NO138563B - PROCEDURE FOR THE PREPARATION OF ALFA-6-DEOXYTE TREACYCLINES - Google Patents
PROCEDURE FOR THE PREPARATION OF ALFA-6-DEOXYTE TREACYCLINES Download PDFInfo
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- NO138563B NO138563B NO737/73A NO73773A NO138563B NO 138563 B NO138563 B NO 138563B NO 737/73 A NO737/73 A NO 737/73A NO 73773 A NO73773 A NO 73773A NO 138563 B NO138563 B NO 138563B
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- Prior art keywords
- deoxy
- complex
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- reaction
- hydrogenation
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- 238000000034 method Methods 0.000 title claims description 10
- 238000002360 preparation method Methods 0.000 title claims description 3
- 239000003446 ligand Substances 0.000 claims description 14
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 238000005984 hydrogenation reaction Methods 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000012429 reaction media Substances 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- 239000004098 Tetracycline Substances 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910000510 noble metal Inorganic materials 0.000 claims description 5
- 229910052703 rhodium Inorganic materials 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 claims description 4
- RXJKFRMDXUJTEX-UHFFFAOYSA-N triethylphosphine Chemical compound CCP(CC)CC RXJKFRMDXUJTEX-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 3
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- LVTCZSBUROAWTE-UHFFFAOYSA-N diethyl(phenyl)phosphane Chemical compound CCP(CC)C1=CC=CC=C1 LVTCZSBUROAWTE-UHFFFAOYSA-N 0.000 claims description 3
- 229910052741 iridium Inorganic materials 0.000 claims description 3
- 229910052697 platinum Inorganic materials 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 229910052707 ruthenium Inorganic materials 0.000 claims description 3
- 150000005846 sugar alcohols Polymers 0.000 claims description 3
- 229940040944 tetracyclines Drugs 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- BPLUKJNHPBNVQL-UHFFFAOYSA-N triphenylarsine Chemical compound C1=CC=CC=C1[As](C=1C=CC=CC=1)C1=CC=CC=C1 BPLUKJNHPBNVQL-UHFFFAOYSA-N 0.000 claims description 3
- YJJKYKYXZZCJEE-UHFFFAOYSA-N 2,2-diphenylethylphosphane Chemical compound C=1C=CC=CC=1C(CP)C1=CC=CC=C1 YJJKYKYXZZCJEE-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 229910052762 osmium Inorganic materials 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- 239000002798 polar solvent Substances 0.000 claims description 2
- 229960002180 tetracycline Drugs 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 8
- 229910052751 metal Inorganic materials 0.000 description 8
- 239000002184 metal Substances 0.000 description 8
- 239000010948 rhodium Substances 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- 239000007857 degradation product Substances 0.000 description 4
- 239000002815 homogeneous catalyst Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 239000004100 Oxytetracycline Substances 0.000 description 3
- 229960000625 oxytetracycline Drugs 0.000 description 3
- 229960004368 oxytetracycline hydrochloride Drugs 0.000 description 3
- RBFQJDQYXXHULB-UHFFFAOYSA-N arsane Chemical group [AsH3] RBFQJDQYXXHULB-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 150000005309 metal halides Chemical class 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 2
- OUULRIDHGPHMNQ-UHFFFAOYSA-N stibane Chemical group [SbH3] OUULRIDHGPHMNQ-UHFFFAOYSA-N 0.000 description 2
- 235000019364 tetracycline Nutrition 0.000 description 2
- -1 triphenylIstibine Chemical compound 0.000 description 2
- 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 1
- KZMAWJRXKGLWGS-UHFFFAOYSA-N 2-chloro-n-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-n-(3-methoxypropyl)acetamide Chemical compound S1C(N(C(=O)CCl)CCCOC)=NC(C=2C=CC(OC)=CC=2)=C1 KZMAWJRXKGLWGS-UHFFFAOYSA-N 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 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
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000002638 heterogeneous catalyst Substances 0.000 description 1
- 238000007172 homogeneous catalysis Methods 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910001507 metal halide Inorganic materials 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000003003 phosphines Chemical group 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000011949 solid catalyst Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229960004989 tetracycline hydrochloride Drugs 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- HVYVMSPIJIWUNA-UHFFFAOYSA-N triphenylstibine Chemical compound C1=CC=CC=C1[Sb](C=1C=CC=CC=1)C1=CC=CC=C1 HVYVMSPIJIWUNA-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Catalysts (AREA)
- Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Description
Fremgangsmåte til fremstilling av a-6-deoksytetracykliner. Process for the production of α-6-deoxytetracyclines.
