DK153400B - PROCEDURE FOR 11A-CHLORATION OF 5-OXYTETRACYCLINE OR ANY ACID ADDITION SALT - Google Patents
PROCEDURE FOR 11A-CHLORATION OF 5-OXYTETRACYCLINE OR ANY ACID ADDITION SALT Download PDFInfo
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- DK153400B DK153400B DK370074AA DK370074A DK153400B DK 153400 B DK153400 B DK 153400B DK 370074A A DK370074A A DK 370074AA DK 370074 A DK370074 A DK 370074A DK 153400 B DK153400 B DK 153400B
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- oxytetracycline
- chloro
- acid addition
- addition salt
- reaction
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
- C07C237/26—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton of a ring being part of a condensed ring system formed by at least four rings, e.g. tetracycline
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/40—Ortho- or ortho- and peri-condensed systems containing four condensed rings
- C07C2603/42—Ortho- or ortho- and peri-condensed systems containing four condensed rings containing only six-membered rings
- C07C2603/44—Naphthacenes; Hydrogenated naphthacenes
- C07C2603/46—1,4,4a,5,5a,6,11,12a- Octahydronaphthacenes, e.g. tetracyclines
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
DK 153400 BDK 153400 B
Opfindelsen angår en forbedret fremgangsmåde til fremstilling af lla-chlor-5-oxytetracyclin-6,12-hemiketal ved lla-chlorering af 5-oxytetracyclin eller et syreadditionssalt deraf som angivet i krav l's indledning.The invention relates to an improved process for the preparation of 11a-chloro-5-oxytetracycline-6,12-hemiketal by 11a-chlorination of 5-oxytetracycline or an acid addition salt thereof as set forth in the preamble of claim 1.
lla-chlor-5-oxytetracyclin-6,12-hemiketal er et værdifuldt mellemprodukt for fremstillingen af de kommercielt vigtige antibiotica 6-demethyl-5-oxytetracyclin og 6a-desoxy-5-oxytetracyclin (US patentskrifter nr. 2 984 686 og nr. 3 200 149). Disse to patentskrifter beskriver forbindelsens-fremstilling ved omsætning af 5-oxytetra-cyclin med et chloreringsmiddel i et reaktionsinert opløsningsmiddel ved en temperatur på fra omkring -25 til omkring 50°C og en pH-værdi nær ved det isoelektriske punkt for 5-oxytetracyclinet.11a-chloro-5-oxytetracycline-6,12-hemiketal is a valuable intermediate for the preparation of the commercially important antibiotics 6-demethyl-5-oxytetracycline and 6a-deoxy-5-oxytetracycline (U.S. Patent No. 2,984,686 and no. 3 200 149). These two patents describe the compound preparation by reacting 5-oxytetracycline with a chlorinating agent in a reaction-inert solvent at a temperature of from about -25 to about 50 ° C and a pH near the isoelectric point of the 5-oxytetracycline.
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DK 153400 BDK 153400 B
Det reaktionsinerte opløsningsmiddel er et med vand blandbart opløsningsmiddel. Produktet udfældes ved fortynding af reaktionsblandingen med vand og filtrering.The reaction-inert solvent is a water-miscible solvent. The product is precipitated by diluting the reaction mixture with water and filtering.
Det belgiske patentskrift nr. 777 356 beskriver chloreringen af 5-oxytetracyclin eller dets syreadditionssalte i et egnet opløsningsmiddel ved en temperatur under 0°C, medens pH-værdien boldes mellem ca. 3,5 og ca. 5, til spontan udfældning af lla-chlor- 5-oxytetracyclin-6,12-hemiketal-basen i enolformen. Hemiketalba-sen isoleres og omdannes derpå til hydrochloridet, sulfosalicylatet eller p-toluensulfonatet ved behandling med den tilsvarende syre ved mellem -10 og 20°C.Belgian Patent No. 777,356 discloses the chlorination of 5-oxytetracycline or its acid addition salts in a suitable solvent at a temperature below 0 ° C, while balancing the pH between approx. 3.5 and approx. 5, to spontaneously precipitate the 11a-chloro-5-oxytetracycline-6,12-hemiketal base in the enol form. The hemiketal base is isolated and then converted to the hydrochloride, sulfosalicylate or p-toluenesulfonate by treatment with the corresponding acid at between -10 and 20 ° C.
