KR790001339B1 - Prozess for producing -6-deoxytertraclines - Google Patents

Abstract

6-Deoxytetracycline (I; R = H, hydroxyl, X = H, Cl, F) was prepd. as α-form mainly with low amts. of β-form by Rh-catalytic hydrogenation of 6-demethyl-6-deoxy-6-methylenetetracycline or its salts, e.g., N-methyl-2-pyrrolidone contg. tert. phosphines and promoters e.g., acids or SnCl2.

Description

Method for preparing 6-deoxytetracycline

The present invention relates to an improved novel process for preparing 6-deoxytetracycline, specifically hydrogen in a reaction-inert solvent medium containing catalytic amount of rhodium metal and 6-demethyl-6-deoxy-6-methylenetetracycline. An improvement in the process of introducing ie an improved method of adding phosphine and promoter to the medium.

According to the method, 6-demethyl-6-methylenetetracycline is converted to 6-deoxytetracycline as a high ratio, and the ratio of α-6-deoxytetracycline to β-6-deoxytetracycline is increased and sensitivity ( The effect of minimizing the formation of the product is achieved.

A new group of tetracycline compounds, generally represented as α-6-deoxytetracycline, has been published, which hydrogenate 6-demethyl-6-deoxy-6-methylenetetracycline under the action of precious metals (including rhodium). To form a mixture of the corresponding α-6-deoxytetracycline and β-6-deoxytetracycline, and then separated and recovered the α-isomer from the mixture.

Under operating conditions suitable for adoption, this method can produce mixtures of up to about 1: 1 alpha-to-isomers.

Given that α-isomers, particularly α-6-deoxy-5-oxytetracycline, have significantly higher activity than the corresponding β-isomers, the α-isomers for α-isomers without reducing the overall yield of the isomeric mixture Increasing the proportion of isomers is very important.

Indeed, an improved method has been disclosed to improve the ratio of α- to β-isomers and to increase the yield of isomeric mixtures in hydrogenating 6-demethyl-6-deoxy-6-methylenetetracycline as a noble metal catalyst.

The method aims to carry out the hydrogenation in the presence of a noble metal catalyst whose catalytic activity is weakened by any one of carbon monoxide, quinoline-sulfur or various thiourea derivatives. The susceptibility to catalysis of metal catalysts has been noted by Maxted (see Advan. Catalysis 3, 129, 1951). As catalyst poisons, various compounds of elemental periodic table V-A and VI-A elements including nitrogen, phosphorus, oxygen and sulfur compounds are mentioned.

Unsaturated hydrocarbons (acetylene and olefins) in an inert homogeneous liquid medium are brought into contact with unsaturated hydrocarbons by contacting hydrogen in the presence of a zero-valent compound of palladium or platinum containing one or more tertiary phosphine ligands dissolved in a liquid medium. Hydrogenation has been announced.

Zero-valent palladium or platinum compounds are usually prepared by reducing divalent palladium or platinum compounds to hydrazine in the presence of excess tertiary phosphine.

Meanwhile, a method of preparing α-6-deoxytetracycline has been disclosed by hydrogenation using a homogeneous catalyst using tris- (trimenylphosphine) chlororodium as a catalyst. The catalyst may be formed in advance or be formed in the reaction mixture by dissolving rhodium chloride and triphenylphosphine or other ligands with a suitable 6-demethyl-6-deoxy-6-methylenetetracycline compound in a suitable solvent prior to hydrogenation. You may. In the preparation of the catalyst, when the molar ratio of triphenylphosphine or other ligand to rhodium (initially present as rhodium chloride) is less than 1: 1, it acts as a heterogeneous catalyst which mainly forms β-isomers rather than the desired α-isomers. It has been reported that this results in the formation of a precipitate of metal in powder form. It is reported that when the molar ratio of triphenyl phosphine or other ligand to metal is greater than 3: 1, the production of a homogeneous catalyst is accompanied with incomplete conversion of the compound and reduced yield of the desired product.

