NO851254L - PROCEDURE FOR PREPARING THE 1-ETHOXYCARBONLOXY ETHYL ESTER OF 6- (D - (-) - ALFA-AMINO-ALFA-PHENYLACETAMIDO) PENICILLANIC ACID - Google Patents

Description

The present invention relates to a new process for the production of 1-ethoxycarbonyloxyethyl esters of 6-(d-(-)-a-

(X-

amino-α-phenylacetamido)penicillin acid of formula I:

Furthermore, the invention concerns

- the new compound α-bromodiethyl carbonate which can be used with great advantage in the aforementioned method for the production of bacampicillin with formula I, and which more generally can be used with advantage in the production of ethoxycarbonyloxyethyl esters of 6-aminopenicillic acid, penicillins and cephalosporins,

- new methods for the production of α-bromodiethyl carbonate,

- new intermediates in the production of α-bromodiethyl carbonate, - the use of α-bromodiethyl carbonate in the production of the ethoxycarbonyloxyethyl ester of 6-amino-enicillic acid, penicillins such as penicillin G, penicillin V and ampicillin, and cephalosporins, - improvements in the process for the production of ethoxycarbonyloxyethyl esters of 6-aminopenicillinic acid, penicillins and cephalosporins.

The compound of formula I is an ampicillin ester which is very important from a therapeutic point of view, as the compound is very well absorbed when administered orally and gives higher blood levels of ampicillin than ampicillin itself.

The ester is isolated in the form of a hydrochloride and it is known as bacampicillin hydrochloride.

important information

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On the basis of previously known methods (conferring Belgian patent no. 772723), bacampicillin hydrochloride can be synthesized using the following two methods: A) Potassium benzylpenicillin can be reacted with α-chlorodiethyl carbonate in organic solvents or in an aqueous solution of 70 % dioxane in the presence of sodium bicarbonate. The 1-ethoxycarbonyloxyethyl ester of benzylpenicillin is then produced, which is then subjected to a reaction where the phenylacetic acid chain is removed via the iminochloride-iminoether, thereby producing the 1-ethoxycarbonyloxyethyl ester of 6-aminopenicillinic acid, which is then isolated as the hydrochloride.

By subsequent condensation of the latter intermediate with D-(-)-cc-phenylglycine, compounds of formula I are obtained. B) One can esterify 6-(D)-(-)-a-azido-a-phenylacetamido) -penicillin acid with α-chlorodiethyl carbonate in a polar solvent.

By subsequent catalytic hydrogenation of the 1-ethoxycarbonyloxyethyl ether of said 6-(D-(-)-a-azido-a-phenylacetamido-penicillinic acid, the compound of formula I is produced.

It appears from the above that these methods are relatively complex, as they involve the use of several starting compounds, and furthermore require a long synthesis time.

It is an aim of the present invention to provide a method for the production of the above-mentioned active ingredient which is easy to carry out and which is industrially more advantageous. A more specific purpose of the invention is to provide a method for the production of bacampicillin using ampicillin as starting material, with a significant simplification of said method and where the desired product is obtained with a higher degree of purity.

The invention also provides the new compound ct-bromodiethyl carbonate, new processes for its preparation; new intermediates in the production of α-bromodiethyl carbonate, the use of α-bromodiethyl carbonate in the production of the ethoxycarbonyloxyethyl ester of 6-aminopenicillin and penicillins such as penicillin G, penicillin V and other penicillins, as well as improvements in the process for the production of ethoxycarbonyloxyethyl esters of 6-aminopenicillin, penicillins and cephalosporins.

α-bromodiethyl carbonate can be used with great advantage as a reactant in these esterification processes. The use of α-bromodiethyl carbonate leads to a particularly high yield and high purity of the end products such as bacampicillin.

It is possible to achieve the aforementioned main purpose in the preparation of the 1-ethoxycarbonyloxyethyl ester of 6-(D (-)-a-amino-a-phenylaceta-midopenicillinic acid with the following formula:

by means of a method which is characterized by means of the following steps: a) one reacts ampicillin, preferably in the form of an alkaline salt, with a reactive derivative of acetoacetic acid, whereby the corresponding enamine with the following formula is produced:

where:

R"*" represents an alkyl group with from 1 to 4 carbon atoms, a substituted or unsubstituted aryl group or an aralkyl group; R 2 represents hydrogen, an alkyl group with from 1 to 4 carbon atoms or a substituted or unsubstituted aryl group or aralkyl group; R 3 represents an alkyl group with from 1 to<j>4 carbon atoms, a substituted or unsubstituted aryl group, an arylalkyl group, an alkoxy group from 1 to 4 carbon atoms, an aryloxy group or an amino group, and X represents an alkali metal, an alkaline earth metal or an organic base; b) after which the resulting intermediate is reacted with an α-bromo-diethyl carbonate of the following formula:

whereby the corresponding ester with the following formula is produced:

12 3

where R , R and R have the same meaning as stated above and

c) carries out a hydrolysis in an acidic medium, whereby the compound of formula I is produced.

The esterification reaction between compounds II and III can be carried out with or without an esterification catalyst.

The addition of a catalyst at this stage significantly shortens the reaction time and gives a higher yield of the product with a higher degree of purity.

For this purpose, the following compound can be used as a catalyst: quaternary ammonium salts, e.g. tetrabutylammonium bromide, the bromides and iodides of alkali metals and cyclic ethers.

The catalyst can be used in an amount varying from 0.05 -

0.10 mol per moles of the compound II to amounts equimolar to the amount of the compound of formula III. In a preferred embodiment, tetrabutylammonium bromide is used in an amount of from 0.01 - 0.1 mol per moles of compound III.

The invention also includes an embodiment of the above-mentioned process for the preparation of bacampicillin which includes reacting a compound of formula II with a compound of formula V:

where Z is Cl or I,

and which is characterized in that the method is carried out in the presence of a catalytic amount of a catalyst as indicated above. The catalyst is suitably used in an amount of from 0.005 - 0.1 mol per moles of the compound of formula V.

