GB1593927A - T-butyl derivatives of 5-hydroxy-tetracycline and a process for preparing the same - Google Patents
T-butyl derivatives of 5-hydroxy-tetracycline and a process for preparing the same Download PDFInfo
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- GB1593927A GB1593927A GB1946078A GB1946078A GB1593927A GB 1593927 A GB1593927 A GB 1593927A GB 1946078 A GB1946078 A GB 1946078A GB 1946078 A GB1946078 A GB 1946078A GB 1593927 A GB1593927 A GB 1593927A
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- United Kingdom
- Prior art keywords
- tetracycline
- hydroxy
- butyl
- deoxy
- methylene
- Prior art date
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- 238000004519 manufacturing process Methods 0.000 title claims description 12
- -1 T-butyl derivatives of 5-hydroxy-tetracycline Chemical class 0.000 title description 4
- 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 38
- 238000000034 method Methods 0.000 claims description 33
- 238000005695 dehalogenation reaction Methods 0.000 claims description 22
- 239000000203 mixture Substances 0.000 claims description 14
- IWVCMVBTMGNXQD-PXOLEDIWSA-N oxytetracycline Chemical class C1=CC=C2[C@](O)(C)[C@H]3[C@H](O)[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-PXOLEDIWSA-N 0.000 claims description 12
- 239000000047 product Substances 0.000 claims description 12
- 229910021604 Rhodium(III) chloride Inorganic materials 0.000 claims description 9
- SONJTKJMTWTJCT-UHFFFAOYSA-K rhodium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Rh+3] SONJTKJMTWTJCT-UHFFFAOYSA-K 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000011541 reaction mixture Substances 0.000 claims description 7
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- RPNNPZHFJPXFQS-UHFFFAOYSA-N methane;rhodium Chemical compound C.[Rh] RPNNPZHFJPXFQS-UHFFFAOYSA-N 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
- 238000010531 catalytic reduction reaction Methods 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
- 239000011707 mineral Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 239000010439 graphite Substances 0.000 claims description 3
- 229910002804 graphite Inorganic materials 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 239000000284 extract Substances 0.000 claims description 2
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims description 2
- MOODSJOROWROTO-UHFFFAOYSA-N salicylsulfuric acid Chemical compound OC(=O)C1=CC=CC=C1OS(O)(=O)=O MOODSJOROWROTO-UHFFFAOYSA-N 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 2
- 235000011152 sodium sulphate Nutrition 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- 239000000243 solution Substances 0.000 description 22
- 238000005984 hydrogenation reaction Methods 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000004098 Tetracycline Substances 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- 238000006722 reduction reaction Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 244000005700 microbiome Species 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 229960002180 tetracycline Drugs 0.000 description 4
- 229930101283 tetracycline Natural products 0.000 description 4
- 235000019364 tetracycline Nutrition 0.000 description 4
- 150000003522 tetracyclines Chemical class 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- SPVRWVNZBKXMQW-UHFFFAOYSA-N ethyl acetate;propan-2-one;hydrate Chemical compound O.CC(C)=O.CCOC(C)=O SPVRWVNZBKXMQW-UHFFFAOYSA-N 0.000 description 3
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 229940040944 tetracyclines Drugs 0.000 description 3
- 241000193755 Bacillus cereus Species 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 229960004132 diethyl ether Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 2
- 229910052753 mercury Inorganic materials 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- NTNBLKOKJNSQQA-XCLVFQIOSA-N (4s,4ar,5r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5-dihydro-4h-tetracene-2-carboxamide Chemical compound C1=CC(O)=C2C(O)=C(C(=O)[C@@]3(O)[C@H]([C@@H](C(C(C(N)=O)=C3O)=O)N(C)C)[C@H]3O)C3=C(C)C2=C1 NTNBLKOKJNSQQA-XCLVFQIOSA-N 0.000 description 1
- 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
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- 244000063299 Bacillus subtilis Species 0.000 description 1
- 235000014469 Bacillus subtilis Nutrition 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 102100038916 Caspase-5 Human genes 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241000194032 Enterococcus faecalis Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 101100112336 Homo sapiens CASP5 gene Proteins 0.000 description 1
- 241000588747 Klebsiella pneumoniae Species 0.000 description 1
