US3849491A - Process of dehalogenation and dehalogenation with simultaneous reduction of 11a-halo-6-deoxy-6-demethyl-6-methylenetetracyclines by hydrazine - Google Patents
Process of dehalogenation and dehalogenation with simultaneous reduction of 11a-halo-6-deoxy-6-demethyl-6-methylenetetracyclines by hydrazine Download PDFInfo
- Publication number
- US3849491A US3849491A US00159458A US15945871A US3849491A US 3849491 A US3849491 A US 3849491A US 00159458 A US00159458 A US 00159458A US 15945871 A US15945871 A US 15945871A US 3849491 A US3849491 A US 3849491A
- Authority
- US
- United States
- Prior art keywords
- dehalogenation
- deoxy
- hydrazine
- demethyl
- methylenetetracyclines
- 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.)
- Expired - Lifetime
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- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 title claims abstract description 38
- 238000000034 method Methods 0.000 title claims abstract description 24
- 238000005695 dehalogenation reaction Methods 0.000 title claims abstract description 19
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 16
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- 239000011541 reaction mixture Substances 0.000 claims abstract description 8
- 229910052697 platinum Inorganic materials 0.000 claims abstract description 7
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 5
- 239000012429 reaction media Substances 0.000 claims abstract description 5
- 230000003197 catalytic effect Effects 0.000 claims abstract description 4
- 229910052703 rhodium Inorganic materials 0.000 claims abstract description 4
- 239000010948 rhodium Substances 0.000 claims abstract description 4
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 29
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 239000002253 acid Substances 0.000 description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 7
- 229940042016 methacycline Drugs 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 6
- XIYOPDCBBDCGOE-IWVLMIASSA-N (4s,4ar,5s,5ar,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methylidene-3,12-dioxo-4,4a,5,5a-tetrahydrotetracene-2-carboxamide Chemical compound C=C1C2=CC=CC(O)=C2C(O)=C2[C@@H]1[C@H](O)[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O XIYOPDCBBDCGOE-IWVLMIASSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
- 239000004098 Tetracycline Substances 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 4
- 238000002955 isolation Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- MOODSJOROWROTO-UHFFFAOYSA-N salicylsulfuric acid Chemical compound OC(=O)C1=CC=CC=C1OS(O)(=O)=O MOODSJOROWROTO-UHFFFAOYSA-N 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 229940071103 sulfosalicylate Drugs 0.000 description 4
- 229960002180 tetracycline Drugs 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- OWFJMIVZYSDULZ-PXOLEDIWSA-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 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)C3=C(O)C2=C1O OWFJMIVZYSDULZ-PXOLEDIWSA-N 0.000 description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N 1,1-Diethoxyethane Chemical compound CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- YCPXWRQRBFJBPZ-UHFFFAOYSA-N 5-sulfosalicylic acid Chemical compound OC(=O)C1=CC(S(O)(=O)=O)=CC=C1O YCPXWRQRBFJBPZ-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 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 2
- 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 2
- 239000007857 degradation product Substances 0.000 description 2
- 229960003722 doxycycline Drugs 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229910000510 noble metal Inorganic materials 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 229910021653 sulphate ion Inorganic materials 0.000 description 2
- 235000019364 tetracycline Nutrition 0.000 description 2
- 229930101283 tetracycline Natural products 0.000 description 2
- 150000003522 tetracyclines Chemical class 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 description 1
- IHGRARUXKULRDG-CVHRZJFOSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide;2-hydroxy-5-sulfobenzoic acid Chemical compound OC(=O)C1=CC(S(O)(=O)=O)=CC=C1O.C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O IHGRARUXKULRDG-CVHRZJFOSA-N 0.000 description 1
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 239000004100 Oxytetracycline Substances 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- -1 alkali metal hydrosulfite Chemical class 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000007813 chromatographic assay Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- ZGCHATBSUIJLRL-UHFFFAOYSA-N hydrazine sulfate Chemical compound NN.OS(O)(=O)=O ZGCHATBSUIJLRL-UHFFFAOYSA-N 0.000 description 1
- CDCUIKNWTWKVLW-UHFFFAOYSA-N hydrazine;palladium Chemical compound [Pd].NN CDCUIKNWTWKVLW-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- FBAFATDZDUQKNH-UHFFFAOYSA-M iron chloride Chemical compound [Cl-].[Fe] FBAFATDZDUQKNH-UHFFFAOYSA-M 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 229960000625 oxytetracycline Drugs 0.000 description 1
- 235000019366 oxytetracycline Nutrition 0.000 description 1
- 229960004368 oxytetracycline hydrochloride Drugs 0.000 description 1
- 238000004816 paper chromatography Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Inorganic materials [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 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
- MWKJTNBSKNUMFN-UHFFFAOYSA-N trifluoromethyltrimethylsilane Chemical compound C[Si](C)(C)C(F)(F)F MWKJTNBSKNUMFN-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
Definitions
- 6-deoxy-6-demethyl6-rnethylenetetracyclines and 6-deoxytetracyclines are valuable antibiotics, of which the most important are 6-deoxy-6-dimethyl-6-methylene-5-hydroxy-tetracycline (methacycline) and a-6-deoxy-5-hydroxytetracycline (deoxycycline).