Foreliggende oppfinnelse angår en fremgangsmåte for fremstilling av cx-6-deoksytetracykliner ved hydrogenering av de tilsvarende 6-demetyl-6-deoksy-6-metylan-tetracykliner. Mere eksakt gjennomføres fremgangsmåten ifølge oppfinnelsen ved hjelp av en homogen katalysemekanisme, hvor mekanismen er basert på bruken av katalysatorer som er oppløselige i reaksjonsmediene. The present invention relates to a method for the production of cx-6-deoxytetracyclines by hydrogenation of the corresponding 6-demethyl-6-deoxy-6-methylene tetracyclines. More precisely, the method according to the invention is carried out using a homogeneous catalysis mechanism, where the mechanism is based on the use of catalysts which are soluble in the reaction media.
Ved å gå ut fra forbindelser av typen By proceeding from connections of the type
hvor Y betyr H, F, Cl, Br eller I; where Y means H, F, Cl, Br or I;
R betyr H, OH eller -0-CO-R' og R means H, OH or -0-CO-R' and
R' betyr C-^-Cg alkylgruppe, R' means C--C8 alkyl group,
eller ved å gå ut i fra salter som oppnås fra de nevnte forbindelser og mineral- eller organiske syrer, eller fra komplekser av de nevnte forbindelser med polyvalente metaller, oppnås det Ot-isomere av de tilsvarende 6-deoksytetracykliner av typen or by starting from salts obtained from the aforementioned compounds and mineral or organic acids, or from complexes of the aforementioned compounds with polyvalent metals, the Ot-isomers of the corresponding 6-deoxytetracyclines of the type are obtained
hvor where
Y og R har den ovenfor angitte betydning. Y and R have the above meaning.
Forbindelsene med formelen II oppnås ifølge oppfinnelsen ved at en forbindelse med formelen I eller et salt eller et kompleks derav, hydrogeneres i nærvær av en katalysator som er oppløselig i reaksjonsmediet og består av et kompleks av edelmetallene Rh, Pd, Ru, Os, Ir, Pt og/eller Ni med elektrondonor-ligander i form av trifenylfosfin, trifenylarsin, trifenylstibin, tributylfosfin, trietylfosfin, dietylfenylfosfin eller difenyletylfosfin, idet hydrogeneringen utføres i et polart løsnings-middel av typen én eller flerverdige alkoholer med 1-4 karbonatomer, N,N'-dimetylformamid, N,N'-dimetylacetamid, dioxan, tetrahydrofuran, metoksyetanol, etoksyetanol, acetonitril eller pyridin, ved en temperatur mellom 0°C og 80°C og i nærvær av hydrogen ved et trykk på 1-150 kp/cm p. The compounds with the formula II are obtained according to the invention by hydrogenating a compound with the formula I or a salt or complex thereof in the presence of a catalyst which is soluble in the reaction medium and consists of a complex of the noble metals Rh, Pd, Ru, Os, Ir, Pt and/or Ni with electron donor ligands in the form of triphenylphosphine, triphenylarsine, triphenylstibine, tributylphosphine, triethylphosphine, diethylphenylphosphine or diphenylethylphosphine, the hydrogenation being carried out in a polar solvent of the type mono or polyhydric alcohols with 1-4 carbon atoms, N,N '-dimethylformamide, N,N'-dimethylacetamide, dioxane, tetrahydrofuran, methoxyethanol, ethoxyethanol, acetonitrile or pyridine, at a temperature between 0°C and 80°C and in the presence of hydrogen at a pressure of 1-150 kp/cm p .