Methylenecyclohexane (Augustine et al. Ann. NY Acad. Sci. 158, 482 91, 1969) using tris (triphenylphosphine) chlororodium as a catalyst: coronophylline (Tetrahedron 25, 807-11, 1969, Ruesch et al.) And hydrogenation by the homogeneous catalyst of the methylene group of the ring used in the intermediate (Sierm et al., Chem. Communs 1069-70, 1969) in the stereoselective total synthesis of szelen.

Suitable temperature in a reaction inert solvent medium containing a catalytic amount of rhodium metal and 6-demethyl-6-deoxy-6-methylenetetracycline selected from the group consisting of compounds of the general formula (I) and acid addition salts and polyvalent metal salts thereof; The introduction of hydrogen until the reduction of the 6-methylene group at pressure occurs is significantly improved by the inclusion of phosphine and promoter in the medium in a reaction inert solvent containing the catalyst and the 6-methylenetetracycline reactant. Found.

Wherein R is hydrogen or a hydroxy group.

According to the method of the present invention, hydrogen is introduced into a reactive inert solvent medium containing a compound of formula I or a salt thereof, a catalytic amount of rhodium metal, an accelerator and a phosphine.

The resulting α-to β-isomer mixture is then recovered by conventional methods including decatalization and rare water of the mixture from the solvent medium. This mixture is worked up according to chromatography or other known methods. Sulfosalicylic acid is added, for example, to predominantly precipitate the α-isomer (see J. Am. Chem. Soc. 84, 2643-51 (1963)), for example as described in the following reference. Representative separation methods are illustrated in the Examples which follow.

The reactive inert solvent medium is a solvent or a suitable suspending agent for the 6-methylenetetracycline reactant, which is stable under hydrogenation drying, and does not impair the effect of the catalyst and does not affect the antibiotic. Polar organic solvents are generally suitable, and basic media are undesirable because they promote degradation and reduce the yield of the desired product.

Methanol, ethanol, acetone, methyl ethyl ketone, dioxane, formamide, monoalkyl- and dialkylformamides having 1-4 carbon atoms in each alkyl group (e.g., N-methylacetamide, N, N-dimethylacetamide , N-methyl-N-acetylformamide, N, N-diethylacetoacetamide), pyrrolidone, N-methyl-2-pyrrolidone, methyl-1-methyl-2-pyrrolidone-4- Excellent results in a wide range of reaction media such as carboxylate, ethylene glycol, propylene glycol, 2-methoxyethanol, 2-ethoxy ethanol, acetonitrile, acetic acid, tetramethylurea, tetrahydrofuran and γ-butyrolactone Is achieved.

Mixtures of these solvents may also be used. Suitable solvents for this reaction are methylformamide, N-methylacetamide, methyl 1-methyl-2-pyrrolidone-4-carboxylate and tetramethylurea, particularly suitable are methanol and N-methyl-2-pi It's Rolidon. Such solvents often provide the best results when they contain about 5-80% water.

Particularly advantageous advantages of the solvents are as follows.

(1) Rhodium metal is relatively stable in these media even before phosphine is added to the media. However, when a solvent such as methanol is used, it is preferable to immediately introduce phosphine in order to avoid the possibility of catalysis.

(2) It is well known in the catalyst art that even the same catalyst shows a change in its function if the lots are different. However, it has been found in the medium that the product is produced in a satisfactory high yield even in a batch reactor of the so-called catalyst, which is considered to be inferior.

(3) Since these media have high solubility, a particularly high substrate concentration of 30% by weight or more can be used.

(4) These media provide optimum results at relatively low weight ratios of catalyst to substrate, often at a ratio of less than about 1: 2.

(5) In these media particularly high conversions of the substrate, high yields of the α-isomers and the main production of the α-isomers are achieved.

(6) Easy recovery of high quality α-isomers.

As with other hydrogenation of tetracycline antibiotics, the temperature is high enough to promote a moderate reaction rate, but is not particularly important unless it is high enough to promote the formation of unwanted byproducts. Generally a temperature of about 0 ° C. to about 100 ° C. may be used. At the lower limit of this temperature range, such as about 10 ° C. or less, the reaction is too slow, so there is little practical value. At the upper limit, such as about 95 ° C. or more, decomposition of the reactant and the product occurs. The range is about 25 ° C. to about 90 ° C. Especially preferable in this range is the temperature of about 70 degreeC-90 degreeC.