Illustrative examples of the radicals R 1, R 2 and R 3 are the following:

alkyl: CH 3 , C 2 , n-C 2 , i-C 3 H 2 , n-C 4 H 2

alkoxy (only R<3>): OCH3, OC2H5, OCH2CH2CH3, OCH (CH3) 2.0 (CH2) 3CH3

ary 1:

substituted aryl: phenyl substituted with halogen such as Cl and Br aryloxy: aralkyl1:

The radical X is chosen from among groups that are well known in the chemical industry, e.g.

alkali metal: Na, K alkaline earth metals: Ca, Mg

organic base: organic bases well known in the synthesis of penicillin, e.g. tertiary ammonium groups, triethylamine, ethylpiperidine and methylmorpholine.

A preferred embodiment of the invention is a group protecting the amino group of ampicillin, a 1-methoxy-carbonyl-propen-2-yl group or a 1-ethoxy-carbonyl-propen-2-yl group, for which the preferred intermediate is the sodium or potassium salt of N-(-l-methoxy-carbonyl-propen-2-yl) penicillin acid, respectively N-(l-ethoxy-carbonylpro<p>en-2-yl-1 2 3 penicillin acid of formula II (R ==methyl, R = methyl, R = methoxy or ethoxy and X is Na or K).

The intermediate product IV is stable in a neutral or alkaline medium, while in an acidic medium it is possible to remove the group that protects the amino group relatively easily, quickly and selectively.

The group that protects the amino group in ampicillin can be chosen, e.g. from the groups mentioned in British patent no. 991586, and from other groups that are well known in the chemical industry.

The α-bromodiethyl carbonate, compound with formula III, which is a new compound and as such forms part of the invention, can be prepared by reacting the corresponding α-chlorodiethyl carbonate with sodium bromide, as e.g. is set out in Example 1 below.

More particularly, a preferred embodiment of the invention thus includes a method with the following steps: - conversion of ampicillin trihydrate in a polar solvent, e.g. N,N-dimethylformamide, to a salt, e.g. potassium salt and then formation of the corresponding enamine (II) by a reaction with a derivative of acetoacetic acid, e.g. methylaceto-acetate, - addition of an esterification catalyst, preferably tetrabutylammonium bromide, - addition of α-bromodiethyl carbonate to the reaction mixture, whereby the l-ethoxycarbonyloxyethyl ester of ampicillin is produced in the form of the enamine (IV), - hydrolysis of the protecting group with HCl diluted in an organic solvent, e.g. n-butyl acetate/water, - recovery of the bacampicillin hydrochloride by saturation in the aqueous phase, e.g. with sodium chloride and extraction with et

suitable solvent, e.g. n-butyl acetate,

- concentration of the solution at low pressure in n-butyl

acetate in order to thereby crystallize the product with high purity, after which the product is isolated by filtration.

Among the main advantages of the present method is that one

by means of this method bacampicillin hydrochloride can be obtained practically in one operation and with a very high degree of purity.

The impurities that may be present in the product manufactured

by means of the present method are negligible compared to what was found in the product from previously known methods.

Another important advantage is that ampicillin trihydrate is used

as starting material, is a known antibiotic that can be easily obtained in pure form and at a low cost.

The intermediate of formula (II) can be easily prepared, e.g.

as described in British patent no. 991586 in a yield - • of over 95% by reacting ampicillin trihydrate with methyl or ethyl acetoacetate in an amount of 10 - 50% more than the stoichiometric ratio, in the presence of an organic base or a alkali metal carbonate, e.g. potassium carbonate.

The intermediate of formula II can be isolated and added to the esterification reaction medium in solid form. However, the formation reaction can also be carried out without isolation of the intermediate product of formula II in the same solvent in which the enamine of formula II was prepared.

The reaction for the preparation of ampicillinamine (II) is carried out

in an aprotic polar solvent such as N,N-dimethylacetamide,

N,N-dimethylformamide, dimethoxyethane, dimethylsulfoxide, tetrahydrofuran or dioxane.

To obtain a complete reaction, it is sufficient that the components of the mixture are kept in contact at a temperature between 0 and 60°, preferably between 20 and 30°C and from 2 to 8 hours, preferably approx. 3 hours.

The compound of formula II can be prepared via a ^-kyle ring of 6-aminopenicillin acid with a corresponding enamine derivative of phenylglycine, whereby the compound of formula II is formed which can then be directly esterified and converted to bacampicillin with isolation of the compound of formula II.

The esterification reaction after addition of the α-bromodiethyl carbonate to said mixture takes place at a temperature of between 45 and 55°C for a period of 1-24 hours, preferably from 5-10 hours.

The esterification reaction is preferably carried out in an organic solvent, such as methylene chloride or acetone, dimethylacetamine, dimethylformamide and dimethylsulfoxide, or in a "mixture" of organic solvents. It is also possible to use an organic solvent containing water. It is desirable similar to using an esterification catalyst when using acetone as solvent for the esterification reaction.

In the easiest and most appropriate method for industrial purposes, the first third enamine of formula (IV) should be isolated by diluting the reaction mixture with water and then carrying out an extraction with a suitable solvent which is immiscible with water, e.g. n-butyl acetate.

The acetate phase is stirred with a dilute solution (0.2-0.3N) of HC1 until the protecting group is completely hydrolysed, which requires a contact time of from 2-8 hours, preferably from 4-5 hours at normal temperatures.

When sodium chloride is added, the compound of formula (I) will separate from the aqueous phase in the form of the hydrochloride, which is then extracted with a suitable solvent, e.g. n-butyl acetate.

By concentrating the organic phase at low pressure and at a temperature of approx. 40°C until a small volume is obtained, then crystallization of the product with formula (I) takes place.

The crystalline product can then be isolated by filtration, it can then be washed and vacuum dried.

The following examples illustrate the invention:

E xample 1 - production of g-bromodiethyl carbonate.

102.9 g of sodium bromide dissolved in 600 ml of acetone was reacted for 2-3 hours at from 20 - 25°C with 152.6 g of α-chlorodiethyl carbonate dissolved in 100 ml of acetone. The mixture was then concentrated under vacuum at a low temperature, maximum 35°C, until a semi-solid mass was obtained. The reaction mixture was then partitioned between water and ethyl ether. The aqueous phase was separated and extracted twice with 400 ml of ethyl ether.

