DE2631676A1 - PROCESS FOR THE PREPARATION OF ANHYDRO-5-HYDROXY-TETRACYCLIN - Google Patents
PROCESS FOR THE PREPARATION OF ANHYDRO-5-HYDROXY-TETRACYCLINInfo
- Publication number
- DE2631676A1 DE2631676A1 DE19762631676 DE2631676A DE2631676A1 DE 2631676 A1 DE2631676 A1 DE 2631676A1 DE 19762631676 DE19762631676 DE 19762631676 DE 2631676 A DE2631676 A DE 2631676A DE 2631676 A1 DE2631676 A1 DE 2631676A1
- Authority
- DE
- Germany
- Prior art keywords
- anhydro
- mixture
- tetracycline
- hydroxy
- hydroxytetracycline
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims description 16
- 238000002360 preparation method Methods 0.000 title claims description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 239000004098 Tetracycline Substances 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 229960002180 tetracycline Drugs 0.000 claims description 7
- 230000018044 dehydration Effects 0.000 claims description 6
- 238000006297 dehydration reaction Methods 0.000 claims description 6
- 229940071103 sulfosalicylate Drugs 0.000 claims description 6
- IWVCMVBTMGNXQD-PXOLEDIWSA-N oxytetracycline Chemical compound C1=CC=C2[C@](O)(C)[C@H]3[C@H](O)[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-PXOLEDIWSA-N 0.000 claims description 5
- MOODSJOROWROTO-UHFFFAOYSA-N salicylsulfuric acid Chemical compound OC(=O)C1=CC=CC=C1OS(O)(=O)=O MOODSJOROWROTO-UHFFFAOYSA-N 0.000 claims description 5
- 229940087646 methanolamine Drugs 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 239000000047 product Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 235000019364 tetracycline Nutrition 0.000 description 5
- 150000003522 tetracyclines Chemical class 0.000 description 5
- 239000012453 solvate Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 229930101283 tetracycline Natural products 0.000 description 4
- WXHLLJAMBQLULT-UHFFFAOYSA-N 2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-n-(2-methyl-6-sulfanylphenyl)-1,3-thiazole-5-carboxamide;hydrate Chemical compound O.C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1S WXHLLJAMBQLULT-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229940040944 tetracyclines Drugs 0.000 description 2
- SVDOODSCHVSYEK-IFLJXUKPSA-N (4s,4ar,5s,5ar,6s,12ar)-4-(dimethylamino)-1,5,6,10,11,12a-hexahydroxy-6-methyl-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide;hydron;chloride Chemical compound Cl.C1=CC=C2[C@](O)(C)[C@H]3[C@H](O)[C@H]4[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]4(O)C(=O)C3=C(O)C2=C1O SVDOODSCHVSYEK-IFLJXUKPSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- IJCMDGBKHKZSJL-UHFFFAOYSA-N acetonitrile sulfuric acid Chemical compound S(=O)(=O)(O)O.S(O)(O)(=O)=O.C(C)#N IJCMDGBKHKZSJL-UHFFFAOYSA-N 0.000 description 1
- 125000001539 acetonyl group Chemical group [H]C([H])([H])C(=O)C([H])([H])* 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- 229940106681 chloroacetic acid Drugs 0.000 description 1
- CYDMQBQPVICBEU-UHFFFAOYSA-N chlorotetracycline Natural products C1=CC(Cl)=C2C(O)(C)C3CC4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O CYDMQBQPVICBEU-UHFFFAOYSA-N 0.000 description 1