- 241000191938 Micrococcus luteus Species 0.000 description 1
- 101100273286 Mus musculus Casp4 gene Proteins 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 241000751182 Staphylococcus epidermidis ATCC 12228 Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- 238000007210 heterogeneous catalysis Methods 0.000 description 1
- 238000007172 homogeneous catalysis Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- QZIQJVCYUQZDIR-UHFFFAOYSA-N mechlorethamine hydrochloride Chemical compound Cl.ClCCN(C)CCCl QZIQJVCYUQZDIR-UHFFFAOYSA-N 0.000 description 1
- 125000002560 nitrile group Chemical group 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
(54) T-BUTYL DERIVATIVES OF 5-HYDROXY
TETRACYCLINE AND A PROCESS FOR
PREPARING THE SAME
(71) We, PLIVA PHARMACEUTICAL AND CHEMICAL WORKS, of
Ive Lole Ribara 89, Zagreb, Yugoslavia, a Yugoslavian Body Corporate, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- The present invention relates to derivatives of 5-hydroxy-tetracycline and is concerned particularly, but not exclusively, with certain t-butyl derivatives thereof, namely N2-t-butyl-6-demethyl-6-deoxy-6-methylene.5-hydroxy tetracycline (which is referred to in the following description as N2-t-butyl-6- methylene-5-hydroxy-tetracycline) and N2-t-butyl-6-deoxy-5-hydroxy- tetracycline. These t-butyl derivatives are new compounds in the series of 5hydroxy-tetracyclines and have anti-microbial activity. The present invention also relates to the preparation of 6-deoxy-5-hydroxy-tetracycline, as well as to processes for preparing these various 5-hydroxytetracycline derivatives.
It is known that N2-alkyl derivatives of anhydrotetracycline, anhydrooxytetracycline and anhydrochlorotetracycline can be prepared by the condensation of olefines or tertiary alcohols on the nitrile group of the corresponding tetracyclines (British Patent Specifications 800,699 and 808,702;
U.S. Patent Specification 3,028,409).
It is also known from our copending Patent Application No. 13428/78 (Serial
No. 1571765) that N2-t-butyl-lla-halo-6-methylene-tetracyclines can be prepared by reaction of the corresponding 1 la-halo-6-methylene-tetracycline nitriles with tbutanol. These products are tetracycline derivatives of the formula:
These products are tetracycline derivatives wherein R represents a hydrogen atom or a hydroxy group and X represents a chlorine or bromine atom.
It has now been found that N2-t-butyl-6-methylene-5-hydroxy-tetracycline (II) can be obtained by the dehalogenation of N2-t-butyl-l la-halo-6-methylene-5hydroxy-tetracycline (I) and that the product (II) can be catalytically reduced to N2-t-butyl-6-deoxy-5-hydroxy-tetracycline (III).
These two processes are illustrated by the following scheme:
CH2 OH NICH32 XOH CONHCICH3)3 I OH 0X dehologenation CH2 OH N ICH3)2 < CONH CI CH 11 OH O OH O + hydrogenation CH3 OH NICH3)2 AXCISCONHCI CH3 111 OH O OH O X=(I,llr According to one aspect of the present invention, therefore, the dehalogenation of N2-t-butyl-l la-halo-6-methylene-5-hydroxy-tetracycline (1) is carried out electrochemically or chemically. 'Electrochemical dehalogenation is carried out, in accordance with a preferred embodiment of the invention, by operating at ambient temperature in an electrolytic cell having a metal or graphite cathode, using a controlled cathode potential or at constant current.
According to another aspect of the invention, dehalogenation is carried out by means of a chemical reducing agent, preferably triphenylphosphine.
The resultant N2-t-butyl-6-methylene-5-hydroxy-tetracycline from any of these dehalogenation procedures can be isolated and recrystallized by usual methods or reduction to N2-t-butyl-6-deoxy-5-hydroxy-tetracycline (111) can be carried out in the reaction solution after completion of the dehalogenation.
Reduction of the exocyclic methylene group can be effected under conditions suitable either for homogeneous or heterogeneous catalysis. According to the first method, the reduction is preferably effected in solution, at a temperature of 50 to 80"C and under a hydrogen pressure of 5 to 75 atmospheres, by the addition of rhodium trichloride and triphenylphosphine (preferably 1:5), which in situ form a soluble complex, whereas according to the second method 5% to 10% by weight rhodium on charcoal and triphenylphosphine are used as a catalyst. In both cases, the alpha-isomer of N2-t-butyl-6-deoxy-5-hydroxy- tetracycline is preferentially formed. However, in the second case, the hydrogenation is desirably carried out at elevated temperature (up to 80 C), e.g.
at 50 to 700 C, and under a hydrogen pressure of 3.5 to 75 atmospheres, e.g. 3.5 to 50 atmospheres. Depending on the pressure and temperature employed, the reduction step is continued for 4 to 24 hours.
