CS203099B2 - Process for the hydrogenation of exocyclic methylene group of 6-desoxy-6-demethyl-6-methylentetracycline - Google Patents

Abstract

Hydrogenation of the exocyclic methylene gp. of a 6-deoxy-6-demethyl-6-methylene-tetracycline (I), or its acid addition salt, in a stereoselective manner giving the alpha-isomer in preference to the beta-isomer, is carried out at 20-100 degrees C and 1-100 atmos. under neutral conditions, or using a weakly acidic acid addn. salt, in the presence of a catalytic amt. of a cpd. of formula Rh(OCOR)2(P C6H5 3) (II) (where R = H, 1-6C alkyl, ClCH2, Cl2CH, Cl3C, FCH2, F2CH, F3C, phenyl, chlorphenyl, tolyl, anisyl). The ratio of alpha-isomer to beta-isomer is >=9:1. Known methods give a less favourable ratio e.g. 1:1.

Description

SUMMARY OF THE INVENTION The present invention provides a process for the preparation of 6-desoxytetracyclines by hydrogenation of an exocyclic methylene group of 6-desoxy-6-demethyl-6-methyl (6-ethoxy) or its addition salts with an acid.

U.S. Pat. No. 3,200,149 discloses the preparation of α-6-desoxytetracycline derivatives by a process comprising the hydrogenation of certain 6-desoxy-6-demethyl-6-methylenetetracyclines in the presence of a catalytically effective amount of a noble metal catalyst such as rhodium or palladium. This procedure also produces + -6-desoxytetracyclines, in addition to the tt-6-desoxytetracyclines. One of the main purposes of the invention is to improve this process so as to obtain a higher relative amount of the α-isomer than the β-isomer.

It has been found that it is possible to achieve a higher ratio of α-isomer to β-isomer when hydrogenating the 6-deso: γ-γ-β-γ-β-isomer mixture. 6 ^ Tilh ^ t (^ IΊtt-trac ¹ ^] klinxvé compounds of a specific soluble rhodnatou compound in a solvent inert to the reactants. the specific soluble rhodnatou compound is dikarboxylarx (rritenylfxsfin) гhodium (II) or dicarboxylato (substituted rrifentlfxsfin) rhodium (Π) .

DOS 2 308 227 describes the use of a soluble rhodium compound for stereoselective reduction. 6-desoxy-6-clemetyl-6-methylenetetracyclines. This publication, however, only mentions the use of monovalent compounds. rhodia. Hui-et al., Published in Inorganic Chemistry, 12, p. 757 (1973) and Journal of the Chemical Society (London), Part D, p. 1195 (1970), states that rhodium (II). However, the use of rhodium (IId) acetate in the process of the present invention does not lead to a favorable ratio of the α-isomer to the β-isomer, producing approximately equal amounts of the α-isomer and / M isomer. Although Legzdins et al. reported in the Journal of the Chemical Society (London), Part D, p. 825 (1969) the use of rhodium acetate in the presence of rexenylxx as a hydrogenation catalyst, their experiments have been carried out in the presence of very high levels. The process of the invention is carried out under neutral conditions with a weakly acidic acid addition salt of tetracycline.

The process of the invention is based on the discovery that by hydrogenating a mixture of 6-desoyl-6-demethyl-4-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2-chloro the specific rhodium compound in an inert solvent achieves hydrogenation of the exocyclic methylene group, which reaction proceeds with stereoselectivity promoting the formation of the α-isomer at the expense of the β-isomers in a ratio of at least 9: 1.

The present invention provides a process for the hydrogenation of an exocyclic methylene group of 6-desoxy-6-demethyl-6-methylenetetracycline of the formula:

where

X is hydrogen or chlorine;

Y is hydrogen, hydroxy or (C 2 -C 7) alkanoyloxy, or an acid addition compound thereof, at a temperature of from 20 to 100 ° C and a pressure of from 1 to 10 MPa in the presence of a catalyst characterized by: The method according to claim 1, wherein a catalyst of the general formula is used

Rh (OCOR) 2 [P (C 6 H 5) 5] where

R is hydrogen, C 1 -C 4 alkyl, and the reaction is carried out at pH 6-8.