The rhodium metal used as the catalyst in the present invention may or may not be supported. Examples of suitable catalyst carriers are carbon, silica, alumina and barium sulfate. Rhodium is preferably used in a supported form such as carbon-phase-rhodium, barium sulfate-phase-rhodium, barium carbonate-phase-rhodium and alumina-phase-rhodium. A particularly suitable form is 5% rhodium on carbon.

As used herein, the expression "catalyst amount" may be well understood by those skilled in the art of hydrogenating tetracycline-type compounds, and representative amounts are exemplified in later examples. Best results are usually achieved with about 0.0001 to 2 parts by weight of catalyst (metal) in dry weight per part of substrate, although higher or lower proportions of catalysts can be used successfully, of course. As a representative example, a molar ratio of 3 to 3 of the catalyst and the 6-methylene tetracycline compound can be used. Particularly suitable catalysts are rhodium on carbon, which is commercially available as a 50% wet (wet by water) mixture containing 5% rhodium on carbon (dry weight) and is convenient to use in this form.

The pressure used during hydrogenation can range from subatmospheric to 2,000 psi, and higher pressures may be used if suitable equipment is available. Pressures up to 100 mmHg or below atmospheric pressures can also be used successfully, but hydrogen pressures of 1 atm or more are usually suitable for reaction rates and convenience. Generally, pressures in the range of up to about 1,000 psi are generally suitable because they promote hydrogenation in a reasonable time. The 6-methylenetetracycline compound to be reduced can be used in the form of amorphous, polyvalent metal salt complexes (such as calcium, barium, zinc, magnesium), or acid addition salts that are suitable or inadequate as medicaments. Suitable salts for medicine include inorganic acid salts such as hydrochloride, hydroiodide, hydrobromide, phosphate, metaphosphate, nitrate, and sulfate salts, tartarate, acetate, citrate, succinate, benzoate, glycolate, gluconate, and pumpkin. Acid salts, aryl sulfonates such as P-toluene sulfonate, sulfosalicylate and the like. Acid addition salts that are not suitable for medicine are hydrofluoride and perchlorate.

It is preferable to use a 6-methylene tetracycline compound (formula I) especially as an acid addition salt. Preferred salts are hydrochloride, sulfosalicylate, P-toluenesulfonate, perchlorate and perborate.

These salts may be formed in advance or may be formed during the reaction by adding an equimolar amount of a suitable acid to the reaction mixture containing 6-methylenetetracycline base to form an acid addition salt. It was observed that the hydrogenation kinetics and the desired yield of α-isomers were unexpectedly improved by the presence of excess acid in excess of the amount necessary to work with the 6-methylenetetracycline reactant to form acid addition salts. In other words, a molar ratio of more than 1: 1 of acid to 6-methylenetetracycline base shows an action to promote reaction rate and yield. The amount of acid present in excess of what is necessary to form excess acid, i.e., the acid addition salt of 6-methylenetetracycline base, may or may not be equal to the amount used to form the acid addition salt of 6-methylenetetracycline.

Importantly, the total amount of acid present should be such that the total molar ratio of acid to 6-methylenetetracycline base is about 1.1-2.0. On the other hand, about 0.1 to about 1.0 molar excess of acid per mole of 6-methylenetetracycline acid addition salt is preferred.

It is preferred that the total molar ratio of acid to 6-methylenetetracycline is from about 1.5 to about 2.0. Larger molar ratios, such as molar ratios up to 5 moles of acid per mole of 6-methylenetetracycline base, do not result in loss of the method.

P-toluene sulfonic acid and hydrochloric acid are particularly useful as promoters.

Other substances also have a facilitating effect on the reaction.

In addition to the above-mentioned acids, it has been observed that the first tin chloride exhibits a markedly facilitating effect over the effects observed with the above-mentioned excess acids. Under a given set of conditions, the use of first tin chloride is more effective than P-toluenesulfonic acid in promoting the reaction. Other metal chlorides, such as chlorides of platinum, cadmium, silver, lead, copper, sodium and mercury, are also useful promoters for reactions in which chlorides are present. Lewis acids have a function as reaction promoters.