- CYDMQBQPVICBEU-XRNKAMNCSA-N chlortetracycline Chemical compound C1=CC(Cl)=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O CYDMQBQPVICBEU-XRNKAMNCSA-N 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000000887 hydrating effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- QZIQJVCYUQZDIR-UHFFFAOYSA-N mechlorethamine hydrochloride Chemical compound Cl.ClCCN(C)CCCl QZIQJVCYUQZDIR-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- FKSLYSSVKFYJKE-UHFFFAOYSA-N n,n-diethylethanamine;methanol Chemical compound OC.CCN(CC)CC FKSLYSSVKFYJKE-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- IWVCMVBTMGNXQD-UHFFFAOYSA-N terramycin dehydrate Natural products C1=CC=C2C(O)(C)C3C(O)C4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-UHFFFAOYSA-N 0.000 description 1
- OFVLGDICTFRJMM-WESIUVDSSA-N tetracycline Chemical compound C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O OFVLGDICTFRJMM-WESIUVDSSA-N 0.000 description 1
- 229940072172 tetracycline antibiotic Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
SCHIFF ν. FÜNER STREHL SCHÜBEL-HOPF EBB1NGHAUSSHIP ν. FÜNER STREHL SCHÜBEL-HOPF EBB1NGHAUS
MArTaHILFPLATZ a & 3, MÖNCHEN 9O Z D J I D / DMARTaHILFPLATZ a & 3, MÖNCHEN 9O Z D J I D / D
PLIVA pharmazeutische und chemische FabrikPLIVA pharmaceutical and chemical factory
TELEFON (ΟΒβ) 48 2Ο64. TELEX β-23 565 AURO DTELEPHONE (ΟΒβ) 48 2Ο64. TELEX β-23 565 AURO D.
14. Juli 1976July 14, 1976
DA-17 098DA-17 098
Priorität : 14. Juli 1975, Jugoslawien, Hr. P1789/75Priority: July 14, 1975, Yugoslavia, Mr. P1789 / 75
tetracyclintetracycline
Die Erfindung betrifft ein Verfahren zur Herstellung von 5a>6-Anhydr-o-5-hydro:xy-tetracycl.\n durch Dehydratation von 5-Hydroxy-tetracyclin.The invention relates to a process for the production of 5a > 6-anhydr-o-5-hydro: xy-tetracycline by dehydrating 5-hydroxy-tetracycline.
Anhydrotetracycline stellen interessante Tetracyclinantibiotika dar, welche gewisse - jedoch von der Wirkung des Tetracycline abweichende - antibakterielle Wirkungen aufweisen (Biochem.Z. 544 (1966) 76). Einige Anhydroderivate werden durch biologische Umwandlung erfolgreich in die entsprechenden Tetracycline überführt (J.Am.CSiem.Soc. 84· (1962) 3023; US-PS 3 053 740). Möglich ist auch die biologische Umwandlung von Anhydrotetracyclinen in 5a(11a)-Dehydrotetracycline (US-PS 2 952 587). Von besonderem Interesse ist jedenfalls die biologische Umwandlung von Anhydrotetracyclinen in α-6-Desoxytetracycline (DT-OS 2 327 990), speziell als Methode zur Gewinnung von a-6~Deso2cy-5-hydroxytetracyclin - ein breites WirkungsSpektrum aufweisendem Antibiotikum.Anhydrotetracyclines are interesting tetracycline antibiotics which have certain antibacterial effects, but which differ from the effects of tetracyclines (Biochem. Z. 544 (1966) 76). Some anhydro derivatives are successfully converted into the corresponding tetracyclines by biological conversion (J. Am. CSiem. Soc. 84 (1962) 3023; US Pat. No. 3,053,740). The biological conversion of anhydrotetracyclines into 5a (11a) -dehydrotetracyclines (US Pat. No. 2,952,587) is also possible. In any case, the biological conversion of anhydrotetracyclines into α-6-deoxytetracyclines (DT-OS 2 327 990) is of particular interest, especially as a method for obtaining α-6 ~ deso2cy-5-hydroxytetracycline - an antibiotic with a broad spectrum of activity.
