CS240398B1 - Process for preparing peniailic acid and its derivatives - Google Patents

Abstract

A method for preparing penicillanic acid and its derivatives of the general formula I ø l 3 { f ø in which n denotes an integer from 0 to 2 and Z a hydrogen atom or an alkali metal. The solution relates to a method for preparing penicillanic acid and its derivatives of the general formula I by hydrogenolysis of 6-mono- or 6,6- -dihalogen derivatives. Its essence lies in the fact that a reaction mixture with a high concentration of the starting material, 20 to 40% by weight, is hydrogenolyzed. At least one degassing during hydrogenolysis and refilling with hydrogen is advantageous, especially for low-pressure technologies. Compared to known methods, the process according to the invention is significantly more productive. The invention relates to the production of drugs, especially in the field of semi-synthetic penicillins.

Description

2

A process for the preparation of penieilanic acid and its derivatives of the general formula I

wherein n is an integer from 0 to 2 and Z is hydrogen or an alkali metal.

The present invention relates to a process for the preparation of penieilanoic acid and its derivatives of the formula I by hydrogenolysis of 6-mono- or 6,6-dihalogenated derivatives. It is characterized in that the reaction mixture is hydrogenolyzed with a high concentration of the starting material, 20 to 40% by weight.

At least one degassing during hydrogenolysis and refilling with hydrogen is preferred, especially for low pressure technologies.

Compared to known methods, the process of the invention is substantially more productive.

The invention relates to the manufacture of medicaments, in particular to the field of semi-synthetic penicillins.

4 0 3 9 7

The invention relates to a process for the preparation of penicillanic acid and its derivatives of the general formula I

(i) wherein n is an integer from 0 to 2 and Z is hydrogen or an alkali metal, especially sodium or potassium.

Penicillanic acid (Formula I, n = 0, Z = H) is known, and its sulfone (Formula I, n = 2, Z = H), also known as sublactam; it in the form of salts or esters inhibits the formation of beta-lactamases and thus greatly improves the effect of penicillins. The invention allows for a more productive and cheaper preparation than the known processes.

Penicillanic acid and its derivatives of the formula I are most often prepared by dehalogenation of the 6-mono- or 6,6-dihalogenated derivative of the penicillanic acid of the formula II

wherein X ¹ and X ² represent chlorine or bromine atoms or X ¹ hydrogen and and Z denotes the same as in formula I by hydrogenolysis with hydrogen at atmospheric or elevated pressure, in the presence of a catalyst such as supported palladium, in particular carbon or calcium carbonate and a halogenating agent, such as sodium or potassium bicarbonate, in water or in a mixture of water and an organic solvent.

In particular, the starting material for the known syntheses of the compounds of formula (I) is 6-aminopenicillanic acid (or its isisulfone), which is diazotized and converted to 6-mono- or 6,6-dihalogenated derivatives (European Published Patent Application No. 93 465; Org. Chem., 27, 2663; 1962; U.S. Pat. No. 3,206,469).

In British Pat. No. 1,072,108 discloses the hydrogenolysis of an about 10% solution of monohalogenpenicilane under a hydrogen pressure of up to 0.5 MPa, using palladium on carbon catalyst and in the presence of a buffer. Yields are not given. Hydrogenolysis of dibrompenicillanic acid has also been reported [J. Chem. Soc. (London, C) 19S9, 2123], in the form of a 5% solution, with the same amount of catalyst (palladium on calcium carbonate) at atmospheric hydrogen pressure. A glassy yield of 72% of the theoretical amount is given. A similar method of hydrogenolysis is described for the synthesis of other derivatives of penicillanic acid (European Published Patent Application No. 18,305).

According to the Belgian Pat. No. 867,859 is based on penicillanic acid or its sulfoxides and the final stage of the preparation of sulbactam (esters) is the oxidation to sulfone. US Pat. No. 4,234,579 describes the conditions of hydrogenolysis and the preparation of sulbactam starting from 6,6-dibrompenicillanic acid 1,1-dioxide. A dilute solution of the dibromo derivative (less than 6%) in ethyl acetate-water is used. For a given, a sequence of reactions (oxidation, and then hydrogenolysis), the general parameters suggested by hydrogenolysis, and the hydrogen pressure to 10 MPa, the temperature from 0 to 60 ^Q C, pH 4-9 and a suitable catalyst in a weight ratio to the starting compound of 0.01 to 2 , 5. Similarly, the effective preparation of sulbactam was first described by oxidation and then by hydrogenolysis (DOS 3 008 257; J. Org. Chem. 1982, 47, 3 344). Without isolation in some intermediate steps, yields of about 54% of theory based on 6-aminopentanilaic acid are achieved. The yield of hydrogeolysis alone is reported to be about 80% of theory (starting material content below 6% in solution). Catalytic hydrogenolysis has also been criticized and recommended by zinc reduction (European Published Patent Application No. 92,286).