Such accelerators are generally used at a value of about 0.1 mole to about 5 moles per mole of 6-methylenetetracycline acid addition salt used. There is no value at higher values. A particularly suitable range is about 0.1 to about 1.0 mole per mole of 6-methylenetetracycline acid addition salt.

Foxpins of value for this improvement method have the following general formula.

R ₁ R ₂ R ₃ P

Wherein R ₁ and R ₂ are each selected from the group consisting of phenyl and substituted phenyl, and the substituents of substituted phenyl are selected from the group consisting of halo, lower alkoxy, dimethylamino and lower alkoxy, dimethylamino and lower alkyl: R ₃ is selected from the group consisting of R ₁ , hydrogen and lower alkyl.

As a particularly suitable phosphine, triphenylphosphine may be preferentially considered in view of being easily available and economical as compared with other phosphines specified in the present specification.

Lower alkoxy and lower alkyl refer to alkoxy and alkyl groups having 1 to 4 carbon atoms.

The 6-demethyl-6-deoxy-6-methylenetetracycline reactant of Formula I is a known compound.

This reactant is prepared by 11a-dehalogenation of the corresponding 11a-halo-6-demethyl-6-deoxy-6-methylenetetracycline by chemical or catalytic reduction. A suitable method is to catalytically reduce 11a-chloro-derivatives in the presence of a noble metal catalyst such as palladium or in particular rhodium in a reactive inert solvent at a temperature of from about 0 ° C. to about 60 ° C. and at a hydrogen pressure of about 1 atmosphere to 1 atmosphere or more. Rhodium is particularly suitable for this reaction because it serves as a catalyst for hydrogenation of 6-methylene groups.

Platinum and palladium are extremely poor in the action of hydrogenation of 6-methylene groups under the conditions of this method, and use different catalysts when the reaction is carried out in a two-step "one-pot" method. Progressing the reaction is not suitable for the dehalogenation step as it is of no benefit.

When the dehalogenation step is carried out by catalytic reduction on a noble metal catalyst, in particular rhodium (supported or unsupported), this step can be carried out as a convenient linkage to the catalytic hydrogenation of 6-methylene groups. . The overall method starting from 11a-halo, in particular 11a-chloro-6-demethyl-6-deoxy-6-methylenetetracycline, is in fact a "want-pot" method.

To the reaction mixture containing 11a-deshalo compound prepared under the above-mentioned conditions is added triphenylphosphine (or other suitable phosphine as defined herein) and usually an additional catalyst, in particular carbon-phase-rhodium, The resulting mixture is contacted with hydrogen under the conditions described herein. If palladium is used in the dehalogenation step, it is necessary to add rhodium in order to satisfactorily perform hydrogenation of the 6-methylene group. If rhodium is used in the dehalogenation step, the rhodium may be added at once or in steps.

An adaptable embodiment of the present invention is the hydrogenation of an acid addition salt of 11a-chloro derivatives under a pressure below atmospheric pressure or above atmospheric pressure on a 5% rhodium on carbon in an inert medium such as a metalol and at a temperature of about 0 ° C to about 60 ° C. It is done. Sufficient hydrogen is introduced to effect 11a-dechlorination only. Among the acceptable salts of the 11a-chloro derivatives are P-toluene sulfonate, perchlorate and perborate. These salts are suitable as such salts of the 11a-deschlorocompounds are particularly valuable for the hydrogenation of subsequent 6-methylene groups as described above.

Other salts of value for 11a-dechlorination are hydrochloride and sulfosalicylates.

This method is particularly suitable for large scale reactions since the reaction mixture of 11a-dechlorinated compound contains some of the suitable catalyst for the final hydrogenation step. In addition, since 11a-chloro compounds converted to 11a-deshalo compounds are produced in an equimolar amount of acid, it is unnecessary to add an additional amount of acid. In order to proceed with the reaction, it is only necessary to add the remainder of the rhodium catalyst (rhodium on carbon is suitable) and only the appropriate phosphine, in particular triphenylphosphine.

Another advantage starting from a suitable 11a-chloro derivative is that some of the non-halogenated 11a-chlororeactors have the opportunity to go to the next step for further dehalogenation treatment.

