CS251086B2 - Method of g-penicilin's ethoxycarbonyloxyethylester production - Google Patents

Description

This invention relates to a new process vý- Robey 6- [D (-) .alpha.-amino-.alpha.-1-fenylacetroby ethoxykarbonylethylesteru penicillin amidojpenicilanové formula IG, which is an important intermediate for the higher _x 3 J ^H

I i | N: w hh.

CO-N-Cyclohexyl-o-cooc

CH, (I)

The compound of formula I is an ampicillin ester which is extremely important from a therapeutic point of view because it absorbs well when administered orally and provides a much higher level of ampicillin in the blood than ampicillin alone.

This ester is isolated in the form of the hydrochloride and is known as bacampicillin hydrochloride.

Based on previously known methods (cf. Belgian Patent No. 772,723), bacampicillin hydrochloride can be synthesized by the following two methods:

AND)

The potassium benzylpenicillin is reacted with α-chlorodiethyl carbonate in organic solvents or in an aqueous solution of 70% dioxane in the presence of sodium bicarbonate. The benzylpenicillin 1-ethoxycarbonyloxyethyl ester obtained is subjected to a reaction to remove the phenylacetate chain via the imino chloride-imino ether to obtain 6-aminopenicillanic acid 1-ethoxycarbonyloxyethyl ester, which is isolated as hyd251086 rochloride.

Subsequent condensation of the latter intermediate with D - (-? -? - phenylglycine) yields a compound of formula I.

(B)

The process according to the invention is based on the use of iodicenoic acid and is subjected to an esterification reaction with α-chlorodiethyl carbonate in a polar solvent.

Subsequent catalytic hydrogenation of 6- [D- (-α-α-azido-a-phenylacetamido) penicillanic acid 1-ethoxycarbonyloxyethyl ester gives the compound of formula I.

Obviously, these methods are too complex because they involve the use of a number of raw materials and the manufacturing process is long.

The primary object of the present invention is to provide a process for the manufacture of an active ingredient that is easier to carry out and more industrially advantageous.

The process of the invention is based on the use of a novel compound, α-bromodiethyl carbonate.

Very preferably, α-bromodiethyl carbonate is used as the reactant. The use of this compound, in particular, results in a high yield and high purity of end products such as bacampicillin.

The present invention provides a process for the preparation of penicillin G ethoxycarbonyloxyethyl ester of formula

CH 2 CO-NHN'COCCHQC-O-C .; ^; '

characterized in that penicillin G is of the formula

or a salt thereof reacted with N -bromodiethyl carbonate of the formula

Br - CH - O - COOC 2 H 5

AND

CH 3 at a temperature up to the reflux temperature of the reaction mixture and, if desired, in the presence of a solvent and / or a catalyst.

The optionally present catalyst is a quaternary ammonium salt, for example tetrabutylammonium bromide.

α-Bromomethyl carbonate is a novel compound that can be produced as described below.

The novel α-bromodiethyl carbonate compound and its use for the preparation of penicillin G ethoxycarbonyloxyethyl ester will now be described, and more detailed examples will be given below.

This aspect of the invention relates to improvements and relates to the preparation of the α-bromodiethyl carbonate of formula II

Br

According to the invention, CH3-CH-O-CO-O-C2H5 (Π) α-Bromodiethyl carbonate II can be used for the synthesis of penicillin G α- (ethoxycarbonyloxy) ethyl ester.

The novel α-bromodiethyl carbonate can be produced, for example, by Method A and Method B, which are described below.

AND.

The first of these processes, Method A, comprises the steps of reacting an aldehyde of formula III

CH3CHO

III) with a carbonyl bromide of formula IV

COBr 2 (IV) to form α-bromo-bromoformate of formula V

Br

CH3-CH-O-CO-Br (V) bj reacts the α-bromo-bromoformate of formula V with an alcohol of formula VI

C 2 H 5 OH (VI) to give the desired α-bromodiethyl carbonate of formula II.

