DK153394B - METHOD FOR PREPARING ALFA-6-DEOXY-5-OXYTETRACYCLINE COMPOUNDS - Google Patents

Description

in

DK 153394 B

This invention relates to a particular process for the preparation of α-6-deoxy-5-oxytetracycline compounds by homogeneous catalytic hydrogenation of the corresponding one-demethyl-6-deoxy-6-methylene-5-oxytetracycline compounds which is characterized by the characterizing part of claim 1.

Starting from 6-demethyl-6-deoxy-6-methylene-5-oxytetracycline (by the generic name methacycline) or its 5-alkanoyl esters of the formula / CH3

9¾ J

In which R is hydrogen or alkanoyl of 1-6 carbon atoms, or from salts thereof with mineral or organic acids, the corresponding 6-deoxy-5-oxytetra-cyclin is obtained in the form of the epimer (with the generic name doxycycline) or its 5-alkanoyl esters of the formula h3cs ch3 H \% (J .OR | Ί (fYYVv »i \ λΛΛ> conh2

OH OH ° H

0 0 wherein R has the above meaning.

It is known from US Patent No. 3,200,149 that hydrogenation of methacycline of formula I (R = H) in the presence of a precious metal catalyst such as rhodium leads to reduction of the methylene group at the 6-position to a

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2 group. Since the methyl group can occupy two stereochemical orientations in space, the hydrogenation reaction forms a mixture of two stereoisomeric compounds (epimers). One of these products, the α-epimer of formula II (R = H), i. doxycycline, is a valuable antibiotic, while the other epimer, with the chemical name β-6-deoxy-5-oxytetracycline, shows little antibiotic effect and does not find medical use.

As a result, the β-epimer represents an undesirable by-product which must be separated and discarded; and to the extent that a substantial proportion of the starting compound is converted to the β-epimer, a corresponding loss in the yield of the desired doxycycline is thus achieved.

To date, the best hydrogenation process for producing doxycycline has been that described in U.S. Patent No. 3,444,198 and corresponding Danish Patent No. 123,763, which states that the initial hydrogenation of methacycline over a precious metal catalyst is carried out in the presence of a catalyst poisoning, leading to an improved ratio of doxycycline to the unwanted β-epimer.

However, the process of the invention provides doxycycline almost without its β-epimer and can be considered stereospecific.

Admittedly, stereospecific methods for the preparation of doxycycline, e.g. from U.S. Patent No. 3,163,531 and from U.S. Patent No. 3,484,483 and corresponding Danish Patent No. 119,826.

However, these are cumbersome multi-step processes which are expensive and environmentally unacceptable due to the use of mercaptans.

The hydrogenation of alkanes over homogeneous catalysts

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3 comprising rhodium and triphenylphosphine were also well known on the priority date of the present application. The most relevant technique is Mitchell, J. Chem. Soc. (B) 1970, pages 823-825, which describes the hydrogenation of 4-t-butyl-1-methylene cyclohexane (containing an exocyclic methylene group on a 6-membered ring) over a rhodium-triphenylphosphine complex. However, the present invention is surprising to Mitchell for three main reasons.

First, metal complexing or coordinating compounds (including excess triphenylphosphine itself) were known to inhibit hydrogenations over rhodium-triphenylphosphine-type complexes. Mitchell's substrate contains no such groups, while metha-cyclin contains two of them, namely the β-diketone systems in the A ring and in the B, C rings. Thus alone, hydrogenation of methacycline to form doxycycline and / or the β-epimer with this type of catalyst was most unexpected.

Second, the hydrogenation of Mitchell's substrate was stereoselective at best, e.g.

/ CH 2

H

Γ3 H

Η H

cis (69%) trans (31%) 4

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while the hydrogenation of the process according to the invention, as previously mentioned, is substantially stereospecific.

Third, Mitchell shows that the addition of hydrogen preferably occurred from the least hindered side of the double bond, although this resulted in predominantly formation of the thermodynamically least stable product in which the methyl group occupies an axial position. An analogous approach of hydrogen from the least hindered side of the 6-methylene group in methacycline would yield the β-epimer, just opposite to what is really happening.

Thus, the present invention is based on the use of hydrogenation catalysts which are soluble in the reaction medium and which consist of rhodium coordination compounds with electron donor ligands comprising triphenylphosphine. The ligand molecules may be partially replaced by the molecules of the solvent in which the reaction takes place. Certain complexes in which the molecules of the solvent partially replace the ligand molecules are so stable that their isolation is possible. Particular mention should be made here of rhodium complexes with triphenylphosphine of the type RhCl (Ph ^ P) j, the dimer Rh ^ C ^ iPh-jP) ^, the hydride and dihydride derivatives RhHC ^ (Ph ^ P) 3, Rhh ^ Cl (Ph ^ P) 3 and the complex Rh (Ph 1 P) 3 Cl 2 prepared according to methods described in the literature (J. Chem. Soc. (A) (19'66) 1711; and J. Chem. Soc.

