DK153393B - METHOD OF PREPARING METACYCLINE BY DEHALOGENING AN ACID ADDITION SALT OF 11A-CHLORO-6-DESOXY-6-DEMETHYL-6-METHYLENE-5-HYDROXYTETRACYCLINE - Google Patents
METHOD OF PREPARING METACYCLINE BY DEHALOGENING AN ACID ADDITION SALT OF 11A-CHLORO-6-DESOXY-6-DEMETHYL-6-METHYLENE-5-HYDROXYTETRACYCLINE Download PDFInfo
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DK 153393 BDK 153393 B
6-Desoxy-6-demetyl-6-metylentetracykliner er værdifulde antibiotika, og det vigtigste deraf er 6-desoxy- 6-demetyl-6-metylen-5-hydroxytetracyklin (metacyklin). Opfindelsen angår en særlig fremgangsmåde til fremstil-5 ling af denne forbindelse ved dehalogenering af et syreadditionssalt af 11a-klor-6-desoxy-6-demetyl-6-metylen- 5- hydroxytetracyklin, ved hvilken metacyklin opnås i næsten støkiometrisk udbytte.6-Deoxy-6-demethyl-6-methylenetetracyclines are valuable antibiotics, the most important of which is 6-deoxy-6-demethyl-6-methylene-5-hydroxytetracycline (methacycline). The invention relates to a particular process for preparing this compound by dehalogenating an acid addition salt of 11α-chloro-6-deoxy-6-demethyl-6-methylene-5-hydroxytetracycline, in which metacycline is obtained in almost stoichiometric yield.
Der har været beskrevet forskellige metoder til 10 fremstilling af 6-desoxy-6-demetyl-6-metylentetracykliner.Various methods have been described for the preparation of 6-deoxy-6-demethyl-6-methylenetetracyclines.
Den første er i portugisisk patentskrift nr. 36.099. Tysk patentskrift nr. 1.156.405, britisk patentskrift nr.The first is in Portuguese Patent Specification No. 36,099. German Patent No. 1,156,405, British Pat.
951.663 samt USA-patentskrift nr. 2.984.686, beskriver forskellige måder til fremstilling af 6-desoxy-6-deme-15 tyl-6-metylentetracykliner.No. 951,663 and U.S. Pat. No. 2,984,686 disclose various ways of preparing 6-deoxy-6-demethyl-6-methylenetetracyclines.
Udgangsmaterialet, for fremgangsmåden ifølge op findelsen er som nævnt 11a-klor-6-desoxy-6-demetyl-6-me-tylen-5-hydroxytetracyklin som først er beskrevet i portugisisk patentskrift nr. 36.099 af 19. maj 1959 og hvis 20 fremstilling beskrives omstående.The starting material for the process according to the invention is, as mentioned, 11a-chloro-6-deoxy-6-methyl-6-methylene-5-hydroxytetracycline first described in Portuguese Patent No. 36,099 of 19 May 1959 and whose preparation the following is described.
Det har vist sig, at 11a-klor-6-desoxy-6-demetyl- 6- metylen-5-hydroxytetracyklin let dehalogeneres uden destruktion af molekylet med hydrazin i en mindst ækvimo-lekylær mængde i nærværelse af en katalysator bestående 25 af palladium på en bærer i et inaktivt reaktionsmedium, hvorved der dannes metacyklin. Fremgangsmåden ifølge opfindelsen er i overensstemmelse hermed ejendommelig ved det i krav 1's kendetegnende del anførte.It has been found that 11α-chloro-6-deoxy-6-demethyl-6-methylene-5-hydroxytetracycline is readily dehalogenated without destroying the molecule with hydrazine in a least equimolecular amount in the presence of a palladium 25 catalyst. a carrier in an inactive reaction medium to form metacycline. Accordingly, the process according to the invention is characterized by the characterizing part of claim 1.
En betydelig fordel ved fremgangsmåden ifølge op-30 findelsen ligger i, at det sekundære produkt, der fås ved omsætningen, er nitrogen, som naturligvis ikke generer isoleringen af slutproduktet i ren form.A significant advantage of the process according to the invention lies in the fact that the secondary product obtained by the reaction is nitrogen which does not, of course, interfere with the isolation of the final product in pure form.