Process A according to the invention can be summarized in a reaction scheme:

251386

Br

AND

CH3CHO + COBr2 - CH3 — CH — O — CO — Br + C2 H5OH

Br

1CH3-CH-O-CO-C2H5 + HBr α-Bromo-bromoformate of formula V as such is a novel compound.

The reaction between the aldehyde of formula CH 3 CHO and carbonyl bromide is most conveniently carried out in the presence of a catalyst, which may for example be a tertiary amine (such as a tertiary aliphatic amine, tertiary mixed alkyl-arylamine or tertiary aromatic amine), tertiary phosphine, amide, substituted urea or thiourea, acid amide a phosphorous, tertiary, oxonium or phosphonium salt or a quaternary ammonium or phosphonium salt. Preferred examples of catalysts for use in process A of the invention are pyridine, dimethylformamide, tetra-n-butyl urea, phosphoric acid hexamethylamide and benzylthimethylammonium bromide.

The catalyst is suitably used in an amount of from 0.05 to 0.5, preferably from 0.05 to 0.15 moles of catalyst per mole of aldehyde.

The reaction between the aldehyde and the carbonyl bromide is conveniently carried out in the presence of a solvent, which may be, for example, an aromatic hydrocarbon such as toluene or a halogenated hydrocarbon such as dichloromethane, carbon tetrachloride or chlorobenzene. The reaction between the aldehyde and the carbonyl bromide is conveniently carried out at a temperature of from -40 to 120 ° C, preferably from 0 to 40 ° C. The carbonyl bromide is usually used in a molar excess relative to the aldehyde, suitably in a molar excess of from 10 to 100%, preferably from 20 to 50 percent.

The intermediate of formula V, the N-bromo-bromoformate produced in step a of process A, need not be isolated prior to reaction with an alcohol of formula C2H5OH, and indeed this isolation is usually not carried out. According to a preferred embodiment of the invention, the reaction mixture obtained in step a) is freed of excess carbonyl bromide, for example by heating under reduced pressure or by purging with nitrogen. The reaction mixture containing crude α-bromo-bromoformate is then reacted with an excess of alcohol. The reaction can usually be carried out by heating the refluxing reaction mixture until the hydrogen bromide evolution ceases or by adding the tertiary base to the mixture and, if necessary, heating it. Certain catalyst residue from step a) or a complex thereof with carbonyl bromide does not appear to affect the subsequent reaction and in some cases proves beneficial.

The resulting crude α-bromocarbonate can be isolated from the reaction mixture in a conventional manner by fractional distillation under reduced pressure.

Method A is illustrated by the examples given for illustrative purposes only.

B.

A second process, Method B for producing N -bromodiethyl carbonate is now described. Method B is exemplified for illustrative purposes only.

Process B relates to manufacturing improvements and relates to the production of α-bromodiethyl carbonate by modifying the Finkelstein reaction, i.e., reacting an alkyl chloride or arylalkyl chloride (or a compound containing such a group) with an alkali metal bromide or alkali metal iodide to replace the chlorine substituent with bromine or iodine as a substituent. or by reacting an alkyl bromide or arylalkyl bromide (or a compound containing such a group) with an alkali metal iodide to replace the bromine with a substituent represented by iodine.

The Filkelstein reaction is useful because the resulting iodides are usually more reactive than bromides, which in turn are more reactive than chlorides. In some cases, only catalytic amounts of alkali metal bromide or iodide are required and the resulting much more reactive substance is reacted with the desired compound, wherein the alkali metal bromide or iodide is regenerated during the ongoing reaction.

Not all of the optionally substituted alkyl chlorides or arylalkyl chlorides can be subjected to the reaction, in particular, it has been found that there are difficulties in carrying out the reaction with α-chloroesters and n-chlorocarbonates, i.e. compounds in which the chlorine atom is attached to a carbon atom end of a group of formula —C (O) —O—. An example of such α-chlorocarbonate is α-chlorodiethyl carbonate, which is a known intermediate for the production of the 6-aminopenicillanic acid ethoxycarbonyloxyethyl esters and penicillins described above.

