FI59395C - FRAMSTAELLNING AV ALFA-6-DEOXI-5-HYDROXITETRACYKLIN - Google Patents

Description

ir- ^ 1 -.1 r_, .... ADVERTISEMENT „„ J & Tjf 11 UTLÄCGNINOSSKRIFT 59395 C (4S) Γαtentti sy'-innetty 10 03 1931 k MMTi Patent raeddelat V '^ (SI) Ky.lk.3 / lnt. C «.3 C 07 C 103/19 ENGLISH I - FI N LAN D (21) EwwttBwhwwm - P« »nttn» ekiWm 753 ^ 59 mm »**» - »* · ***. 09.12.75 'ΓΙ' (23) Alkupllvl — GIMfh «t * dag 09-12-75 (41) Tullut lulkiMksI - SIMt offmdlg 20.06-76 PUMM-μ rrtbUrihdlltu. (44) ΝΚΜΗρ »μ, ..

Patent and regulatory proceedings AimMcm uthgd och utl. * Krift * n puMtcand 30.04. Ö1 (32) (33) (31) ryydMty «« «Xkwt — tagird prtoriut 19-12-7 ^ USA (US) 53UU52 (71) Pfizer Inc., 235 East U2nd Street, New York, NY, USA (US) (72) Herman Paubl, Mystic, Connecticut, USA (7 **) 0y Preparation of Roister Ab (5 ^) n (J-6-deoxy-5-hydroxytetracycline - Framstalining av ° <s-6-deoxy-5 -hydroxitetracyklin

The invention relates to a process of formula ch3 oh n (ch3) 2

-OH

For the catalytic hydrogenation of O, N-6-deoxy-5-hydroxytetracycline or an acid addition salt thereof according to CONH 2 OH 0 OH 0.

U.S. Patent 3,200 11 * 9 discloses the preparation of α-β-deoxytetracycline derivatives by a process in which certain 6-deoxy-6-demethyl-6-methylenetetracyclines are hydrogenated using catalytic amounts of a noble metal catalyst such as rhodium or palladium. Both γS-6-deoxytetracyclines and β-deoxytetracyclines are obtained in the process. It is a main object of the present invention to improve this process by obtaining a higher ratio of the cis-isomer to the γ6-isomer.

It has now been found that a higher ratio of the β-isomer to the γ-isomer can be obtained by hydrogenating in a reaction-inert solvent a mixture of a 6-deoxy-6-demethyl-6-methylene-5-hydroxytetracycline compound and a certain soluble rhodium (II) compound. Such a soluble rhodium (II) compound is dicarboxylate (triphenylphosphine) rhodium (II).

DE-A-2 308 227 discloses the use of widely soluble rhodium compounds for the stereoselective reduction of 6-deoxy-6-demethyl-6-methylenetetracyclines. However, there are examples in this DE application of the use of rhodium (I) compounds alone. Hui et al. Inorganic Chemistry, 12 (1973) 757 and Journal of the Chemical Society (London), Part D, 1195 (1970) disclose that rhodium (II) diacetate is an effective hydrogenation catalyst. However, the use of rhodium (II) di-acetate in the process according to the invention does not lead to a preferred ratio of oi- and β-compounds: approximately equal amounts of oi- and β-isomers are formed. Triphenylphosphine ligand is an essential condition for stereoselective reduction. Although Legzdins et al., Journal of the Chemical Society (London), Part D, 825 (1969), have proposed rhodium diacetate for use as a hydrogenation catalyst in the presence of triphenylphosphine, their experiments were performed in the presence of a very strong acid. The process according to the invention is carried out under neutral conditions or with weakly acidic acid addition salts of tetracycline.

The present invention is based on the finding that upon hydrogenation in a reaction-inert solvent of a mixture of 6-deoxy-6-demethyl-6-methylene-5-hydroxytetracycline and a certain rhodium compound, the exocyclic methylene group is hydrogenated and the hydrogenation occurs stereoselectively at the expense of at least 9 The invention thus relates to a hydrogenation process which is characterized in that the formula ch2 oh n (ch3) 2

i) -0H

I .OH

- 6-deoxy-6-demethyl-6-methylene-5-hydroxytetracycline of the formula Zh according to conh2 OH 0 0 3 59395

I I

irr or o =

OH

or an acid addition salt thereof is hydrogenated at a temperature of U0 ~ 70 ° C with a hydrogenation pressure of about 5 atm in the presence of the formula

A rhodium catalyst according to Rh (OCOR) 2 (P / C6H573), in which R is alkyl having 1 to 3 carbon atoms, in an amount of 1 to 10 mol%, based on the amount of tetracycline.