Forbindelsene med formelen I kan fremstilles ifølge de fremgangsmåter som er beskrevet i de britiske patenter nr. 951.663 og 995.031, i US-patent nr. 2.984.686 og i tysk patent nr. 2.037.292. The compounds of formula I can be prepared according to the methods described in British Patent Nos. 951,663 and 995,031, in US Patent No. 2,984,686 and in German Patent No. 2,037,292.
6-deoksytetracyklinene er kjente antibiotika; i US-patentene nr. 3.019-260 og 3-200.149, i syd-afrikansk patent nr. 674.307j i britisk patent nr. 845.649, i fransk patent nr. I.238.750 og i belgisk patent nr. 565.025 gis det en beskrivelse av deres fremstilling med bruken av edelmetaller som bæres på forskjellig måte eller som i ethvert tilfelle oppnås ved reduk-sjon av deres salter eller oksyder til et metallisk pulver; og både <X- og p-isomerformene av de hydrogenerte produkter oppnås på denne måte. The 6-deoxytetracyclines are known antibiotics; in US Patent Nos. 3,019-260 and 3-200,149, in South African Patent No. 674,307j in British Patent No. 845,649, in French Patent No. I,238,750 and in Belgian Patent No. 565,025 a description is given of their preparation with the use of precious metals which are carried in different ways or which in any case are obtained by reduction of their salts or oxides to a metallic powder; and both the <X- and p-isomer forms of the hydrogenated products are obtained in this way.
Likeledes er det kjent å benytte delvis forgiftede faste katalysatorer, slik som beskrevet i fransk patent nr. 1.557-.970, noe som favoriserer dannelsen av cr-isomere i forhold til p-isomere; det er imidlertid, selv med denne forbedrede fremgangsmåte en dannelse av uønsket forringede produkter som stammer fra sidereaksjoner, noe som senker utbyttene av hydrogenert produkt og hvilke sideprodukter må fjernes ved hjelp av renseprosesse: Foreliggende oppfinnelse er basert på bruken av katalysatorer som er oppløselige i reaksjonsmediene og som består av koordinasjonsforbindelser av edelmetaller med elektrondonorligande: Komplekser av denne type og spesielt de som dannes fra Rh, Ru, Ir, Os, Pd, Pt, Ni med tertiære arsiner, fosfiner og stibiner er kjent i litteraturen som homogene katalysatorer for den selektive hydrogenering av de terminale C=C. Likewise, it is known to use partially poisoned solid catalysts, such as described in French patent no. 1,557-970, which favors the formation of cr-isomers in relation to p-isomers; however, even with this improved method, there is a formation of undesired degraded products originating from side reactions, which lowers the yields of hydrogenated product and which side products must be removed by means of a purification process: The present invention is based on the use of catalysts which are soluble in the reaction media and which consist of coordination compounds of noble metals with electron donor ligands: Complexes of this type and especially those formed from Rh, Ru, Ir, Os, Pd, Pt, Ni with tertiary arsines, phosphines and stibines are known in the literature as homogeneous catalysts for the selective hydrogenation of the terminal C=C.
Egnede ligander er: trifenylfosfin, trifenylarsin, trifenyIstibin, tributylfosfin, trietylfosfin, dietylfenylfosfin, di f eny le ty lf os f in. Suitable ligands are: triphenylphosphine, triphenylarsine, triphenylIstibine, tributylphosphine, triethylphosphine, diethylphenylphosphine, di f eny le ty lf os f ine.