It has now been discovered that this problem can be overcome by carrying out the reaction using a two-phase solvent system, where one phase is water and the other phase is a water-immiscible organic solvent, in the presence of a phase transfer catalyst.

Process B therefore provides a process for the preparation of α-bromodiethyl carbonate by reacting α-chlorodiethyl carbonate with an alkali metal bromide, the process characterized in that the reaction is carried out in a two-phase solvent system comprising water and an organic solvent immiscible with water in the presence of a phase transfer catalyst. .

Suitable water-immiscible organic solvents for use herein include halogenated hydrocarbons such as halogenated saturated aliphatic hydrocarbons such as dichloromethane and aromatic hydrocarbons such as toluene. Suitable phase transfer catalysts include quaternary ammonium salts, for example tetraalkylammonium salts such as cetyltrimethylammonium bromide and tetra-n-butylammonium hydrogen sulfate. A preferred alkali metal bromide is, for example, sodium, potassium or lithium bromide. Lithium bromide is preferred.

In process B, the α-chlorodiethyl carbonate of formula IX

Cl O

I II

CH3-CH-O-C-O-C2H5 (IX) is reacted in a two-phase solvent system wherein one phase is water and the other phase is a water-immiscible organic solvent with an alkali metal bromide of formula X

R-Br (X) where

R is an alkali metal such as sodium, potassium or lithium to form a compound of formula II

Br O

CH3 — CH — O — C — O — C2H5 (II)

As mentioned above, the preferred alkali metal R is lithium, such that lithium bromide is used as the preferred reagent of formula X.

In connection with method B, it has been found that preferably lithium bromide can be used in the usual Finkelstein reaction (i.e. using a single phase organic solvent system), for example for the halogenation of α-chlorocarbonate. This method is illustrated by way of example below.

The invention relating to the use of the novel compound, α-bromodiethyl carbonate, for the preparation of penicillin G ethoxycarbonyloxyethyl ester is described below.

In summary, the present invention encompasses a process for preparing penicillin G ethoxycarbonyloxyethyl ester, which comprises reacting penicillin G or a salt thereof with α-bromodiethyl carbonate to form penicillin G ethoxycarbonylethyl ester.

In this process, a quaternary ammonium compound is preferably used, wherein the quaternary ammonium compound is present in an amount of 1 to 25%, preferably 1 to 10%, based on the equimolar amount of penicillin G.

Penicillin G ethoxycarbonyloxyethyl ester is used as a known group in the art in the manufacture of some desired semi-synthetic penicillin esters by acylation of the amino group at the 6-position, and after removal of the side chain, for example, penicillin G.

The reaction of metal salts of carboxylic acids with alkyl halides or arylalkyl halides to form esters is well known. However, yields are not particularly high and the reaction usually requires sharper conditions such as higher temperatures and / or longer reaction times. These sharper conditions limit the usefulness in the synthetic reaction and industrial applicability, due to the thermal sensitivity and instability of substances such as pyrethroids, prostaglandins, peptides, penicillins and cephalosporins.

British Patent No. 1,443,738 discloses the use of a quaternary ammonium salt of penicillins and cephalosporins instead of their metal salts in the manufacture of penicillin and cephalosporin esters.

Production of a quaternary ammonium acid salt can be time consuming and expensive. However, as disclosed in British Patent No. 1,443,738, it is not necessary to first produce the quaternary ammonium salt of penicillin or cephalosporins, but the reaction can be carried out by reacting a metal salt of a carboxylic acid, i.e., 6-aminopenicillanic acid, penicillin or cephalosporins. with an alkyl halide or arylalkyl halide in the presence of a quaternary ammonium salt other than a carboxylic acid salt.

It has now been found that it is not necessary to use said quaternary ammonium salts in stoichiometric amounts based on penicillin G, but that less than stoichiometric relative to penicillin G is sufficient.