609885/1 17fi609885/1 17fi
Es ist bekannt, dass Tetracyclin und Chlortetracyclin in sauren Lösungen leicht unter Bildung der C-5a : C-6-Anhydroderivate dehydratisiert werden. Es werden zahlreiche Mineralsäuren wie Schwefelsäure, Salzsäure, Phosphorsäure u.a., sowie organische Säuren wie p-Toluolsulfonsäure, Chloressigsäure, Benzolsulfonsäure u.a. als Behydratationsmittel angeführt. Die Herstellung von AßhydrotetracyliB (Formel I) ist. in US-PS 2 744 932 und in J.Am.Chem.Soc. J± (1952) 4981, ibid. 76 (1954) 3568 und J.Pnarm.Sci. ££ (1966) 1313 "beschrieben. It is known that tetracycline and chlorotetracycline are easily dehydrated in acidic solutions to form the C-5a: C-6 anhydrous derivatives. Numerous mineral acids such as sulfuric acid, hydrochloric acid, phosphoric acid and others, as well as organic acids such as p-toluenesulphonic acid, chloroacetic acid, benzenesulphonic acid and others are listed as hydrating agents. The preparation of AßhydrotetracyliB (Formula I) is . in U.S. Patent 2,744,932 and in J.Am.Chem.Soc. J ± (1952) 4981, ibid. 76 (1954) 3568 and J.Pnarm.Sci. ££ (1966) 1313 ".
CHCH
I = EH II = E-OHI = EH II = E-OH
I. A. Hochs te in et al. (J.Am.Chem.Soc. 21 (1955) 5^55, ibid. 26 (1954·) 3568 und J.Org.Chem. 22 (1962) 2525) haben jedoch gefunden, dass beim 5~2ydroxytetracyclin unter ähnlichen Bedingungen eine weitgehende umwandlung, welche ausser der Dehydratation von 0-5a und C-6 auch die Spaltung zwischen den Positionen C-12 und C-12a unter Bildung von isomeren α- und ß-Apoterramycinen einschliesst, stattfindet. Die Autoren nehmen an, dass diese aus serordentliche Labilität des Anhydro-5-hydroxytetracyclins durch den intramolekularen Angriff der 5-Hydroxygruppe auf die Carbonylgruppe bei C-12 bedingt ist.IA Hochs te in et al. (J.Am.Chem.Soc. 21 (1955) 5 ^ 55, ibid. 26 (1954 ·) 3568 and J.Org.Chem. 22 (1962) 2525) have found that the 5-2 hydroxytetracycline under similar conditions an extensive conversion, which, in addition to the dehydration of 0-5a and C-6, also includes the cleavage between positions C-12 and C-12a with the formation of isomeric α- and ß-apoterramycins, takes place. The authors assume that this is due to the extreme lability of the anhydro-5-hydroxytetracycline due to the intramolecular attack of the 5-hydroxyl group on the carbonyl group at C-12.
609885/117 5609885/117 5
Da am C-5 des Anhydrotetracylins und Anhydro-Cl-tetracylins Iceine Hydroxy!gruppen vorhanden sind, ist eine derartige Umwandlung "bei diesen Verbindungen nicht möglich.Since at C-5 of the anhydrotetracycline and anhydro-Cl-tetracycline If a hydroxyl group is present, such a conversion is not possible with these compounds.
