DE2437115A1 - 2,5-DIDEOXYSTREPTAMINE DERIVATIVES AND THE PROCESS FOR THEIR PRODUCTION - Google Patents
2,5-DIDEOXYSTREPTAMINE DERIVATIVES AND THE PROCESS FOR THEIR PRODUCTIONInfo
- Publication number
- DE2437115A1 DE2437115A1 DE2437115A DE2437115A DE2437115A1 DE 2437115 A1 DE2437115 A1 DE 2437115A1 DE 2437115 A DE2437115 A DE 2437115A DE 2437115 A DE2437115 A DE 2437115A DE 2437115 A1 DE2437115 A1 DE 2437115A1
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- Germany
- Prior art keywords
- hydrogen
- compounds
- formula
- ftg
- compound
- 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.)
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Links
- 238000000034 method Methods 0.000 title claims description 16
- NCLVCCNBKRLETR-FBXFSONDSA-N (1s,3r,4r,6s)-4,6-diaminocyclohexane-1,3-diol Chemical class N[C@H]1C[C@@H](N)[C@H](O)C[C@@H]1O NCLVCCNBKRLETR-FBXFSONDSA-N 0.000 title claims description 6
- 238000004519 manufacturing process Methods 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 30
- 239000001257 hydrogen Substances 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 7
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 239000007868 Raney catalyst Substances 0.000 claims description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 4
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- KWKAKUADMBZCLK-UHFFFAOYSA-N methyl heptene Natural products CCCCCCC=C KWKAKUADMBZCLK-UHFFFAOYSA-N 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 235000015097 nutrients Nutrition 0.000 description 4
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 239000011261 inert gas Substances 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000218919 Micromonospora inyonensis Species 0.000 description 2
- ZWWVMGQAOAIIQO-UHFFFAOYSA-N Mutamicin 2 Natural products CNC1C(O)C(OC2CC(OC3OC(=CCC3N)CN)C(N)CC2N)OCC1(C)O ZWWVMGQAOAIIQO-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 239000002647 aminoglycoside antibiotic agent Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 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 1
- DTFAJAKTSMLKAT-JDCCYXBGSA-N 2-deoxystreptamine Chemical compound N[C@H]1C[C@@H](N)[C@H](O)[C@@H](O)[C@@H]1O DTFAJAKTSMLKAT-JDCCYXBGSA-N 0.000 description 1
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- 229940093475 2-ethoxyethanol Drugs 0.000 description 1
- OCKGFTQIICXDQW-ZEQRLZLVSA-N 5-[(1r)-1-hydroxy-2-[4-[(2r)-2-hydroxy-2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]-4-methyl-3h-2-benzofuran-1-one Chemical compound C1=C2C(=O)OCC2=C(C)C([C@@H](O)CN2CCN(CC2)C[C@H](O)C2=CC=C3C(=O)OCC3=C2C)=C1 OCKGFTQIICXDQW-ZEQRLZLVSA-N 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- CLGDBARJCPDLTN-UHFFFAOYSA-N OC1C2N(NC(C(C1)O)C2)CC Chemical compound OC1C2N(NC(C(C1)O)C2)CC CLGDBARJCPDLTN-UHFFFAOYSA-N 0.000 description 1
- UOZODPSAJZTQNH-UHFFFAOYSA-N Paromomycin II Natural products NC1C(O)C(O)C(CN)OC1OC1C(O)C(OC2C(C(N)CC(N)C2O)OC2C(C(O)C(O)C(CO)O2)N)OC1CO UOZODPSAJZTQNH-UHFFFAOYSA-N 0.000 description 1
- URWAJWIAIPFPJE-UHFFFAOYSA-N Rickamicin Natural products O1CC(O)(C)C(NC)C(O)C1OC1C(O)C(OC2C(CC=C(CN)O2)N)C(N)CC1N URWAJWIAIPFPJE-UHFFFAOYSA-N 0.000 description 1
- 229930192786 Sisomicin Natural products 0.000 description 1
- 229930183544 Streptamin Natural products 0.000 description 1
- ANLMVXSIPASBFL-UHFFFAOYSA-N Streptamin D Natural products NC1C(O)C(N)C(O)C(O)C1O ANLMVXSIPASBFL-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- WHRIKZCFRVTHJH-UHFFFAOYSA-N ethylhydrazine Chemical compound CCNN WHRIKZCFRVTHJH-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 150000002429 hydrazines Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 229960000318 kanamycin Drugs 0.000 description 1
- 229930027917 kanamycin Natural products 0.000 description 1
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 1
- 229930182823 kanamycin A Natural products 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229960001914 paromomycin Drugs 0.000 description 1
