DK141847B - Process for the preparation of 7-amino-cephalosporanoic acid. - Google Patents
Process for the preparation of 7-amino-cephalosporanoic acid. Download PDFInfo
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- DK141847B DK141847B DK516765A DK516765A DK141847B DK 141847 B DK141847 B DK 141847B DK 516765 A DK516765 A DK 516765A DK 516765 A DK516765 A DK 516765A DK 141847 B DK141847 B DK 141847B
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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
- 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
- C07D501/18—7-Aminocephalosporanic or substituted 7-aminocephalosporanic acids
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- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
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- C01B17/69—Sulfur trioxide; Sulfuric acid
- C01B17/74—Preparation
- C01B17/76—Preparation by contact processes
- C01B17/78—Preparation by contact processes characterised by the catalyst used
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Description
141847141847
Patent nr. 118^06 angår en fremgangsmåde til fremstilling af 7-amino-cephalosporansyre med formlenPatent No. 118,66 relates to a process for preparing 7-amino-cephalosporanoic acid of the formula
y-i—Ay-I-A
A—γ-®2-Ε 1A — γ-®2-Ε 1
OOOHOOOH
eller estere heraf, hvori R betyder en eventuelt under 5 lactondannelse med 4-carboxy gruppen foresteret hydroxygruppe, og denne fremgangsmåde er ejendommelig ved, at man behandler et derivat af cephalosporin C med formlen HOOCL A · >-(oh2)3-cc,hn-^\or esters thereof, wherein R is optionally below 5 lactone formation with the 4-carboxy group esterified hydroxy group, and this process is characterized by treating a derivative of cephalosporin C of the formula HOOCL A · - (oh2) 3-cc, hn - ^ \
COOHCOOH
hvori R har den ovenfor angivne betydning, og hvori amino-10 gruppen er blokeret ved substitution med alkyl-, aryl-eller acylgrupper, og carboxylgrupperne er blokeret ved forestering eller ringdannelse, med syrehalogenider, som afledes af phosphor og dettes oxygenholdige syrer, omdanner det opnåede imidhalogenid med en aliphatisk eller ara-15 liphatisk alkohol til den tilsvarende iminoether og hydrolyserer denne til dannelse af den ønskede 7-aminocephalo-sporansyre og om ønsket fraspalter den gruppe, der blokerer carboxylgruppen, ved hydrogenolyse eller sur hydrolyse.wherein R is as defined above and wherein the amino group is blocked by substitution with alkyl, aryl or acyl groups, and the carboxyl groups are blocked by esterification or cyclization, with acid halides derived from phosphorus and its oxygen-containing acids converting it obtained imide halide with an aliphatic or ara-lipatic alcohol to the corresponding imino ether and hydrolyzes it to give the desired 7-aminocephalo-sporanoic acid and, if desired, the group blocking the carboxyl group by hydrogenolysis or acid hydrolysis.
20 Ved denne fremgangsmåde kan man få fremstillet 7-amino-cephalosporansyre-benzhydrylester ved en forenklet reak-tionsfølge og med en kort reaktionstid, nån man går frem på følgende måde: 2 U1847 1. Yed omsætningen af phthaloyl-cephalosporin C-dibenz-hydrylester med phosphorpentachlorid i nærværelse af tertiære aminer, f.eks. pyridin, i et inert opløsnings-middel, f.eks. methylenchlorid, bør molforholdet mellem 5 cephalosporinderivat, phospborpentacblorid og am,in være ca. 1:3:12. Temperaturen bør boldes ved ca. 10°C for at formindske dannelsen af biprodukter. Ee aktionstiden er under disse forbold 30-40 minutter.In this process, 7-amino-cephalosporanoic acid benzhydryl ester can be prepared in a simplified reaction sequence and with a short reaction time, as follows: 2 U1847 1. Prepare the reaction of phthaloyl-cephalosporin C-dibenzyl ester with phosphorus pentachloride in the presence of tertiary amines, e.g. pyridine, in an inert solvent, e.g. methylene chloride, the molar ratio of 5 cephalosporin derivative, phosphorus pentaclor chloride to am should be approx. 1: 3: 12th The temperature should bale at approx. 10 ° C to reduce the formation of by-products. The action time during these sessions is 30-40 minutes.