Dieselben Autoren (J.Am.Chem.Soc. ££ (1955) 5^55) haben jedoch erfolgreich das Anhydro-5-hydroxytetracyclin (der Formel II) gemäss einem Verfahren, welches die Behandlung von 5-Hydroxytetracyclin mit einem Gemisch von wasserfreiem Aceton und wasserfreier HCl im Laufe von 11 Stunden bei -5 bis 5°C einschliesst, hergestellt. Aus dem Reaktionsgemisch wird das Produkt in Form von Acetonylanhydro^-hydrorxytetracyclin-Hydro·- chlori'd durch Ausfällen mit trockenem Sther isoliert. Es wird angeführt, dass man nach Umkristallisierung das erwünschte Produkt in 50 %iger Ausbeute erhält. Durch eine weitere Behandlung der wässrigen Lösung des Produktes mit einer 5 $igen Lösung von Uatriumbicarbonat wird das amorphe Anhydroderivat, welches mit Aceton ein Acetonsolvat bildet, isoliert. Die Ausbeuten der Endstufe sind nicht angegeben.However, the same authors (J.Am.Chem.Soc. ££ (1955) 5 ^ 55) have successfully used the anhydro-5-hydroxytetracycline (of formula II) according to a method which involves the treatment of 5-hydroxytetracycline with a mixture of anhydrous Including acetone and anhydrous HCl in the course of 11 hours at -5 to 5 ° C. The product is isolated from the reaction mixture in the form of acetonyl anhydro ^ -hydrorxytetracycline hydrochloride by precipitation with dry ether. It is stated that after recrystallization the desired product is obtained in 50% yield. A further treatment of the aqueous solution of the product with a 5% solution of sodium bicarbonate isolates the amorphous anhydride derivative, which forms an acetone solvate with acetone. The yields of the final stage are not given.
Es wurde eine Reihe von Anhydro-Verbindungen einiger 5-Hydroxytetracyclinderivate, wie Aiihydrodedimethylaminooxytetracyclin, Anhydrodiacethyloxytetracyclin, Anhydrodedimethylaminodesoxy-5-hydroxytetracyclin u.a., hergestellt (GB-PS 785 04-7). In der Patentschrift wird die TJnumgänglichkeit eines schonenden Reaktionsverlaufs, um einen weiteren Abbau des gewonnenen Produktes zu verhindern, hervorgehoben.A number of anhydro compounds of some 5-hydroxytetracycline derivatives, such as aiihydrodedimethylaminooxytetracycline, anhydrodiacethyloxytetracycline, anhydrodedimethylaminodeoxy-5-hydroxytetracycline et al. (GB-PS 785 04-7). In the Patent specification is the inevitability of a gentle course of the reaction in order to further decompose the Product highlighted.
Es wurde nun gefunden, daß man das Anhydro-5-hydroxytetracylin in einer vorzüglichen Ausbeute und Reinheit herstellen kann, wenn das Dehydratationsverfahren unter Verwendung eines Acetonitril-Schwefelsäure-Gemisches als Dehydratationsmittel ausgeführt wird. Dieses Gemisch wurde schon früher als ein hervorra gendes Mittel zur Dehydratation von äußerst empfindlichen 11-Brom-Derivaten des Tetracylins und 5-Hydroxytetracylins (D2-0S 2 216 459) empfohlen. It has now been found that anhydro-5-hydroxytetracyline can be produced in excellent yield and purity if the dehydration process is carried out using an acetonitrile-sulfuric acid mixture as the dehydrating agent. This mixture was previously recommended as an excellent agent for the dehydration of extremely sensitive 11-bromo derivatives of tetracycline and 5-hydroxy-tetracycline (D2-0S 2 216 459).
Das Verfahren umfaßt die Behandlung von 5-Hydroxytetracylin- . Hydrochlorid mit einem Gemisch aus Acetonitril und etwa 96 The method comprises the treatment of 5-Hydroxytetracylin-. Hydrochloride with a mixture of acetonitrile and about 96
B09885/ 1175B09885 / 1175
Schwefelsäure (6:1) unter Kühlen und Rühren im Laufe von 25 Minuten. Durch den Zusatz einer wässrigen Lösung von SuIfosalicylsäure wird das. reine Anhydro-5-hydroxytetracylin als kristallines Sulfosalicylat in 80 $iger Ausbeute ausgefällt, flach Behandlung des gewonnenen Sulfosalicylats mit einem Methanol-Triäthylamin-Gemisch(insbesondere im YoL-Yerhältnis 8:0,2), insbesondere mit einem auf 3°C abgekühlten Gemisch aus Methanol und Triäthylamin, scheidet sich die reine Base des Anhydro-5-hydroxytetracylins in einer 67 $igen Ausbeute aus. Anschließend kann das auskristallisierte Produkt filtriert, mit kaltem Methanol gewaschen und in Yakuum getrocknet werden. Es ist vorteilhaft, das erhaltene Filtrat noch etwa 2 Stunden unter Kühlung zu rühren.Sulfuric acid (6: 1) with cooling and stirring in the course of 25 minutes. By adding an aqueous solution of sulfosalicylic acid is the. pure anhydro-5-hydroxytetracycline as crystalline sulfosalicylate precipitated in 80% yield, Flat treatment of the sulfosalicylate obtained with a methanol-triethylamine mixture (in particular in the YoL-Y ratio 8: 0.2), in particular with a mixture of methanol and cooled to 3 ° C Triethylamine, the pure base of the anhydro-5-hydroxytetracycline separates in 67 $ yield. The product which has crystallized out can then be filtered using cold methanol washed and dried in yakuum. It is advantageous to add the filtrate obtained for a further 2 hours while cooling stir.