When the process is carried out by the "want-pot" method starting from the 11a-chloro derivative of the compound of general formula I, dehalogenation is achieved by catalytic reduction. The amount of catalyst used, in particular the 5% rhodium on carbon, is the amount of catalyst having the above-described rules. Suitable solvents are lower alkanols such as methanol, ethanol and other various solvents such as those exemplified above in connection with the hydrogenation of 6-methylene groups.

Subsequently, additional catalyst such as 5% rhodium on carbon is added to the dehalogenation reaction mixture. The amount of catalyst added at this point can vary widely and is employed in the range of 1-50 times the amount used in the dehalogenation step. From an economic point of view, about 2-about 25 times the amount of catalyst used in the dehalogenation step is a substantial addition of additional catalyst. Another method is to add all of the rhodium to be used in the overall process in the dehalogenation step and add only the appropriate phosphine in the subsequent hydrogenation step. However, it is advisable to add rhodium step by step, and from about 25% to about 50% of the total rhodium addition amount to the 11a-dehalogenation step and the remainder to the hydrogenation step.

Phosphine can also be added to the reaction mixture prior to dehalogenation. However, the yield of 6-deoxytetracycline obtained by this method is lower than the yield obtained when phosphine is added after the dehalogenation step, ie, after the reaction of about 1 mole of hydrogen per mole of 11a-halotetracycline present.

The amount of addition of phosphine, in particular acceptable triphenylphosphine, can also vary widely. In the method of the present invention, a molar ratio of about 2 to about 10 of the phosphine and the precious metal catalyst is satisfactory. Advantageous molar ratios are 3-9, and particularly suitable ratios are about 3 to about 6 moles of phosphine per mole of total precious metal used.

Another acceptable embodiment of the present invention is the 11a-dechlorolation by treating a suitable 11a-chloro-6-demethyl-6-deoxy-6-methylenetetracycline with tertiary phosphine. Secondary phosphines or tertiary phosphites may also be used. Tertiary phosphines are particularly suitable because tertiary aryl phosphines, in which the aryl group is phenyl or substituted phenyl as defined above, provide good yields.

This method uses 11a-chloro-6-demethyl-6-deoxy-6-methylenetetracycline in the form of normal hydrochloride or P-toluenesulfonate (since 11a-chloro is generally isolated). -Treatment with about 1 to about 3 moles of phosphine per mole of chloro compound. This reaction is carried out in a hydroxyl group-containing solvent such as water or lower alkanols (particularly preferred methanol or ethanol) with a reaction time of about 20 ° C. up to 3 hours below the boiling point of the solvent system.

A catalytic amount of a noble metal and a suitable phosphine as defined above are added to the reaction mixture containing this dehalo compound. Hydrogen is then introduced into the system and hydrogenation of the 11a-deshalo compound is carried out in the manner described above.

The reaction mixture was subjected to approximate progression of the reaction by thin layer chromatography on a silica gel plate buffered to pH 6 using a solvent system of tetrahydrofuran-water (95-5) and the α-to β-isomer. Analyze and examine the approximate yield. The plate is developed with ammonia and visualized with ultraviolet light (366 mμ). More accurate measurements of the degree and yield of reactions are achieved by high pressure liquid chromatography. This is accomplished using Chromatronix 3100 Chromatography (reference: Chromatronix Inc., Berkeley, Calif.). The column used was Dupont SAX, or "Zipax" coated with methacrylate polymer substituted with 1% by weight of quaternary ammonium (EI Dupont Denemours & Co. Inc., Wilmington, Delaware, USA). 2m x 2.1mm column filled with.

The solvent system is added 0.005 M sodium acetate (adjusted to pH 6.0 with acetic acid) to 0.001 M ethylenediaminetetraacetic acid. A pressure of 1,250 Lbs (equivalent to 0.5 ml per minute) is used. The device has a 12mμ injection valve.