Det er nå funnet at disse komplekser er aktive ved hydrogenering av heksocykliske dobbeltbindinger i substratene i formel I, mens de interne dobbeltbindinger ikke påvirkes. Videre fører hydrogeneringen på selektiv måte til dannelse av af-isomere. Ligandermolekylene kan lett erstattes av de i oppløsningsmidlet i hvilket reaksjonen"inntrer. Visse komplekser med oppløsningsmidde molekyler som erstatter ligandmolekylene er så stabile at de til-later isolering. Spesielt skal det fremheves komplekser av rodium med trifenylfosfin, av typen RhClCPh^P)^, dimere Rh2Cl2(Ph^P)^, hydrid- og dihydridderivatene Rh H Cl^Ph^P)^, Rh H~2 CKPh^P)^ og komplekset Rh(Ph^P)^Cl-j hvilket fremstilles i henhold til de fremgangsmåter som er beskrevet i "J. Chem. Soc." (A) (1966, 1711 og "J. Chem. Soc." (A) (1966, 1670 og "J. Chem. Soc." (1964) 2508). It has now been found that these complexes are active when hydrogenating hexocyclic double bonds in the substrates of formula I, while the internal double bonds are not affected. Furthermore, the hydrogenation selectively leads to the formation of af isomers. The ligand molecules can easily be replaced by those in the solvent in which the reaction takes place. Certain complexes with solvent molecules that replace the ligand molecules are so stable that they allow isolation. In particular, complexes of rhodium with triphenylphosphine, of the type RhClCPh^P)^, should be highlighted. dimers Rh2Cl2(Ph^P)^, the hydride and dihydride derivatives Rh H Cl^Ph^P)^, Rh H~2 CKPh^P)^ and the complex Rh(Ph^P)^Cl-j which is prepared according to the methods described in "J. Chem. Soc." (A) (1966, 1711 and "J. Chem. Soc." (A) (1966, 1670 and "J. Chem. Soc." (1964) 2508).
I oppløsningen kan komplekset Rh Cl(Ph^P)^ delvis dissosieres og den følgende likevekt kan oppnås: In the solution, the complex Rh Cl(Ph^P)^ can be partially dissociated and the following equilibrium can be achieved:
I nærvær av hydrogen dannes det en mere kompleks liKeveKt: In the presence of hydrogen, a more complex liquid is formed:
Fikseringsmekanismen for hydrogenet og koordinasjonen for olefinet på metallet kan illustreres som følger: The fixation mechanism for the hydrogen and coordination for the olefin on the metal can be illustrated as follows:
hvor S betyr et oppløsningsmiddelmoleky1. Som ligand kan det istedenfor trifenylfosfin benyttes trietylfosfin eller tributylfosfin eller også alkylfosforsyreestere, triarylarsiner eller triarylstibiner. where S means a solvent molecule1. Triethylphosphine or tributylphosphine or also alkyl phosphoric acid esters, triaryl arsines or triaryl stibines can be used as ligand instead of triphenylphosphine.
Molforholdet mellom ligand og metall kan f.variere fra The molar ratio between ligand and metal can, for example, vary from
1 til 4. Den oppløselige katalysator kan også fremstilles direkte i reaksjonsmediet ved oppløsning i et egnet oppløsningsmiddel av metallhalogenidet sammen med et antall mol av liganden større enn 1 pr. mol metall. Etter fremgangsmåten ifølge oppfinnelsen opp-løses en forbindelse fra gruppen tetracykliner med den generelle formel I og en katalytisk mengde av et kompleks av den ovenfor nevnte type, dannet av et edelmetall og en egnet ligand, i et egnet oppløsningsmiddel og bringes i kontakt med hydrogen ved egnet temperatur og trykk i et tidsrom tilstrekkelig til å oppnå den totale omdanning til hydrogenert forbindelse. 1 to 4. The soluble catalyst can also be prepared directly in the reaction medium by dissolving in a suitable solvent the metal halide together with a number of moles of the ligand greater than 1 per moles of metal. According to the method according to the invention, a compound from the group of tetracyclines with the general formula I and a catalytic amount of a complex of the above-mentioned type, formed by a noble metal and a suitable ligand, are dissolved in a suitable solvent and brought into contact with hydrogen by suitable temperature and pressure for a period of time sufficient to achieve the total conversion to the hydrogenated compound.
Ved slutten av reaksjonen skjer det ved hjelp av kry-stallisering en separering fra oppløsningen av meget høye utbytter av Of-6-deoksytetracyklinene med den generelle formel II, mens den homogene katalysator forblir oppløst i moderluten. At the end of the reaction, crystallization separates from the solution very high yields of the Of-6-deoxytetracyclines of the general formula II, while the homogeneous catalyst remains dissolved in the mother liquor.