The combined organic phases containing the α-bromodiethyl carbonate were washed with

800 ml of water

1000 ml 1% sodium metabisulphate aqueous solution 1000 ml NaCl-saturated solution

The organic phase was dried over Mg-sulphate, and then concentrated under vacuum at a low temperature, maximum 35°C, whereby the title product was obtained in a yield of 60% in the form of a liquid which was initially colorless or slightly yellowish brown.

It was used directly in the esterification step as described in example 2.

Example 2

25.08g (0.181 mol) of finely ground anhydrous potassium carbonate was suspended in 200 ml of N,N-dimethylacetamide and 32.4 ml (0.3 mol) of methyl acetoacetate and 60.4g (0.15 mol) of ampicillin trihydrate.

The mixture was kept under vigorous stirring for 5 hours at 20-25°C, after which 46.1g (0.234 mol) of bromodiethyl carbonate, 6g (0.02 mol) of tetrabutylammonium bromide and 100 ml of N,N-dimethylacetamide were added. .

The mixture was heated under the tube for 10 hours at 40-42°C, after which the reaction mass was poured into a mixture consisting of 1200 ml of water and 400 ml of n-butyl acetate.

The aqueous phase was collected and extracted with an additional 100 ml of n-butyl acetate.

The combined organic phase was washed twice with 100 ml of water each time. 150 ml of N HC1 and 370 ml of water were then added, after which the whole was vigorously stirred and allowed to stand under stirring at 22-23°C for 4 hours.

The aqueous phase was collected while the organic phase was extracted with 100 ml of water.

The combined aqueous phases were adjusted to pH 4 with 10% aqueous solution of Na2CO^, after which bleached carbon was added to

the mixture which was then filtered.

The aqueous filtrate was then added with 300 ml of n-butyl acetate and

80g sodium chloride. The organic phase was separated while the aqueous phase was extracted with 200 ml of n-butyl acetate.

The combined phase n-butyl acetate was concentrated at low pressure at 40° to a volume of approx. 300 ml. The product was set aside for crystallization for 15 hours at +5°.

The product was filtered, washed with 100 ml of n-butyl acetate and

100 ml ethyl acetate. It was then vacuum dried at 40°C for 24 hours.

Yield: 54.2g (72%) 1-ethoxycarbonyloxyethyl ester of 5-(D(-)

-a-amino-a-phenylacetamido) penicillic acid with a melting point of 160-162°C. (d) and with properties that were consistent with authentic hydrochloride sample.

Example 3

36.4g (0.075 mol) potassium N-(1-methoxycarbonyl-propen-2-yl)-6-

(D (-)-α-amino-ct-phenylacetamido) penicillate was added to a solution of 17.8 g (0.116 mol) α-chlorodiethyl carbonate and 3 g (0.01 mol) tetrabutylammonium bromide in 150 ml of N,N-dimethylformamide . With stirring, the temperature was raised to 45°C and held at 45 - 50°C for 5 hours.

Then the reaction mixture was all over in a mixture of

300 ml of 14% aqueous sodium chloride solution and 600 ml of n-butyl acetate. The mixture was stirred for 10 minutes, after which the organic phase was separated while the aqueous phase was extracted with 100 ml of n-butyl acetate. After two washings with 75 ml of 14% sodium chloride solution, the combined organic phases were concentrated at low pressure until an oil was obtained.

The oil was mixed with 200 ml of tetrahydrofuran and 100 ml of water, after which the prepared solution with a pH of 4.8 was adjusted to pH 1.5 by adding 12 ml of 6N HCl over 1 hour.

The solution was then allowed to stand for 1 hour at ordinary room temperature, after which the tetrahydrofuran was removed at low pressure at 40°C, 150 ml of n-butyl acetate was added to the remaining aqueous phase of 150 ml, after which 15 g of sodium chloride was added.

The organic phase was separated while the aqueous phase was extracted with 100 ml of n-butyl acetate.

The combined organic phases were concentrated under vacuum at

40°C to 120 ml.

The product was allowed to crystallize for 15 hours at 5°C. It was then filtered off, washed with 50 ml of n-butyl acetate and 50 ml of ethyl acetate.

It was then vacuum dried at 40°C.

The following was obtained: 25.2 g (66.9%) of the 1-ethoxycarbonyloxyethyl ester of 6-(D-(-)-α-amino-α-phenylacetamido)penicillinic acid hydrochloride with a melting point of 160-162°C.

Analytical determinations:

Titration: 97.82%

Rotation: +166.3° (c=1, EtOH95°)

pH: 4.05 (2% aqueous solution)

Moisture content: 0.82%

Remaining solvents: ethyl acetate 0.45; n-butyl acetate

0.98%

IR and NMR spectra are standard

Residual ampicillin: 0.06%.

Example 4

16.2 ml (0.15 mol) of methyl acetoacetate and 30.2 g (0.075 mol) of anroicil trihydrate were added to a suspension of 12.55 g (0.0907 mol) of 1 finely powdered anhydrous potassium carbonate in 100 ml of N,N-dimethylformamide.

The mixture was stirred at 22-23°C for 3 hours and then a significant fluidization of the mass was obtained.

17.8 g (0.117 mol) α-chlorodiethyl carbonate, 3 g (0.01 mol) tetrabutylammonium bromide and 50 ml N,N-dimethylformamide were then added.

The mixture was heated with stirring for 5 hours at 45 - 50°C and then left at +5° for 15 hours.

The reaction mixture was then poured into a mixture consisting of 600 ml of water and 200 ml of n-butyl acetate and stirred until a complete solution was obtained, after which the aqueous phase was collected and extracted with a further 50 ml of n-butyl acetate.

The combined organic phases were washed twice with 50 ml of water. 75 ml of II HCl and 185 ml of water were then added, after which the organic phase was stirred and left with stirring at 22-23°C for 24 hours.