De hidtil kendte fremgangsmåder giver ujævne og/eller relativt små udbytter af lla-chlor-5-oxytetracyclin-6,12-hemiketal-hydro-chlorid eller andet syreadditionssalt, hvis kvalitet ikke altid er ensartet, hvilket giver anledning til vanskeligheder ved de efterfølgende fremgangsmådetrin, for hvilke hemiketalproduktet tjener som mellemprodukt. Desuden kræver de isolering af hemike-talbasen før fremstillingen af et syreadditionssalt deraf.The known methods give uneven and / or relatively small yields of 11a-chloro-5-oxytetracycline-6,12-hemiketal hydrochloride or other acid addition salt, the quality of which is not always uniform, causing difficulties in subsequent process steps. , for which the hemiketal product serves as an intermediate. Furthermore, they require isolation of the hemical base prior to the preparation of an acid addition salt thereof.
Det har nu vist sig, at lla-chlor-5-oxytetracyclin-6,12-hemi-ketal kan fremstilles som syreadditionssalt af ensartet og udmærket kvalitet og i alment højt udbytte ved fremgangsmåden ifølge opfindelsen, som er ejendommelig ved det i krav l's kendetegnende del anførte.It has now been found that 11a-chloro-5-oxytetracycline-6,12-hemi-ketal can be prepared as acid addition salt of uniform and excellent quality and in general high yield by the process according to the invention, which is characterized by the characterization of claim 1. part stated.
Fremgangsmåden tillader normalt let udvinding af lla-chlor-5-oxy-tetracyclin-6,12-hemiketalen som et stabilt, krystallinsk syreadditionssalt ved filtrering eller centrifugering. Det således opnåede produkt giver, når det dehydratiseres med hydrogenfluorid, i hovedsagen kvantitative udbytter af lla-chlor-6-demethyl-6-desoxy-6-me-thylen-5-oxytetracyclin. Denne sidstnævnte forbindelse er et vigtigt mellemprodukt ved syntesen af 6-demethyl-6-desoxy-6-methylen- 5-oxytetracyclin og af 6cc-desoxy-5-oxytetracyclin.The process usually allows easy recovery of 11a-chloro-5-oxy-tetracycline-6,12-hemiketal as a stable crystalline acid addition salt by filtration or centrifugation. The product thus obtained, when dehydrated with hydrogen fluoride, provides substantially quantitative yields of 11a-chloro-6-demethyl-6-deoxy-6-methylene-5-oxytetracycline. This latter compound is an important intermediate in the synthesis of 6-demethyl-6-deoxy-6-methylene-5-oxytetracycline and of 6cc-deoxy-5-oxytetracycline.
Ved fremgangsmåden ifølge opfindelsen omsættes 5-oxytetracyclin med et chloreringsmiddel i et reaktionsinert opløsningsmiddel. Egnede chloreringsmidler er chlor; N-chlor-lavere-alkansyreamider,In the process of the invention, 5-oxytetracycline is reacted with a chlorinating agent in a reaction-inert solvent. Suitable chlorinating agents are chlorine; N-chloro-lower-alkansyreamider,
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f.eks. N-chloracetamid; N-chlor-carbonhydriddicarboxylsyreimider, f.eks. N-chlorsuccinimid, N-chlor-phthalimid, N-chlor-N-lavere-alkanoylanilider, f.eks. N-chloracetanilid og N-chlor-propionani-lid; 3-chlor- og 3,5-dichlor-5,5-dimethylhydantoin, pyridinium-perchlorid-hydrohalogenider, f.eks. pyridiniumperchlorid-hydro-chlorid; og lavere-alkylhypochloriter, f.eks. tertiært butylhypo-chlorit. Det er klart, at de chloreringsmidler, som er almindeligt aivendte indenfor teknikken, i almindelighed kan anvendes, men de ovenstående foretrækkes. Det foretrukne chloreringsmiddel er N-chlorsuccinimid på grund af dets lette håndtering og brug, dets hurtige reaktion med 5-oxytetracyclin og de høje udbytter af chlo-reret produkt, som det giver.eg. N-chloroacetamide; N-chloro-hydrocarbon dicarboxylic acid imides, e.g. N-chlorosuccinimide, N-chloro-phthalimide, N-chloro-N-lower alkanoylanilides, e.g. N-chloroacetanilide and N-chloro-propionanilide; 3-chloro- and 3,5-dichloro-5,5-dimethylhydantoin, pyridinium perchloride hydrohalides, e.g. pyridiniumperchlorid-hydro-chloride; and lower alkyl hypochlorites, e.g. tertiary butyl hypochlorite. It will be appreciated that the chlorinating agents commonly used in the art can generally be used, but the above are preferred. The preferred chlorinating agent is N-chlorosuccinimide because of its ease of handling and use, its rapid reaction with 5-oxytetracycline and the high yields of chlorinated product it provides.