- UOZODPSAJZTQNH-LSWIJEOBSA-N paromomycin Chemical compound N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)N)O[C@@H]1CO UOZODPSAJZTQNH-LSWIJEOBSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- UKPBXIFLSVLDPA-UHFFFAOYSA-N propylhydrazine Chemical compound CCCNN UKPBXIFLSVLDPA-UHFFFAOYSA-N 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229960005456 sisomicin Drugs 0.000 description 1
- URWAJWIAIPFPJE-YFMIWBNJSA-N sisomycin Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H](CC=C(CN)O2)N)[C@@H](N)C[C@H]1N URWAJWIAIPFPJE-YFMIWBNJSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/30—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds
- C07C209/42—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitrogen-to-nitrogen bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/42—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/44—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton bound to carbon atoms of the same ring or condensed ring system
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (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)
Description
2,5-DIDEOXYSTREPTAMINDERIVATe UND JULI-8-19742,5-DIDEOXYSTREPTAMINE DERIVATIVES AND JULY-8-1974
2O58-FTG-2 VERFAHREN ZU IHRER HERSTELLUNG SK/cti2O58-FTG-2 PROCESS FOR THEIR PRODUCTION SK / cti
Die Erfindung bezieht sich auf gewisse Aminocyclitole und deren Säureadditionssalze, auf ein neues chemisches Verfahren zur Herstellung solcher Verbindungen und auf gewisse neue Zwischenprodukte und deren Säureadditionssalze die im neuen Verfahren anfallen. .The invention relates to certain aminocyclitols and their acid addition salts, to a new chemical one Process for the preparation of such compounds and certain new intermediates and their acid addition salts that arise in the new process. .
Die erfindungsgemässen Verbindungen können durch die allgemeine Formel IV dargestellt werdenThe compounds according to the invention can by general formula IV are shown
R1NR3 R 1 NR 3
(IV),(IV),
worin eines vonin which one of
OH und ROH and R
Wasserstoff und das andereHydrogen and the other
Wasserstoff oder einegeradkettige Alkylgruppe mit 1 "bis 4 Kohlenstoffatomen, und R_ und R. entweder beideHydrogen or a straight chain alkyl group of 1 "to 4 carbon atoms, and R_ and R. either both
3 43 4
Wasserstoff oder zusammen eine Bindung zwischen den zwei Stickstoffatomen darstellen. Umfasst sind auch Säureadditionssalze solcher Verbindungen.Hydrogen or together a bond between the two Represent nitrogen atoms. Acid addition salts are also included such connections.
Die Aminocyclitole dieser Erfindung sind 2,5-Dideoxystreptamine der allgemeinen Formel IThe aminocyclitols of this invention are 2,5-dideoxystreptamines of the general formula I.
NHRNHR
NHR,NHR,
(D,(D,
worin eines von R. und R- Wasserstoff und das andere Wasserstoff oder eine geradkettige Alkylgruppe mit 1 bis 4 Kohlenstoffatomen bedeuten. Sie sind also Verbindungen der Formel IV, worin R3 und R4 Wasserstoff und R- und R„ wie oben definiert sind.wherein one of R. and R- is hydrogen and the other is hydrogen or a straight-chain alkyl group having 1 to 4 carbon atoms. They are therefore compounds of the formula IV in which R 3 and R 4 are hydrogen and R and R "are as defined above.
50 9808/1U850 9808 / 1U8
JULI-8-1974JULY-8-1974
2O5Ö-PTG-32O5Ö-PTG-3
SK/chSK / ch
Aminocyclitole sind Bestandteile des Moleküls vieler Aminoglycosid-Antibiotika. Das am häufigsten vorkommende· Aminocyclitol ist 2-Deoxystreptamin, das einen Bestandteil der bekannten Antibiotika Gentamicin, Kanamycin, Neomycin, Paromomycin und Sisomicin bildet. Diese Antibiotika werden üblicherweise durch Kultivierung bestimmter Mikroorganismen in einem üblichen Nährmedium hergestellt.Aminocyclitols are part of the molecule of many Aminoglycoside antibiotics. The most common Aminocyclitol is 2-deoxystreptamine, the one Forms part of the well-known antibiotics gentamicin, kanamycin, neomycin, paromomycin and sisomicin. These antibiotics are usually produced by cultivating certain microorganisms in a common nutrient medium manufactured.