A particularly preferred catalyst is a rhodium compound of the formula R is methyl.

The following compounds ch2 oh n (ch3) 2 are used as starting materials of the present invention

-0H

^ -CONH2 OH 0 OH o CH2 OH 1j (CH3) 2

v —0H

OH 0 0 0 and their acid addition salts.

The preparation of these starting materials is fully disclosed and described in U.S. Patent 3,200-1h. hydrofluoric acid or the like. Hydrogen fluoride is most preferred. The best conditions can be easily determined by conventional experiments. Generally, the selected 11α-chloroketal is only added to the selected acid and the reaction is preferably allowed to proceed at a temperature in the range of 0-50 ° C for several hours. Upon completion of the reaction, the product is recovered in a suitable manner, for example by using a volatile acid by evaporation to give an evaporation residue, and in other cases by standard methods such as stirring the reaction mixture with an insoluble solvent, for example diethyl ether. These 6-methylene compounds can be converted to acid addition salts or polyvalent metal complexes by conventional methods prior to hydrogenation.

When the desired starting material is 11α-dechloro-6-deoxy-6-demethyl-6-methylene tetracycline, the 11α-dechlorination can be performed by either chemical or catalytic reduction using methods well known in the art. Example XXXVII of U.S. Patent 3,200-1,9 describes the hydrogen reduction of 11α-chloro-6-deoxy-6-demethyl-6-methylenetetracycline hydrochloride to the corresponding 11α-dechloro compound.

formula

Rh (0C0R) 2Q

The rhodium compounds of the invention are either known or simple analogs or homologues of the known compounds and can be prepared by the methods described by Stephenson et al., Journal of the Chemical Society (London), 3632 (1965). According to these methods of preparation, rhodium carboxylates are prepared by boiling rhodium hydroxide hydrate, recovering, for example, an excess of acetic or propionic acid and ethanol. The yellow solutions gradually turn amber and then green. The resulting solutions are cooled and the precipitated dark green powders are filtered and recrystallized from methanol or water. These products have been found to be stable up to temperatures up to 2U0 ° C. The final catalyst complex is prepared by adding triphenylphosphine and diethyl ether to a cold ethanol solution of rhodium carboxylate.

Suitable reaction-inert solvents for use in the present invention are those capable of substantially dissolving the starting materials or product. Examples of such solvents are e.g. 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, mono- and polyhydric lower alcohols such as methanol, ethanol, such as methanol isopropanol, ethylene glycol, propylene glycol and diethylene glycol, lower alkoxy-substituted alkanols such as 2-methoxyethanol and 2- (2-ethoxyethoxy) ethanol, lower alkanoic acids such as acetic acid and propionic acid, tertiary amides such as Ν, N-dimethylacetamide and N-methylpyrrolidone and mixtures thereof.

The introduction of hydrogen gas into a reaction-inert solvent containing a rhodium compound and a tetracycline is generally carried out in a sealed reaction vessel under a hydrogen atmosphere or in a mixture of hydrogen and an inert diluent gas such as nitrogen or argon. The hydrogenation pressure is about 5 atm.

The hydrogenation is generally carried out at temperatures of about UO to about 70 ° C. Using the preferred temperature and pressure conditions, the hydrogenation usually takes a few hours, for example from about 2 hours to about 10 hours.

Upon hydrogenation of 11a-chloro, the 6-methylene-6-deoxy-6-demethyltetracycline starting material by the process of this invention removes the 11a-chloro betentifier.

The preferred amount of catalyst to be used is from about 1 to about 10 mole percent based on the amount of tetracycline.

The reaction product of the present invention can be isolated from the reaction medium by standard methods. For example, the product can often be precipitated by the addition of a non-solvent such as hexane or water, or by the addition of certain substances that form insoluble salts with the product. Alternatively, the crude product can be isolated by evaporating the solvent or diluting the reaction mixture with a large excess of water and then extracting the product into a water-insoluble organic solvent and finally evaporating the water-insoluble solvent.