The aqueous phase was collected and the organic phase was extracted with 50 ml of water. The combined organic phases were adjusted to pH 4 with 10% aqueous solution of Na-^CO^, after which bleached carbon was added and the whole was filtered.

150 ml of n-butyl acetate and 40 g of sodium chloride were then added to the aqueous filtrate.

The organic phase was separated, while the aqueous phase was extracted with 100 ml of n-butyl acetate.

The combined phases in butyl acetate were concentrated at low pressure at 40°C to a volume of approx. 150 ml.

The product was set aside for crystallization for 15 hours at +5°.

It was then filtered off, washed with 50 ml of n-butyl acetate and

50 ml ethyl acetate.

It was then dried under vacuum of 10 ml Hg in the presence of humidity at 25°C for 24 hours.

Yield: 20.8g (55%) of pure 1-ethoxycarbonyloxyethyl ester of 6-(D(-)-α-amino-α-phenylacetamido)penicillinic acid hydrochloride with a melting point of 159-161°C and characteristics which were according to an authentic sample.

Tests on the esterification of ampicillin salt with ethyl acetoacetate using the method described above.

Modifications:

Addition of chlorodiethyl carbonate was carried out in two phases:

First phase 9g immediately, 2nd phase a further 9g after 2 hours, the mixture was then set aside for 3 hours at 45°C.

Example 5

A mixture of 160 ml of acetone, 22.6 g (0.075 mol) of the potassium salt of D-(-)-N-methoxycarbonylpropen-2-y1-aminophenylacetic acid, 6.9 ml (0.088 mol) of ethyl chloroformate and 3 drops of N-methylmorpholine was stirred for 15 minutes at -20 to -30°C. To the reaction mixture was added a solution of 16.2 g of 6-amino<p>enicillic acid dissolved in 35 ml of water together with 7.6 g (0.075 mol) of triethylamine, after which the mixture was diluted with 90 ml of acetone and cooled to -20°C .

After stirring for 45 minutes without further cooling, 23.4 g (0.117 mol) of α-bromodiethyl carbonate, 3 g (0.01 mol) of tetrabutylammonium bromide and 250 ml of N,N-dimethylformamide were added. The mixture was stirred for 18 hours at 20°C. The reaction mixture was then poured into a mixture consisting of 600 ml of water and 200 ml of n-butyl acetate and stirred until a complete solution was obtained. The aqueous phase was collected and extracted with an additional 50 ml of n-butyl acetate.

The combined organic phases were washed twice with 50 ml

water. 180 ml of water was added to the organic phase, after which N HCl was added dropwise with stirring until a pH

of 1.9. The mixture was stirred at 22-23°C for 4 hours. The aqueous phase was separated while the organic phase was extracted with 50 ml of water. The combined aqueous phases were adjusted to pH4 with 10% aqueous solution of sodium carbonate, activated carbon was

then added and the whole filtered. 150 ml of n-butyl acetate and 40 g of sodium chloride were added to the aqueous filtrate.

The organic phase was separated while the aqueous phase was extracted with 100 ml of n-butyl acetate. The combined phases in butyl acetate were concentrated at low pressure at 40°C to a volume of approx. 150 ml. The product was set aside for crystallization for 15 hours at +5°.

The product was filtered off and washed with 25 ml of n-butyl acetate and 25 ml of ethyl acetate. It was then dried under vacuum with 10 mg of Hg at 25°C for 24 hours. Yield: 1.17g of the 1-ethoxycarbonyloxyethyl ester of 6-(D(-)-α-amino-α-phenylacetamidopenicillin acid hydrochloride with melting point 159-161°C and properties (NMR,TLC) which are in accordance with an authentic sample.

Example 5a

The procedure from example 5 was repeated with the difference that the 6-aminopenicillin acid was dissolved in 20 ml of water instead of 35 ml.

Yield: 1.05 g of the ethoxycarbonyloxyethyl ester of 6-(D(-)-α-amino-α-phenylacetamidopenicillinic acid hydrochloride as a white crystalline powder, mp 14 8-151°C with decomposition and properties (TLC,IR) that were consistent with an authentic sample.

Example 6

6.25g (0.045 mol) of finely ground, anhydrous potassium carbonate was suspended in 50 ml of dimethylsulfoxide and 8.1 ml (0.075 mol) of dimethyl acetoacetate and 15.lg (0.0375 mol) of ampicillin trihydrate were added.

The mixture was stirred for 5 hours at 20-25°C, and then 11.5 g (0.059 mol) of bromodiethyl carbonate and 25 ml of dimethyl sulphoxide were added.

The mixture was stirred for 17 hours at 35-37°C and then poured into one

<r>mixture consisting of 300 ml of water and 100 ml of n-butyl acetate.

The aqueous phase was separated and further extracted with

100 ml of n-butyl acetate.

The combined organic phases were washed twice with 25 ml of water.

92.5 ml of water and 7.0 ml of NHCl were added to a pH of 1.9, and the organic phase was then stirred for 2.5 hours at 22-23°C.

The aqueous phase was collected, while the organic phase was extracted with 25 ml of water.

The combined aqueous phases were adjusted to pH 4 with 10% aqueous solution of sodium carbonate and then activated carbon was added and filtered.

75 ml of n-butyl acetate and 37 g of sodium chloride were added to the aqueous filtrate.

The organic phase was separated while the aqueous phase was extracted with 50 ml of n-butyl acetate.

The combined phases in n-butyl acetate were concentrated at low pressure at 40°C to a volume of approx. 75 ml. The product was set aside for crystallization for 15 hours at +5°C.

It was then filtered, washed with 25 ml of n-butyl acetate and 25 ml of ethyl acetate. It was then vacuum dried at 40°C for 3 hours.

Yield: 1.9g (10%) of the 1-ethoxycarbonyloxyethyl ester of 6-(D (-)-ct-amino-α-phenylacetamido)penicillic acid with a melting point of 160-162°C and properties which were consistent with an authentic sample of the hydrochloride (eg IR:V 1790cm ^, 3-lactam carbonyl).

The new compound α-bromodiethyl carbonate according to the present invention, new processes for the preparation of this compound and its use in the preparation of the ethoxycarbonyloxyethyl esters of 6-aminopenicillin acid, penicillins such as penicillin G, penicillin V and ampicillin as well as cephalosporins, will now be described in more detail .