The preparation of the starting materials is described and explained in detail in U.S. Patent No. 3,200,149. According to the procedure described therein, the 11a-chloro-6,12-heimiketal of the respective tetracyclic compound is treated with a strong dehydrating acid such as sulfuric acid, trifluoroacetic, polyphosphoric, perchloric, hydrofluoric acid and the like. Of these acids, hydrofluoric acid is the preferred acid. Optimal conditions are readily determined experimentally. Usually, the respective 11a-chloroquetal is only added to the selected acid and allowed to react, preferably at a temperature in the range of 0 to 50 degrees Celsius for up to several hours. After completion of the reaction, the product is isolated by a suitable method, for example in the case of volatile acids, evaporation of the product yields the product as a residue; in other cases, the product is isolated by a conventional method, such as by stirring with a non-solvent such as diethyl ether, whereby the product precipitates as a precipitate. These 6-methylene compounds can be converted into acid addition salts or complex salts of polyvalent metals by conventional methods prior to hydrogenation.

When the starting compound used is 11a-de-chloro-6-desoxy-6-demethyl-6-methylenetetracycline, dechlorination at the 11a position can be achieved by either chemical or catalytic reduction according to known procedures. Example 37 of U.S. Patent 3,200,149 describes the hydrogenation reduction of 11a-chloro-6-desoxy-6-demethyl-6-methylenetetracycline hydrochloride to give the corresponding 11a-dechlorinated compound.

If Y in the starting compounds of the process of the invention is C 2 -C 7 alkanoyloxy, it is appropriate to use the process described in British Patent 1,287,493 to prepare the starting material. Accordingly, the corresponding 11a-chloro-6-demethyl-6- The deoxy-6-methylene-5-hydroxytetracycline in the form of the free base or addition polysalt acts with a carboxylic acid of 2 to 7 carbon atoms per molecule in the presence of methanesulfonic, ethanesulfonic or hydrofluoric acid, preferably at a temperature of 20 to 70 ° C. from 2 to 20 hours. The product obtained can then be reduced to the 11-dechlorine compound as described above.

Rhodium compounds of general formula

Rh (OCOR) 2 (P [СбН5] з) are either known or are simple analogs or homologues of known compounds, and procedures such as those described by Stephenson et al. in the Journal of the Chemical Society (London), p. 3632 (1965). According to these procedures, the rhodium carboxylates * are prepared by heating the rhodium hydroxide hydrate under reflux with an excess of, for example, formic, acetic or propionic acid in ethanol. The resulting yellow solutions gradually darken and then turn green. The resulting solutions were cooled and the dark green precipitated powder precipitates were filtered off and recrystallized from methanol or water. They are stable at temperatures up to 240 ° C. The final complex catalyst is prepared by adding triphenylphosphine and diethyl ether to a cold ethanolic solution of rhodium carboxylate.

Suitable inert solvents in the process of the invention are those which practically dissolve the starting materials or product. Examples of such solvents are ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, lower aliphatic ketones such as acetone and methyl ethyl ketone, low molecular weight esters such as ethyl acetate and butyl acetate, monovalent and polyvalent lower alcohols such as methanol , ethanol, isopropanol, ethylene glycol, propylene glycol and diethylene glycol, alkanols substituted with lower alkoxy groups such as

2-methoxyythanol a

2- (2-ethoxyethoxy) ethanol, lower alkanoylic acids such as acetic acid and propionic acid, tertiary amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N, N-dimethylacetamide and N, N-dimethylacetamide, and their mixtures.

The introduction of hydrogen gas into an inert solvent reaction medium containing the rhodium compound and tetracycline is usually carried out by carrying out the reaction in a closed vessel under a hydrogen or hydrogen atmosphere mixed with an inert diluent, such as nitrogen or argon. The pressure in the reaction vessel may vary between 0.1 and 10 MPa. When the atmosphere in the reaction vessel is practically pure hydrogen, a preferred pressure range is 70 to 700 kPa.

The hydrogenation is usually carried out at a temperature. in the range of 20 to 100 ° C, preferably in the range of 40 to 70 ° C. At preferred temperature and pressure values, hydrogenation usually takes a few hours, for example 2 to about 10 hours.

In the hydrogenation of the 7-substituted dimethylene-desoxy-d-demethyltetracycline starting material, the 7-position halogen substituent remains virtually intact. In contrast, the chlorine substituent at position 11a is removed.

The above term "catalytically effective amount" is apparent to those skilled in the art of hydrogenating tetracycline. This amount is usually 0.1 to 100 mol. ·% Based on tetracycline. The preferred amount is 1 to 10 mol. %.

The reaction product obtained by the process according to the invention is isolated from the reaction medium by known methods. For example, can the product be precipitated by the addition of a non-solvent such as hexane or water _? or by adding some agents which form insoluble salts with the product. On the other hand, the crude product can be isolated by evaporating the solvent or diluting the reaction mixture with a large excess of water, followed by extracting the product with a water-immiscible organic solvent and evaporating with the water-immiscible solvent.