Det vides at hydrazin i nærværelse af palladium nedbrydes til nitrogen og hydrogen, som oplyst af A.It is known that hydrazine in the presence of palladium is degraded to nitrogen and hydrogen, as stated by A.
35 Fuerst et al. i Chem. Rev. ^5, 51-68 (1964). Nedbrydningen sker formentlig via dimeren:Fuerst et al. in Chem. Rev. 5, 51-68 (1964). The decomposition is probably via the dimer:
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NH, NH NNH, NH N
j -) || + H2->|H + 2H2j -) || + H2-> | H + 2H2
NH2 NH NNH2 NH N
5' En konkurrerende nedbrydning er: NH2 3 | —> 4NH3 + N2 NH2 10 hvilket viser at der fortrinsvis skal bruges overskud af hydrazin.5 'A competing decomposition is: NH2 3 | -> 4NH3 + N2 NH2 10 which shows that excess hydrazine should preferably be used.
Ved fremgangsmåden beskrevet i tysk patentskrift nr. 1.156.405 og i britisk patentskrift nr. 951.663 fås 6-desoxy-6-demetyl-6-metylentetracykliner ved syrebehandling 15 af 12-svovlsyreesteren af tetracyklin. Udbytterne er relativt lave på grund af partiel dekomponering af metylen-tetracyklinerne i de stærkt sure medier. Portugisisk patentskrift nr. 36.099 beskriver dehalogenering af 11a-ha-logen-6-desoxy-6-demetyl-6-metylentetracykliner med hydro-20 sulfit, og ifølge USA-patentskrift nr. 2.984.686 udføres 11a-dehalogenering med zink og en mineralsyre; jern og fortyndet saltsyre; alkalimetalhydrosulfit i vandige medier; natriumjodid i et medium der optager halogen, såsom acetone; eller ved katalytisk hydrogenering. Ved de nævnte 25 fremgangsmåder undtagen ved den katalytiske hydrogenering dannes der biprodukter såsom zinkklorid, jernklorid, frit svovl (ofte i kolloid tilstand), natriumjodid eller natriumklorid, som skal adskilles fra de ønskede metylen-tetracykliner. Imidlertid er fraskillelse af urenhederne 30 vanskelig, og udbytterne formindskes i betydelig grad.By the process described in German Patent No. 1,156,405 and in British Patent No. 951,663, 6-deoxy-6-demethyl-6-methylenetetracyclines are obtained by acid treatment of the 12-sulfuric acid ester of tetracycline. The yields are relatively low due to partial decomposition of the methylene tetracyclines in the highly acidic media. Portuguese Patent Specification No. 36,099 discloses dehalogenation of 11α-ha-logene-6-deoxy-6-demethyl-6-methylenetetracyclines with hydrosulfite, and in U.S. Pat. ; iron and dilute hydrochloric acid; alkali metal hydrosulfite in aqueous media; sodium iodide in a halogen-absorbing medium such as acetone; or by catalytic hydrogenation. By the aforementioned processes except for the catalytic hydrogenation, by-products such as zinc chloride, iron chloride, free sulfur (often in colloidal state), sodium iodide or sodium chloride are formed which must be separated from the desired methylene tetracyclines. However, separation of the impurities is difficult and the yields are greatly reduced.
Ved den katalytiske hydrogenering fås der ikke sekundære produkter ved selve omsætningen, men det molekyle der skal dehalogeneres, sønderdeles i betydelig grad, og endvidere har nærværende opfinder fundet at der dannes a-35 og β-desoxytetracykliner, selv hvis hydrogeneringen standses når der er optaget nøjagtigt den ækvimolekylære mængde hydrogen der er nødvendigt til dehalogenering.In the catalytic hydrogenation, secondary products are not obtained by the reaction itself, but the molecule to be dehalogenated is decomposed to a considerable extent, and further, the present inventor has found that α-35 and β-desoxytetracyclines are formed even if the hydrogenation is stopped when taken up. exactly the equimolecular amount of hydrogen needed for dehalogenation.