Man hat neulich entdeckt, dass gewisse Stämme von bekannten Arten von Mikroorganismen, die nicht imstande sind, ein Antibiotikum zu produzieren, wenn man sie in einem üblichen Nährmedium kultiviert, sehr wohl Antibiotika erzeugen, wenn dem Nährmedium ein Aminocyclitol hinzugefügt wird. [Siehe: W.Thomas Shier et al; Proceedings of the National Academy of Science, 63: 19.8-204 (1969)].It has recently been discovered that certain strains of known types of microorganisms are unable to are to produce an antibiotic when grown in a common nutrient medium, very much antibiotics when an aminocyclitol is added to the nutrient medium. [See: W. Thomas Shier et al; Proceedings of the National Academy of Science, 63: 19.8-204 (1969)].
Die erfindungsgemassen Aminocyclitole können verwendet werden, um neue Aminoglycosid-Antibiotika, nämlich Mutamicin 2 und N-niedrig Alkylderivate davon, herzustellen. Man hat gefunden, dass falls man einen mutanten Stamm von Micromonospora inyoensis, nämlich M.inyoensis Stamm 1550P-IG, in einem Nährmedium, das eines der erfindungsgemassen Aminocyclitole enthält, kultiviert, so entstehen antibiotisch wirksame Substanzen der allgemeinen Formel IIThe aminocyclitols of the invention can be used to prepare new aminoglycoside antibiotics, namely mutamicin 2 and N-lower alkyl derivatives thereof. It has been found that if a mutant strain of Micromonospora inyoensis , namely M.inyoensis strain 1550P-IG, is cultivated in a nutrient medium which contains one of the aminocyclitols according to the invention, then antibiotically active substances of the general formula II are formed
509808/1 U8509808/1 U8
JULI-8-1974JULY-8-1974
2O58-PTG-42O58-PTG-4
SK/chSK / ch
-5--5-
KHRn KHR n
NHR,NHR,
worin R. und R_ wie oben definert sindwherein R. and R_ are as defined above
Die Verbindung der Formel II worin R1 und R_ beide Wasserstoff sind, wird Mutamicin 2 genannt. Die Herstellung von VerbindungenThe compound of the formula II in which R 1 and R_ are both hydrogen is called mutamicin 2. Making connections
der Formel II wird in den Patentgesuchen Nr formula II is used in patent applications no
(Fall 2O56A) und Nr ..'... (Fall 2O69X) eingehend(Case 2O56A) and no ..'... (Case 2O69X) in detail
beschrieben.described.
Die erfindungsgemässen Zwischenprodukte entstehen in der ersten Stufe des erfindungsgemässen Verfahrens und sind Verbindungen der allgemeinen Formel IIIThe intermediate products according to the invention arise in the first stage of the process according to the invention and are compounds of the general formula III
-NR,-NO,
(III),(III),
OHOH
worin R und R wie oben definiert sind.wherein R and R are as defined above.
Sie sind alsoso you are
Verbindungen der Formel IV , worin R und R zusammen eine Bindung zwischen den zwei Stickstoffatomen bilden.Compounds of the formula IV, in which R and R together form a bond between the two nitrogen atoms.