Catalyst preparation A. Preparation of rhodium (II) acetate dimer

A mixture of 1.72 g of rhodium hydroxide hydrate / Rh(0H) ^.H2Q7, 6 ml of glacial acetic acid and 15 ml of ethanol was heated under reflux for 2 hours. The reaction mixture was cooled, the volatiles removed by evaporation in vacuo to give the crude product. The crude product was purified by dissolving it in acetone, allowing the solvent to slowly evaporate and then filtering the precipitated solid.

B, Preparation of diacetato (triphenylphosphine) rhodium (II);

A mixture of 110 mg of rhodium (H) acetate dimer and 100 ml of methanol was cooled to 17 ° C, and a stirred solution of 131 mg of triphenylphosphine in 5 ml of ether was added to the mixture. Stirring was continued at room temperature for 2 hours, then the precipitate was removed by filtration. 219 mg of diacetato (triphenylphosphine) rhodium (II) were obtained, m.p. 203-20U ° C.

6 5 $ 39 5

Comparative Example Reduction of 6-deoxy-6-demethyl-6-methylene-5-hydroxytetracycline using rhodium (II) diacetate

A solution of 2.0 g (1 +, 1β mmol) of 6-deoxy-6-demethyl-6-methylene-5-hydroxytetracycline hydrochloride and 1 + 6 mg (5 mol) of rhodium (II) diacetate in 30 ml degassed methanol, was shaken under a hydrogen atmosphere at 65-70 ° C for 5-25 hours. The hydrogen pressure in the reaction vessel was 1 +, 56-1 +, 91 kg / cm 2. The cooled reaction vessel was opened and its contents filtered. The filtrate was examined by high pressure liquid chromatography. This indicated that the solution contained? -6-deoxy-5-hydroxytetracycline and? -6-deoxytetracycline in a ratio of about 2: 3 together with a small amount of non-reducing starting material.

The following example illustrates the invention.

Example Reduction of 6-methylene-6-demethyl-6-deoxy-5-hydroxytetracycline using diacetate (triphenylphosphine) rhodium (II)

A solution of 2.0 g (1 +, 18 mmol) of 6-methylene-6-demethyl-6-deoxy-5-hydroxytetracycline hydrochloride and 0.088 g of (U, U molar) diacetato (triphenylphosphine) rhodium (II) in 30 ml of gas-free methanol, was shaken ........ - in a hydrogen atmosphere in a sealed vessel at 60-70 ° C for 5.75 hours, the hydrogen pressure in reaction vessel 2 was 1 +, 63-1 +, 98 kg / cm 3, The vessel was then opened and the reaction solution was filtered. The filtrate was examined by high performance liquid chromatography, which showed that it contained the desired o <-6-deoxy-5-hydroxytetracycline with an impurity of 2-3? its C-6 epimer.

Then, 20 ml of water and 30 ml of a 10 .mu.l aqueous solution of sulfosalicylic acid were added to the filtrate with stirring. Stirring was continued overnight, and then the precipitate was filtered to give 2.62 g (95% yield) of N, N-6-deoxy-5-hydroxy-tetracycline as the sulfosalicylate salt, and UV spectroscopy showed the product to be 93% pure.

Claims (1)

A process for the preparation of oC-6-deoxy-5-hydroxytetracycline or an acid addition salt thereof according to the formula ch3 oh n (ch3) 2 T1-OHHOH H2OH O OH O by catalytic hydrogenation, characterized in that the formula ch2 oh n (ch3) ) 6-deoxy-6-demethyl-6-methylene-5-hydroxytetracycline of formula 2 --- OH OH 0 0, wherein Z is II or Cl H or = OH or an acid addition salt thereof is hydrogenated at a temperature of 1 + 0-70 ° C under a hydrogenation pressure in the presence of about 5 atm in the presence of a rhodium catalyst of the formula Rh (OCOR) 2 (PZ56H3), in which R is alkyl having 1 to 3 carbon atoms, in an amount of 1 to 10 mol%, based on the amount of tetracycline.