Die Struktur der Base ist durch die UY-Absorption gesichtert,woraus die charakteristischen Maxima der Anhydroderivate ersichtlich sind: λ 271 nm (log£ 4,74) und 420 nm (log £3,97). (J1Ur das Acetonsolvat des Anhydro-5-hydroxytetracylins wird angeführt :λ mQV271 nmThe structure of the base is secured by the UY absorption, from which the characteristic maxima of the anhydro derivatives can be seen: λ 271 nm (log £ 4.74) and 420 nm (log £ 3.97). (J 1 Ur the acetone solvate of anhydro-5-hydroxytetracyline is given: λ mQV 271 nm
HI CJaHI CYes
(log £4,56) und 425 nm (logS3,80) J.Am.Chem.Soc. 7£ (1953) 5455).(log £ 4.56) and 425 nm (log S3.80) J.Am.Chem.Soc. £ 7 (1953) 5455).
Das Anhydro-5-hydroxy-tetracylin ist durch das Auflösen in Aceton und Einengen der Acetonlösung unter vermindertem Druck tuakristallisierbar. Aus 'dem eingeengten Volumen scheidet sich das kristalline Produkt aus. Ein derart umkristallisiertes Anhydroderivat bildet kein Acetonsolvat.The anhydro-5-hydroxy-tetracycline is by dissolving in Acetone and concentration of the acetone solution under reduced pressure turkey. From 'the restricted volume is separated the crystalline product. An anhydro derivative recrystallized in this way does not form any acetone solvate.
Die Dünnschichtchromatogramme der gewonnenen Substanzen weisen keine Verunreinigungen durchs- und ß-Apotetracylin auf; die einfache Durchführung des Verfahrens und dessen vollständige Wiederholbarkeit und hervorragende Ausbeute zeichnen das vorliegende Verfahren im Vergleich mit bisher bekannten Methoden aus.The thin-layer chromatograms of the substances obtained show no contamination by- and ß-apotetracylin; the simple implementation of the process and its complete repeatability and excellent yield characterize the present Procedure in comparison with previously known methods.
Das Verfahren soll durch folgende Beispiele erläutert werden.The following examples are intended to illustrate the process.
609885/ 1175609885/1175
Beispiel 1 . Example 1 .
5-Hydroxytetracyclin-Hydro chlo rid (1,4 g, 0,00282 Mol) werden
portionsweise in ein gekühltes (von 0 bis 4-0C) Gemisch aus
Acetonitril und etwa 96 J&Lger Schwefelsäure (8:1,4) gegeben. Bs
wird 25 Minuten unter Kühlen gerührt. Anschliessend wird
eine wässrige Lösung von SuIfοsalicylsäure (1,4- g Sulfosalicylsäure
in 16 ml HgO) eingegossen. Die Lösung wird
anfangs langsam, dann jedoch schnell unter Einhaltung der
Temperatur bis 150C zugesetzt. Es wird unter Kühlen weitere
2 Stunden gerührt. Nach etwa 5 Minuten fängt die Ausscheidung
des kristallinen Produktes an (gegebenenfalls impfen). Das
gewonnene Anhydro-5-liydroxytetracyclin-Sulfosalicylat (195 g.,.