This aspect of the invention relates to improvements in the production of α-bromodiethyl carbonate with the following formula:

The ct-bromodiethyl carbonate of formula (III) can, according to another aspect of the invention which will be described in more detail below, be used in the synthesis of α-ethoxycarbonyloxyethyl esters of 6-aminopenicillin acid, penicillins and cephalosporins, e.g. the antibiotic bacampicillin. The α-bromodiethyl carbonate can thus be advantageously used in the production of ethoxycarbonyloxyethyl esters of 6-aminopenicillin, penicillin G, penicillin V and ampicillin.

The present invention thus provides two new methods, hereinafter referred to as method A and method B, for the production of α-bromodiethyl carbonate with formula III.

A. The first of these methods, method A, includes the following steps

a) one reacts an aldehyde with formula

with carbonyl bromide where an a-bromo-bromoformate with the following formula is obtained

and:

b) after which the a-bromo-bromoformate of formula VIII is reacted with an alcohol of formula C2H,--OH, which gives

desired α-bromodiethyl carbonate of formula III.

Method A in accordance with the present invention can therefore be indicated by means of the following reaction core:

The a-bromo-bromoformate of formula VIII is in itself a new compound, and as such forms part of the invention.

The reaction with the aldehyde, CH^CHO and carbonyl bromide can most suitably be carried out in the presence of a catalyst, and this can for example be a tertiary amine, such as a tertiary aliphatic amine, a tertiary mixed alkyl/aryl amine or a tertiary aromatic amine, a tertiary phosphine, amide, substituted urea or thiurea, phosphoric acid amide, tertiary axonium or sulfonium salt, or a quaternary ammonium or phosphonium salt. Preferred examples of catalysts for use in method A according to the present invention include pyridine, dimethylformamide, tetra-n-butylurea, hexamethylphosphoric triamide and benzyltrimethylammonium bromide.

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

The reaction between the aldehyde and the carbonyl bromide is conveniently carried out

in the presence of a solvent such as can be an aromatic hydrocarbon such as toluene or a halogenated hydrocarbon such as dichloromethane, carbon tetrachloride or chlorobenzene. The reaction can conveniently be carried out at temperatures between -40 and 120°C, preferably 40°C. One would normally use the carbonyl bromide in a

molar excess with respect to the aldehyde, preferably in the form of a molar excess of from 10-100%, preferably 20-50%.

The intermediate a-bromo-bromoformate of formula VTII prepared

in step a of method A in the present invention, does not need to be isolated before the reaction with the alcohol C2H^OH,

and it is usually preferred not to perform such isolation. In accordance with a preferred embodiment of the invention, one can thus use the reaction mixture from step a which is first released from an excess of carbonyl bromide, e.g. by heating under reduced pressure or purging with nitrogen.

The impure α-bromo-bromoformate-containing reaction mixture is reacted as an excess of the alcohol. The reaction can conveniently be carried out by heating the mixture by refluxing until the evolution of hydrogen bromide stops or by adding a tertiary base to the mixture and, if necessary, heating it. Any residual catalyst from step a or its complex with carbonyl bromide does not affect the subsequent reaction and appears to be beneficial in certain cases.

The resulting impure α-bromocarbonate can conveniently be isolated from the reaction mixture by fractional distillation under reduced pressure.

Method A is illustrated in Examples 7 and 8 which are shown by way of illustration only.

B. The second method, method B according to the present invention, for the production of α-bromodiethyl carbonate will now be described. Method B is exemplified in Example 9, which is given as an illustration.

Process B according to the present invention relates to the production of α-bromodiethyl carbonate with a modification of

The Finkelstein reaction, i.e. a reaction between an alkyl chloride or an arylalkyl chloride (or a compound containing such a group) with an alkali metal bromide or alkali metal iodide to replace the chlorine substituent with a bromine or iodine substituent respectively, or by reacting an alkyl bromide or arylalkyl bromide (or a compound containing such a group) with an alkali metal iodide to replace the bromo substituent with a bromo substituent.

The Finkelstein reaction is advantageous as the resulting iodides are generally less reactive than the bromides which in turn are more reactive than the chlorides. In certain cases, only catalytic amounts of the alkali metal bromide or iodide are required, and the resulting more reactive compounds can sow. is reacted with the desired substrate, so that a regeneration of the alkali metal bromide or iodide is obtained, so that the reaction continues.

Not all optionally substituted alkyl chlorides or arylalkyl chlorides will react, and more. in particular, it has been found difficult to carry out the reaction with α-chloroesters and α-chlorocarbonates, i.e. compounds where the chlorine atom is attached to a carbon atom, which is then attached to one of the ends of a group -C(0)- 0-. An example of such an α-chlorocarbonate is α-chlorodiethyl carbonate, which is a known intermediate for the production of ethoxycarbonyloxyethyl esters of 6-aminopenicillin acid and penicillins as described above.

It has also been found in accordance with the present invention that this problem can be avoided by carrying out the reaction in a two-phase solvent system, one phase of which is water while the other is a water-immiscible organic solvent, in the presence of a phase transfer catalyst.

Method B according to the present invention thus provides a method for producing α-bromodiethyl carbonate by reacting α-chlorodiethyl carbonate with an alkali metal bromide, and this method is characterized by the operation being carried out in a two-phase solvent system consisting of water and water-immiscible organic solvent in the presence of a phase transition catalyst.

Suitable water-immiscible organic solvents which can be used in this process include halogenated hydrocarbons, e.g. halogenated paraffins, such as dichloromethane, and aromatic hydrocarbons such as toluene. Suitable phase transfer catalysts include quaternary ammonium salts, e.g. tetraalkylammonium salts such as cetyltrimethylammonium bromide and tetra-n-butylammonium hydrogen sulfate. The alkali metal bromide can e.g. be sodium, potassium or lithium bromide and lithium bromide is preferred.