509808/1148509808/1148
JULI-8-1974·JULY-8-1974
2O58-FTG-52O58-FTG-5
SK/chSK / ch
Das erfindungsgemässe Verfahren zur Herstellung der Verbindungen der Formel IV ist dadurch geknnezeichnet, dass manThe process according to the invention for the preparation of the compounds of the formula IV is characterized by that he
(i) cis-4,8-Dioxatricyclo[5.1.0.0 * joctan mit einer Verbindung der Formel NH2-NHR, worin R Wasserstoff oder eine geradkettige Alkylgruppe mit 1 bis 4 Kohlenstoffatomen darstellt, umsetzt, dass man, gewünschtenfalls,(i) cis-4,8-Dioxatricyclo [5.1.0.0 * joctane with a compound of the formula NH 2 -NHR, in which R is hydrogen or a straight-chain alkyl group having 1 to 4 carbon atoms, is reacted that, if desired,
(ii) eine so erhaltene Verbindung der allgemeinen Formel III(ii) a compound of the general formula III thus obtained
(III),(III),
worin R, und R_ beide Wasserstoff sind, oder ein so erhaltenes Racemat zweier Verbindungen der Formel III, worin eines von R1 oder R2 Wasserstoff und das andere niedriges Alkyl darstellt, oder ein isoliertes Isomer dieser racemischen Mischung, hydrogenolysiert, und die so erhaltene Verbindung der Formel I als solche oder als Säureadditionssalz, entweder in reiner Form oder in Form einer Mischung aus der 1-N-niedrigalkyl- und der entsprechenden 3-N-niedrigalkylsubstituierten Verbindung, isoliert.wherein R, and R_ are both hydrogen, or a thus obtained racemate of two compounds of the formula III, in which one of R 1 or R 2 is hydrogen and the other is lower alkyl, or an isolated isomer of this racemic mixture, hydrogenolyzed, and the resultant Compound of the formula I as such or as an acid addition salt, either in pure form or in the form of a mixture of the 1-N-lower alkyl and the corresponding 3-N-lower alkyl-substituted compound, isolated.
509808/1148509808/1148
JULI-8-1974JULY-8-1974
2O58-FTG-62O58-FTG-6
SK/chSK / ch
Die Stufe (i) wird vorzugsweise bei erhöhter Temperatur, beispielsweise bei Siedetemperatur des verwendeten Lösungsmittels ,durchgeführt. Als Lösungsmittel eigen sich insbesondere Toluen, Xylen, 2-Aethoxyäthanol und, vorzugs- * weise, 2-Methoxyäthanol. Die Umsetzung wird vorteilhaft in Anwesenheit von Magnesiumsulfat als Dehydratizierungsmittel vorgenommen. Das Magnesiumsulfat könnte ausserdem als Komplexbildner wirken und dadurch die Oeffnung der"Epoxidringe an den gewünschten Stellen günstig beeinflussen. Die Reaktion wird unter Inertgas (Stickstoff oder Argon) durchgeführt und beansprucht etwa 18 bis 28, vorzugsweise etwa 24 Stunden.Stage (i) is preferably carried out at an elevated temperature, for example at the boiling point of the solvent used. Suitable as solvents in particular toluene, xylene, 2-ethoxyethanol and, preferably * wise, 2-methoxyethanol. The implementation will be beneficial made in the presence of magnesium sulfate as a dehydrating agent. The magnesium sulfate could also be used as Complexing agents act and thereby favorably influence the opening of the "epoxy rings" at the desired points. The reaction is carried out under an inert gas (nitrogen or argon) and takes about 18 to 28, preferably about 24 hours.
Es ist leicht ersichtlich, dass falls ein niedrigalkylsubstituiertes Hydrazin in der Reaktion eingesetzt wird/ so erhält man eine Mischung aus zwei Verbindungen der Formel III: Eine Verbindung, in der die Alkylgruppe sich in der 6-Stellung, und eine Verbindung, in. der die Alkylgruppe sich in 7-Stellung befindet. Konfigurationsmässig ist die eine dieser Verbindungen ein Spiegelbild der anderen. Sie können durch allgemein bekannte Verfahren getrennt werden. Die Stellungen 6 und 7 der Formel III entsprechen den Postionen N-I und N-3 des 2,5-Dideoxystreptamines. Die Erfindung umfasst also 2,5-Dideoxystreptamin, 1-N-niedrigalkylsubstituierte Streptamine, - ' 3-N-niedrigalkylsubstituierte Streptamine, Mischungen von zwei der letztgenannten Verbindungen, sowie Säureadditions-. salze. Ausserdem werden das 6/7-Diaza-2,4-dihydroxybicyclo F3.2.1]octan, 6-N und 7-N-niedrigalkylsubstituierte Derivate davon, sowie auch Säureadditionssalze solcher Verbindungen beansprucht.It can easily be seen that if a lower alkyl-substituted hydrazine is used in the reaction / a mixture of two compounds of the formula III is obtained: a compound in which the alkyl group is in the 6-position, and a compound in which the The alkyl group is in the 7-position. In terms of configuration, one of these connections is a mirror image of the other. They can be separated by well known methods. The positions 6 and 7 of the formula III correspond to the positions NI and N-3 of the 2,5-dideoxystreptamine. The invention thus comprises 2,5-dideoxystreptamine, 1-N-lower alkyl-substituted streptamines, - '3-N-lower alkyl-substituted streptamines, mixtures of two of the last-mentioned compounds, and acid addition. salts. Also claimed the 6/7-diaza-2,4-dihydroxybicyclo F3.2.1] octane, 6-N and 7-N-niedrigalkylsubstituierte derivatives thereof, as well as acid addition salts of such compounds.