Egnede oppløsningsmidler er: en- eller flerverdige alkoholer med fra 1 til 4 karbonatomer, N,N'-dimetylaeetamider, dioxan, tetrahydrofuran, metoksy-etanol, etoksy-etanol, acetonitril og pyridin. Reaksjonshastigheten og omdanningsgraden avhenger relativt sterkt av temperaturen: ved temperaturer under 0°C er reaksjonen langsom, mens temperaturer over 80°C kan forårsake dekomponering av utgangsstoffene. Det foretrukne temperaturområdet er 15-80°C. Trykkområdet er som nevnt 1-150. kg/cm<2>. Reaksjons-tiden som er nødvendig for total omdanning avhenger ay temperaturen, trykket og typen katalysator som benyttes, men er vanligvis innen 1 til 8 timer. Den foretrukne katalysator er RhCl(PhjP)n, hvor n kan være 2 eller 33 fordi med denne katalysator oppnås det så Suitable solvents are: monohydric or polyhydric alcohols with from 1 to 4 carbon atoms, N,N'-dimethylacetamides, dioxane, tetrahydrofuran, methoxyethanol, ethoxyethanol, acetonitrile and pyridine. The reaction rate and degree of conversion depend relatively strongly on temperature: at temperatures below 0°C the reaction is slow, while temperatures above 80°C can cause decomposition of the starting materials. The preferred temperature range is 15-80°C. As mentioned, the pressure range is 1-150. kg/cm<2>. The reaction time required for total conversion depends on the temperature, pressure and type of catalyst used, but is usually within 1 to 8 hours. The preferred catalyst is RhCl(PhjP)n, where n can be 2 or 33 because with this catalyst it is achieved
og si total omdanning til oc-isomere, som har den-største biolo-giske virkning, mens det kun oppnås neglisjerbare mengder" av p -isomere og spormengder av nedbrytningsprodukter. Tynnsjiktskromatografi av den klare urene reaksjonsoppløsning ved ferdig hydrogenering viser at forholdet mellom ct- og p -isomeren er lik eller større enn 20:1, og at prosentandelen av nedbrytningspro-dukter ikke overskrider 2- 3%- Fra ferdige råprodukt oppløsninger av denne type er de isolerte produkter med utmerket kvalitet i utbytter over 75%- Som nevnt ovenfor kan den homogene katalysator fremstilles direkte i reaksjonsmediet ved oppløsning av edelmetall-halogenidet i nærvær av et tilstrekkelig antall mol ligand; substratet bringes i oppløsning og hydrogeneringen gjennomføres på den ovenfor beskrevne måte. Hvis, når det gjelder komplekset av rodium med trifeny1fos fin, f.eks. antallet mol av liganden er mellom 1 og 3 pr. mol av metallet oppnås de samme resultater som når katalysatoren er fremstilt separat. Mengder av liganden på under ett mol pr. mol metall fører til dannelse av avsetninger av metall i pulverform, hvilke virker som heterogen katalysator med den overveiende dannelse av fj -epimer. Mengder av ligand på over 3 mol pr. mol metall fører til homogene katalysatorer med gradvis redusert utbytte og ufullstendig omdanning av substratet mens stereospesifiteten forblir høy, idet at det er en overveiende dannelse av er-epimer sammen med ikke omdannet substrat, og mengden av £-epimer forblir ekstremt lav. De følgende eksempler gis for å illustrere oppfinnelsen. and say total conversion to oc-isomers, which have the greatest biological effect, while only negligible amounts of p-isomers and trace amounts of degradation products are obtained. Thin-layer chromatography of the clear impure reaction solution upon complete hydrogenation shows that the ratio between ct- and the p -isomer is equal to or greater than 20:1, and that the percentage of degradation products does not exceed 2-3% - From finished crude product solutions of this type, the isolated products are of excellent quality in yields above 75% - As mentioned above the homogeneous catalyst can be prepared directly in the reaction medium by dissolving the noble metal halide in the presence of a sufficient number of moles of ligand; the substrate is brought into solution and the hydrogenation is carried out in the manner described above. If, in the case of the complex of rhodium with triphenyphosfin, e.g. e.g. the number of moles of the ligand is between 1 and 3 per mole of the metal, the same results are obtained as when the catalyst is prepared separately. Amounts of the ligand of less than one mole per moles of metal leads to the formation of deposits of metal in powder form, which act as heterogeneous catalysts with the predominant formation of fj -epimers. Amounts of ligand of more than 3 mol per mol metal leads to homogeneous catalysts with gradually reduced yield and incomplete conversion of the substrate while the stereospecificity remains high, in that there is a predominant formation of er-epimers together with unconverted substrate, and the amount of £-epimers remains extremely low. The following examples are given to illustrate the invention.