In method B according to the present invention, an α-chlorodiethyl carbonate with the following formula is thus formed:

reacted in a two-phase solvent system, one phase of which is water while the other is a water-immiscible organic solvent, with an alkali metal bromide of formula where R is an alkali metal such as Na, K and Li, whereby a compound with the formula is formed:

As mentioned above, the preferred alkali metal R is Li, so that LiBr is the preferred reagent of formula X.

In connection with method B, it has been found that lithium bromide can be advantageously used in a normal Finkelstein reaction

(that is, where a single-phase organic solvent system is used) e.g. to halogenate an α-chlorocarbonate. This method is exemplified in example 10. • The present invention also provides, in accordance with a further practice, a method for the production of α-bromodiethyl carbonate which includes reacting α-chlorodiethyl carbonate with lithium bromide.

Suitable solvents for such a process include lower aliphatic alcohols, lower aliphatic ketones, lower aliphatic ethers and lower aliphatic amides of formic acid.

The aspect of the invention which concerns the use of the new compound α-bromodiethyl carbonate in the production of ethoxycarbonyloxyethyl esters of 6-amino<p>enicillic acid, penicillins and cephalosporins will now be described.

One aspect of the invention includes the following features.

1. The use of α-bromodiethyl carbonate in the preparation of ethoxycarbonyloxyethyl esters of 6-aminopenicillinic acid, penicillins such as penicillin G, penicillin V and ampicillin as well as cephalosporins. 2. A method for the production of ethoxycarbonyloxyethyl esters of 6-aminopenicillin acid, penicillins and cephalosporins, characterized by reacting 6-amino<p>penicillin acid, penicillin or the cephalosporin or a salt thereof, with α-bromo-diethyl carbonate to thereby to obtain the ethoxycarbonyloxyethyl ester of 6-aminopenicillinic acid, the penicillin and the cephalosporin respectively. 3. An improved esterification reaction between an α-halodiethyl carbonate and 6-apa, a penicillin or a cephalosporin, which includes using a quaternary ammonium compound in the esterification step, and where said quaternary ammonium compound is present in an amount of from 1-25, preferably from 1-10% of the equimolar amount with respect to the amount of 6-apa, penicillin or cephalosporin.

The ethoxycarbonyloxyethyl ester, especially of 6-apa and of penicillin G, can be used in the preparation of any desired semi-synthetic penicillin ester by alkylating the 6-NH 2 group after removing the side chain, e.g. in the penicillin G ester produced.

This aspect of the invention relates to improvements in the production of esters by reacting salts of carboxylic acid with α-bromodiethyl carbonate.

The reaction between metal salts of carboxylic acid with alkyl halides or arylalkyl halides to produce esters is well known. However, the yield is not very high, and the reaction usually requires stressful conditions, such as high temperature and/or long reaction times. These conditions limit the commercial applicability of the reaction, and it cannot be commercially applied to heat-sensitive and labile compounds such as pyrethroids,<p>rostaglandins, peptides,<p>enicillins and cephalosporins.

British Patent No. 1443738 describes the use of a quaternary ammonium salt of penicillins and cephalosporins instead of a metal salt of said compounds, in the preparation of esters of penicillins and cephalosporins.

However, the preparation of the quaternary ammonium salt of the acid is time-consuming and expensive. However, it is also described in British patent no. 144 3738 that it is not necessary to first prepare the quaternary ammonium salt of a penicillin or a cephalosporin, but that the reaction can be carried out by reacting a metal salt of the carboxylic acid, that is 6 -apa, penicillin or cephalosporin, with the alkyl or arylalkyl halide in the presence of a quaternary ammonium salt different from the salt of the carboxylic acid.

It has now been found according to the present invention that it

it is not necessary to use such quaternary ammonium salt in a stoichiometric amount with respect to the carbinylic acid, i.e. 6-apa, the penicillin or the cephalosporin, but that less than a stoichiometric amount with respect to the carboxylic acid, i.e. 6-apa, is sufficient , penicillin or cephalosporin.

The present invention thus provides a method for the production of an ethoxycarbonyloxyethyl ester of 6-apa, penicillin or a cephalosporin, by reacting a metal salt of 6-apa, penicillin or cephalosporin with an α-halogendiethyl carbonate in the presence of a quaternary ammonium salt.. (different from a salt of said carboxylic acid) and wherein said quaternary ammonium compound is present in a less than stoichiometric amount with respect to said 6-apa, penicillin or cephalosporin.

In accordance with the present invention, between 1 and 25% of one equivalent of the quaternary ammonium salt for each equivalent of the metal salt of the carboxylic acid, more preferably between 1 and 10% of one equivalent of the quaternary α-ammonium salt.

The quaternary ammonium salt of the carboxylic acid is suitably prepared by reacting a metal salt of the carboxylic acid with a quaternary ammonium salt or an acid which is different from said carboxylic acid, typically a mineral acid, such as hydrochloric acid, hydrobromic acid or sulfuric acid.

Suitable metal salts of carboxylic acid for use in accordance with the present aspect of the invention (either as carboxylic acid quaternary ammonium salt precursors or as sulfur) are alkali metal or alkaline earth metal salts such

such as sodium, potassium, lithium, magnesium or calcium salts. Suitable quaternary ammonium salts of acids other than carboxylic acid (for use either as precursors of the quaternary ammonium salt of the carboxylic acid or as such) include e.g. tetraalkylammonium salts such as tetra-n-butylammonium bromide and cetyltrimethylammonium bromide and quaternary pyridinium salts such as cetylpyridinium bromide. Suitable halides include fluorides, chlorides, bromides and iodides, preferably activated fluorides or activated chlorides or bromides or iodides.

The esterification reaction in accordance with this aspect of the invention can be carried out in the presence or absence of a solvent. Suitable solvents include lower aliphatic alcohols, lower aliphatic ketones, lower aliphatic amides of formic acid and dimethylsulfoxide. Alternatively,

when no solvent is used, an excess of the ester-formed halide can be used, especially if this is liquid at the reaction temperature.