509808/1148'509808/1148 '
JULI-8-1974JULY-8-1974
2O58-FTG-72O58-FTG-7
SK/chSK / ch
Stufe (ii) des Verfahrens wird vorzugsweise bei Zimmertemperatur und erhöhtem Druck durchgeführt. Die Reaktion beansprucht ebenfalls etwa 18 bis 28, vorzugsweise 24 Stunden. Als Lösungsmittel wird Wasser bevorzugt, aber auch Mischungen aus Wasser und mit Wasser mischbaren organischen Lösungsmitteln, die gegenüber Katalytischer Hydrierung inert sind, wie z.B. Alkohole, können Verwendung finden. Als Katalysator verwendet man vorzugsweise einen für Hydrierung bzw. Hydrogenolyze gebräuchlichen Metallkatalysator. Als Beispiele seien hier Palladium, Platin, Rhodium und, als bevorzugter Kalalysator, Raney-Nickel angeführt.Step (ii) of the process is preferably carried out at room temperature and elevated pressure. The reaction also takes about 18 to 28 hours, preferably 24 hours. As a solvent is Water preferred, but also mixtures of water and water-miscible organic solvents, which are inert to catalytic hydrogenation, such as alcohols, can be used. as The catalyst is preferably a metal catalyst customary for hydrogenation or hydrogenolysis. Examples are palladium, platinum, rhodium and, as a preferred Kalalysator, Raney Nickel cited.
In der Weiterverarbeitung werden die erfindungsgemässen Verbindungen normalerweise als freie Stickstoff basen eingesetzt, jedoch können auch ihre Salze verwendet werden. Die Säureadditionssalze werden in üblicher Art erhalten, beispielsweise durch Hinzufügen eines Ueberschusses der betreffenden Säure zu einer Lösung der freien Base und nachfolgendes Fällen des Salzes mit Hilfe eines Fällungsmittels. Die Salzbildung kann ausserdem dazu dienen, die freien Basen in sehr reiner Form zu gewinnen.In the further processing, the inventive Compounds normally used as free nitrogen bases, but their salts can also be used be used. The acid addition salts are obtained in the usual way, for example by adding an excess of the acid in question to a solution of the free base and subsequent precipitation of the Salt with the help of a precipitant. The salt formation can also serve to remove the free bases to be obtained in a very pure form.
509808/1148509808/1148
JULI-2-1974 2058-FTG-SJULY-2-1974 2058-FTG-S
Herstellung von 2,5-Dideoxystreptamin und dessen • Dihydrochlorids Preparation of 2,5-Dih • Dideoxystreptamin and its ydrochl orids
A. 6,7-Diaza-2 ,4-äihvdroxvbicvcloi:3.2.11octanA. 6,7-Dia za-2, 4-äihvdr oxvbi cvcloi : 3.2.11octane
Eine Mischung aus 70 g cis-4,.'8-Dioxatr-icyclo[5.1.0.0 " 3 octan, 80 ml Hydrazinhydrat und 80 g wasserfreiem Magnesiumsulfat in 7000 ml 2-Methoxyäthanol werden 24 Stunden unter Inertgas (EL oder Ar ) auf Rückflusstemperatur erhitzt. Danach wird das Lösungsmittel unter Vakuum abgedampft und der Rückstand mit heissemMethanol (1500 ml) extrahiert. Nach Verdampfen das Methanols fällt das Produkt als weisse, kristalline Masse an.A mixture of 70 g of cis -4,. '8-Dioxatr-icyclo [5.1.0.0 "3 octane, 80 ml hydrazine hydrate and 80 g anhydrous magnesium sulfate in 7000 ml of 2-methoxyethanol are refluxed for 24 hours under inert gas (EL or Ar) heated. The solvent is then evaporated off under vacuum and the residue with hot methanol (1500 ml) extracted. After the methanol has evaporated, the product is obtained as a white, crystalline mass.