2. For hurtigst muligt og mest kvantitativt at omdanne 10 imidchloridet til iminoetber anvender man et stort overskud af alkobol, f.eks. ca. 100 mol metbylalkobol pr. mol·, og lader først reagere ved lav temperatur (ca. 30 minutter ved -10°0, derpå ca. én time ved stuetemperatur.2. In order to convert as quickly as possible and most quantitatively the imide chloride into imino ether, a large excess of alcohol is used, e.g. ca. 100 moles of methyl alcohol per mol ·, and first react at low temperature (about 30 minutes at -10 ° 0, then about one hour at room temperature.
3· Hydrolysen af iminoetber en til 7-amino-cephalosporan-15 syre-benzbydrylester udføres med fordel i en metbylen-cblorid-vand-blanding. I dette opløsningsmiddel er den afsluttet i løbet af ca. 45 minutter ved stuetemperatur, når man anvender fortyndet, vandig saltsyre som hydrolyseringsmiddel .3 · The hydrolysis of imino ether one to 7-amino-cephalosporanic acid benzebydryl ester is advantageously carried out in a methylbenzyl chloride-water mixture. In this solvent, it is completed in approx. 45 minutes at room temperature using dilute aqueous hydrochloric acid as a hydrolyzing agent.
20 Fremgangsmådetrinene 1-3 udføres altså alle i samme reaktionsbeholder og med methylenchlorid som hovedopløsningsmiddel. Den således vundne 7-amino-c ephalosp oransyre-benz-hydrylester spaltes ved hjælp af trifluoreddikesyre i nærværelse af anisol, hvorefter trifluor eddike syren skilles 25 fra den i reaktionsmediet værende 7-amino-cephalosporansyre, f.eks. ved afdampning under formindsket tryk.Thus, steps 1-3 are all carried out in the same reaction vessel and with methylene chloride as the main solvent. The 7-amino-cephalospanoic acid benz hydrolyster thus obtained is cleaved by trifluoroacetic acid in the presence of anisole, whereupon the trifluoroacetic acid is separated from the 7-amino-cephalosporanoic acid present in the reaction medium, e.g. by evaporation under reduced pressure.
Nærværende opfindelse angår en fremgangsmåde ifølge patent nr, 118.506 til fremstilling af 7-amino-cephalosporansyre, ved hvilken man ved omsætning af N,N-phthaloyl-cephalosporin 0-30 dibenzhydrylester med phosphorpentachlorid, omdannelse af det dannede imidchlorid til en lavalkyliminoether og hydrolyse af iminoetheren med vand i surt medium får dannet 7-amino-cephalo-sporansyrebenzhydrylester, der derefter spaltes ved forsæbning UT847 3 med tri fluoreddike syre i nærværelse af anisol til 7-amino-cephalosporansyre, hvilken fremgangsmåde er ejendommelig ved, at man efter spaltningen af 7-amlno-cePhaiosp°ransyre-benz-hydrylesteren omdanner trifluoreddikesyren i et polært opløs-5 ningsmiddel til trifluoracetatet med en tertiær amin og udkrystalliserer 7-amino-cephalosporansyren af opløsningen.The present invention relates to a process according to Patent No. 118,506 for the preparation of 7-amino-cephalosporanoic acid, wherein by reacting N, N-phthaloyl-cephalosporin 0-30 dibenzhydryl ester with phosphorus pentachloride, conversion of the formed imide chloride to a low alkyl imino ether and hydrolysis of the imino ether with acidic water is formed 7-amino-cephalo-sporanoic acid benzhydryl ester, which is then digested by saponification UT847 3 with trifluoroacetic acid in the presence of anisole to 7-amino-cephalosporanoic acid, the process of which after the digestion of 7 The amino-cephalospanoic acid benz hydrolyster converts the trifluoroacetic acid in a polar solvent to the trifluoroacetate with a tertiary amine and crystallizes the 7-amino-cephalosporanoic acid of the solution.