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Dehalogenering udført med hydrazin under anvendelse af en katalysator bestående af palladium på kul er mere fordelagtigt end den direkte katalytiske hydrogenering og kræver ikke anvendelse af forhøjet tryk eller spe-5 cielt apparatur. Den er mindre risikabel end katalytisk hydrogenering? der sker ikke sønderdeling af det molekyle der skal dehalogeneres, og ledsagende dannelse af a-og β-6-desoxytetracykliner er forsvindende.Dehalogenation performed with hydrazine using a palladium-based catalyst on coal is more advantageous than the direct catalytic hydrogenation and does not require the use of elevated pressure or special apparatus. It is less risky than catalytic hydrogenation? there is no decomposition of the molecule to be dehalogenated and concomitant formation of α- and β-6-deoxytetracyclines is vanishing.
Det ved fremgangsmåden ifølge opfindelsen anvend-10 te udgangsmateriale er som nævnt et syreadditionssalt af 11a-klor-6-desoxy-6-demetyl-6-metylen-5-hydroxytetracyklin, fx hydrokloridet, hydrofluoridet eller p-toluensulfonatet.The starting material used in the process according to the invention is, as mentioned, an acid addition salt of 11a-chloro-6-deoxy-6-methylene-5-hydroxytetracycline, for example the hydrochloride, hydrofluoride or p-toluenesulfonate.
Passende reaktionsmedier til udførelse af reduktionen med hydrazin er lavere alifatiske alkoholer, te-15 trahydrofuran, dioxan, lavere dialkylformamider, acetone, vand og blandinger heraf. Når udgangs-pH-værdien er højere end 3, foretrækkes det at anvende vandfri medier som reaktionsmedium. Til udførelse af denne metode kan der anvendes hydrazinhydrat eller et hydrazin-syreadditions-20 salt, fx hydrokloridet eller sulfatet.Suitable reaction media for carrying out the reduction with hydrazine are lower aliphatic alcohols, tetrahydrofuran, dioxane, lower dialkyl formamides, acetone, water and mixtures thereof. When the initial pH is higher than 3, it is preferred to use anhydrous media as the reaction medium. To carry out this method, hydrazine hydrate or a hydrazine acid addition salt may be used, for example the hydrochloride or sulfate.
Reaktionstemperaturen er ikke kritisk, idet den ligger mellem -10° og +50°C.The reaction temperature is not critical since it is between -10 ° and + 50 ° C.
Den anvendte mængde palladium til reaktionen er ikke kritisk, idet så lidt som 0,001 vægtdel af 5%s palla-25 dium på kul pr. vægtdel 11a-klormetacyklin allerede vil fremme dehalogeneringen, selv om reaktionen så er langsom.The amount of palladium used for the reaction is not critical as as little as 0.001 part by weight of 5% palladium on coal per kilogram. weight portion 11a-chloromethacycline will already promote dehalogenation, although the reaction is slow.
Isoleringen af metacyklin kan let udføres på konventionel måde, fx ved filtrering af reaktionsblandingen og sur-gøring med ætanolisk eller metanolisk hydrogenklorid, 30 hvorved hydrokloridet fås i ren form. På samme måde fås andre syreadditionssalte af 6-metacyklin ved behandling af den filtrerede reaktionsblanding med den ønskede syre og udkrystallisering ved tilsætning af et ikke-opløsnings-middel.The isolation of metacycline can be readily carried out in a conventional manner, for example, by filtration of the reaction mixture and acidification with ethanolic or methanolic hydrogen chloride to give the hydrochloride in pure form. Similarly, other acid addition salts of 6-metacycline are obtained by treating the filtered reaction mixture with the desired acid and crystallizing by the addition of a non-solvent.
35 Fremgangsmåden ifølge opfindelsen skal i det føl gende belyses nærmere ved eksemplerne 1-3; forud for dem beskrives fremstilling af udgangsmaterialet.The method according to the invention will now be illustrated in more detail by Examples 1-3; prior to them is described the preparation of the starting material.