Ausbeute : 75 g, F.p.l99°-2OO°C (Zers.) Analyse : Berechnet für C6Hi2N2°2: c=49'85% * Yield (dec.) 75 g, Fpl99 -2OO ° ° C Analysis: Calculated for C 6 H 2 i2 N ° 2: c = 49 '85% *
H=8,25%; N--19,40% Gefunden: C=5C,15%; H=8,59% '; N=19,33%H = 8.25%; N - 19.40% Found: C = 5C, 15%; H = 8.59% '; N = 19.33%
B. 2,5-Dideoxystreptamin .B. 2,5-Dideoxys t reptamine .
100 mg des Produktes der Stufe A werden in 30 ml. Wasser bei 42 p.s.i. über 20 mg Raney—Nickel 24 Stunden lang hydriert. Danach wird der Katalysator abfiltriert und das Lösungsmittel unter Vakuum abgedampft.100 mg of the product of stage A are in 30 ml. Water at 42 p.s.i. over 20 mg Raney nickel for 24 hours hydrogenated. The catalyst is then filtered off and the solvent is evaporated off in vacuo.
Ausbeute: 100 mg. F.p,187°C (Zers).Yield: 100 mg. M.p., 187 ° C (dec).
C. 2, S-DideoxystreptamincTihydrochlorid C. 2, S-dideoxystreptam i ncTihydrochloride
Zu einer Lösung von 73 mg 2,5-Dideoxystreptamin in 5 ml. Wasser werden 1,1 ml. IN ChlorwasserstoffsäurelösungTo a solution of 73 mg 2,5-dideoxystreptamine in 5 ml. Water become 1.1 ml. IN hydrochloric acid solution
509808/1148509808/1148
JULI-2-1974 2O58-FTG-9JULY-2-1974 2O58-FTG-9
hinzugefügt und die Mischung 10 Minuten-gerührt. Die entstandene Lösung wird lyophilisiert und man erhält 106 mg des gewünschen Produkts das, durch Urnkristallisierung aus Aethanol greinigt wird. F.p. 34O C.added and the mixture stirred for 10 minutes. the The resulting solution is lyophilized and 106 mg of the desired product are obtained by crystallization is cleaned from ethanol. F.p. 34O C.
Analyse: Berechnet für C^II1 ΛΝ_0,, .2HCl: C=32,88%; H=7,37%;Analysis: Calculated for C ^ II 1 Λ Ν_0 ,, .2HCl: C = 32.88%; H = 7.37%;
N=12,78%
Gefunden: C=32,73%; H-7,24%; N=12,31%N = 12.78%
Found: C = 32.73%; H-7.24%; N = 12.31%
Beispiel 2
ι (--) -Monodiazabicyclo f 3.2.ljoctanExample 2
ι (-) -Monodiazabicyclo f 3.2.ljoctane
Herstellung von (-") -Mono-N-methyl-2, 5-dideoxystreptaminPreparation of (- ") -mono-N-methyl-2, 5-dideoxystreptamine
's C 's C
2g cis^iB-DioxatricyclofS.l.O Joctan, 0,8 g Monomethylhydrazin
und 1,4 g wasserfreies Magnesiumsulfat werden mit 200 ml 2-Methoxyäthanol gemischt. Die Mischung wird unter
Inertgas (Ar) 24 Stunden unter Rückfluss erhitzt. Das Lösungsmittel wird unter Vakuum abgedampft und der Rückstand
mit 100 ml heissem Methanol extrahiert. Nach Filtrieren wird das Filtrat unter Vakuum auf etwa 20 ml
eingedampft. Nach dem Abkühlen fällt das Produkt aus und wird abfiltriert.
Ausbeute: 2,1 g. F.p.l77°-178°C.2g of cis ^ iB-DioxatricyclofS.lO joctane, 0.8 g of monomethylhydrazine and 1.4 g of anhydrous magnesium sulfate are mixed with 200 ml of 2-methoxyethanol. The mixture is refluxed under an inert gas (Ar) for 24 hours. The solvent is evaporated off in vacuo and the residue is extracted with 100 ml of hot methanol. After filtering, the filtrate is evaporated to about 20 ml in vacuo. After cooling, the product precipitates and is filtered off.
Yield: 2.1 g. Mpl77 ° -178 ° C.