Eksempel 1 Example 1
10 g 6-demetyl-6-deoksy-6-metylen-5-oksytetracyklin hydroklorid ble oppløst i 1000 ml metanol; dertil ble det satt 2,2 g av komplekse RhCl(Ph^P)... Den oppnådde oppløsningen ble anbragt i en autoklav og hydrogenert ved 100 kg/cm 2 og 40 oC i 4 timer. Autoklaven ble tømt og det ble oppnådd en klar oppløsning av lett gul farge som hurtig ble mørk. Tynnsjiktskromatografi (gjennomført på kiselgurbelagte plater som var bufferet til pH 9'. og med vann-aceton i et forh.old på 1:10,' som- e lue rings middel Og ved bruk av U.V.-lys for detektering) på oppløsningen av det rå reaks j ons produkt ga det følgende resultat: or-6-deoksy-5-oksy-tetracyklin omtrent 95% ; 0-6-deoksy-5-oksytetracyklin mindre enn 5 % ; lette spor av nedbrytningsprodukter. 10 g of 6-demethyl-6-deoxy-6-methylene-5-oxytetracycline hydrochloride was dissolved in 1000 ml of methanol; to this was added 2.2 g of complex RhCl(Ph^P)... The obtained solution was placed in an autoclave and hydrogenated at 100 kg/cm 2 and 40 oC for 4 hours. The autoclave was emptied and a clear solution of light yellow color was obtained which quickly darkened. Thin-layer chromatography (carried out on diatomaceous earth-coated plates which were buffered to pH 9'. and with water-acetone in a ratio of 1:10,' as eluent and using U.V. light for detection) on the solution of the crude reaction product gave the following result: or-6-deoxy-5-oxy-tetracycline about 95%; 0-6-deoxy-5-oxytetracycline less than 5%; light traces of degradation products.
Oppløsningen ble konsentrert under vakuum og produktet ble krystallisert ved hjelp av metanol, mens katalysatoren forble oppløst i moderluten. Ved bruk av standard teknikker ble det oppnådd et utbytte på 7,1 g 6-deoksy-5-oksytetracyklin base, med en spektro-fotometrisk renhet på 99, 5%. The solution was concentrated under vacuum and the product was crystallized using methanol, while the catalyst remained dissolved in the mother liquor. Using standard techniques, a yield of 7.1 g of 6-deoxy-5-oxytetracycline base was obtained, with a spectrophotometric purity of 99.5%.
Eksempel 2 Example 2
4 g demetyl-6-deoksy-6-metylen-5-oksytetracyklin hydroklorid, 0,5 g trifenylfosfin, 0,2 g RhC1^.3H20 ble oppløst i 500 ml metanol. Hydrogeneringen ble gjennomført slik som beskrevet i eksempel 1 og det ble oppnådd en oppløsning som ved tynnsjiktskromatografi viste seg å ha følgende sammensetning: of-6-deoksy-5-oksytetracyklin omtrent 95%, p-epimer mindre enn 5% ; 4 g of demethyl-6-deoxy-6-methylene-5-oxytetracycline hydrochloride, 0.5 g of triphenylphosphine, 0.2 g of RhCl 3 H 2 O were dissolved in 500 ml of methanol. The hydrogenation was carried out as described in example 1 and a solution was obtained which by thin-layer chromatography proved to have the following composition: of-6-deoxy-5-oxytetracycline approximately 95%, p-epimer less than 5%;
spor av nedbrytningsprodukter. traces of degradation products.