Det har vist sig, at man herved kan forbedre udbyttet af opnået 7-amino-cephalo sporansyre.It has been found that this can improve the yield of 7-amino-cephalo-sporanoic acid obtained.
Som amin kan f.eks. anvendes en tri-lavalkylamin, fremfor 10 alt triethylamin eller tri-n-buty 1 amin. Det med aminen damede trifluoracetat bør være opløseligt i det polære opløsningsmiddel; egnede opløsningsmidler er f.eks. dimethyl-formamid, acetonitril eller fortrinsvis en lavalkanol, fremfor alt methyl alkohol. Krystallisationen af 7-amino-15 cephalosporansyre sker fortrinsvis i methanolisk opløsning.As amine, e.g. a tri-lower alkylamine, above all triethylamine or tri-n-buty 1 amine, is used. The trifluoroacetate-dammed amine should be soluble in the polar solvent; suitable solvents are e.g. dimethylformamide, acetonitrile or preferably a lower alkanol, especially methyl alcohol. Preferably, the crystallization of 7-amino-cephalosporanoic acid occurs in methanolic solution.
Den vundne, krystalliserede 7—emino-cephalosporansyre vaskes med fordel med methylalkohol, methylenchlorid og ethylether efter hinanden, for at befri den for vedhængende, fra reaktionsmediet stammende forureninger (apaltnings-20 produkter, opløsningsmidler). Man får således 7-amino-cephalosporansyren uden omkrystallisation med en renhed på over 97%.The obtained crystallized 7-emino-cephalosporanoic acid is advantageously washed with methyl alcohol, methylene chloride and ethyl ether one after the other, to relieve the contaminants emanating from the reaction medium (apalting products, solvents). Thus, the 7-amino-cephalosporanoic acid is obtained without recrystallization with a purity above 97%.
Fremgangsmåden ifølge opfindelsen beskrives nærmere i de efterfølgende eksempler.The process according to the invention is described in more detail in the following examples.
25 Eksempel 1 26,5 g krystalliseret N-phthaly1-cephalosporin C-di-benz-hydrylester opløses i 1 liter absolut methylenchlorid; der tilsættes 29 ml absolut pyridin og afkøles til -10°C. Derpå tilsætter man inden for 2 minutter 187 ml af en 10%'s phos-50 phorpentachloridopløsning i absolut methylenchlorid og omrører i 1/2 time, hvorved temperaturen hele tiden holdes på -10°0. Herpå tilsætter man til opløsningen inden for 1/2 minut hurtigt 200 ml iskoldt, absolut methylalkohol og holder temperaturen i yderligere 30 minutter på -10°C. Man f£T847 4 opvarmer i vandbad til +20°C og omrører 'ved denne temperatur i i time. Til opløsningen sættes derpå under omrøring hurtigt (inden for 1/2 minut) 500 ml af en iskold, vandig opløsning af 35 ml af en 85$'s orthophosphorsyre og omrø-5 rør 1 1/2 time ved 20°C. Der indstilles på pH 8,0 ved hjælp af ca. 530 ml 50%*s vandig trikaliumphosphatopløsning, og det underste lag methylenchlorid skilles fra. Den vandige, øverste fase ekstraheres efter med 500 ml methylenchlorid.Example 1 26.5 g of crystallized N-phthalyl-cephalosporin C-di-benzhydryl ester are dissolved in 1 liter of absolute methylene chloride; 29 ml of absolute pyridine is added and cooled to -10 ° C. Then, within 2 minutes, 187 ml of a 10% phos-50 phorpentachloride solution in absolute methylene chloride is added and stirred for 1/2 hour, keeping the temperature at -10 ° 0 all the time. Then add 200 ml of ice-cold, absolutely methyl alcohol to the solution within 1/2 minute and keep the temperature for a further 30 minutes at -10 ° C. The T847 4 is heated in a water bath to + 20 ° C and stirred at this temperature for one hour. To the solution, 500 ml of an ice-cold, aqueous solution of 35 ml of an orthophosphoric acid and stirring are added rapidly (within 1/2 minute) with stirring (1/2 hour) at 20 ° C. Adjust to pH 8.0 using approx. 530 ml of 50% aqueous tricalium phosphate solution and the lower layer of methylene chloride is separated. The aqueous upper phase is then extracted with 500 ml of methylene chloride.