(A) (1966) 1670; and J. Chem. Soc. (1964, 2508)).

In solution, the RhCl (Ph 2 P) 2 complex can be partially dissociated and the following equilibrium can be obtained:

RhCl (Ph3P) 3 <- - RhCl (Ph3P) 2 + Ph? P

In the presence of hydrogen, more complex equilibria are formed: 5

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H2

RhCl (P Ph3) ± Rh II2C1 (P Ph3) 3

A A

'PPh3 PPh3

V h2 V

RhCl (PPh3) 2 3 = ± RhH2Cl (PPh3) 2

The mechanism of the attachment of the hydrogen and the coordination of the olefin to the metal can be illustrated as follows:

! RhH2Cl (PPh 3) 2 S

S H2 \ alken

RhCl (PPh3) 3 <= ± RliCl (PPh3) 2S RhH2Cl (PPhJ2 alkeri!

RhCl (PPh3) 2 (alkene) / fast / ~ __S__RhCl (PPh3) 2 + products where S represents a solvent molecule.

The ligand / metal molar ratio can range from 1 to 4. The soluble catalyst can also be prepared directly in the reaction medium by dissolving in the appropriate solvent the metal halide with more than 1 mole of ligands per moles of metal. In accordance with the process of the invention, a 6-demethyl-6-deoxy-6-methyl-5-oxytetracycline compound of formula I is dissolved and a catalytic amount of a complex of the aforementioned type formed from rhodium and triphenylphosphine, in a suitable solvent and contacted with the hydrogen at a suitable temperature and pressure for a time sufficient to achieve complete conversion to the hydrogenated compound.

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6

At the end of the reaction, a very high yield of the α-6-deoxy-5-oxytetracycline compound of formula II can be separated from the solution by crystallization, while the homogeneous catalyst remains dissolved in the mother liquor.

Suitable polar solvents are e.g. mono or polyhydroxy alcohols having 1 to 4 carbon atoms, N, N-dimethylformamide, N, N-dimethylacetamide, dioxane, tetrahydrofuran, methoxyethanol, ethoxyethanol, acetonitrile and pyridine. The reaction rate and rate of conversion depend quite critically on the temperature: at temperatures lower than 15 ° C, the reaction is too slow, while temperatures higher than 80 ° C can cause the decomposition of the starting materials. The temperature range used is 15 - 80 ° C. The pressures may be lower than 0.1 MPa, but the preferred operating range is 0.1 - 14.7 MPa.

The reaction time required for complete conversion depends on the temperature, pressure and catalyst type used, but is usually within 1-8 hours. The preferred catalyst is RhCl (Ph 2 P) n, where n can be 2 or 3, since this catalyst gives almost complete conversion to the α-epimer, meaning greater biological activity, while only negligible amounts of β-epimer and little trace of degradation products. At the end of hydrogenation, thin layer chromatography of the clear, crude reaction solution shows that the ratio of mono to β-epimer is equal to or greater than 20: 1 and that the percent content of degradation products does not exceed 2 - 3%.

From finished raw solutions of this kind, there are 7

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been isolated products of excellent quality in yields higher than 75%. As previously mentioned, the homogeneous catalyst can be prepared directly in the reaction medium by dissolving the rhodium chloride in the presence of a sufficient number of moles of triphenylphosphine. The substrate is dissolved and the hydrogenation is carried out in the manner already described. You get, for example. if the number of ligand molecules is between 1 and 3 per moles of metal, the same results as with a separately produced catalyst. Ligand amounts of less than 1 mole per moles of metal lead to the formation of powdered metal deposits, which act as heterogeneous catalysts, preferably forming the β-epimer. Ligand amounts greater than 3 moles per moles of metal lead to homogeneous catalysis during gradually decreasing yields and incomplete conversion of the starting material; the stereo preference remains high in that, in the presence of unreacted substrate, preference is given to the formation of the ot epimer, while the | 3 epimer men: gden remains extremely low.

The process according to the invention is illustrated in more detail by the following examples.

EXAMPLE 1 10 g of 6-demethyl-6-deoxy-6-methylene-5-oxytetracycline hydrochloride was dissolved in 1000 ml of methanol. 2.2 g of the RhCl (Ph 2 P) 3 complex was added to the solution. The resulting solution was placed in an autoclave and hydrogenated at 9.8 MPa and 40 ° C for 4 hours. The autoclave was emptied and it was noticed that the clear solution, which was light yellow in color, quickly darkened. Thin layer chromatography (performed with silica coated plates adjusted to pH 9 and eluted with water acetone (1:10) using ultraviolet light to determine) on the crude reaction solution gave the following result: α-6-deoxy-5 oxytetracycline Ci 95% p-6-deoxy-5-oxytetracycline 8

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4.5 “ό; small traces of degradation products.