Accordingly, in one aspect of the invention, the process for preparing ethoxycarbonyloxyethyl ester of penicillin G is carried out by reacting a metal salt of penicillin G with α-bromodiethyl carbonate in the presence of a quaternary ammonium salt, wherein the quaternary ammonium compound is present in less than stoichiometric relative to penicillin G.

According to this feature of the invention, 1 to 25% equivalent of quaternary ammonium salt is used for each equivalent of penicillin G metal salt, and suitably 1 to 10% equivalent of quaternary ammonium salt is used.

The quaternary ammonium salt of penicillin G is conveniently produced by reacting a metal salt of penicillin G and a quaternary ammonium salt of an acid other than penicillin G, typically a mineral acid such as hydrochloric acid, hydrobromic acid or sulfuric acid.

Suitable penicillin G metal salts for use according to this aspect of the invention (either as precursors of quaternary ammonium salt of penicillin G or as such) are alkali or alkaline earth salts such as sodium, potassium, lithium, magnesium and calcium salts. Suitable quaternary ammonium salts of acids other than penicillin G (for use as or as precursors to quaternary ammonium salts of penicillin G include, for example, tetraalkylammonium salts such as tetra-n-butylammonium bromide and cetyltrimethylsmonium bromide and quaternary pyridinium salts such as cetylbromide). Suitable halides include fluorides, chlorides, bromides and iodides, preferably activated fluorides or activated chlorides, or bromides or iodides.

The esterification according to this feature of the invention may be carried out in the presence or absence of a solvent. Suitable solvents include lower aliphatic alcohols, lower aliphatic ketones, lower aliphatic formic amides and dimethylsulfoxide. Unless solvents are used alternatively, an excess of the ester-forming halide may be used, especially if it is liquid at the reaction temperature.

In the previously described feature of the present invention concerning the use of α-bromodiethyl carbonate for the preparation of penicillin G ethoxycarbonyloxyethyl ester, a catalyst is optionally used. An approximately equimolar amount of the quaternary ammonium salt of the carboxylic acid and the ester-forming halide may be used in the reaction. Preferably, 5- to 100% of the ester-forming halide is used for each equivalent of penicillin G salt used, and preferably an excess of 20 to 60% of the ester-forming halide.

In order to provide a good understanding of the invention, the following examples are provided, which are provided merely by way of illustration.

Example 1

A mixture of 44 g (1 mol) of acetaldehyde, 300 ml of carbon tetrachloride and 235 g (1.25 mol) of freshly distilled carbonyl bromide was cooled to 0 ° C and held at this temperature for 1 hour, by external cooling during the addition of 11.9 g (0). , 15 mol) of pyridine.

The mixture was allowed to warm to room temperature and then warmed to 50 ° C and held at this temperature for 3 hours, during which time a precipitate formed.

Evaporation of the reaction mixture under reduced pressure at 50 ° C afforded a semi-solid oily matter which was readily dissolved in 92 g (2 moles) of ethanol while hot and heated to reflux. After further heating at reflux for 2 hours, the excess ethanol was evaporated under reduced pressure and the residue was triturated with 100 ml of water and 200 ml of dichloromethane.

Separation of the organic layer and fractional distillation gave 130 g (66% yield) of pure ethyl [α-bromoethyl carbonate], which had a boiling point of 90-92 ° C at 310 kPa and was identical in all directions to the authentic sample.

Example 2

A mixture of 44 g (1 mol) of acetaldehyde, 300 ml of dichloromethane and 17.9 g (0.1 mol) of phosphoric acid hexamethylamide is cooled to -10 ° C and 207 g (1.1 mol) of freshly added gradually over 4 hours. distilled carbonyl bromide, during which time the temperature was allowed to rise to 10 ° C.

The mixture was then heated under gentle reflex to about 40 ° C for 4 hours. 69 g (1.5 mol) of ethanol are again added over 1 hour at reflux and heating at reflux is continued for 1 hour.

Fractionated distillation of the resulting mixture directly afforded 114 g (58% yield) of pure ethyl [N-bromoethyl carbonate].