De forenede og over natriumsulfat tørrede methylenchlorid— 10 ekstrakter giver ved inddampning i vakuum 34-40 g (alt efter tørringsgraden) flydende remanens, der tørres i endnu ca. 1/2 time ved 0,1 mm Hg-tryk og stuetemperatur#- Denne ' remanens indeholder 7-amino-cephalo sporansyr e-benzhydryl-esteren. Den optages i 15 ml anisol, og der tilsættes 15 under afkøling 45 ml trifluoreddikesyre. Man fremskynder opløsningen af remanensen ved kraftig bevægelse og holder temperaturen i 15 minutter på ca. 20°C. Derpå hældes opløsningen hurtigt i 700 ml omrørt, kold methylalkohol, og samtidig indstilles den methanoliske opløsnings pH 20 (pH-meter) på værdien 355 ved tilsætning af ca. 135 ml tri-n-butylamin. Derpå finindstiller man ρΞ-værdien, idet man fortynder 0,5 ml-prøver med 4,5 ml vand til hver og måler nu disse med pH-meteret. Opløsningen holdes afkølet i 2-15 timer ved +5 til +10°C og filtreres så. Den med 25 methylalkohol, methylenchlorid og ethylether efter hin an-• den vaskede remanens giver ved tørring i vakuum 6,68 g (= 81% af det teoretiske) 7-amino-cephalosporansyre.The combined methylene chloride-dried and sodium sulfate-dried extracts, by evaporation in vacuo, yield 34-40 g (depending on the degree of drying) of liquid residue, which is dried for a further approx. 1/2 hour at 0.1 mm Hg pressure and room temperature # - This residue contains the 7-amino-cephalo sporanoic acid e-benzhydryl ester. It is taken up in 15 ml of anisole and 15 with cooling 45 ml of trifluoroacetic acid are added. The solution of the residue is accelerated by vigorous movement and the temperature is maintained for 15 minutes at approx. 20 ° C. Then the solution is quickly poured into 700 ml of stirred cold methyl alcohol, and at the same time the pH 20 (pH meter) of the methanolic solution is adjusted to the value of 355 by adding approx. 135 ml of tri-n-butylamine. The ρΞ value is then fine-tuned, diluting 0.5 ml of samples with 4.5 ml of water for each and now measuring them with the pH meter. The solution is kept cool for 2-15 hours at +5 to + 10 ° C and then filtered. The one with 25 methyl alcohol, methylene chloride and ethyl ether after the other washed residue, upon drying in vacuo, gives 6.68 g (= 81% of theory) of 7-amino-cephalosporanoic acid.
Ultraviolet-absorptionsspektrum (i 0,1 ΪΓ natriumhydrogen-carbonatopløsning): λ- χ.263 mp (e = 8000). [a]^° = +118° 30 (c = 2 i 0,5 S natriumhydrogencarbonatopløsning).Ultraviolet absorption spectrum (in 0.1 ΪΓ sodium hydrogen carbonate solution): λ- χ.263 mp (e = 8000). [α] D = + 118 ° (c = 2 in 0.5 S sodium bicarbonate solution).