Example 1

5% rhodium on carbon (2.88 g of 50% wet material: 0.70 mmol of rhodium), triphenyl phosphine (0.55 g, 2.1 mmol) and N-methyl-2-pyrrolidone (10 ml) in a container of a parr device ) And then the mixture was shaken at 70 ° C. for 0.5 h under 10 psi of nitrogen, then 6-demethyl-6-deoxy-6-methylene-5 in N-methyl-2-pyrrolidone (40 ml). A slurry of hydroxy-tetracycline hydrochloride (3.70 g, 7.7 mmol) and stannous chloride (0.329 g, 1.5 mmol) was added into the vessel via an injector. The vessel was then charged with 50 psi of hydrogen and shaken at 70 ° C. for 18 hours. Thin layer chromatography of the reaction mixture showed that the reaction was complete and 96% α-6-deoxy-5-hydroxytetracycline and 4% β-isomer were obtained.

Thin layer chromatography was performed on silica gel plates. This plate was prepared by spray saturation with phosphate-citric acid buffer pH 6.0 followed by drying. A solvent system of 85% tetrahydrofuran-5% water was added and the plate developed in ammonia and visualized under 366 μm ultraviolet radiation. 6-demethyl-6-deoxy-methylene-5-hydroxy tetracycline in this system has an Rf value of 0.31; The 6α-5-hydroxy tetracycline was Rf = 0.50 and the 6β-5-hydroxytetracycline was Rf = 0.25.

Known mixtures of these compounds are used for comparison.

Example 2

Charge 5% rhodium (0.572g, 50% wetting substance: 0.14 mmol rhodium), triphenylphosphine (0.113g, 0.43 mmol) and 1.26ml concentrated hydrochloric acid on carbon in the Parr's container, followed by 7.0 mmol A solution of 6-demethyl-6-deoxy-6-methylene-6-hydroxytetracycline hydrochloride (3.39 g, 7.0 mmol) in methanol (35 ml) containing P-toluenesulfonic acid was added, followed by 50 psi hydrogen. Was charged to a vessel and shaken at 75 ° C. for 20 hours. Thin layer chromatography of the reaction mixture showed the presence of α-6-deoxy-5-hydroxytetracycline, trace amounts of starting material and 6β-epimer as main components.

Example 3

2.88 g of 5% rhodium on carbon (50% wetting substance, 0.70 mmol rhodium) and tri- (4-chlorophenyl) phosphine (0.76 g, 2.0 mmol) and 70.0 mmol P-toluene in a stainless steel autoclave A solution of 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline (33.9 g, 70.0 mmol) in 360 cc of methanol containing sulfonic acid was charged. The reaction mixture was pressurized to 200 psi as hydrogen gas, the temperature was adjusted to 75 ° C. and the reaction mixture was stirred for 17 hours. High pressure chromatography of the reaction mixture showed the presence of 81% α-6-deoxy-5-hydroxy tetracycline and 1.6% β-epimer. Addition of 340 cc of 10% 5-sulfosalicylic acid aqueous solution results in an α-6-deoxy-5-hydroxy tetracycline varying in yield of 80% as the 5-sulfosalicylic acid salt.

Example 4

Charge 5% rhodium on carbon (2.88g, 50% wetting substance: 0.70 mmol rhodium) and tri- (4-chlorophenyl) phosphine (0.76g, 2.1 mmol) in 13 cc methanol, The forming mixture was shaken at 62 DEG C for 30 minutes under a nitrogen atmosphere, and finally 3.39 g, 7.0 mmol of 6-deoxy-6-demethyl-6-methylene-5-hydroxytetracycline hydrochloride was 7.0 mmol of P-toluenesulphate. A solution obtained by dissolving in 37 cc of methanol containing phonic acid was added. The vessel was charged with 50 psi of hydrogen and shaken at 75 ° C. for 18 hours. High pressure liquid chromatography of the reaction mixture showed the presence of 80% α-6-deoxy-5-hydroxytetracycline and 1.5% β-epimer. α-6-deoxy-5-hydroxytetracycline can be isolated in 78% yield in the form of a 5-sulfosalicylic acid salt.

Example 5

The following acid addition salt of 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline was used, and the process of Example 1 was repeated except the conditions which adopt the following temperature, pressure, a solvent, and a phosphine.

Example 5

Example 5 continued

Example 6

(A) 5% rhodium on carbon (2.88g, 50% wetting substance: 0.70 mmol rhodium), triphenylphosphine (0.55 g, 2.1 mmol) and N-methyl-2-pyrrolidone (13 ml) Was charged into a Parr, heated and shaken at 70 ° C for 30 minutes. A slurry of 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline hydrochloride (3.7 g, 7.72 mmol) in N-methyl-2-pyrrolidone (37 ml) was then added in a nitrogen atmosphere.