After hydrogenation has been completed, the reaction solution may be filtered, the filtrate evaporated to dryness under reduced pressure and alpha-N2-tbutyl-6-deoxy-5-hydroxy-tetracycline isolated from the residue. By thin-layer chromatography (stationary phase: silica gel in a 5% solution of the sodium salt of
EDTA, pH 7.5; mobile phase: acetone-ethyl acetate-water 8:4:1.2) it has been ascertained that, by the reduction, the alpha-isomer of N2-t-butyl-6-deoxy-5hydroxy-tetracycline is formed nearly quantitatively, whereas the beta-isomer is present only in traces.
The structure of the new compounds has been confirmed by IR-, UV- and
NMR-spectra and also by carrying out certain chemical reactions. For instance, by hydrolysis of the butyl group of N2-t-butyl-6-deoxy-5-hydroxy-tetracycline by means of strong mineral acids, 6-deoxy-5-hydroxy-tetracycline can be obtained.
The IR-spectrum of the starting material, N2-t-butyl-l la-halo-6-methylene-5hydroxy-tetracycline, is characterized by absorption at 3.38u, which corresponds to the C-H-vibrations, and by a very strong band at 5.7,u, typical of the C12- ketones of tetracycline. In the dehalogenated product, i.e. N2-t-butyl-6methylene-5-hydroxy-tetracycline, the band at 5.7,u is no longer present.
The UV-spectrum of N2-t-butyl-6-methylene5-hydroxy-tetracycline is characterized by a broad maximum at 250 nm, which is typical of 6-methylenetetracyclines, and a maximum at 342 nm, which excludes the possibility of formation of anhydro derivatives. The NMR-spectra of the new compounds exhibit a distinctive band at 1.53b, which designates the presence of the t-butyl group.
In vitro testing of the new compounds shows high anti-microbial activity against certain microorganisms. Table I below shows results obtained by determination of minimum inhibitory concentration (MIC) against a number of microorganisms. The tests were carried out by the series dilution method (Reihenverdiinnung) on a nutrient substrate. From the Table, it can be seen that the activity in vitro of the new compounds, that is, compounds numbered 2 and 3, on some microorganisms is on a level with that of the corresponding starting substances, that is, substances numbered 1 and 4, respectively, whereas against some others (e.g. Staph. epidermidis and B.cereus var. myc.) a higher activity is exhibited.
TABLE I
Minimum Inhibitory Concentration (mcg/ml)
Microorganism 1 2 3 4
Staphylococcus aureus ATCC 6538-p 0.5 0.5 0.5 0.5
Staphylococcus epidermidis ATCC 12228 5.0 2.5 2.0 5.0 Micrococcus pyogenes aur. NCTC 2097 0.5 2.5 2.5 1.0
Streptococcus faecalis ATCC 8043 0.5 2.0 1.5 0.5
Sarcina lutea ATCC 9341 0.5 5.0 Escherichia coli ATCC 10536 0.5 50.0 50.0 1.0
Bacillus subtilis ATCC 6633 0.75 1.0 0.1 0.05 Bacillus cereus var.myc. ATCC 11778 0.5 0.1 0.1 0.5 Klebsiella pneumoniae ATCC 10031 0.1 2.0 1.5 0.5
Pseudomonas aeruginosa NCTC 10490 1.0 50.0 50.0 10.0
1. 6-methylene-5-hydroxy-tetracycline
2. N2-t-butyl-6-methylene-5-hydroxy-tetracycline
3. N2-t-butyl-6-deoxy-5-hydroxy-tetracycline
4. 6-deoxy-5-hydroxy-tetracycline The invention is illustrated by the following Examples:
Example 1
N2-t-butyl-6-methylene-5-hydroxy-tetracycline
0.53 g (1 mmole) of N2-t-butyl-11a-chloro-6-methylene-5-hydroxy tetracycline was dissolved in 50 ml of methanol and 0.1 ml of concentrated hydrochloric acid and the resultant solution was placed in the cathode chamber of an electrolytic cell consisting of a vessel with a volume of about 100 ml, with a mercury cathode and a platinum anode. A reference electrode (SCE) was leant against the mercury surface and dehalogenation was carried out under stirring, at a controlled potential of -0.40 V vs. SCE, until it could be ascertained polarographically that the band which corresponds to the presence of chlorine at the position 1 lea was missing. The dehalogenated solution was evaporated under reduced pressure to a dry residue. By re-crystallisation from i-propanol N2-t-butyl6-methylene-5-hydroxy-tetracycline was obtained.