The principal disadvantages of the processes described above for the preparation of penicillanic acid and its derivatives of the general formula I are low concentrations of the starting material, in particular 6,6-dibrompenicillanic acid 1,1-dioxide (not more than 10% by weight) in the reaction mixture, when hydrogenolysis is classified as. the last stage of sulbactam synthesis; the use of high hydrogen pressures (up to 10 MPa) appears; if the sequence is reversed, i.e. hydrogenolysis is followed by oxidation, pressures up to 0.5 MPa are used in hydrogenolysis, the reaction time required is long and higher catalyst feed rates are required.

The disadvantages of the above-mentioned disadvantages are the process for the preparation of penicillanic acid and its derivatives of the formula I according to the invention, characterized in that the reaction mixtures containing the compound of the formula II in an amount of 10 to 60% by weight, preferably 20 to 40% by weight are catalytically hydrogenolyzed. based on the starting amount of the liquid phase, under a hydrogen pressure of 0.1 to 10.0 MPa, preferably 0.5 to 6.0 MPa, at a temperature of -20 to 80 ° C, preferably 20 to 60 ° C.

In some cases, it is expedient for the reactor to be degassed at least once during hydrogenolysis and to react after completion of the hydrogen treatment under the original conditions until completion.

In the process according to the invention, the work with high concentrations of hydrogenolyzed substance is made possible by maintaining in the reactor the partial pressure of hydrogen over the pressure of the carbon dioxide formed. This is accomplished by operating at high pressure in the reactor (e.g., above 20 bar), with hydrogen pressure prevailing throughout the reaction. In a second possible mode of operation in a low-pressure embodiment (e.g. at total pressures below 20 bar), the reactor is degassed (at least once) and pressurized with hydrogen. Thereby, the reaction mixture is freed from. carbon dioxide. The predominance of carbon dioxide would otherwise prevent the desired conversion of the starting material and the yield would be low. Examples 3 and 4 illustrate the situation. In the case of discontinuous operation, the partial pressure conditions can be controlled by the degree of autoclave filling. ·

In the investigation of the synthesis conditions, it has been found that, in particular in terms of yields at higher concentrations of the starting material, it is appropriate to hydrolyze the compound of formula II where n = 0 and oxidize the obtained product to sulbactam. . This herring reaction is referred to in the literature as considerably loss-making.

Other known conditions relating to hydrogenolysis may be utilized in the synthesis, for example:

a) It is possible to use raw materials of different qualities, resp. without insulation. Preferably pure raw materials are applied, the degree of catalyst deactivation is then low.

b) The hydrogen halide formed in the reaction is bound by a buffering agent, maintaining the pH at 4-9 with a pH.

c) May react in a non-isothermal mode.

A suitable catalyst, preferably palladium on carbon, is used. its quantity and quality (in addition to pressure, temperature and other factors) determine the reaction rate. It is used, for example, from 1 to 100% by weight of the starting material, preferably from 1 to 10%. Reuse is not excluded.

According to the technological conditions, the hydrogenolysis times are chosen from 10 min to 3 h.

f) The isolation of the substances is carried out according to known methods (catalyst filtration, acidification, extraction, or concentration) Crystalline products (salts) are prepared by precipitation with salts of other acids, or by direct neutralization possibly associated with extractions.

An advantage of the process according to the invention is to work at high concentrations of starting materials (for example, a suspension is used), while attaining high yields. The process is simple, fast, unpretentious and simple to isolate a product of satisfactory quality. Although many known conditions are used, high efficiency and productivity are achieved.

The following examples illustrate the process but do not limit it in any way.