Med '’reaktionsinerte opløsningsmidler" menes opløsningsmidler, som under reaktionens betingelser ikke reagerer på uønsket måde med hverken udgangsforbindelserne eller slutprodukterne. Et minimum af laboratorieforsøg vil muliggøre udvælgelsen af egnede opløsningsmidler for fremgangsmåden ifølge opfindelsen. Disse opløsningsmidler er med vand blandbare opløsningsmidler og blandinger deraf med vand. Som eksempler på sådanne opløsningsmidler kan nævnes dioxan, tetrahydrofuran, acetone, dimethylether af diethylenglycol (diglym), dimethylether af ethylenglycol (mono-glym), acetonitril, methylethylketon, monoethylether af ethylenglycol, Ν,Ν-dimethylformamid, N,N-dimethylacetamid og blandinger af sådanne opløsningsmidler med vand. Sådanne opløsningsmidler kan udgøre en enkeltfase-reaktionsblanding for chlorerings-reaktionen og tillader let og fuldstændig udvinding af det ønskede hemiketal-syreadditionssalt. Et særlig nyttigt opløsningsmiddel er en blanding af acetone og vand.By "reaction-inert solvents" is meant solvents which, under the conditions of the reaction, do not react undesirably with either the starting compounds or the final products. A minimum of laboratory tests will allow the selection of suitable solvents for the process of the invention. These solvents are water miscible solvents and mixtures thereof. Examples of such solvents include dioxane, tetrahydrofuran, acetone, dimethyl ether of diethylene glycol (diglyme), dimethyl ether of ethylene glycol (monoglyc), acetonitrile, methyl ethyl ketone, monoethyl ether of ethylene glycol, Ν, Ν-dimethylformamide, N, N-dimethylacamide and such mixtures of such solvents with water Such solvents may constitute a single phase reaction mixture for the chlorination reaction and allow easy and complete recovery of the desired hemiketal acid addition salt. A particularly useful solvent is a mixture of acetone and water.
Chloreringen udføres ved en temperatur fra -10 til -40°C og mest ønskeligt ved mellem -30 og -40°C.The chlorination is carried out at a temperature of -10 to -40 ° C and most desirably at -30 to -40 ° C.
5-oxytetracyclinet kan anvendes i baseform eller som et syre-additionssalt.- Hydrochlorid-saltet er det foretrukne salt, da det er en stabil, let tilgængelig form af antibioti.cummet.The 5-oxytetracycline can be used in base form or as an acid addition salt. The hydrochloride salt is the preferred salt as it is a stable, readily available form of the antibiotic.
Der anvendes almindeligvis et svagt overskud af chloreringsmidlet, mest ønskeligt fra 1,1 til 1,4 mol pr. mol 5-oxytetracyclinbaseGenerally, a slight excess of the chlorinating agent is used, most desirably from 1.1 to 1.4 moles per liter. mole of 5-oxytetracycline base
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eller syreadditionssalt deraf. Reaktionshastigheden afhænger selvfølgelig af det valgte chloreringsmiddel, men reaktionen fuldføres almindeligvis i løbet af minutter.or acid addition salt thereof. The reaction rate, of course, depends on the chlorinating agent of choice, but the reaction is usually completed within minutes.
pH-værdien eller mere passende, når der arbejdes i et yandfrit opløsningsmiddel, den tilsyneladende pH-værdi af chloreringsreak-tionsblandingen ligger i området fra 6,5 til 7,7 og skal mest fordelagtigt være i området 7>3-7,5 for at opnå optimalt udbytte.The pH or more suitably when working in a non-solvent, the apparent pH of the chlorination reaction mixture is in the range of 6.5 to 7.7 and most preferably should be in the range of 7> 3-7.5 for to achieve optimal yield.