Nitrogen was purged, hydrogen (50 psi) was introduced and the mixture was heated to 70 ° C. and shaken for 16 hours.

Analysis of the reaction mixture showed that 55% of α- and 5% of β-6-deoxy-5-hydroxytetracycline and 45% of starting material were present.

(B) The reaction mixture was filtered, reloaded 5% rhodium on carbon (2.88 g, 50% wet material) and triphenylphosphine (0.55 g), hydrogenated as above for 16 hours and then assayed. , 82% yield of α- and 3% yield of β-isomer was produced and 15% of starting material still remained.

Example 7

The process A of Example 6 was repeated except that P-toluenesulfonic acid (1.465 g, 7.72 mmol) was added to the initial charge catalyst and triphenylphosphine.

After 16 hours of reaction time, the assay confirmed the presence of 82% α- and 2% β-6-deoxy-5-hydroxytetracycline and 16% starting material.

The reaction mixture was further hydrogenated according to step B of Example 6, followed by the complete conversion of the starting material and the 95% yield of α- and 2% yield of β-6-deoxy-5-hydroxytetracycline. Generation was confirmed. The remaining 3% of the material is an unidentified product.

Example 8

Repeat step A of Example 6 except that a 1: 1 solvent system of N-methyl-2-pyrrolidone and water is used instead of N-methyl-2-pyrrolidone as a solvent, and the assay of Example 1 was repeated. As a result, it was confirmed that 55% of α-6-deoxy-5-hydroxytetracycline and 45% of unreacted material were obtained.

Example 9

The procedure A of Example 6 was repeated except that a 1: 1 solvent system of N-methyl-2-pyrrolidone and methanol was used instead of N-methyl-2-pyrrolidin as a solvent. The presence of% α-6-deoxy-5-hydroxytetracycline and 20% unreacted material was confirmed.

Example 10

Example 6-A was repeated except that BF ₃ (C ₂ H ₅ ) ₂ O (0.68 mmol) was added to the first charge catalyst and triphenylphosphine, and the reaction mixture was assayed. The presence of α-6-deoxy-5-hydroxytetracycline, 10% of the starting product and 5% of the degradation product was confirmed.

Example 11

The procedure of Example 7 was repeated except that tetrahydrofuran was used instead of N-methyl-2-pyrrolidone as the solvent, and after 16 hours of reaction time, 76% α- and 1% β-6- The presence of deoxy-5-hydroxytetracycline and 23% of unreacted start was confirmed.

Example 12

According to the process of Example 1, hydrogenation of 6-demethyl-6-deoxy-6-methylenetetracycline yields the -isomer as a main product.

Example 13

Repeating the process of Example 3 using 6-demethyl-6-deoxy-6-methylenetetracycline as a substrate yields a product whose main component is 6-α-deoxy tetracycline.

Claims (1)

Hydrogen was introduced into a reaction inert medium containing a catalytic amount of rhodium metal and a tetracycline compound selected from the group consisting of a tetracycline base of the following formula (I) and an acid addition salt thereof, and a temperature of about 0 ° C. to 100 ° C. under rhodium and a tertiary phosphine catalyst. And contacting the reaction mixture with hydrogen at a pressure between about 1 atm and about 2,000 psi.

Wherein R is hydrogen or hydroxyl and X is hydrogen, chloro or fluoro. The reaction is carried out at about 2 to about 10 moles of formula R ₁ R ₂ R ₃ P per mole of rhodium metal, wherein R ₁ and R ₂ are the same or different and represent phenyl or substituted phenyl, wherein the substituent is halo, lower alkoxy , Dimethylamino or lower alkyl, R ₃ is R ₁ , hydrogen or lower alkyl, and about 1 mole per mole of tetracycline base, especially about 1.1 to about 2.0 moles of acid, or about 0.1 to 1 mole of tetracyclic acid addition salt. A process for preparing 6-deoxytetracycline, which is carried out in the presence of 1.0 mole of tin 1 chloride.