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Fremstilling af udgangsmaterialer I. Fremstilling af 1. la-klor-5-hydroxytetracyklin i overensstem-meise_me<3_ portugisisk j>a±er^sjg^i_f_fc_ _nr_._ _3_6_._0_9_9______________ a) 0,7 g vandfrit klor i 25 ml 1,2-dimetoxyætan 5 sættes hurtigt til 9f5 g oxytetracyklin-hydroklorid med høj renhed i 25 ml diætoxyætan indeholdende 5,6 ml tri-ætylamin ved en temperatur på 0°C, hvorpå der tilsættes 125 ml af en blanding af vand og is, der efterfølges af en tilsætning af yderligere 300 ml af en blanding af vand 10 og is efter 12 minutters forløb. Bundfaldet frafiltreres, vaskes med vand og acetone og tørres derpå ved 10°C, hvorved der vindes 11a-klor-5-hydroxytetracyklin i form af 6,12-hemiketalet. Smeltepunkt 177-17 8°C (dekompone-ring), [a] = -27,5 (c = 1 i metanol indeholdende 1% kon- ^ 1 CJ.Preparation of Starting Materials I. Preparation of 1.la-chloro-5-hydroxytetracycline in accordance with Portuguese <3_ Portuguese j> a ± is ^ sjg ^ i_f_fc_ _nr _._ _3_6 _._ 0_9_9______________ a) 0.7 g anhydrous chlorine in 25 ml 2-Dimethoxyethane 5 is rapidly added to 9f5 g of high purity oxytetracycline hydrochloride in 25 ml of diethoxyethane containing 5.6 ml of triethylamine at a temperature of 0 ° C, to which is added 125 ml of a mixture of water and ice, followed by the addition of an additional 300 ml of a mixture of water 10 and ice after 12 minutes. The precipitate is filtered off, washed with water and acetone and then dried at 10 ° C to give 11a-chloro-5-hydroxytetracycline in the form of the 6,12-hemiketal. Melting point 177-17 8 ° C (decomposition), [α] = -27.5 (c = 1 in methanol containing 1% conc -1 CJ.
15 centreret saltsyre), E'° =430 ved 266 + 2nm i metanol indeholdende 1% koncentreret saltsyre. Den infrarøde kurve har intet absorptionsmaksimum i området omkring 5,9μ.= 430 at 266 + 2nm in methanol containing 1% concentrated hydrochloric acid. The infrared curve has no absorption maximum in the range of about 5.9µ.
b) 13,5 g N-klorsuccinimid tilsættes hurtigt til en opløsning indeholdende 46,5 g vandfrit oxytetracyklin- 20 base i 200 ml diætoxyætan og 0,5 ml triætylamin ved 0°C under kraftig omrøring. Efter 6 minutters forløb tilsættes 1000 ml vand (pH-værdien indstilles automatisk til tilnærmelsesvis det isoelektriske punkt), hvorved der fås et smudsighvidt bundfald. Det filtreres og vaskes med 25 vand, hvorved der fås 11,6 g 11a-klor-5-hydroxytetracyk-lin som 6,12-hemiketalet.b) 13.5 g of N-chlorosuccinimide are rapidly added to a solution containing 46.5 g of anhydrous oxytetracycline base in 200 ml of diethoxyethane and 0.5 ml of triethylamine at 0 ° C with vigorous stirring. After 6 minutes, 1000 ml of water is added (the pH value is automatically adjusted to approximately the isoelectric point) to give a dirty white precipitate. It is filtered and washed with 25 water to give 11.6 g of 11α-chloro-5-hydroxytetracycline as the 6,12 hemiketal.