C26H30N2O3.0.5 C3H80.0.5 H20 Calc.: C6l.70% H6.34% N5.22% Found: C61.76% H6.200/d, N5.72% IR (CHCl3) 3.38y UV (0.01 N HCl/methanol) 250, 342 nm
NMR (CF3COOH) 81.53(s), a5.35(s), 5.6(s) Rf (silica gel, acetone-ethyl acetate-water 8:4:1.2): 0.66
Example 2
N2-t-butyl-6-methylene-5-hydroxy-tetracycline
0.575 g (1 mmole) of N2-t-butyl-l la-bromo-6-methylene-5-hydroxytetracycline was dissolved in 50 ml of methanol and dehalogenated and the desired product isolated as described in Example 1. The resultant N2-t-butyl-6methylene-5-hydroxy-tetracycline was identical with the product of Example
Example 3
N2-t-butyl-6-methylene-5-hydroxy-tetracycline
0.53 g (1 mmole) of N2-t-butyl-l la-chloro-6-methylenc-5-hydroxytetracycline was dissolved in 20 ml of methanol and 0.26 g (I mmole) of triphenylphosphine was added to the solution and stirred for 30 minutes at 600 C.
By running the dehalogenated solution through a column filled with ion exchange resin, e.g. that sold under the Regd. Trademark "Amberlyst A-15", and eluting the adsorbed substance, N2-t-butyl-6-methylene-5-hydroxy-tetracycline was isolated by using methods and was found to be identical with the product obtained in Example 1.
Example 4 N2-t-butyl-6-deoxy-5-hydroxy-tetracycline 0.5 g (1 mmole) of N2-t-butyl-6-methylene-5-hydroxy-tetracycline was dissolved in 20 ml of methanol, a suspension of catalyst, containing 0.13 g (0.5 mmole) of triphenylphosphine and 0.024 g (0.09 mmole) of rhodium trichloride in
10 ml of methanol, was added and hydrogenation was carried out for 4 hours at 50 to 550C under a hydrogen pressure of 75 atmospheres. The hydrogenated mixture was cooled, filtered and evaporated to a dry residue. By suspending the raw hydrogenated product in diethyl ether, the catalyst was removed, which is soluble in ether, and then, by recrystallisation from i-propanol, N2-t-butyl-6deoxy-5-hydroxy-tetracycline was obtained.
C26H32N2O8.0.5 C3HsO.0.5 H20
Calc.: C6l.20% H6.9l% N5.l9% Found: C61.27% H6.85% N5.33 IR (CHCl3) 3.37y UV (0.01 N HCl/methanol) 267, 351 nm
NMR (CF3COOH) 61.53(s)
Rf (silica gel, acetone-ethyl acetate-water 8:4:1.2): 0.76
Example 5 N2-t-butyl-6-deoxy-5-hydroxy-tetracycline 0.5 g (1 mmole) ot N2-t-butyl-6-methylene-5-hydroxy-tetracycline was dissolved in 30 ml of methanol, 0.13 g 0.5 mmole) of triphenylphosphine and 0.024 g (0.09 mmole) of rhodium trichloride were added and hydrogenation was carried out for 24 hours at 500C and under a hydrogen pressure of 5 atms. The hydrogenated mixture was filtered and the filtrate evaporated to dryness. By treating the dry residue with diethylether and recrystallising from i-propanol, N2t-butyl-6-deoxy-5-hydroxy-tetracycline was isolated, which was identical with the compound obtained in Example 4.