I betragtning af vanskeligheden ved måling af tilsyneladende pH-.værdi er det mere hensigtsmæssigt, i det mindste udfra et praktisk synspunkt, når der anvendes 5-oxytetracyclin-hydrochlorid som reaktant, at definere denne parameter som den mængde base, der anvendes til at neutralisere hydrochloridsaltet. På denne basis anvendes 0,20-0,40 g triethylamin pr. g 5-oxytetracyclin-hydrochlorid (ækvivalent med 1-2 mol triethylamin pr. mol oxytetra-cyclin-hydrochlorid eller et andet monobasisk syreadditionssalt) til at opnå det passende pH-område.Given the difficulty of measuring apparent pH, it is more convenient, at least from a practical point of view, when using 5-oxytetracycline hydrochloride as a reactant, to define this parameter as the amount of base used to neutralize the hydrochloride salt. On this basis, 0.20-0.40 g of triethylamine is used per day. g of 5-oxytetracycline hydrochloride (equivalent to 1-2 moles of triethylamine per mole of oxytetra-cyclin hydrochloride or another monobasic acid addition salt) to obtain the appropriate pH range.
Umiddelbart efter chloreringsreaktionen, som sker hurtigt, behandles reaktionsblandingen med en stærk mineralsyre for at sænke pH-værdien til under 1,0. Der anvendes mineralsyrer, såsom saltsyre, svovlsyre, hydrogenfluoridsyre, hydrogenbromidsyre og perchlorsyre. Den foretrukne mineralsyre er saltsyre, enten i gasform eller opløst form, da den danner det stabile, let isoler-bare hydrochlorid, det salt af lla-chlor-5-oxytetracyclin-6,12-hemiketal, der almindeligvis anvendes ved den industrielle fremstilling af 6oc-desoxy-5-oxytetracyclin.Immediately after the rapid chlorination reaction, the reaction mixture is treated with a strong mineral acid to lower the pH to below 1.0. Mineral acids such as hydrochloric acid, sulfuric acid, hydrofluoric acid, hydrobromic acid and perchloric acid are used. The preferred mineral acid is hydrochloric acid, either in gaseous or dissolved form, as it forms the stable, easily insulable hydrochloride, the salt of 11a-chloro-5-oxytetracycline-6,12-hemiketal commonly used in the industrial preparation of 6oC-deoxy-5-oxytetracycline.
lla-chlor-5-oxytetracyclin-6,12-hemiketal-saltet kan udvindes fra den sure blanding ved tilsætning af et ikke-opløsningsmiddel for saltet. Uopløseligheden af hydrochloridsaltet i acetone er hovedgrunden til at en blanding af acetone og vand er det foretrukne opløsningsmiddel for denne fremgangsmåde, og grunden til at hydrogenchlorid er det foretrukne syrningsmiddel for det afsluttende trin af fremgangsmåden.The 11a-chloro-5-oxytetracycline-6,12-hemiketal salt can be recovered from the acidic mixture by the addition of a non-solvent to the salt. The insolubility of the hydrochloride salt in acetone is the main reason why a mixture of acetone and water is the preferred solvent for this process, and the reason why hydrogen chloride is the preferred acidifier for the final step of the process.
Udvælgelsen af de bedste reaktionsbetingelser, f.eks. temperatur, opløsningsmiddel, chloreringsmiddel, syrningsmiddel og isolerings-metode, er et anliggende for rutineforsøg.The selection of the best reaction conditions, e.g. temperature, solvent, chlorinating agent, acidifying agent and isolation method, are a matter of routine experimentation.