c) 25 g oxytetracyklin-hydroklorid i 225 ml dime-tylformamid og 7,1 ml triætylamin i 25 ml dimetylforma-_ mid blandes, og blandingen afkøles til -10°C under kraf- 30 tig omrøring. 7 g N-klorsuccinimid tilsættes hurtigt og efter 2,5 minutters forløb tilsættes der 750 ml af en blanding af vand og is. Efter 12 minutters forløb fortyndes det således frembragte tætte bundfald ved tilsætning af 375 ml af en blanding af vand og is. Det filtre-35 res, vaskes med vand og acetone og tørres, hvorved der fås 11a-klor-5-hydroxytetracyklin-6,12-hemiketal. Smp. 180-185°C (dekomponering), [a]D -25 - 2,5 (c = 1% i meta-c) Mix 25 g of oxytetracycline hydrochloride in 225 ml of dimethylformamide and 7.1 ml of triethylamine in 25 ml of dimethylformamide and cool the mixture to -10 ° C with vigorous stirring. 7 g of N-chlorosuccinimide are added rapidly and after 2.5 minutes 750 ml of a mixture of water and ice are added. After 12 minutes, the dense precipitate thus produced is diluted by adding 375 ml of a mixture of water and ice. It is filtered, washed with water and acetone and dried to give 11a-chloro-5-hydroxytetracycline-6,12-hemiketal. Mp. 180-185 ° C (decomposition), [α] D -25-2.5 (c = 1% in meta-
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5 1 % nol indeholdende 1% koncentreret saltsyre), E, 432 ved 1 cm 266 nm og 91 ved 340 til 345 nm i metanol indeholdende 1% koncentreret saltsyre.5, 132 nol containing 1% concentrated hydrochloric acid), E, 432 at 1 cm 266 nm and 91 at 340 to 345 nm in methanol containing 1% concentrated hydrochloric acid.
5 II. Fremstilling af 11a-klor-6-desoxy-6-demetyl-6-me-j-Yl^Bz^zhYdroxytetracyklin i) 5 g 11a-klor-5-hydroxytetracyklin i form af 6,12-hemiketalbasen opnået ved metoden beskrevet under a), b) eller c) blandes med 4 ml metanol og 30 ml isopropyl-10 alkohol. Der tilsættes derpå 26 ml absolut ætanol indeholdende 17 vægt% vandfrit hydrogenklorid. Produktet opløses og begynder derpå at udkrystallisere. Efter 18 timers henstand ved stuetemperatur filtreres bundfaldet og vaskes med isopropylalkohol. Den ikke-omsatte del af 11a-15 klor-5-hydroxytetracyklinet, der forefindes som hydroklo-ridet, elimineres fra blandingen ved filtrering (smeltepunkt: 212-216°C, [a] -22,5 (c = 1% i metanol indehol- ^ 19* dende 1% koncentreret saltsyre), E'° = 400 ved 266-268 mp og 85 ved 337-341 mp). Ved tilsætning af isopropylæter 20 til filtratet udfælder 1,1 g 11a-klor-6-desoxy-6-deme-tyl-6-metylen-5-hydroxytetracyklin-hydroklorid, der kun har ét maksimum indenfor 5-6p området, og det ligger ved 5,72μ.II. Preparation of 11α-Chloro-6-deoxy-6-demethyl-6-meth-γ-Yl ^Bz ^zhydroxytetracycline i) 5 g of 11α-chloro-5-hydroxytetracycline in the form of the 6,12-hemiketal base obtained by the method described under a. ), b) or c) are mixed with 4 ml of methanol and 30 ml of isopropyl alcohol. Then 26 ml of absolute ethanol containing 17% by weight of anhydrous hydrogen chloride is added. The product dissolves and then crystallizes out. After standing for 18 hours at room temperature, the precipitate is filtered and washed with isopropyl alcohol. The unreacted portion of the 11α-15-chloro-5-hydroxytetracycline, which is present as the hydrochloride, is eliminated from the mixture by filtration (m.p. 212-216 ° C, [α] -22.5 (c = 1% in methanol) containing 1% concentrated hydrochloric acid), E + = 400 at 266-268 mp and 85 at 337-341 mp). When adding isopropyl ether 20 to the filtrate, 1.1 g of 11α-chloro-6-deoxy-6-demethyl-6-methylene-5-hydroxytetracycline hydrochloride, which has only one maximum within the 5-6p range, precipitates at 5.72µ.
3,3 g af det ikke-omsatte 11a-klorderivat isole-25 ret ovenfor som hydrokloridet behandles med 10 ml vandfrit hydrogenklorid ved en temperatur på -5°C i 3 timer.3.3 g of the unreacted 11α-chloro derivative isolated above as the hydrochloride is treated with 10 ml of anhydrous hydrogen chloride at a temperature of -5 ° C for 3 hours.