Oppløsningen ble konsentrert til tørr tilstand, krystallisert med metanol for å fjerne katalysatoren og basen ble viderebehandlet på vanlig måte. Utbytte: 2,9 g cf-6-deoksy-5-oksytetracyklinbase med en spektrofotometrisk renhet på 99,3%. The solution was concentrated to dryness, crystallized with methanol to remove the catalyst and the base was further worked up in the usual manner. Yield: 2.9 g of cf-6-deoxy-5-oxytetracycline base with a spectrophotometric purity of 99.3%.
Eksempel 3 Example 3
5 g 6-deoksy-6-demety1-6-metylen-5-oksytetracyklin hydroklorid ble suspendert i 150 ml NN' dimetylacetamid. 1,1 g av komplekset RhC.l(PhxP), ble deretter tilsatt og hydrogeneringen ble gjennomført ved 20 kg/cm 2 og 50 oC i 4 timer. 5 g of 6-deoxy-6-demethyl-6-methylene-5-oxytetracycline hydrochloride was suspended in 150 ml of NN' dimethylacetamide. 1.1 g of the complex RhC.1(PhxP) was then added and the hydrogenation was carried out at 20 kg/cm 2 and 50 oC for 4 hours.
Etter hvert som reaksjonen skred frem ble oppløs-ningen klarere og til slutt ble det oppnådd en klar oppløsning, hvorfra det på kjent måte ble isolert 3,5. g CÉ-6-deoksy-5-oksy-tetracyklinbase, med en spektrofotometrisk renhet på 99, 2%. As the reaction progressed, the solution became clearer and finally a clear solution was obtained, from which 3.5 was isolated in a known manner. g CÉ-6-deoxy-5-oxy-tetracycline base, with a spectrophotometric purity of 99.2%.
Eksempel 4 Example 4
2 g 6-deoksy-6-demety1-6-metylen tetracyklin hydroklorid ble hydrogenert ifølge den fremgangsmåte som er beskrevet . i eksemplene 1 og 2, og totalomdanning ble oppnådd etter 4 timers reaksjonstid ved 40°C og 80 kg/cm<2>. Kromatografiske analyser .viste et forhold mellom or- og p-epimer på mer enn 20:1. 2 g of 6-deoxy-6-demethyl-6-methylene tetracycline hydrochloride was hydrogenated according to the method described. in examples 1 and 2, and total conversion was achieved after 4 hours of reaction time at 40°C and 80 kg/cm<2>. Chromatographic analyzes showed a ratio of or- and p-epimers of more than 20:1.
Eksempel 5 Example 5
2 g 6-demetyl-6-deoksy-6-metylen-5-acetoksy-tetracyklin og 0,4 g RhCl(Ph,P), ble oppløst i dimetylformamid og hydrogenert ved 35 o C og 20 kg/cm 2 i 4 timer. Tynnsjiktskromatografi av den oppløsning som ved ferdig reaksjon ble oppnådd, viste totalomdanning til of-6-deoksy-5-acetoksytetracyklin. 2 g of 6-demethyl-6-deoxy-6-methylene-5-acetoxy-tetracycline and 0.4 g of RhCl(Ph,P) were dissolved in dimethylformamide and hydrogenated at 35 o C and 20 kg/cm 2 for 4 hours . Thin-layer chromatography of the solution obtained at the end of the reaction showed total conversion to of-6-deoxy-5-acetoxytetracycline.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT2095972 | 1972-02-24 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NO138563B true NO138563B (en) | 1978-06-19 |
| NO138563C NO138563C (en) | 1978-09-27 |
Family
ID=11174633
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO737/73A NO138563C (en) | 1972-02-24 | 1973-02-23 | PROCEDURE FOR THE PREPARATION OF ALFA-6-DEOXYTE TREACYCLINES |
