° C for 30 minutes and further at room temperature for 30 minutes. The reaction mixture is distilled under reduced pressure to remove the solvent. The resulting residue is suspended in 30 ml of dichloromethane and 2.5 ml of triethylamine is added. To the mixture is added at once a mixed acid anhydride prepared from 0.96 g of 1H-tetrazole-1-acetic acid and 0.97 g of pivalic acid in the usual manner under ice-cooling with concentrated hydrochloric acid and extracted with ethyl acetate. To the extract is added a saturated aqueous sodium hydrogen carbonate solution and the aqueous phase is separated. To the wall phase is added ethyl acetate, the mixture is acidified with concentrated salsal acid, and
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP25177271 | 1971-12-23 | ||
| JP25177271 | 1971-12-23 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DK154889B true DK154889B (en) | 1989-01-02 |
| DK154889C DK154889C (en) | 1989-06-12 |
Family
ID=17227685
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK638172A DK154889C (en) | 1971-12-23 | 1972-12-21 | METHOD OF PRODUCING CEFAZOLINE |
Country Status (4)
| Country | Link |
|---|---|
| DK (1) | DK154889C (en) |
| ES (1) | ES410009A1 (en) |
| GB (1) | GB1414324A (en) |
| SE (1) | SE428693B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2055796C2 (en) * | 1969-11-17 | 1982-04-01 | Fujisawa Pharmaceutical Co., Ltd., Osaka | Process for the preparation of 7-aminocephalosporanic acid derivatives |
| DE1953861C2 (en) * | 1969-10-25 | 1982-12-23 | Fujisawa Pharmaceutical Co., Ltd., Osaka | 7-tetrazolylacetamido-3-thiomethyl-3-cephem-4-carboxylic acids |
-
1972
- 1972-12-20 GB GB5894772A patent/GB1414324A/en not_active Expired
- 1972-12-20 SE SE7216747A patent/SE428693B/en unknown
- 1972-12-21 DK DK638172A patent/DK154889C/en active
- 1972-12-23 ES ES410009A patent/ES410009A1/en not_active Expired
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1953861C2 (en) * | 1969-10-25 | 1982-12-23 | Fujisawa Pharmaceutical Co., Ltd., Osaka | 7-tetrazolylacetamido-3-thiomethyl-3-cephem-4-carboxylic acids |
| DE2055796C2 (en) * | 1969-11-17 | 1982-04-01 | Fujisawa Pharmaceutical Co., Ltd., Osaka | Process for the preparation of 7-aminocephalosporanic acid derivatives |
| DK147597B (en) * | 1969-11-17 | 1984-10-15 | Fujisawa Pharmaceutical Co | PROCEDURE FOR THE PREPARATION OF 7-AMINOCEPHALOSPORANIC ACID DERIVATIVES |
Also Published As
| Publication number | Publication date |
|---|---|
| ES410009A1 (en) | 1975-12-01 |
| SE428693B (en) | 1983-07-18 |
| GB1414324A (en) | 1975-11-19 |
| DK154889C (en) | 1989-06-12 |
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