In the previously described aspect of the invention which concerns the use of α-bromodiethyl carbonate in the production of ethoxycarbonyl-1-oxyethyl esters of 6-apa, penicillins and cephalosporins, a catalyst can optionally be used. Approximately equivalent amounts of the quaternary ammonium salt of the carboxylic acid and the ester-forming halide can be used in the reaction. Preferably between 5 and 100% excess of the ester-forming halide is used for each equivalent of the salt of the carboxylic acid, and more preferably an excess of between 20 and 60% of the ester-forming halide.

The improvements in the present esterification process are particularly well suited for the production of esters of 6-apa, penicillins and cephalosporins, and in accordance with a preferred embodiment of the invention, the carboxylic acid has one of the following formulas:

or where R"'" is a hydrogen atom or alkyl group, preferably a substituted acetyl group, such as phenylacetyl; α-aminophenyl-acetyl; α-aminoparahydroxyphenylacetyl; phenoxyacety 1; ct-carboxyphenylacetyl or a-carboxy-3-thienylacetyl group, or when the carboxylic acid has formula XII, and a group with the following formula:

where R<3> is a hydrogen atom or an amino protecting group such as a benzyloxycarboxyl; trimethylsilyl or t-butyloxycarboxyl group; and

R 2 is a hydrogen atom; an alkyl group (e.g. a methyl group), a substituted alkyl group, e.g. a hydroxymethylene group, alkoxy or aryloxymethylene or acetoxymethylene group) or an acetoxy or substituted acetoxy group (e.g.

an alkylacetoxy, arylacetoxy or arylalkylacetoxy group or the group CgH5.CHOH.CO-).

In the preparation of esters of penicillins and cephalosporins according to the present invention, the subsequent halide can be an α-halogendialkylcarbonate with the following formula

where X is a chlorine, iodine or bromine atom, preferably a bromine atom.

In accordance with a preferred embodiment of the present invention for the preparation of esters of penicillins and cephalosporins, the quaternary ammonium salt used is tetra-n-butylammonium bromide.

The following examples illustrate the invention.

Example 7

A mixture of 44g of acetaldehyde 1 mol, 300 ml of carbon tetrachloride and 235g of freshly distilled carbonyl bromide (1.25 mol) was cooled to 0°C and was maintained at this temperature by means of external cooling, while in the course of 1 hour 11.9 g (0.15 mol) pyridine.

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

Evaporation of the reaction mixture under reduced pressure at 50°C gave a semi-solid oily mass which was quickly dissolved in 92g of ethanol (2 mol) under heating and refluxing. After refluxing for a further 2 hours, the excess was of ethanol removed in vacuo, and the residue treated with 100 ml of water and 200 ml of methylene dichloride.

Separation of the organic layer and fractional distillation

gave 130g of pure ethyl-a-bromo-ethyl pcarbonate (66% yield) with a boiling point of 90-92°C at 45 mm hg pressure, and the product was identical in all respects to an authentic sample.

Example 8

A mixture of 44 g 1 mol acetaldehyde, 300 ml dichloromethane and 17.9 g 0.1 mol hexamethylphosphoric triamide was cooled to -10°C and 207 g (1.1 mol) freshly distilled carbonyl bromine was added over 4 hours. while the temperature slowly rose to 10°C.

The mixture was then boiled under gentle reflux (approx. 40°C)

for 4 hours. During reflux, 69 g (1.5 mol) of ethanol were added to the mixture after 1 hour and reflux continued for a further 1 hour.

Fractional distillation of the resulting mixture gave

114g (58% yield) pure ethyl-a-bromomethyl-carbonate.

The identity of the produced ethyl1-a-bromomethyl1-carbonate was confirmed by analysis and an independent synthesis achieved the following method: 118g, 1.0 mol of diethyl carbonate was stirred and heated to between 110 and 120°C and illuminated with a 150W Tungsten lamp. 96g, 0.6 mol bromine was added dropwise over 3-4 hours and in such an amount that the mixture did not become more colored a pale orange.

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

Fractional distillation of the resulting mixture gave 84.2g 70% yield of authentic ethyl-a-bromo-ethylcarbonate with b.p.

at 87-88°C with 40 mm hg pressure.

Example 9

A mixture of 43 g (0.5 mol) lithium bromide, 15.3 g 0.1 mol ethyl-α-chloroethyl carbonate, 100 ml water, 100 ml dichloromethane and 1.5 g cetyltrimethylammonium bromide was stirred at room temperature for 24 hours. The aqueous layers were 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. After stirring for a further 24 hours while the temperature rose to 35°C, the organic layer was separated, dried and vacuum distilled, so that after repeated fractionation the new compound ethyl-a-bromo-ethyl carbonate was obtained in an amount of 15.Og (76% yield) with a boiling point of 90-92°C at 35 mm of mercury pressure.

The NMR spectrum had the following peaks:

Example 10

17.4g, 0.2 mol of lithium bromide was dissolved in 150 ml of dimethylformamide, and the mixture cooled at room temperature. 30.5g, 0.2

mol of ethyl-α-chloroethyl carbonate was added and the mixture was stirred at room temperature for 24 hours. The separated lithium chloride was filtered off, and the filtrate vacuum distilled and, after careful fractionation, gave ethyl 1-α-bromomethylcarbonate in a surface yield of 76% based on recovered ethyl 1-α-chloroethyl carbonate.

Example 11

The identity of the aforementioned new compound ethyl-a-bromo-ethylcarbonate was confirmed by an independent synthesis as follows: A mixture of 35g, 0.3 mol of diethyl carbonate in 50 ml of carbon tetrachloride and 0.lg of a-azo-isobutyronitrile (AIBN ) was heated to gentle boiling under reflux and 28.6g of 0.1 mol dibromodimethylhydantoin was added in smaller portions over 8 hours, while further portions of AIBN were added at the same time

(8 x 0.05g). Care was taken to ensure that free bromine did not accumulate in the reaction mixture. After the reaction was complete, the mixture was subjected to vacuum fractional distillation to give 32.3g, 82% yield of pure ethyl-a-bromomethylcarbonate which is identical in all respects to the products of Examples 9 and 10.