5 DK 153400BDK 153400B
Fremgangsmåden ifølge opfindelsen belyses nærmere ved det følgende eksempel.The method according to the invention is illustrated in more detail by the following example.
EKSEMPELEXAMPLE
lla-chlor-5-oxytetracyclin-6,12-hemiketalhydrochloridlla-chloro-5-oxytetracycline-6,12-hemiketalhydrochlorid
En glasforet reaktor med. kappe, påfyldt 24 liter acetone, 4,5 liter afioniseret vand og 5 kg (10,06 mol) 5-oxytetracyclin omrøres og afkøles til -40°C ved hjælp af flydende nitrogen. Der tilsættes 1,6 liter (il,5 mol) triethylamin, forafkølet til -40°C, i løbet af 30 sekunder under samtidig tilsætning af flydende nitrogen for at holde temperaturen ved -40°C. Derpå tilsættes en opslæmning af 1,695 kg (11,5 mol) N-chlorsuccinimid i 3,8 liter acetone, forafkølet til -40°C, i løbet af 2 minutter under samtidig og fortsat tilsætning af flydende nitrogen for at holde temperaturen ved ~40°C.'Efter at tilsætningen er fuldført, standses indførelsen af flydende nitrogen, og reaktionsblandingen omrøres i 3 minutter. Derpå indføres en opløsning af 54 liter acetone, forafkølet til 8°C, hvortil der er sat 1,2 kg (33 mol) hydrogenohloridgas, i reaktionsblandingen i løbet af 2 minutter. For at fremskynde udfældningen af hydrochlorid-saltet sættes 125 g krystallinsk 11a-chlor-5-oxytetracyclin-6,12-hemiketal-hydrochlorid til reaktionsblandingen, når tilnærmelsesvis halvdelen af acetone-HCl-opløs-ningen er tilsat. Krystallisationen begynder straks. Reaktionsblandingen opvarmes til 15-18°C ved anvendelse af 60 0C varmt vand i kappén. Produktet granuleres i 1 time ved 15-20°C og derpå i 1,5 time ved mellem -5 og -10°C. Produktet udvindes ved filtrering, vaskes med acetone (3x3 liter) og tørres ved 30-35°C i en vacuumtørrer (udbytte 78,4%).A glass-lined reactor with. sheath, filled with 24 liters of acetone, 4.5 liters of deionized water and 5 kg (10.06 mol) of 5-oxytetracycline are stirred and cooled to -40 ° C by liquid nitrogen. 1.6 liters (1L, 5 moles) of triethylamine, pre-cooled to -40 ° C, are added over 30 seconds while simultaneously adding liquid nitrogen to keep the temperature at -40 ° C. Then a slurry of 1,695 kg (11.5 mol) of N-chlorosuccinimide in 3.8 liters of acetone, cooled to -40 ° C, is added over 2 minutes under simultaneous and continued addition of liquid nitrogen to keep the temperature at ~ 40 After completion of the addition, the introduction of liquid nitrogen is stopped and the reaction mixture is stirred for 3 minutes. Then a solution of 54 liters of acetone, pre-cooled to 8 ° C, to which 1.2 kg (33 moles) of hydrogen oloride gas is added, is added to the reaction mixture over 2 minutes. To accelerate the precipitation of the hydrochloride salt, 125 g of crystalline 11α-chloro-5-oxytetracycline-6,12-hemiketal hydrochloride is added to the reaction mixture when approximately half of the acetone-HCl solution is added. The crystallization begins immediately. The reaction mixture is heated to 15-18 ° C using 60 ° C hot water in the jacket. The product is granulated for 1 hour at 15-20 ° C and then for 1.5 hour at between -5 and -10 ° C. The product is recovered by filtration, washed with acetone (3x3 liters) and dried at 30-35 ° C in a vacuum dryer (yield 78.4%).