The solution was evaporated in vacuo and the product crystallized with methanol while the catalyst remained dissolved in the mother liquor. By dissolving the crystallized HCl salt in methanol and water and adjusting the pH to 5.7 with triethylamine as indicated by Stephens et. al., J. Am. Chem. Soc. Vol. 85, pp. 2643-256 (1963), a yield of 7.1 g of α-6-deoxy-5-oxytetracycline base was obtained with a spectroscopic purity of 99.5 / o. From the same source, it is known to isolate the sulfosalicylate salt from such a methanolic reaction mixture and then convert it to the free base or HCl salt as desired.

EXAMPLE 2 4 g of 6-demethyl-6-deoxy-6-methylene-5-oxytetracycline hydrochloride, 0.5 g of triphenylphosphine, 0.2 g of RhCl 2 H 2 O were dissolved in 500 ml of methanol. Performing the hydrogenation as described in Example 1, a solution was obtained which showed by thin layer chromatography the following mixture: α-6-deoxy-5-oxytetracycline 95%, β-epimer 4.5%, small traces of degradation products.

The solution was evaporated to dryness and the residue was recrystallized from methanol to remove the catalyst, and the base was isolated in the same manner as in Example 1. Yield: 2.9 g of α-6-deoxy-5-oxytetracycline base with a spectrophotometric purity of 99 , 3%.

EXAMPLE 3 5 g of 6-deoxy-6-demethyl-6-methylene-5-oxytetracycline hydrochloride

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chloride was suspended in 150 ml of N, N-dimethylacetamide.

Then, 1.1 g of the RhCl (Ph 2 P) 3 complex was added and hydrogenation was carried out at 2 MPa and 50 ° C for 4 hours.

During the reaction, the solution became clearer and at the end a clear solution was obtained, from which known methods such as Example 1 isolated 3.5 g of cx-é-deoxy-5-oxytetracycline base with a spectrophotometric purity of 99.2 %.

EXAMPLE 4 2 g of 6-deoxy-6-demethyl-6-methylenetetracycline hydrochloride was hydrogenated in accordance with the procedure described in Examples 1 and 2 to obtain complete conversion after 4 hours of reaction at 40 ° C and a pressure. at 7.8 MPa.

Chromatographic analysis showed an α-epimer / β-epimer ratio greater than 20: 1.

EXAMPLE 5 2 g of 6-demethyl-6-deoxy-6-methylene-5-acetoxytetracycline and 0.4 g of RhCl (Ph 2 P) 2 were dissolved in dimethylformamide and hydrogenated at 35 ° C and 2 MPa for 4 hours. Thin-layer chromatography, which was performed on the solution obtained at the end of the reaction, showed complete conversion to α-6-deoxy-5-acetoxytetracycline.

Claims (5)

A process for the preparation of α-6-deoxy-5-oxyte-tracycline compounds of the formula h3cx ch3 H CH3 H / OR p Γ II - c ° nh2 OH OH ° H 0 0 wherein R is hydrogen or alkanoyl of 1- 6 carbon atoms, by homogeneous catalytic hydrogenation of 6-de-methyl-6-deoxy-6-methylene-5-oxytetracycline compounds of the formula / "3" 2 * 1. "OR ORιίιίΥ'0" γγΥίϊ OH 0 0H wherein R is as defined above, or salts thereof with mineral or organic acids, characterized in that a hydrogenation catalyst soluble in the reaction medium consisting of a complex comprising rhodium and triphenylphosphine is used, and that the hydrogenation is carried out in a mono-polar polar solvent. or polyhydroxy alcohols having 1-4 carbon atoms, N, N-dimethylformamide, N, N-dimethylacetamide, dioxane, tetrahydrofuran, methoxyethanol, ethoxyethanol, acetonitrile or pyridine at a temperature between 15 and 80 ° C and for a period of time increase under a hydrogen pressure sufficient to obtain o formation to the hydrogenated compound. Process according to claim 1, characterized in that the hydrogenation is carried out for a period of from 1 to 8 hours. Process according to claim 1 or 2, characterized in that the hydrogen pressure is between 0.1 and 14.7 MPa. Process according to any one of claims 1-3, characterized in that as a homogeneous catalyst RhCl (Ph ^ P) ^ or RhCKPh ^ P) ^, the dimer Rh2Cl2 (Ph ^ P) ^, the hydride derivative RhHCl2 (Ph ^ P) ^, the dihydride derivative Rhh ^ Cl (Ph ^ P) ^ or one of the solvates obtained from the aforementioned complexes in solution in the solvents mentioned in claim 1. Process according to claim 4, characterized in that the soluble catalyst RhCl (Ph 2 P) 2 or its derivatives according to claim 4 is prepared in situ in the reaction medium by reaction of RhCl-j or RhCl3, 3H2Q with triphenylphosphine, wherein the latter is used in quantities of 1 - 4 moles: per moles of metal salt.