- the 6-deoxytetracyclines are obtained through catalytic hydrogenation of tetracycline, oxytetracycline and chlorotetracycline, yielding the 3-6-isomers (U.S. Pat. No. 3,019,- 260), or through catalytic hydrogenation of methacycline or lla-halo-methacycline, yielding a mixture of the aand fi-isomers in a variable proportion (US. Pat. No. 3,200,149).
- the a-isomers, without the concomitant [3- isomer are obtained according to U.S. Pat. Nos. 3,165,531 and 3,484,483, and Portuguese Pat. No. 52,217.
- the present invention provides a new process to obtain in a nearly stoichiometric yield the 6-methylenetetracyclines and in a satisfactory yield the 6-deoxytetracyclines, by avoiding the inconveniences of the previous processes.
- the starting material used to perform the present invention is the 1la-chloro-6-deoxy-6-clemethyl-6-methylenetetracyclines, which were first described in Portuguese Pat. No. 36,099 of May 19, 1959.
- a considerable advantage of the present process lies in the fact that the secondary product of the reaction is nitrogen, which naturally does not interfere with isolation of the final product in pure state.
- the Ila-dehalogenation is carried out by zinc and a mineral acid, iron and diluted hydrochloric acid, alkali metal hydrosulfite in aqueous media, sodium iodide in a halogen acceptor medium, such as acetone, and by catalytic hydrogenation.
- catalytic hydrogenation by-products, such as zinc chloride, iron chloride, free sulphur (often in collodial state), sodium iodide and chloride are formed, which have to be separated from the methylenetetracyclines thus prepared.
- this is a difficult procedure and diminishes considerably the final yield.
- the catalytic hydrogenation does not yield secondary products per se, but it provokes destruction, to a considerable extent, of the molecules to be dehalogenated, as well as a concomitant formation of uand B- deoxytetracyclines, according to my experience, even if the hydrogenation were stopped when exactly an equimolar amount of hydrogen, necessary for dehalogenation, has been taken up.
- the hydrazine-palladium charcoal dehalogenation is more advantageous than the direct catalytic hydrogenation insofar as it does not require pressure or a special apparatus. It is less hazardous than catalytic hydrogenation, causes no destruction of the molecules to be dehalogenated, and finally the concomitant formation of uand fi-6-deoxytetracyclines is negligible if none or only a slight excess over the equimolecular amount of hydrazine is used, the catalyst being preferably palladium on charcoal.
- 6-deoxy-6-dimethyl-G-methylenetetracyclines When preparing the 6-deoxytetracyclines, a certain amount of 6-deoxy-6-dimethyl-G-methylenetetracyclines will also be formed in the reaction mixture, and in view of the fact that these latter are also valuable commercialized antibiotics, they may be isolated together with the 6- deoxytetracyclines and subsequently separated.
- My copending Portuguese application No. 54,109 which corresponds to US. application 159,462, filed on July 2, 1971, provides a process for performing such isolation and separation.
- the starting material used in the present invention is the 11a-chloro-6-deoxy-6-demethyl 6 methylcnetetracyclines, under the form of free base, an acid addition salt, such as hydrochloride, hydrofluoride, p-toluene-sulfonate.