The authenticity of the resulting ethyl [α-bromoethyl carbonate] was confirmed by analysis and independent synthesis as follows:

118 g (1.0 mol) of diethyl carbonate are mixed and heated to a temperature between 110 and 120 ° C and illuminated with a 150 W tungsten filament lamp. 96 grams (0.6 moles) of bromine are added dropwise over 3 to 4 hours at such a rate that the mixture does not darken under a pale orange color.

After the bromine addition was complete, the mixture was cooled to room temperature and 20 g of sodium bicarbonate was added.

Distillation and fractionation of the resulting mixture afforded 84.2 g (70% yield) of the authentic ethylphosphromethyl carbonate], which had a boiling point of 87-88 ° C at 50 mbar.

Example 3

A mixture of 43 g (0.5 mol) of lithium bromide, 15.3 g (0.1 mol) of ethyl [α-chloroethyl carbonate], 100 ml of water, 100 ml of dichloromethane and

1.5 g of cetyltrimethylammonium bromide was stirred at room temperature for 24 hours. The aqueous layer was then removed and replaced with a fresh solution of 26 g (0.3 mol) of lithium bromide in 40 ml of water containing 1 g of cetyltrimethylammonium bromide. It is then stirred for an additional 24 hours, during which the temperature rises to 35 ° C, the organic layer is separated, dried and distilled under reduced pressure to give a new compound, ethylphromomethyl carbonate], weighing 15.0 g (76 g). % yield) having a boiling point of 90-92 ° C at a pressure of 240 kPa.

Analysis:

calculated:

30.7% C, 4.8% H, 40.1% Br, found:

30.5% C, 4.6% H, 40.5% Br.

The NMR spectrum has the following peaks:

1.2 - 1.6 (3H, triplet) - CH2 --CH3

2.0-2.2 (3H, doublet) —CH — C'H5 -

4.1-4.5 (2H, quartet) —CH2-CH3

6.5 - 6.8 (1H, quartet) —CH — Cl3

25108S

Example 4

17.4 g (0.2 mol) of lithium bromide are dissolved in 150 ml of dimethylformamide and the mixture is cooled to room temperature. 30.5 g (0.2 mol) of ethyl [alpha] -chloroethyl carbonate are then added and the mixture is stirred at room temperature for 24 hours. The precipitated lithium chloride was filtered off and the filtrate was distilled under reduced pressure, and after careful re-fractionation, ethyl [alpha] -bromoethyl carbonate was obtained in a yield of 76% based on the recovered ethyl [n -chloroethyl carbonate].

Example 5

A process for the preparation of benzylpenicillin ethoxycarbonyloxyethyl ester

A mixture of penicillin G potassium salt (7.4 g, 20 mmol), ethyl [.alpha.-chloroethyl carbonate) (4.6 g, 30 mmol), tetra-n-butylammonium bromide (0.8 g, 2.5 mmol) and acetone (80 ml) was stirred and Heat at moderate reflux for 4 hours. The excess acetone was distilled off under partially reduced pressure and the residue was triturated with an ice-cold mixture of water and methyl isobutyl ketone. Evaporation of dry methyl isobutyl ketone under reduced pressure gave 3.8 g of semi-crystalline oil. From this, 0.9 g of white crystals of .alpha .- (ethoxycarbonyloxy) ethyl ester of penicillin G are obtained by trituration with ethanol, which has a purity of 98-99% according to HPLC.

Analysis:

found:

H, 7.4; N, 7.7.

% C, 43.4%;% H, 7.4%;

Example 6

A process for the preparation of benzylpenicillin ethoxycarbonyloxyethyl ester

The procedure of the preceding Example 5 was repeated using 5.9 g (30 mmol) of ethyl [.alpha.-bromoethyl carbonate] in place of ethyl [.alpha.-chloroethyl carbonate] to give 6.0 g of semi-crystalline oil after evaporation of methyl isobutyl ketone. Trituration of this oil with hot ethanol followed by cooling gave 2.5 g (35% yield) of white crystals of penicillin G ethyl- (ethoxycarbonyloxy) ethyl ester.