E xample 12 - Ben zylpenici Hine took sy carbony loks ve ty le ter

A mixture of 7.4g, 20mmol potassium penicillin G, 4.6g, 30mmol ethyl-α-chloroethylcarbonate, 0.8g, 2.5mmol tetra-n-butylammonium bromide and 80ml acetone was stirred and boiled gently until -back race for 4 hours. Excess acetone was removed under partial vacuum, and the residue treated in ice-cold water and methyl isobutyl ketone. Evaporation of the dried methyl isobutyl ketone under vacuum gave a semi-crystalline oil of 3.8g which, on treatment with ethanol, deposited 0.9g of white crystals of the α-ethoxycarbonyl-oxyethyl ester of penicillin G with a purity of 98-99% at

HPLC.

E xample 13 - Benzyinenici11inethoxycarbonyloxyethyl ester The experiment from example 12 was repeated by using

5.9g, 30mmol ethyl-a-bromo-ethylcarbonate instead of ethyl-a-chloro-ethylcarbonate, whereby after evaporation of the methyl isobutyl ketone 6.0g of a semi-crystalline oil was obtained. Treatment of

this with hot ethanol and cooling gave 2.5g, 35% yield of white crystals of a-(ethoxycarbonyloxy)ethyl esters of penicillin G.

Example 14 - Benzylpenicillin ethoxycarbonyloxyethyl ester 25.08g, 66.7mmol of potassium benzylpenicillinate, 0.5g, 6mmol of sodium bicarbonate and 2.15g (6.67mmol) of tetrabutylammonium bromide were carefully stirred in 41ml of methylene chloride and heated to 40°C. When this temperature was reached, 17.16 g of 86.7 mmol of α-bromomethyl carbonate were added and the suspension was stirred for 4 hours.

30 ml of water was added full of mineral acid to a pH of approx.

5. The mixture was stirred for approx. 4 hours and 4% sodium hydroxide solution was added to keep the pH between 2.5 and 3.0. 50 ml of methylene chloride was added and the mixture set aside for separation for a few minutes. The organic phase was taken out and washed with 65 ml of water and then evaporated under reduced pressure. The oily product obtained was dissolved in 100 ml of methylene chloride and evaporated again. The remaining oil was dissolved in methylene chloride to a total volume of 100 ml.

HPLC analysis of the methylene chloride solution showed a yield of the benzylpenicillin ethoxycarbonyloxyethyl ester of 96-97%.

Example 15 - Benzylpenicillinethoxycarbonyloxyethyl ester

5.02 g, 13.3 mmol of potassium benzene penicillinate and 2.99 g, 38.3 mmol of potassium bicarbonate in 13.5 mL of dimethyl sulfoxide were gently stirred in an ice bath. 3.7g of 18.6 mmol of α-bromodiethyl carbonate was carefully added over 30-40 minutes using a syringe pump. Stirring was continued while keeping the reaction mixture in an ice bath. High-pressure liquid chromatography analysis showed that the yield was approx. 70% of the benzylpenicillin ethoxycarbonyloxyethyl ester within 5-10 minutes.

Example 16 - Benzylpenicilline toxycarbonyloxyhydrogen ester 47.03g, 125 mmol of potassium benzylpenicillinate, 0.94g, 11 mmol of sodium bicarbonate and 201g, 6.25 mmol of tetrabutylammonium bromide were carefully stirred in 77 ml of acetone and heated at 40°C. When this temperature was reached, 26.06 g of 131 mmol of a-bromo-diethyl carbonate were added, and the suspension was stirred for \\ hour. 56 ml of water was added full of a mineral acid to a pH of approx. 5. The mixture was stirred for approx. 3 hours and a sodium hydroxide solution (4%) was added to keep the pH between 4.5 and 4.8. 100 ml of butyl acetate was then added, and the mixture set aside for separation for a few minutes. The organic phase was washed with 80 ml of water and then evaporated under reduced pressure. The remaining oily product was dissolved in methylene chloride to a total volume of 250 ml. High pressure liquid chromatography analysis of the methylene chloride<p>solution showed a yield of the benzylpenicillin ethoxycarbonyloxyethyl ester now 98-99%.'

Claims (1)

1. Process for the preparation of the 1-ethoxycarbonyloxyethyl ester of 6-(D-(-)-ct-amino-ct-phenylacetamido)penicillanic acid with the formula: characterized by the fact that one: <a) reacts ampicillin, preferably in the form of an alkali salt, with a reactive derivative of acetoacetic acid, thereby producing the corresponding enamine with the formula: where R is an alkyl group with 1-4 carbon atoms, a substituted or unsubstituted aryl group or an aralkyl group; R <2> is hydrogen, an alkyl group with 3.-4 carbon atoms, a substituted or unsubstituted O/W '- n '^ <»p^ or an aralkyl group; R<3> represents an alkyl group of 1-4 carbon atoms, a substituted or unsubstituted alkyl group, an aryl, alkyl group, an alkoxy group of 1-4 carbon atoms, an aryloxy group or an amine group, and X is an alkali metal, an alkaline earth metal or an organic base;b) reacting the resulting intermediate with ct-halodiethyl carbonate of the formula: where X is Cl or I, thereby to have it produced to corresponding to the ester with the formula: where R 1, R 2 and R 3 have the same meaning as stated above, c) carries out a weak hydrolysis in an acidic medium to thereby produce the compound of formula (I), l^^^^ j^ trr- ®^-^'' / ^ presence of a catalyst?) ; dU^ l- a <'■ s« $ ¥' 1^ 0, v-*-" 2. Method according to claim 1, characterized in that the esterification reaction of the enamine (II) is carried out by the reaction mixture being added to the α-halo-diethyl carbonate (V), and that the reaction is carried out at a temperature between 15 and 80°C, preferably between 45 and 55°C, for a period of from 1 to 24 hours, preferably from 5 to 10 hours. 3. Method according to claim 1, characterized in that the catalyst is selected from quaternary ammonium salts such as tetrabutylammonium bromide, alkali metal bromides, alkali metal iodides and cyclic ethers. 4. Method according to claims 1-3, characterized in that the catalyst is present in an amount of 0.05-0.10 mol, preferably 0.01-0.10 mol per moles of the compound of formula III and V, respectively. /