- the suitable reaction medium for performing the hydrazine reduction is a lower aliphatic alcohol, tetrahydrofuran, dioxane, lower dialkylformamide, acetone, water, or mixtures thereof.
- 11a-chloro-6-deoxy-6-demethyl-6-methylene-5-hydroxytetracycline is the starting material and the initial pH is higher than 3, it is preferred to use anhydrous media to perform the reaction.
- hydrazine hydrate or a hydrazine acid addition salt such as hydrochloride or sulphate.
- the reaction temperature is not critical, being comprised between 10 to +50 C. However, when preparing the 6-deoxytetracyclines, a higher temperature range, between 25 to 50 C. is preferred.
- the noble metal catalyst preferred is palladium, when preparing the 6 methylenetetracyclines, and platinum, when preparing the 6-deoxytetracyclines; however, rhodium may also be used.
- the amount of catalyst used for preparing the 6-methylenetetracyclines is not critical; as little as 0.001 part of 5% palladium charcoal per part of lla-halo-tetracycline will readily promote the dehalogenation, although the reaction is slow.
- approximately 0.1 part of platinum on a suitable support, such as carbon is necessary. These amounts may be increased up to 2 parts, without provoking a further destruction of the molecules.
- 6-methylenetetracyclines can easily be performed by conventional methods, such as by filtering the reaction mixture and acidifying it with ethanolic or methanolic hydrogen chloride, thus yielding the hydrochloride in pure state.
- any other acid addition salt of the 6-methylenetetracyclines can be obtained by treating the filtered reaction mixture with the desired acid and provoking crystallization by addition of a non-solvent.
- a process for the isolation and purification of 6-deoxytetracyclines is described in my co-pending Portuguese No. 54,109.
- the non-reacted portion of the lla-chloro-S-hydroxytetracycline is present as hydrochloride (melting point 212216 C., [04],; 22.5 (c.:1% in methanol containing 1% concentrated hydrochloric acid),
- the infrared curve shows a sole maximum in the 56 region at 5.72 1.
- Examples according to the present invention (1) 2.5 grs. of 10% palladium on charcoal and 2 mls. of diluted hydrazine hydrate 15% are added to 5 grs. of 11a-chloro-6-deoxy-6-demethyl 6 methylene-S-hydroxytetracycline hydrofluoride in 100 mls. of ethanol. 2.7 mls. of 15% hydrazine hydrate is added at the end of 15 minutes. After stirring overnight, the reaction mixture is filtered, and 5 grs. of S-sulfosalicyclic acid and 200 mls. of water are then added. After stirring during 1 hour, it is filtered, washed and dried. 5.5 grs.
- the crude sulfosalicylate shows a shoulder in its infrared curve at 10 indicating the presence of doxycycline.
- Example 3 The procedure of Example 3 is repeated, but using platinum on charcoal instead of palladium.
- a noble metal catalyst selected from the group consisting of palladium, platinum, and rhodium in an inert reaction medium
- the 11achlorotetracyclines are the lla-chloro derivatives of 6- deoxy 6 demethyl-6-methylenetetracycline, 6-deoxy-6- demethyl-6-methylene 5 hydroxytetracycline, 6-deoxy- 6-demethyl-6-rnethylene 7 chlorotetracycline and 6-deoxy-6-dernethyl-6-methylene 5 hydroxy-7-chlorotetracycline, in a form selected from free base and acid addition salts.