Example 6 N2-t-butyl-6-deoxy-5-hydroxy-tetracycline 2.44 g (4.6 mmoles) of N2-t-butyl-l la-chloro-6-methylene-5-hydroxytetracycline was dissolved in 50 ml of methanol and dehalogenated as described in
Example 1. The reaction mixture was then introduced into a Parr hydrogenation flask, 0.9 g of 5% rhodium on charcoal (0.44 mmole) and 0.32 g (1.21 mmoles) of triphenylphosphine were added thereto and the reaction mixture was hydrogenated for 20 hours at 700C and 3.5 atms. The hydrogenated mixture was filtered and treated as in Example 4.
Example 7
N2-t-butyl-6-deoxy-5-hydroxy-tetracycline
2.44 g (4.6 mmoles) of N2-t-butyl-l la-chloro-6-methylene-5-hydroxytetracycline was dissolved in 50 ml of methanol and dehalogenated as described in
Example 1. To the dehalogenation solution, 0.9 g of 5% rhodium on charcoal (0.44 mmole) and 0.32 g (1.21 mmoles) of triphenylphosphine were added and hydrogenation was continued for 5 hours at 50"C and 50 atms. The hydrogenated solution was treated as in Example 6.
Example 8
N2-t-butyl-6-deoxy-5-hydroxy-tetracycline
2.44 g (4.6 mmoles) of N2-t-butyl-l la-chloro-6-methylene-5-hydroxytetracycline was dissolved in 50 ml of methanol and dehalogenation was carried out as in Example 1 .035 (1.3 mmoles) of triphenylphosphine and 0.5 g of 10% rhodium on charcoal (0.49 mmole) were added to the reaction solution and hydrogenation was continued for 18 hours at 500C and 5 atms. The hydrogenated solution was treated as in Example 6.
Example 9
N2-t-butyl-6-deoxy-5-hydroxy-tetracycline
0.53 g (1 mmole) of N2-t-butyl- 1 la-chloro-6-methylene-5-hydroxy- tetracycline was dehalogenated as in Example 1, 0.13 g (0.5 mmole) of triphenylphosphine and 0.03 g (0.11 mmoles) of rhodium trichloride were added to the reaction solution and hydrogenation was continued for 24 hours at 500C and 5 atms. The hydrogenated solution was filtered and treated as in Example 6.
Example 10
N2-t-butyl-6-deoxy-5-hydroxy-tetracycline
0.53 g (1 mmole) of N2-t-butyl-1 la-chloro-6-methylene-5-hydroxy- tetracycline was dehalogenated as in Example 1, 0.13 g (0.5 mmole) of triphenylphosphine and 0.03 g (0.11 mmoles) of rhodium trichloride were added to the dehalogenated solution and hydrogenation was carried out for 5 hours at 500C and 75 atms. The hydrogenated solution was treated as in Example 6.
Example 11
N2-t-butyl-6-deoxy-5-hydroxy-tetracycline
0.53 g (1 mmole) of N2-t-butyl-l la-chloro-6-methylene-5-hydroxytetracycline was dissolved in 30 ml of methanol and dehalogenated as described in
Example 3. To the dehalogenated solution, 0.13 g (0.5 mmole) of triphenylphosphine and 0.024 g (0.09 mmole) of rhodium trichloride were added and the mixture hydrogenated for 5 hours at 500C and 75 atms. The hydrogenated solution was treated as in Example 6.
Example 12
N2-t-butyl-6-deoxy-5-hydroxy-tetracycline
2.44 g (4.6 mmoles) of N2-t-butyl-l la-chloro-6-methylene-5-hydroxytetracycline was dissolved in 80 ml of methanol, 1.2 g (4.6 mmoles) of triphenylphosphine were then added and the mixture was stirred for 30 minutes at 60"C. To the dehalogenated solution, 40 ml of methanol, 0.63 g (2.3 mmoles) of triphenylphosphine and 0.11 g (0.42 mmole) of rhodium trichloride were added and the reaction mixture was hydrogenated for 24 hours at 500C and 5 atms. The hydrogenated solution was treated as in Example 6.
Example 13
N2-t-butyl-6-deoxy-5-hydroxy-tetracycline
2.44 g (4.6 mmoles) of N2-t-butyl-l la-chloro-6-methylene-5-hydroxy- tetracycline were dissolved in 30 ml of methanol and 4 ml of water, 1.2 g (4.6 mmoles) of triphenylphosphine was added thereto and the mixture was stirred for 30 minutes at 600 C. After complete dehalogenation, hydrogenation and isolation were carried out as in Example 6.