Derpå afdestilleres hydrogenkloridet, og remanensen opløses i vandfrit metanol, idet pH-værdien indstilles til 5,5 med triætylamin,11a-klor-6-desoxy-6-demetyl-6-me-30 tylen-5-hydroxytetracyklinbasen udkrystalliserer langsomt som solvatet» Den vandfri base har følgende egenskaber: dekomponering ved 176°C, [a]n +35 (c=1% i meta- ^ 1 % nol indeholdende 1% koncentreret saltsyre), E., 371 ved J 1 cm 270 mp og 430 ved 237-239 mp i metanol indeholdende 1% 35 saltsyre; 100 mg opløses i 18 ml ætanol, 440 ml metanol, 22 ml dioxan, 60 ml acetone og 1 ml dimetylformamid. Den infrarøde kurve viser hovedmaksima ved 2,8p, 2,98p, 3,25p,The hydrogen chloride is then distilled off and the residue is dissolved in anhydrous methanol, the pH adjusted to 5.5 with triethylamine, 11a-chloro-6-deoxy-6-methylene-5-hydroxytetracycline base, which crystallizes slowly as the solvate. The anhydrous base has the following properties: decomposition at 176 ° C, [a] n + 35 (c = 1% in meta ^ 1% nol containing 1% concentrated hydrochloric acid), E., 371 at J 1 cm 270 mp and 430 at 237-239 mp in methanol containing 1% hydrochloric acid; Dissolve 100 mg in 18 ml of ethanol, 440 ml of methanol, 22 ml of dioxane, 60 ml of acetone and 1 ml of dimethylformamide. The infrared curve shows the main maxima at 2.8p, 2.98p, 3.25p,
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6 5,72μ, 6,08μ, 6,3μ, 7,8μ, 8,1μ, 8,42μ, 9,0μ, 9,18μ, 0,73μ, 10,6μ, 10,76μ, 10,82μ, 11,6μ, 12,1μ og 12,3μ.6 5.72µ, 6.08µ, 6.3µ, 7.8µ, 8.1µ, 8.42µ, 9.0µ, 9.18µ, 0.73µ, 10.6µ, 10.76µ, 10.82µ, 11 , 6µ, 12.1µ and 12.3µ.
ii) 5 g ikke-omsat 11a-klor-5-hydroxytetracyklin-hydroklorid opnået efter metoden mærket i) suspenderes i 5 15 ml af en blanding af 1:3 ætylcellosolve og butanol, hvorpå der tilsættes 15 ml hydrogenfluorid ved -18°C.ii) 5 g of unreacted 11α-chloro-5-hydroxytetracycline hydrochloride obtained by the method labeled i) are suspended in 5 ml of a mixture of 1: 3 ethylcelllosolve and butanol, to which 15 ml of hydrogen fluoride is added at -18 ° C.
Efter omrøring i 3 timer ved en temperatur mellem -4°C til 0°C fjernes hydrogenkloridet ved hjælp af en nitrogenstrøm, og produktet udfældes ved tilsætning af isopro-10 pylæter, hvorved der fås 4,4 g 11a-klor-6-desoxy-6-deme-tyl-6-metylen-5-hydroxytetracyklin-hydrofluorid, som de-komponerer ved 220°C, e}% 421 ved 235 mp, 272 ved 272- 274 mp og 60 ved 377-379 mp i metanol indeholdende 1% koncentreret saltsyre. Den infrarøde kurve har et enkelt 15 maksimum indenfor 5,6μ området, nemlig ved 5,72μ.After stirring for 3 hours at a temperature between -4 ° C to 0 ° C, the hydrogen chloride is removed by a stream of nitrogen and the product precipitated by the addition of isopropyl ether to give 4.4 g of 11α-chloro-6-deoxy -6-demethyl-6-methylene-5-hydroxytetracycline hydrofluoride, which decomposes at 220 ° C, e}% 421 at 235 mp, 272 at 272-2274 mp, and 60 at 377-379 mp in methanol containing 1% concentrated hydrochloric acid. The infrared curve has a single maximum within the 5.6µ range, namely at 5.72µ.