- reaction temperature is comprised between -10 to C.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PT5410870 | 1970-07-03 | ||
| PT5410670 | 1970-07-03 | ||
| PT5410770 | 1970-07-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3849491A true US3849491A (en) | 1974-11-19 |
Family
ID=27354088
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US00159458A Expired - Lifetime US3849491A (en) | 1970-07-03 | 1971-07-02 | Process of dehalogenation and dehalogenation with simultaneous reduction of 11a-halo-6-deoxy-6-demethyl-6-methylenetetracyclines by hydrazine |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US3849491A (enrdf_load_stackoverflow) |
| CA (1) | CA942743A (enrdf_load_stackoverflow) |
| CH (1) | CH582132A5 (enrdf_load_stackoverflow) |
| DE (1) | DE2131944B2 (enrdf_load_stackoverflow) |
| FR (1) | FR2108191B1 (enrdf_load_stackoverflow) |
| GB (1) | GB1360006A (enrdf_load_stackoverflow) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4500458A (en) * | 1982-01-19 | 1985-02-19 | Plurichemie Anstalt | Process for the preparation of α-6-deoxytetracyclines |
| US4597904A (en) * | 1983-08-17 | 1986-07-01 | Hovione Inter Ltd. | Process for the preparation of α-6-deoxy-tetracyclines |
| USRE32535E (en) * | 1982-01-19 | 1987-10-27 | Plurichemie Anstalt | Process for the preparation of α-6-deoxytetracyclines |
| US4911865A (en) * | 1982-12-30 | 1990-03-27 | Plurichemie Anstalt | Process of preparation of novel rhodium hydrogenation catalysts |
| US20060179617A1 (en) * | 2005-02-17 | 2006-08-17 | Preformed Line Products Company | Formed wire dead-end appliance for high temperature linear bodies |
| CN113929592A (zh) * | 2021-12-20 | 2022-01-14 | 山东国邦药业有限公司 | 一种强力霉素中间体的制备方法 |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK153393C (da) * | 1970-07-03 | 1988-11-28 | Ivan Villax | Fremgangsmaade til fremstilling af metacyklin ved dehalogenering af et syreadditionssalt af 11a-klor-6-desoxy-6-demetyl-6-metylen-5-hydroxytetracyklin |
| GB1459861A (en) * | 1973-06-21 | 1976-12-31 | Pfizer | Process for 11a-dehalogenation of 11a-halotetracyclines |
| YU41093B (en) * | 1978-04-12 | 1986-12-31 | Pliva Pharm & Chem Works | Process for preparing 6-deoxy-5hydroxy-tetracycline |
| HU188367B (en) * | 1983-09-02 | 1986-04-28 | Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt,Hu | Process for preparing 6-demethy-6-deoxy-6-methylene-5-exytetracycline and 11a-chloro-derivative thereof |
-
1971
- 1971-06-25 CA CA116,690A patent/CA942743A/en not_active Expired
- 1971-06-26 DE DE19712131944 patent/DE2131944B2/de not_active Ceased
- 1971-06-28 GB GB3012071A patent/GB1360006A/en not_active Expired
- 1971-06-30 CH CH961371A patent/CH582132A5/xx not_active IP Right Cessation
- 1971-07-02 FR FR717124328A patent/FR2108191B1/fr not_active Expired
- 1971-07-02 US US00159458A patent/US3849491A/en not_active Expired - Lifetime
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4500458A (en) * | 1982-01-19 | 1985-02-19 | Plurichemie Anstalt | Process for the preparation of α-6-deoxytetracyclines |
| US4550096A (en) * | 1982-01-19 | 1985-10-29 | Plurichemie Anstalt | Homogeneous catalytic system comprising rhodium, hydrazine and phosphine and a process for the preparation of same |
| USRE32535E (en) * | 1982-01-19 | 1987-10-27 | Plurichemie Anstalt | Process for the preparation of α-6-deoxytetracyclines |
| US4911865A (en) * | 1982-12-30 | 1990-03-27 | Plurichemie Anstalt | Process of preparation of novel rhodium hydrogenation catalysts |
| US4597904A (en) * | 1983-08-17 | 1986-07-01 | Hovione Inter Ltd. | Process for the preparation of α-6-deoxy-tetracyclines |
| US20060179617A1 (en) * | 2005-02-17 | 2006-08-17 | Preformed Line Products Company | Formed wire dead-end appliance for high temperature linear bodies |
| CN113929592A (zh) * | 2021-12-20 | 2022-01-14 | 山东国邦药业有限公司 | 一种强力霉素中间体的制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| DE2131944B2 (de) | 1973-05-10 |
| GB1360006A (en) | 1974-07-17 |
| CH582132A5 (enrdf_load_stackoverflow) | 1976-11-30 |
| CA942743A (en) | 1974-02-26 |
| FR2108191A1 (enrdf_load_stackoverflow) | 1972-05-19 |
| DE2131944A1 (de) | 1972-01-20 |
| FR2108191B1 (enrdf_load_stackoverflow) | 1973-06-29 |
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