Claims (6)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US38496973A | 1973-08-02 | 1973-08-02 | |
| US38496973 | 1973-08-02 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK370074A DK370074A (en) | 1975-04-01 |
| DK153400B true DK153400B (en) | 1988-07-11 |
| DK153400C DK153400C (en) | 1988-11-28 |
Family
ID=23519498
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK370074A DK153400C (en) | 1973-08-02 | 1974-07-10 | PROCEDURE FOR 11A-CHLORATION OF 5-OXYTETRACYCLINE OR ANY ACID ADDITION SALT |
Country Status (28)
| Country | Link |
|---|---|
| JP (1) | JPS5835982B2 (en) |
| AR (1) | AR199626A1 (en) |
| AT (1) | AT333426B (en) |
| AU (1) | AU476600B2 (en) |
| BE (1) | BE817406A (en) |
| CA (1) | CA1008068A (en) |
| CH (1) | CH582650A5 (en) |
| CS (1) | CS183754B2 (en) |
| DD (1) | DD113527A5 (en) |
| DE (1) | DE2433608C2 (en) |
| DK (1) | DK153400C (en) |
| ES (1) | ES428365A1 (en) |
| FI (1) | FI59394C (en) |
| FR (1) | FR2239450B1 (en) |
| GB (1) | GB1465542A (en) |
| HK (1) | HK28479A (en) |
| HU (1) | HU170051B (en) |
| IE (1) | IE39803B1 (en) |
| IL (1) | IL45119A (en) |
| KE (1) | KE2934A (en) |
| LU (1) | LU70504A1 (en) |
| MY (1) | MY7900241A (en) |
| NL (1) | NL177596C (en) |
| PH (1) | PH10821A (en) |
| PL (1) | PL94201B1 (en) |
| SE (1) | SE416727B (en) |
| YU (1) | YU39463B (en) |
| ZA (1) | ZA744126B (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2984686A (en) * | 1960-12-19 | 1961-05-16 | Pfizer & Co C | 6-deoxy-6-demethyl-6-methylene-5-oxytetracyclines |
-
1974
- 1974-02-04 GB GB512474A patent/GB1465542A/en not_active Expired
- 1974-06-24 SE SE7408295A patent/SE416727B/en not_active IP Right Cessation
- 1974-06-24 CA CA203,251A patent/CA1008068A/en not_active Expired
- 1974-06-25 IL IL45119A patent/IL45119A/en unknown
- 1974-06-26 YU YU1788/74A patent/YU39463B/en unknown
- 1974-06-26 IE IE1360/74A patent/IE39803B1/en unknown
- 1974-06-26 ZA ZA00744126A patent/ZA744126B/en unknown
- 1974-06-27 PH PH15989A patent/PH10821A/en unknown
- 1974-07-05 FI FI2072/74A patent/FI59394C/en active
- 1974-07-05 AU AU70885/74A patent/AU476600B2/en not_active Expired
- 1974-07-09 JP JP49078645A patent/JPS5835982B2/en not_active Expired
- 1974-07-09 NL NLAANVRAGE7409249,A patent/NL177596C/en not_active IP Right Cessation
- 1974-07-09 BE BE1006064A patent/BE817406A/en not_active IP Right Cessation
- 1974-07-09 FR FR7423842A patent/FR2239450B1/fr not_active Expired
- 1974-07-10 DK DK370074A patent/DK153400C/en not_active IP Right Cessation
- 1974-07-10 CH CH950974A patent/CH582650A5/xx not_active IP Right Cessation
- 1974-07-10 DE DE2433608A patent/DE2433608C2/en not_active Expired
- 1974-07-11 LU LU70504A patent/LU70504A1/xx unknown
- 1974-07-12 AT AT579274A patent/AT333426B/en not_active IP Right Cessation
- 1974-07-17 HU HUPI426A patent/HU170051B/hu not_active IP Right Cessation
- 1974-07-17 ES ES428365A patent/ES428365A1/en not_active Expired
- 1974-07-17 PL PL1974172793A patent/PL94201B1/pl unknown
- 1974-07-18 AR AR254757A patent/AR199626A1/en active
- 1974-07-18 CS CS7400005144A patent/CS183754B2/en unknown
- 1974-07-18 DD DD179987A patent/DD113527A5/xx unknown
-
1979
- 1979-03-16 KE KE2934A patent/KE2934A/en unknown
- 1979-05-03 HK HK284/79A patent/HK28479A/en unknown
- 1979-12-30 MY MY241/79A patent/MY7900241A/en unknown
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