Eksempel 1 2,5 g 10%s palladium på kul og 2 ml 15%s hydra-2Q zinhydrat sættes til 5 g (10,06 mmol) 11a-klor-6-desoxy- 6-demetyl-6-metylen-5-hydroxytetracyklin, hydrofluorid i 100 ml ætanol. Der tilsættes 2,7 ml 15%s hydrazinhydrat (dvs. sammenlagt 14,08 mmol) efter 15 minutters forløb.Example 1 2.5 g of 10% s palladium on coal and 2 ml of 15% s of hydra-2Q zine hydrate are added to 5 g (10.06 mmol) of 11α-chloro-6-deoxy-6-demethyl-6-methylene-5- hydroxytetracycline, hydrofluoride in 100 ml of ethanol. 2.7 ml of 15% hydrazine hydrate (ie a total of 14.08 mmol) is added after 15 minutes.
Efter omrøring natten over frafiltreres reaktionsblandin-2^ gen og der tilsættes 5 g 5-sulfosalicylsyre og 200 ml vand. Efter henståen i 1 time under omrøring filtreres og bundfaldet vaskes og tørres. Der vindes 5,5 g 6-desoxy- 6-demetyl-6-metylen-5-hydroxytetracyklin som sulfosalicy-latet, der smelter ved 189-193°C og har en specifik drej-ning [a]D = -220 (c=1 i metanol indeholdende 1% koncentreret saltsyre), eI* = 397 ved 238 nm og 219 ved 345 nm.After stirring overnight, the reaction mixture-2β gene is filtered off and 5 g of 5-sulfosalicylic acid and 200 ml of water are added. After standing for 1 hour with stirring, filter and wash the precipitate and dry. 5.5 g of 6-deoxy-6-demethyl-6-methylene-5-hydroxytetracycline is obtained as the sulfosalicylate, which melts at 189-193 ° C and has a specific rotation [a] D = -220 (c = 1 in methanol containing 1% concentrated hydrochloric acid), eI * = 397 at 238 nm and 219 at 345 nm.
35 7 DK Ί53393Β35 7 DK Ί53393Β
Eksempel 2 1,25 g 5%s palladium på kul suspenderes i 15 ml 70%s vandigt dimetylformamid. 5 g (7,70 mmol) 11a-klor- 6-desoxy-6-demetyl-6-metylen-5-hydroxytetracyklin-p-tolu-5 ensulfat opløses i 25 ml 70%s vandigt dimetylformamid og der tilsættes 2 g (15,37 mmol) hydrazinsulfat. Efter omrøring natten over filtreres og der tilsættes 33 ml vand og 5 g 5-sulfosalicylsyre, hvorved der vindes 4,9 g meta-cyklin-sulfosalicylat der svarer til det i eksempel 1 op-10 nåede.Example 2 1.25 g of 5% palladium on coal is suspended in 15 ml of 70% aqueous dimethylformamide. Dissolve 5 g (7.70 mmol) of 11α-chloro-6-deoxy-6-demethyl-6-methylene-5-hydroxytetracycline-p-toluene sulfate in 25 ml of 70% aqueous dimethylformamide and add 2 g (15 g). , 37 mmol) hydrazine sulfate. After stirring overnight, filter and add 33 ml of water and 5 g of 5-sulfosalicylic acid to give 4.9 g of meta-cyclin-sulfosalicylate corresponding to that obtained in Example 1.