Eksempel 2 26,3 g krystalliseret H-phthalyl-cephalosporin C-di-benz-hydrylester opløses i 263 ml absolut methylenchlorid, der tilsættes 23 ml absolut pyridin og afkøles til -10°C. Så 35 tilsættes under omrøring inden for 2 minutter 150 ml af en 10%'s phosphorpentachloridopløsning i absolut methylen- 5 UT&47 chlorid, og man omrører i 1/2 time, hvorved temperaturen hele tiden holdes på -10°C. Til opløsningen sættes herpå inden for 1/2 minut hurtigt 100 ml iskold, absolut methylalkohol, og temperaturen holdes i yderligere 30 minutter på -10°C.Example 2 26.3 g of crystallized H-phthalyl-cephalosporin C-di-benzhydryl ester are dissolved in 263 ml of absolute methylene chloride, 23 ml of absolute pyridine is added and cooled to -10 ° C. Then, with stirring, within 2 minutes, 150 ml of a 10% phosphorus pentachloride solution in absolute methylene UT & 47 chloride is added and stirred for 1/2 hour, keeping the temperature at -10 ° C all the time. To the solution, 100 ml of ice-cold, absolutely methyl alcohol is quickly added within 1/2 minute and the temperature is maintained for a further 30 minutes at -10 ° C.
5 Der opvarmes i vandbad til +20°C og omrøres ved denne temperatur i 1 time. Til opløsningen sættes så under omrøring hurtigt (inden for 1/2 minut) 250 ml iskold, vandig 1 li saltsyre, og der omrøres i 3/4 time ved 20°C.5 Heat in water bath to + 20 ° C and stir at this temperature for 1 hour. To the solution is then quickly added (within 1/2 minute) 250 ml of ice cold aqueous 1 l hydrochloric acid and stirred for 3/4 hour at 20 ° C.
Der tilsættes 50 ml 50%'s vandig trikaliumphosphatopløsning,50 ml of 50% aqueous tricalcium phosphate solution is added,
10 og der indstilles på pH 8,0 ved hjælp af ca. 230 ml 2 N10 and adjust to pH 8.0 using approx. 230 ml 2 N
vandig natriumhydroxidopløsning. Af blandingen, som har tilbøjelighed til at danne en emulsion, skilles methylenchlor^ idlaget fra ved hjælp af en centrifuge, og den vandige fase ekstraheres efter ved hjælp af 200 ml methylenchlorid. De 15 forenede og over natriumsulfat tørrede methylenchlorid-ekstrakter giver ved inddampning i vakuum 34—3S g (alt efter tørringsgraden) flydende remanens, som yderligere tørres i ca. 1/2 time ved 0,1 mm Hg-tryk og stuetemperatur. Remanensen indeholder 7-smino-cephalosporansyre-benz-20 hydrylesteren. Den omdannes som i eksempel 1 til den frie 7-amino-c epha 1 osporansyre. Denne har samme renhedsgrad som i eksempel 1.aqueous sodium hydroxide solution. From the mixture which tends to form an emulsion, the methylene chloride layer is separated by centrifuge and the aqueous phase is extracted with 200 ml of methylene chloride. The 15 combined and sodium sulfate dried methylene chloride extracts, by evaporation in vacuo, yield 34-3 g (depending on the degree of drying) of liquid residue, which is further dried for approx. 1/2 hour at 0.1 mm Hg pressure and room temperature. The residue contains the 7-smino-cephalosporanoic acid benzhydryl ester. It is converted as in Example 1 to the free 7-amino-c epha 1 osporanoic acid. This one has the same degree of purity as in Example 1.
Eksempel 3 1 kg krystallinsk N-phthalyl-cephalosporin C-di-benzhydryl-25 ester opløses i 30 liter absolut methylenchlorid*, der tilsættes 1,15 kg absolut pyridin og afkøles til -16°C.Example 3 1 kg of crystalline N-phthalyl-cephalosporin C-di-benzhydryl ester is dissolved in 30 liters of absolute methylene chloride *, 1.15 kg of absolute pyridine is added and cooled to -16 ° C.
Derpå tilsætter man under omrøring og inden for 10 minutter en opløsning af 750 g phosphorpentachlorid i 13 liter methylenchlorid, hvorved temperaturen stiger til -13°C.Then, with stirring and within 10 minutes, a solution of 750 g of phosphorus pentachloride in 13 liters of methylene chloride is added, raising the temperature to -13 ° C.