The following examples illustrate the invention.

Example 1

Reduction of 6-imino-6-demethyl-6-demethyl-6-de-soxyl-1-lhexylcyclopropane using diacetate-triphenylphosphine-iodine (ii)

A solution of 2.0 g (4.18 mmol) of J hydrochloride

6-trimethylene-6-dimethyl-6-decoxy-5-hydroxy tetracycline and 0.088 g (4.4 mol%) of diacetate (triphenylphosphine) rhodium (ii) in 30 ml of degassed methanol are shaken under a hydrogen atmosphere in a sealed vessel at 60 up to 70 DEG C. for 5.75 hours The hydrogen overpressure in the reaction vessel was 40 to 490 kPa, after completion of the reaction, the vessel was opened and the reaction solution filtered and the filtrate was chromatographed under high pressure liquid, resulting in analysis. It is evident that it contains the desired α-6-desoxy-5-hydroxytetracycline contaminated with 2 to 3% of its C-6 eplmer.

A mixture of 20 ml of water with 30 ml of 10% aqueous sulfosalicylic acid is then added to the filtrate with stirring. Stirring was continued overnight, after which time the precipitate was filtered off to give 2.62 g (95% yield) of α-6-desoxy-5-hydro-tert-l-acycline as the sulfosalicylate. spectroscopy had a product of 93% purity.

Example 2

The procedure described in Example 1 was repeated except that an equimolar amount of the following compounds was used in place of 6-diethylene-1-dimethylethyl-6-desoxy-hydroxytelecycline:

6-methylene-6-demethyl-6-desoxy-tetracycline,

6-methylene-6-demethyl-6-desoxy-5-ac ethoxytetracycline,

6-methylene-6-dimethylethyl-6-desoxy-5-methoxy-5-oxo-oxo-2-carboxylic acid;

6-methylene-6-dimethyl-6-desoxy-5-butyryloxytetracycline,

6-methylene-6-dimethoxy-6-desoxy-11-methyl-6-methyl-6-methoxy-4-carboxylic acid,

6-Methylene-6-demethyl-6-desoxy-5-hexanoyl oxyl etracycline;

-y-chlortetracycline,

6-methylene-6-demethyl-6-desoxy-7-chloro-5-hydroxytetracycline,

6-methylene-6-demethyl-6-desoxy-7-chloro-5-acetoxytetracycline,

6-methylene-6-demethyl-6-desoxy-7-chloro-5-isobutyryloxytetracycline,

6-methylene-6-demethyl-6-desoxy-7-chloro-5-isovaleroyloxytetracycline; and

6-methylene-6-demethyl-6-desoxy-7-chloro-5-heptanoyloxytetracycline, and instead of diacetato (triphenylphosphine) rhodium (II), an equimolar amount of the following compounds is used:

rhodium (II), dibenzoato (triphenylphosphine) rhodium (II), dibutyrato (triphenylphosphine) rhodium (II), di (p-chlorobenzoato) (triphenylphosphine) rhodium (II), dibenzoato (triphenylphosphine) rhodium (II), diformiato (triphenylphosphine) rhodium (II), diacetate (triphenylphosphine) rhodium (II), dibenzoate (triphenylphosphine) rhodium (II), di (m-toluato) (triphenylphosphine) rhodium (II) , dihexanoato (triphenylphosphine) rhodium (II), diheptanoato (triphenylphosphine) rhodium (II) and di (p-methoxybenzoate) (triphenylphosphine) rhodium (II).

Using the above compounds, the following compounds are obtained:

α-6-desoxytetracycline, α-6-desoxy-5-acetoxytetracycline, α-6-desoxy-5-propionyloxytetracycline, α-6-desoxy-5-butyryloxytetracycline, α-6-desoxytetracycline, α-6-desoxy-5- hexanoyloxytetracycline, α-6-desoxy-7-chlorotetracycline, α-6-desoxy-7-chloro-5-hydroxytetracycline, α-6-desoxy-7-chloro-5-acetoxytetracycline, α-6-desoxy-7-chloro-5- isobutyryloxytetracycline, α-6-desoxy-7-chloro-5-isovaleryloxytetracycline, and α-6-desoxy-7-chloro-5-heptanoyloxytetracycline.