Eksempel 3 7,43 g 5%s palladium på kul (indeholdende 57% vand) suspenderes i 57 ml vand og der tilsættes 120 ml isopropylalkohol. Blandingen opvarmes til 50°C og der tilsættes 50 g (77,03 mmol) 11a-klor-6-desoxy-6-deme-tyl-6-metylen-5-hydroxytetracyklin-p-toluensulfonat. I løbet af 20 minutter tilsættes der 4 ml (82,30 mmol) hy-2q drazinhydrat i 4 ml ætanol. Reaktionsblandingen omrøres i 35 minutter ved 50°C og filtreres derpå gennem et cellulose-f ilterhjælpemiddel. Under omrøring tilsættes der 120 ml koncentreret saltsyre, blandingen omrøres i 2,5 timer, afkøles til 80°C og filtreres. Det opsamlede fa-2^ ste stof vaskes med hexan, vand og acetone og tørres ved 35°C til frembringelse af 26,9g 6-desoxy-6-demetyl-6-me-tylen-5-hydroxytetracyklin-hydroklorid. Produktet har [a] = -302,8° (c=1 i metanol indeholdende 1% koncentre- ^ 15- ret saltsyre) og °cm = 307 ved 344-346 nm. 1 35Example 3 7.43 g of 5% palladium on coal (containing 57% water) is suspended in 57 ml of water and 120 ml of isopropyl alcohol is added. The mixture is heated to 50 ° C and 50 g (77.03 mmol) of 11α-chloro-6-deoxy-6-demethyl-6-methylene-5-hydroxytetracycline p-toluenesulfonate are added. Over 20 minutes, add 4 ml (82.30 mmol) of hydroxydrine hydrate in 4 ml of ethanol. The reaction mixture is stirred for 35 minutes at 50 ° C and then filtered through a cellulose filter aid. With stirring, 120 ml of concentrated hydrochloric acid are added, the mixture is stirred for 2.5 hours, cooled to 80 ° C and filtered. The collected solid is washed with hexane, water and acetone and dried at 35 ° C to give 26.9g of 6-deoxy-6-demethyl-6-methylene-5-hydroxytetracycline hydrochloride. The product has [a] = -302.8 ° (c = 1 in methanol containing 1% concentrated hydrochloric acid) and ° cm = 307 at 344-346 nm. 1 35
Claims (3)
Applications Claiming Priority (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PT5410870 | 1970-07-03 | ||
| PT5410670 | 1970-07-03 | ||
| PT5410670 | 1970-07-03 | ||
| PT5410770 | 1970-07-03 | ||
| PT5410870 | 1970-07-03 | ||
| PT5410770 | 1970-07-03 | ||
| PT5410871 | 1971-05-03 | ||
| PT5410871 | 1971-05-03 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DK153393B true DK153393B (en) | 1988-07-11 |
| DK153393C DK153393C (en) | 1988-11-28 |
Family
ID=27484428
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK318271A DK153393C (en) | 1970-07-03 | 1971-06-29 | METHOD OF PREPARING METACYCLINE BY DEHALOGENING AN ACID ADDITION SALT OF 11A-CHLORO-6-DESOXY-6-DEMETHYL-6-METHYLENE-5-HYDROXYTETRACYCLINE |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JPS5248982B1 (en) |
| AR (1) | AR194079A1 (en) |
| DK (1) | DK153393C (en) |
| HK (1) | HK78779A (en) |
Family Cites Families (6)
| 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 |
| FR1430859A (en) * | 1960-05-23 | 1966-05-25 | ||
| ES262850A1 (en) * | 1960-07-23 | 1961-02-01 | Hovione Soc Ind Y Com De Produ | Process of fermentation of chlortetracycline and tetracycline antibiotics |
| US3183267A (en) * | 1962-09-06 | 1965-05-11 | Pfizer & Co C | 6-methylenetetracycline derivatives |
| US3444198A (en) * | 1967-02-13 | 1969-05-13 | Pfizer & Co C | Process for producing alpha-6-deoxytetracyclines |
| CA942743A (en) * | 1970-07-03 | 1974-02-26 | Ivan Villax | Process for producing 6-methylenetetracyclines and 6-deoxytetracyclines |
-
1971
- 1971-06-29 DK DK318271A patent/DK153393C/en not_active IP Right Cessation
- 1971-07-02 JP JP4869871A patent/JPS5248982B1/ja active Pending
- 1971-07-02 AR AR23657971A patent/AR194079A1/en active
-
1979
- 1979-11-15 HK HK78779A patent/HK78779A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| HK78779A (en) | 1979-11-23 |
| DK153393C (en) | 1988-11-28 |
| JPS5248982B1 (en) | 1977-12-14 |
| AR194079A1 (en) | 1973-06-22 |
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