Falls gewünscht, können die Isomere nach bekannten Verfahren getrennt werden und man erhältIf desired, the isomers can be prepared according to known methods be separated and one receives
2,4-Dihydroxy-6-N-methy1-6,7-diazabicyclo[3.2.11octan und 2,4-Dihydroxy-7-N-methy1-6,7-diazabicycloI3.2.1ιoctan.2,4-dihydroxy-6-N-methy1-6,7-diazabicyclo [3.2.11octane and 2,4-dihydroxy-7-N-methy1-6,7-diazabicycloI3.2.1ιoctane.
509808/1148509808/1148
JULI-?.--1974 2Ö58--FTG-1OJULY -? - 1974 2Ö58 - FTG-1O
- «J- «J
B: (-)-Mono-N-mcthyl·^ , 5-dideoxystreptamin B: (-) - Mo no-Nm cthyl ^, 5- did eoxy stre ptamin
2.1 g (i)-2,4-Dihydroxy-inono-N-in£!thyl-6> 7-dia2abicycloC3.2.Ijoctan und 0,5 g Raney-Nickel werden in 90 ml Wa'sser gemischt und bei Zimmertemperatur hydriert (Anfangsdruck 60 p.s.i.) bis keine Aufnahme von Wasserstoff mehr erfolgt, (etwa 36 Stunden). Der Katalysator wird abfiltriert und die Lösung lyophilisiert und man erhält das gewünschte Produkt.2.1 g of (i) -2,4-dihydroxy-inono-N-ynethyl-6 > 7-dia2abicycloC3.2.ijoctane and 0.5 g of Raney nickel are mixed in 90 ml of water and hydrogenated at room temperature (Initial pressure 60 psi) until there is no more uptake of hydrogen (about 36 hours). The catalyst is filtered off and the solution lyophilized and the desired product is obtained.
Ausbeute: 2,12 g. P.p. 156°-157°C.Yield: 2.12 g. P.p. 156 ° -157 ° C.
C: l-N-Methyl-2,5-dideoxystreptamin C: IN- methyl-2,5-dideoxystreptamine
Verwendet man statt dem Racemat 2,4-Dihydroxy-6-N-methyl-6,7-diazabicyclo[3.2.1loctan als Ausg^ngsverbindung in dem unter (B) beschriebenen Verfahren, so erhält man l-N-Methyl-2,5-dideoxystreptamin.If you use 2,4-dihydroxy-6-N-methyl-6,7-diazabicyclo [3.2.1 octane instead of the racemate as the starting connection in the process described under (B), l-N-methyl-2,5-dideoxystreptamine is thus obtained.
Ersetzt man im Beispiel 2A das Monomethy!hydrazin durch andere Monoalkylhydrazine, wie beispielsweise Monoäthylhydrazin oder Monopropylhydrazxn,so erhält man die ent-If the monomethylhydrazine is replaced in Example 2A other monoalkylhydrazines, such as, for example, monoethylhydrazine or monopropylhydrazine, one obtains the
4*4 *
sprechenden MonoalkyIderivate, d.h. (-)-2,4-Dihydroxymono-N-äthyl-6, 7-diazabicyclo[3.2.lJoctan, bzw. (-)-2,4-Dihydroxy-mono-N-propyl-6,7-diazabicyclo[3.2.l3octan. speaking monoalkyl derivatives, i.e. (-) - 2,4-dihydroxymono-N-ethyl-6, 7-diazabicyclo [3.2.13 octane or (-) - 2,4-dihydroxy-mono-N-propyl-6,7-diazabicyclo [3.2.13octane.
Die so erhaltenen optischen Isomere kör^^en durch bekannte
Verfahren getrennt werden und man erhält
^-Dihydroxy-ö-N-äthyl-e,7-diazabicyclo[3.2.1}octan ;
2,4-Dihydroxy-7-N-äthyl-6,7-diazabicyclo[3.2.l]octan ;The optical isomers thus obtained can be separated by known methods and are obtained
^ -Dihydroxy-ö-N-ethyl-e, 7-diazabicyclo [3.2.1} octane; 2,4-dihydroxy-7-N-ethyl-6,7-diazabicyclo [3.2.1] octane;
509808/1 US.509808/1 US.