Example 7

A process for the preparation of benzylpenicillin ethoxycarbonyloxyethyl ester

25.08 g (66.7 mmol) of potassium benzylenicillinate, 0.50 g (6.0 mmol) of sodium bicarbonate and 2.15 g (6.67 mmol) of tetrabutylammonium bromide are carefully stirred in 41 ml of methylene chloride and heated to 40 ° C. At this temperature, 17.16 g (86.7 mmol) of α-bromodiethyl carbonate are added and the suspension is stirred for 4.0 hours, then 30 ml of water and mineral acid are added until the pH reaches about 5. The mixture is stirred for about 4 hours. During this time, 4% sodium hydroxide solution was added to maintain the pH between 2.5 and 3.0, then 50 ml of methylene chloride was added and the mixture was allowed to separate for a few minutes.The organic phase was washed with 65 ml of water and then evaporated under reduced pressure. The oily product thus obtained is dissolved in 100 ml of methylene chloride and evaporated again, and the remaining oil is dissolved in methylene chloride to a total volume of 100 ml.

High pressure liquid chromatography of the methylene chloride solution shows a yield of ethoxycarbonyloxyethyl benzylpenicillin ester of 96-97%.

Example 8

A process for the preparation of benzylpenicillin ethoxycarbonyloxyethyl ester

5.02 g (13.3 mmol) of potassium benzylpenicillinate and 2.99 g (38.3 moles) of potassium bicarbonate in 13.5 ml of dimethyl sulfoxide are carefully stirred in an ice bath. 3.70 g (18.6 mmol of .alpha.-bromodiethyl carbonate) was added via a syringe pump over a period of 30-40 minutes, and stirring was continued while the reaction mixture was maintained on an ice bath. High pressure liquid chromatography showed that a yield of about 70% in 5 to 10 minutes.

Example 9

A process for the preparation of benzypenicillin ethoxycarbonyloxyethyl ester

47.03 g (125 mmol) of potassium benzylnicenilicate, 0.94 g (11 mmol) of sodium bicarbonate and 2.01 g (6.25 mmol) of tetrabutylammonium bromide are carefully stirred in 77 ml of acetone and heated to 40 ° C. At this temperature, 26.08 t (131 mmol) of α-bromodiethyl carbonate are added and the suspension is stirred for 4.5 hours. Then 56 ml of water and then mineral acid are added to adjust the pH to approximately 5. The mixture is stirred for about 3 hours, during which time 4% sodium hydroxide solution is added to maintain the pH between 4.5 and 4.8. Butyl acetate (100 ml) was added and the mixture was allowed to separate for a few minutes. The organic phase is washed with 80 ml of water and then evaporated under reduced pressure. The remaining oily product was dissolved in methylene chloride and made up to a total volume of 230 ml.

High pressure chromatographic analysis of the methylene chloride solution shows a yield of benzylpenicillin ethoxycarbonyloxyethyl ester of 98-99%.

Claims (5)

SUBJECT OF THE INVENTION A process for the preparation of penicillin ethoxycarbonyloxyethyl ester of formula G / i Wr characterized in that penicillin G of the formula zCr > COOH or a salt thereof is reacted with an α-bromodiethyl carbonate of the formula Br - CH - O - COOC 2 H 5 CH3 Analysis: at a temperature up to the reflux temperature of the reaction mixture. 2. A process according to claim 1 wherein the reaction is carried out in the presence of a catalyst. 3. The process of claim 2 wherein the catalyst is a quaternary ammonium salt. 4. The process according to claim 2, wherein tetra-n-butylammonium bromide is used as the catalyst. 5. The method of claims 2 to 4, wherein the quaternary ammonium salt is used in an amount of from 1 to 25%, preferably from 1 to 10%, of the quaternary ammonium salt equivalent for each equivalent of penicillin G.