80 °/o) wird mit Aceton gewaschen und in Vakuum getrocknet»5-hydroxytetracycline hydrochloride chlo chloride (1.4 g, 0.00282 mol) is added portionwise into a cooled (0 to 4 0 C) mixture
Acetonitrile and about 96% sulfuric acid (8: 1.4) are added. Bs is stirred for 25 minutes with cooling. Then will
an aqueous solution of sulfosalicylic acid (1.4 g sulfosalicylic acid in 16 ml HgO) poured. The solution will be
slowly at the beginning, but then quickly while observing the
Temperature up to 15 0 C added. It will continue under cooling
Stirred for 2 hours. After about 5 minutes, the crystalline product begins to excrete (vaccinate if necessary). That
obtained Anhydro-5-liydroxytetracyclin-sulfosalicylate (1 9 5 g.,. 80 ° / o) is dried in vacuum and washed with acetone "
Zur Analyse wird die Substanz durch Auflösen (0,5 g) in 20 ml
eines Methanol/n-Butanol-Gemisches (1:1) unter Erwärmen umkristallisiert.
Nach der Behandlung mit Aktivkohle und Filtrieren wird die Lösung über Nacht bei Raumtemperatur stehengelassen.
Das erhaltene kristalline JPräzipitat wird mit Aceton
gewaschen und in Vakuum getrocknet.For analysis, the substance is recrystallized by dissolving (0.5 g) in 20 ml of a methanol / n-butanol mixture (1: 1) with warming. After treatment with activated charcoal and filtration, the solution is left to stand overnight at room temperature. The crystalline J precipitate obtained is treated with acetone
washed and dried in vacuum.
Analyse: C2QH28N2O14S 2H2O - 969,66Analysis: C 2 QH 28 N 2 O 14 S 2H 2 O- 969.66
Ber.: C 50,00 H 4-,63 N 4-,02 S 4,60 %
Gef. : C 50,38 H 4,86 N 4,08 S 4,67 %Ber .: C 50.00 H 4-, 63 N 4-, 02 S 4.60%
Found: C 50.38 H 4.86 N 4.08 S 4.67%
UV (MeOH - 0,01 N HCl) 214, 2?2 und 420 nmUV (MeOH - 0.01 N HCl) 214, 2? 2 and 420 nm
Beispiel 2 Anhydro-5-hydroxytetracyclin-BaseExample 2 Anhydro-5-hydroxytetracycline base
Anliydro-5-hydroxytetracylin-Sulf osalicylatf (1,5 g,Anliydro-5-hydroxytetracycline sulfosalicylate (1.5 g,
0,00227 Mol) wird auf einmal in ein auf 3°C gekühltes Gemisch aus· Methanol und Triäthylamin (12:0,3) gegeben. Nach0.00227 mol) is poured into a mixture cooled to 3 ° C all at once given from methanol and triethylamine (12: 0.3). To
6 0 9885/11 756 0 9885/11 75
10-sd.nutigem Rühren wird die Lösung filtriert und das Ii!trat wird unter Kühlen in verschlossenem System weitergerührt. £Tach etwa 30 Minuten fängt die Ausscheidung der Base an. !fach weiteren 2 Stunden wird das erhaltene Produkt abgesaugt und mit wenig kaltem Methanol gewaschen. Es wird 0,67 g (67 %) der Aiihydro-5-liydroxy-.tetracyclin-Base erhalten.The solution is filtered for 10 seconds of slow stirring and the mixture is extracted is stirred further with cooling in a closed system. £ Tach The base begins to precipitate about 30 minutes. !subject The product obtained is filtered off with suction for a further 2 hours and washed with a little cold methanol. It will be 0.67 g (67%) of the Aiihydro-5-hydroxy-tetracycline base obtained.