2058-F'I'G -λ 12058-F'I'G -λ 1
εκ/chεκ / ch
2,4--Dihydroxy-6--N-propyl~6, 7-di&z&bicyclo [3.2.11 oc1:;:n ; und 2,4-Dihydroxy-7~N-propyl~6,7-dia?,abicyclo [3.2.11 octan .2,4 - Dihydroxy-6 - N-propyl ~ 6, 7-di & z? Bicyclo [3.2.11 oc1:;: n; and 2, 4-dihydroxy-7 ~ ~ N-propyl-6,7 dia?, abicyclo [3.2.11 octane.
Werden diese RaceKiate, bzv/. Einzelverbindungen wie unter Beispiel 2B weiterbehandelt,so erhält manWill these RaceKiate, or /. Individual connections as below Example 2B treated further, one obtains
'(-) -Mono-N-äthyl-2,5-dideoxystreptamin ;'(-) -Mono-N-ethyl-2,5-dideoxystreptamine;
(-) ■~Mono~N-propyl-2,5-dideoxystreptainin; bzw. l-N-Aethyl-2,5-dideoxystreptarain und l-N-Propyl~2,5-dideoxystrcptaminl sowie die entsprechenden 3-N-Analoge.(-) ■ ~ mono ~ N-propyl-2,5-dideoxystreptainine; or IN-ethyl-2,5-dideoxystreptarain and IN-propyl-2,5-dideoxystreptamine I and the corresponding 3-N analogues.
ORIGINALORIGINAL
509808/1U8509808 / 1U8
Claims (2)
4R. both hydrogen:
4th
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US38576473A | 1973-08-06 | 1973-08-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE2437115A1 true DE2437115A1 (en) | 1975-02-20 |
Family
ID=23522782
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE2437115A Withdrawn DE2437115A1 (en) | 1973-08-06 | 1974-08-01 | 2,5-DIDEOXYSTREPTAMINE DERIVATIVES AND THE PROCESS FOR THEIR PRODUCTION |
Country Status (12)
| Country | Link |
|---|---|
| JP (1) | JPS5047947A (en) |
| BE (1) | BE818430A (en) |
| CH (1) | CH602570A5 (en) |
| DE (1) | DE2437115A1 (en) |
| FR (1) | FR2240017B1 (en) |
| GB (1) | GB1428938A (en) |
| IE (1) | IE40389B1 (en) |
| IL (1) | IL45386A (en) |
| IT (1) | IT1033086B (en) |
| NL (1) | NL7410359A (en) |
| SE (1) | SE7409947L (en) |
| ZA (1) | ZA744937B (en) |
-
1974
- 1974-07-31 CH CH1060074A patent/CH602570A5/xx not_active IP Right Cessation
- 1974-08-01 IE IE1640/74A patent/IE40389B1/en unknown
- 1974-08-01 ZA ZA00744937A patent/ZA744937B/en unknown
- 1974-08-01 SE SE7409947A patent/SE7409947L/xx not_active Application Discontinuation
- 1974-08-01 FR FR7426817A patent/FR2240017B1/fr not_active Expired
- 1974-08-01 GB GB3396674A patent/GB1428938A/en not_active Expired
- 1974-08-01 DE DE2437115A patent/DE2437115A1/en not_active Withdrawn
- 1974-08-01 IT IT25837/74A patent/IT1033086B/en active
- 1974-08-01 NL NL7410359A patent/NL7410359A/en not_active Application Discontinuation
- 1974-08-02 JP JP49088163A patent/JPS5047947A/ja active Pending
- 1974-08-02 IL IL45386A patent/IL45386A/en unknown
- 1974-08-02 BE BE147233A patent/BE818430A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| FR2240017B1 (en) | 1977-06-03 |
| IE40389L (en) | 1975-02-06 |
| FR2240017A1 (en) | 1975-03-07 |
| JPS5047947A (en) | 1975-04-28 |
| CH602570A5 (en) | 1978-07-31 |
| IT1033086B (en) | 1979-07-10 |
| NL7410359A (en) | 1975-02-10 |
| IL45386A (en) | 1978-10-31 |
| IE40389B1 (en) | 1979-05-23 |
| AU7194174A (en) | 1976-02-05 |
| ZA744937B (en) | 1975-08-27 |
| IL45386A0 (en) | 1974-11-29 |
| GB1428938A (en) | 1976-03-24 |
| SE7409947L (en) | 1975-02-07 |
| BE818430A (en) | 1975-02-03 |
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