Country Status (15)
| Country | Link |
|---|---|
| JP (1) | JPS6114145B2 (en) |
| AT (1) | AT320627B (en) |
| AU (1) | AU477038B2 (en) |
| CA (1) | CA1003410A (en) |
| CH (1) | CH579531A5 (en) |
| DE (1) | DE2308227C2 (en) |
| DK (1) | DK153394C (en) |
| ES (1) | ES411982A1 (en) |
| GB (1) | GB1418137A (en) |
| IL (1) | IL41600A (en) |
| NL (1) | NL178591C (en) |
| NO (1) | NO138563C (en) |
| PH (1) | PH10072A (en) |
| SE (1) | SE389862B (en) |
| ZA (1) | ZA731178B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE435619C (en) * | 1973-02-01 | 1985-11-18 | Pfizer | PROCEDURE FOR PREPARING A 6ALFA DEOXYTETRACYCLINE |
| US3954862A (en) * | 1973-04-20 | 1976-05-04 | Pfizer Inc. | Process for producing α-6-deoxytetracyclines |
| PT74303B (en) * | 1982-01-19 | 1983-08-08 | Joao Emerico Villax | PROCESS FOR THE PREPARATION OF NEW CATALYZERS CONTAINING RHODIUM AND USE THEREOF |
| JPH047001Y2 (en) * | 1986-10-15 | 1992-02-25 | ||
| CN111732522B (en) * | 2020-07-21 | 2022-10-18 | 山东国邦药业有限公司 | Preparation method of doxycycline |
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| FR1430859A (en) * | 1960-05-23 | 1966-05-25 |
-
1973
- 1973-02-19 GB GB811973A patent/GB1418137A/en not_active Expired
- 1973-02-19 CH CH234973A patent/CH579531A5/xx not_active IP Right Cessation
- 1973-02-20 ZA ZA731178A patent/ZA731178B/en unknown
- 1973-02-20 CA CA164,204A patent/CA1003410A/en not_active Expired
- 1973-02-20 DE DE2308227A patent/DE2308227C2/en not_active Expired
- 1973-02-21 SE SE7302447A patent/SE389862B/en unknown
- 1973-02-21 DK DK093273A patent/DK153394C/en not_active IP Right Cessation
- 1973-02-22 AT AT155773A patent/AT320627B/en not_active IP Right Cessation
- 1973-02-22 IL IL41600A patent/IL41600A/en unknown
- 1973-02-22 NL NLAANVRAGE7302506,A patent/NL178591C/en not_active IP Right Cessation
- 1973-02-22 PH PH14362*A patent/PH10072A/en unknown
- 1973-02-22 AU AU52502/73A patent/AU477038B2/en not_active Expired
- 1973-02-23 ES ES411982A patent/ES411982A1/en not_active Expired
- 1973-02-23 NO NO737/73A patent/NO138563C/en unknown
- 1973-02-24 JP JP48022592A patent/JPS6114145B2/ja not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| ES411982A1 (en) | 1976-01-01 |
| ZA731178B (en) | 1973-11-28 |
| NL178591C (en) | 1992-09-16 |
| IL41600A0 (en) | 1973-04-30 |
| NL178591B (en) | 1985-11-18 |
| IL41600A (en) | 1975-07-28 |
| GB1418137A (en) | 1975-12-17 |
| CH579531A5 (en) | 1976-09-15 |
| CA1003410A (en) | 1977-01-11 |
| SE389862B (en) | 1976-11-22 |
| DK153394C (en) | 1993-08-02 |
| JPS4897864A (en) | 1973-12-13 |
| NO138563C (en) | 1978-09-27 |
| JPS6114145B2 (en) | 1986-04-17 |
| AU5250273A (en) | 1974-08-22 |
| AT320627B (en) | 1975-02-25 |
| PH10072A (en) | 1976-08-05 |
| AU477038B2 (en) | 1976-10-14 |
| NL7302506A (en) | 1973-08-28 |
| DE2308227A1 (en) | 1973-08-30 |
| DE2308227C2 (en) | 1983-01-13 |
| DK153394B (en) | 1988-07-11 |
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