Zur Analyse wird die Substanz durch Auflösung (0,5 g) in Aceton (I5 ml) und Einengen der Acetonlösung auf etwa 2 "bis 3 ml unter vermindertem Druck umkrxstallisiert. Aus dem eingeengten Volumen scheidet sich das kristalline Produkt aus. Dessen IR-Spektrum weist keine Absorption bei 5,-8'3/U- auf, welche für das Acetonsolvat charakteristisch ist.The substance is analyzed by dissolving (0.5 g) in Acetone (15 ml) and concentrate the acetone solution to about 2 "to 3 ml re-crystallized under reduced pressure. The crystalline product separates out of the restricted volume. Whose IR spectrum shows no absorption at 5, -8'3 / U-, which for the acetone solvate is characteristic.
Analyse:Analysis:
Bero; C 59»72 H 5,02 IT 6,33 %
Gef. : C 59,83 H 4,80 IT 6,14 %Ber o ; C 59 »72 H 5.02 IT 6.33 %
Found: C 59.83 H 4.80 IT 6.14%
Wmax (Me0H - °>01 H HC1) 2?1 nm Clog£ 4,74) und 420 nm (logg. 3,-97) W max ( Me0H - °> 01 H HC1 ) 2 ? 1 nm clog £ 4.74) and 420 nm (logg. 3, -97)
6 0 9 8 8 5/1 1 756 0 9 8 8 5/1 1 75
Claims (5)
Hilfe von Schwefelsäure, dadurch gekennzeichnet , daß man die Dehydratisierung mit Hilfe eines Gemisches aus Acetonitril und konzentrierter Schwefelsäure durchführt und das erhaltene Sajo-Anhydro-S-hydroxy-tetracyclin aus dem Reaktionsgemisch in üblicher Weise isoliert.1. Process for the preparation of 5a, 6-anhyäro-5-hyäroxy-tetracycline by dehydrating 5-hydroxytetracycline with
The aid of sulfuric acid, characterized in that the dehydration is carried out with the aid of a mixture of acetonitrile and concentrated sulfuric acid and the sajo-anhydro-S-hydroxy-tetracycline obtained is isolated from the reaction mixture in the customary manner.
etwa 0 bis Λ0°0 durchführt.3. The method according to claim 2, characterized in that the dehydration "at a temperature of
about 0 to Λ0 ° 0.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| YU178975A YU37118B (en) | 1975-07-14 | 1975-07-14 | Process for preparing 5a,5-anhydro-5-hydroxy-tetracycline |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE2631676A1 true DE2631676A1 (en) | 1977-02-03 |
Family
ID=25555580
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19762631676 Withdrawn DE2631676A1 (en) | 1975-07-14 | 1976-07-14 | PROCESS FOR THE PREPARATION OF ANHYDRO-5-HYDROXY-TETRACYCLIN |
Country Status (5)
| Country | Link |
|---|---|
| AT (1) | AT344323B (en) |
| DE (1) | DE2631676A1 (en) |
| FR (1) | FR2318146A1 (en) |
| GB (1) | GB1509677A (en) |
| YU (1) | YU37118B (en) |
-
1975
- 1975-07-14 YU YU178975A patent/YU37118B/en unknown
-
1976
- 1976-07-05 AT AT487976A patent/AT344323B/en not_active IP Right Cessation
- 1976-07-06 GB GB2807876A patent/GB1509677A/en not_active Expired
- 1976-07-13 FR FR7621453A patent/FR2318146A1/en active Granted
- 1976-07-14 DE DE19762631676 patent/DE2631676A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| FR2318146B1 (en) | 1980-08-29 |
| AT344323B (en) | 1978-07-10 |
| GB1509677A (en) | 1978-05-04 |
| FR2318146A1 (en) | 1977-02-11 |
| ATA487976A (en) | 1977-11-15 |
| YU37118B (en) | 1984-08-31 |
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