Example 14
N2-t-butyl-6-deoxy-5-hydroxy-tetracycline
2.44 g (4.6 mmoles) of N2-t-butyl-l la-chloro-6-methylene-5-hydroxytetracycline was dehalogenated as in Example 13 and then the dehalogenated solution was hydrogenated as described in Example 7.
Example 15
6-Deoxy-5-hydroxy-tetracycline
1 g (2 mmoles) of N2-t-butyl-6-deoxy-5-hydroxy-tetracycline was suspended in
10 ml of 48% hydrobromic acid and the mixture was stirred for 4 hours while being heated to 700 C. The reaction solution was carefully poured into 300 ml of a mixture of water and ice, whereby a flaky precipitate was formed. The resultant suspension was extracted three times with 300 ml of n-butanol, to obtain the desired 6-deoxy-5-hydroxy-tetracycline. The extracts were combined and well washed with water saturated with n-butanol, dried over sodium sulphate and evaporated to a dry residue under reduced pressure. By crystallisation from a mixture of methanol-water (1:1) with the addition of sulphosalicylic acid, 6deoxy-5-hydroxy-tetracycline sulphosalicylate was isolated.
WHAT WE CLAIM IS:
1. N2-t-butyl.6-demethyl-6-deoxy-6-methylene-5-hydroxy-tetracycline.
2. N2-t-butyl.6-deoxy-5-hydroxy-tetracycline.
3. A process for preparing a derivative of 5-hydroxy-tetracycline, which comprising subjecting a N2-t-butyl-l la-halo-6-methylene-5-hydroxy-tetracycline to dehalogenation to obtain N2-t-butyl-6-methylene-5-hydroxy-tetracycline.
4. A process for preparing a derivative of 5-hydroxy-tetracycline, which comprises subjecting N2-t-butyl-6-methylene-5-hydroxy-tetracycline to catalytic reduction to obtain N2-t-butyl-6-deoxy-5-hydroxy-tetracycline.
5. A process according to claim 3, wherein the dehalogenation is carried out at ambient temperature in an electrolytic cell having a metal or graphite cathode, using a controlled cathode potential or at constant current.
6. A process according to claim 3, wherein the dehalogenation is carried out by means of a chemical reducing agent.
7. A process according to claim 6, wherein the reducing agent used is triphenylphosphine.
8. A process according to any of claims 3 and 5 to 7, wherein, after the dehalogenation, N2-t-butyl-6-methylene-5-hydroxy-tetracycline is isolated from the reaction mixture.
9. A process according to any of claims 3 and 5 to 8, wherein a dehalogenation product obtained by a procedure according to claim 8 or a mixture containing it obtained by a procedure according to claim 5, 6 or 7 is catalytically reduced in the presence of rhodium trichloride and triphenylphosphine at a temperature of 50 to 800C and under a hydrogen pressure of 5 to 75 atmospheres.
10. A process according to any of claims 3 and 5 to 8, wherein a dehalogenation product obtained by a procedure according to claim 8 or a mixture containing it obtained by a procedure according to claim 5, 6 or 7 is catalytically reduced in the presence of 5% to 10% by weight rhodium on charcoal at 50 to 700C and under a hydrogen pressure of 3.5 to 50 atmospheres.
11. A process according to claim 4, wherein, after the catalytic reduction, the reaction mixture is filtered, the filtrate is evaporated to dryness under reduced pressure and N2-t-butyl-6-deoxy-5-hydroxy-tetracycline is isolated from the dry residue.
12. A process for preparing a derivative of 5-hydroxy-tetracycline, substantially as herein described with reference to any of the foregoing Examples 1 to 3.
13. A process for preparing a derivative of 5-hydroxy-tetracycline, substantially as herein described with reference to any of the foregoing Examples 4 to 14.
14. A process for preparing 6-deoxy-5-hydroxy-tetracycline, which comprises subjecting N2-t-butyl-6-deoxy-5-hydroxy-tetracycline to strong mineral acid hydrolysis.
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (17)
1. N2-t-butyl.6-demethyl-6-deoxy-6-methylene-5-hydroxy-tetracycline.
2. N2-t-butyl.6-deoxy-5-hydroxy-tetracycline.
3. A process for preparing a derivative of 5-hydroxy-tetracycline, which comprising subjecting a N2-t-butyl-l la-halo-6-methylene-5-hydroxy-tetracycline to dehalogenation to obtain N2-t-butyl-6-methylene-5-hydroxy-tetracycline.