Example 3

Rhodium (II) acetate dimer

A mixture of 1.72 g of rhodium hydroxide monohydrate [Rh (OH) 3. H2O], 6 ml of glacial acetic acid and 15 ml of ethanol are heated at reflux for 24 hours. Then the reaction mixture was cooled and the volatiles were removed by evaporation under reduced pressure to give the crude product. The crude product is then purified by dissolution in acetone; the solution obtained is allowed to stand to slowly evaporate the solvent and the precipitated solid is filtered off.

Example 1 a d 4

Following the procedure described in Example 3, reaction of rhodium hydroxide monohydrate with the appropriate carboxylic acid affords the following rhodium (II) carboxylates:

rhodium (II) propionate, rhodium (II) benzoate, rhodium (II) butyrate, rhodium (II) -p-chlorobenzoate, rhodium (II) formate, rhodium (II) -m-toluate, rhodium (II) hexanoate, rhodium (II) heptanoate, rhodium (II) -p-methoxybenzoate, rhodium (11) chloroacetate, rhodium (II) dichloroacetate, rhodium (II jtrichloroacetate, rhodium (II) fluoroacetate, rhodium (II jdifluoroacetate, and rhodium (II jtrifluoroacetate) .

Example 1 a d 5

Rhodium (II) Diacetato (tr if enylphosphine)

A mixture of 110 mg of rhodium (II) acetate dimer and

10

100 mL of methanol was cooled to 17 ° C and a solution of 131 mg of triphenylphosphine in 5 mL of ether was added with stirring. Stirring is continued for 2 hours at room temperature, then the precipitate formed is filtered off. This gives 219 mg of the title compound of melting point 203-204 ° C.

Example 6

The procedure is as described in Example 5, but using the appropriate rhodium (II) carboxylate instead of the rhodium dimer (II acetate) to give the following rhodium organic compounds:

Rhodium (II) dipropionate (triphenylphosphine) rhodium (II), rhodium (II) dibenzoate (triphenylphosphine) rhodium (II), rhodium (II) dibuto (triphenylphosphine) dibenzoate, rhodium (II) di (p-chlorobenzoate), triphenylphosphine ormiato (triphenylphosphine) rhodium (II), di (m-toluato) [triphenylphosphine) rhodium (II), dihexanato (triphenylphosphine) rhodium (II), diheptane (triphenylphosphine) rhodium (II), di (p-methoxy benzoate) (triphenylphosphine) rhodium (II), di (chloroacetate) (triphenylphosphine) rhodium (II), di (dichloroacetate) (triphenylphosphine) rhodium (II), di (trichloroacetate) (triphenylphosphine) rhodium (II) , di (fluoroacetato) (triphenylphosphine) rhodium (II), di (difluoroacetato) (triphenylphosphine) rhodium (II) and di (trifluoroacetato) (triphenylphosphine) rhodium (II).

Example 7

Reduction of 6-desoxy-6-demethyl-6-methylene-5-hydroxytetracycline using rhodium (II) diacetate

A solution of 2.0 g (4.18 mmol) of 6-desoxy-6-demethyl-6-methylene-5-hydroxytetracycline hydrochloride and 46 mg (5 mol%) of rhodium (II) diacetate in 30 ml of degassed methanol is shaken. in a hydrogen atmosphere at a temperature of 65 to 70 ° C for. 5.25 hours. The hydrogen overpressure in the reaction vessel was 455 to 490 kPa. After cooling, the reaction vessel is opened and the contents are filtered. The filtrate is chromatographed using a high pressure liquid; the result of this analysis shows that it contains α-6-desoxy-5-hydroxytetracycline and β-6-desoxytetracycline in a ratio of about 2: 3, together with a small amount of non-reduced starting material.

I will invent the subject

Claims (1)

I will invent the subject Process for hydrogenation of 6-desoxy-6-demethyl-6-methylenetetracycline exocyclic methylene group л сн ₂ Y • Til ГОН | -он -conh ₂ OH 0 он 0 or X <СН & II ΗθΗ \ Γ ° ^Η κίν \ r ^C0NH z он о о О where X is hydrogen or chlorine; Y is hydrogen, hydroxy or (C 2 -C 7) alkanoyloxy, or an acid addition compound thereof, at a temperature of 20 to 100 ° C under a pressure of 1 to 10 MPa in the presence of a catalyst, characterized in that the catalyst of the general formula is used Rh (OCOR) 2 - [P (C 6 H 5) ₃ ] where R is hydrogen, C 1 -C 4 alkyl, and the reaction is carried out at pH 6-8. Severography. n. p., Duke 7, Most