30 Man omrører derpå i 40 minutter ved -12°C. Herpå sættes til opløsningen inden for 3 minutter 7>5 liter absolut methylalkohol (ca. -20°C), hvorved reaktionsblandingens temperatur stiger til -10°C. Der omrøres så i 1/2 time ved -10°G, opvarmes ved hjælp af et vandbad til +20°C og omrø-35 res så i yderligere en time. Til opløsningen sættes under omrøring 25 liter 1 H vandig saltsyre (ca. +10°C), og der omrøres i 3/4 time ved 20°C. Der tilsættes 1,9 literIt is then stirred for 40 minutes at -12 ° C. Then, within 3 minutes, add 7> 5 liters of absolute methyl alcohol (about -20 ° C) to the solution, raising the temperature of the reaction mixture to -10 ° C. It is then stirred for 1/2 hour at -10 ° G, heated by a water bath to + 20 ° C and then stirred for an additional hour. To the solution, add 25 liters of 1 H aqueous hydrochloric acid (about + 10 ° C) and stir for 3/4 hour at 20 ° C. 1.9 liters are added
Claims (2)
Priority Applications (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR34084A FR89317E (en) | 1964-02-14 | 1965-10-07 | New process for the preparation of amino compounds, in particular 7-amino-cephalosporanic acid |
| DE19651545704 DE1545704C3 (en) | 1964-02-14 | 1965-10-07 | Process for the preparation of 7-aminocephalosporanic acid |
| IT2233965A IT1050651B (en) | 1964-02-14 | 1965-10-07 | PROCEDURE TO PRODUCE 7 AMINOCEPHALOSPORANIC ACID AND ITS DERIVATIVES |
| DK516765A DK141847B (en) | 1964-02-14 | 1965-10-08 | Process for the preparation of 7-amino-cephalosporanoic acid. |
| NL6513095A NL148610B (en) | 1963-02-18 | 1965-10-08 | PROCESS FOR PREPARING CEPHALOSPORANIC ACID. |
| GB4310765A GB1119806A (en) | 1963-02-18 | 1965-10-11 | Process for the manufacture of 7-amino-cephalosporanic acid |
| US200511A US3697515A (en) | 1963-02-18 | 1971-11-19 | Process for splitting the 7-n-acyl group from cephalosporin compounds |
| US293906A US3875151A (en) | 1963-02-18 | 1972-10-02 | Process for the manufacture of amino-compounds |
Applications Claiming Priority (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK72864A DK118506B (en) | 1963-02-18 | 1964-02-14 | Process for the preparation of 7-aminocephalosporanic acid or esters thereof. |
| DK72864 | 1964-02-14 | ||
| CH1316664 | 1964-10-09 | ||
| CH1316664A CH467803A (en) | 1963-02-18 | 1964-10-09 | New process for the production of 7-aminocephalosporanic acid |
| CH1469664 | 1964-11-13 | ||
| CH1469664 | 1964-11-13 | ||
| DK516765A DK141847B (en) | 1964-02-14 | 1965-10-08 | Process for the preparation of 7-amino-cephalosporanoic acid. |
| DK516765 | 1965-10-08 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DK141847B true DK141847B (en) | 1980-06-30 |
| DK141847C DK141847C (en) | 1980-11-17 |
Family
ID=27429481
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK516765A DK141847B (en) | 1963-02-18 | 1965-10-08 | Process for the preparation of 7-amino-cephalosporanoic acid. |
Country Status (3)
| Country | Link |
|---|---|
| DE (1) | DE1545704C3 (en) |
| DK (1) | DK141847B (en) |
| IT (1) | IT1050651B (en) |
-
1965
- 1965-10-07 DE DE19651545704 patent/DE1545704C3/en not_active Expired
- 1965-10-07 IT IT2233965A patent/IT1050651B/en active
- 1965-10-08 DK DK516765A patent/DK141847B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DE1545704B2 (en) | 1973-05-24 |
| IT1050651B (en) | 1981-03-20 |
| DK141847C (en) | 1980-11-17 |
| DE1545704A1 (en) | 1972-01-20 |
| DE1545704C3 (en) | 1974-01-03 |
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