EXAMPLE 1 To a solution of 40 g of potassium 6,6-dibrompenicilane in 80 ml of water, 18 g of sodium bicarbonate and 2 g of 5% palladium on carbon were successively added. The suspension was poured into an autoclave (0.3 liter volume, 2000 pbr / min stirring), after rinsing with 30 ml of water and after flushing the autoclave with nitrogen and hydrogen, a reaction lasting about 10 min. the reduction time was 20 min. After filtering off the catalyst and washing it with water, about 200 ml of the filtrate was added with 100 ml of butyl acetate and acidified dropwise with dilute hydrochloric acid (1: 1) to pH 1.8 with stirring. After filtering through a pad of diatomaceous earth on paper and washing the filter with butyl acetate, the organic layer was separated and the aqueous layer was shaken 3 times with 100 ml of butyl acetate. The combined butyl acetate portions were precipitated with a 40% butanolic solution of sodium n-ethylcaproic acid. After stirring for 1 h, the precipitated sodium penicilane was aspirated, washed with butyl acetate and dried. The yield of white slightly yellowish product was 87.3% of theory. [Α] _D 20 ₌ 252 ° (c = 1; water).

Example 2

The procedure was the same as in Example 1 except that ethyl acetate was used instead of butyl acetate. After treatment as in the above example and isolation of the cyclohexylamine penicillan product, including recovery of the concentrated mother liquor, it was found that the hydrogenolysis proceeded in a yield of about 90% of theory,

Example 1 and d 3

The procedure was the same as in Example 1 except that the hydrogenolysis was carried out at a hydrogen pressure of 1.5 MPa for 90 min. It was extracted 4 times with ethyl acetate. Isolation with sodium ethyl caproate resulted in poor product precipitation. It was found that there was still a starting material in the reaction mixture.

He attaches

The procedure of Example 3 was repeated except that during the hydrogenolysis, the autoclave was degassed 3 times and recharged with hydrogen to the original pressure (after 3, 16 and 30 minutes of reaction). The total reaction time was 110 min. The yield of sodium penicilane (isolation with sodium ethyl caproate) was 81% of theory.

Example 5

To a solution of potassium 6,6-dibrompenicilane (20 g) in water (60 ml) was added sodium bicarbonate (9 g) and 5% palladium on carbon (1 g). The suspension was heated to 50 ° C and poured into an autoclave (placed in a 50 ° C bath) and rinsed with 35 mL of water. Hydrogenolysis was then carried out at 1.5 MPa for 25 min. without degassing the reaction mixture. After isolation as in Example 1, yellowish sodium penicilane was obtained in a yield of 71% of theory. [.Alpha.] D @ ³⁰ = 307 DEG, (c = 1, water).

Example 6

To a solution of potassium 6,6-dibrompenicilane (20 g) in water (60 ml) was added sodium bicarbonate (9 g) and 5% Pd / C (2 g).

After rinsing with 30 ml of water, it was hydrogenolysed at 0.6 MPa at room temperature for 70 min. During the reaction, it was degassed 3 times (after 2, 14 and 40 min). Isolation as in Example 1 afforded sodium penicilan in a yield of 82% of theory. [α] _D ²⁰ = 331 °, (c = 1, water).

Example 7

To a solution of potassium 6,6-dibromo-pentilane (16 g) in 60 ml of water was added 6.6 g of sodium bicarbonate and 1 g of 5% Pd / C. After pouring the suspension into the autoclave and rinsing with 35 ml of water, it was hydrogenolyzed at room temperature at 6 MPa for 16 min. Isolation as in Example 1 gave sulbactam sodium in a yield of 65% of theory. [α] _D ²⁰ = 265 °, (c = 1, water).

Claims (2)

PftEDMET A process for the preparation of penicillanic acid and its derivatives of the general formula I in which n is an integer from 0 to 2 and Z is hydrogen or an alkali metal, especially sodium or potassium, by dehalogenation of a 6-mono- or 6,6-dihalogenated penicillanic acid derivative of the general formula II of the invention in which X ¹ and X ² denote chlorine or bromine atoms or X ¹ hydrogen and and Z denotes the same as in formula I by hydrogenolysis with hydrogen at atmospheric or elevated pressure, in the presence of a catalyst, for example palladium on supported, especially coal or calcium carbonate, and a hydrogen halide-binding agent, for example sodium or potassium bicarbonate, in water or a mixture of water and an organic solvent, characterized in that the hydrogenolysis is carried out with a reaction mixture containing a compound of formula II in an amount of 10 to 60 wt. %, preferably 20 to 40% by weight, based on the amount of liquid phase under a hydrogen pressure of 1 to 10 MPa, preferably 0.5 to 6.0 MPa, at a temperature of -20 to 80 ° C, preferably 20 to 60 ° C. 2. A process according to claim 1, wherein during the hydrogenolysis the reactor is degassed at least once and, after hydrogen filling, is hydrogenolysed under the original conditions until completion of the reaction.