4. A process for preparing a derivative of 5-hydroxy-tetracycline, which comprises subjecting N2-t-butyl-6-methylene-5-hydroxy-tetracycline to catalytic reduction to obtain N2-t-butyl-6-deoxy-5-hydroxy-tetracycline.
5. A process according to claim 3, wherein the dehalogenation is carried out at ambient temperature in an electrolytic cell having a metal or graphite cathode, using a controlled cathode potential or at constant current.
6. A process according to claim 3, wherein the dehalogenation is carried out by means of a chemical reducing agent.
7. A process according to claim 6, wherein the reducing agent used is triphenylphosphine.
8. A process according to any of claims 3 and 5 to 7, wherein, after the dehalogenation, N2-t-butyl-6-methylene-5-hydroxy-tetracycline is isolated from the reaction mixture.
9. A process according to any of claims 3 and 5 to 8, wherein a dehalogenation product obtained by a procedure according to claim 8 or a mixture containing it obtained by a procedure according to claim 5, 6 or 7 is catalytically reduced in the presence of rhodium trichloride and triphenylphosphine at a temperature of 50 to 800C and under a hydrogen pressure of 5 to 75 atmospheres.
10. A process according to any of claims 3 and 5 to 8, wherein a dehalogenation product obtained by a procedure according to claim 8 or a mixture containing it obtained by a procedure according to claim 5, 6 or 7 is catalytically reduced in the presence of 5% to 10% by weight rhodium on charcoal at 50 to 700C and under a hydrogen pressure of 3.5 to 50 atmospheres.
11. A process according to claim 4, wherein, after the catalytic reduction, the reaction mixture is filtered, the filtrate is evaporated to dryness under reduced pressure and N2-t-butyl-6-deoxy-5-hydroxy-tetracycline is isolated from the dry residue.
12. A process for preparing a derivative of 5-hydroxy-tetracycline, substantially as herein described with reference to any of the foregoing Examples 1 to 3.
13. A process for preparing a derivative of 5-hydroxy-tetracycline, substantially as herein described with reference to any of the foregoing Examples 4 to 14.
14. A process for preparing 6-deoxy-5-hydroxy-tetracycline, which comprises subjecting N2-t-butyl-6-deoxy-5-hydroxy-tetracycline to strong mineral acid hydrolysis.
15. A process according to claim 14, wherein the mineral acid used is
hydrobromic acid.
16. A process according to claim 14, substantially as herein described with reference to the foregoing Example 15.
17. A derivative of 5-hydroxy-tetracycline, when prepared by a process according to any of claims 3 to 16.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB1946078A GB1593927A (en) | 1978-05-15 | 1978-05-15 | T-butyl derivatives of 5-hydroxy-tetracycline and a process for preparing the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB1946078A GB1593927A (en) | 1978-05-15 | 1978-05-15 | T-butyl derivatives of 5-hydroxy-tetracycline and a process for preparing the same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB1593927A true GB1593927A (en) | 1981-07-22 |
Family
ID=10129737
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB1946078A Expired GB1593927A (en) | 1978-05-15 | 1978-05-15 | T-butyl derivatives of 5-hydroxy-tetracycline and a process for preparing the same |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB1593927A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2550788A1 (en) * | 1983-08-17 | 1985-02-22 | Hovione Int Ltd | NEW PROCESS FOR THE PREPARATION OF A-6-DESOXYTETRACYCLINES |
-
1978
- 1978-05-15 GB GB1946078A patent/GB1593927A/en not_active Expired
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2550788A1 (en) * | 1983-08-17 | 1985-02-22 | Hovione Int Ltd | NEW PROCESS FOR THE PREPARATION OF A-6-DESOXYTETRACYCLINES |
| EP0137661A2 (en) * | 1983-08-17 | 1985-04-17 | Hovione Inter Ltd. | A new process for the preparation of alpha-6-deoxy-tetracyclines |
| EP0137661A3 (en) * | 1983-08-17 | 1987-08-19 | Hovione Inter Ltd. | A new process for the preparation of alpha-6-deoxy-tetracyclines |
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| PS | Patent sealed | ||
| PCNP | Patent ceased through non-payment of renewal fee |