DK159821B - METHOD FOR PREPARING THE 1-AETOXY CARBONYLOXYA ETHYL ESTER OF 6- (D - (-) - ALFA-AMINO-ALFA-PHENYLACETAMIDO) -PENICILLANIC ACID - Google Patents

Description

DK 159821 B

The present invention relates to a particular process of the kind set forth in the preamble of claim 1 for the preparation of the 1-ethoxycarbonyloxyethyl ester of 6- (D - (-) - α-amino-α-phenylacetamido) -penicillanoic acid of formula I 5 y_CH-C0-NH-CH-C ^ S "(j: ^ lcH3

nh2 CO-N- CH-COO-CH-O-COOC-Hc I

CH3 10

The compound of formula I is an ampicillin ester which is highly significant from a therapeutic point of view because it is well absorbed by oral administration and produces far higher blood concentrations of ampicillin than the compound ampicillin itself. This ester is isolated in the form of a hydrochloride and is known by the name bacampicillin hydrochloride.

Based on known methods (see, for example, Belgian Patent No. 772723), bacampicillin hydrochloride can be synthesized by the following two methods: A) in the presence of sodium bicarbonate. The obtained 1-ethoxycarbonyloxyethyl ester of benzylpenicillin is subjected to a reaction to remove the phenylacetic acid chain via the iminochloride imino ether to obtain the 1-ethoxycarbonyloxyethyl ester of 6-aminopenicillanic acid which is isolated as the hydrochloride.

Subsequent condensation of the latter intermediate with D - (-) - α-phenylglycine gives the compound of formula 30 I.

B) Esterification reaction of 6- (D - (-) - α-azido-α-phenylacetamido) -penicillanic acid with α-chloro diethyl carbonate in a polar solvent.

Then, the compound of formula I is obtained by catalytic hydrogenation of the 1-ethoxycarbonyloxyethyl ester of 6- (D - (-) - α-azido-α-phenylacetamido) -penicillanic acid.

As can be seen, these methods are quite complex since they involve the use of numerous raw materials and long 2

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process times.

It is an object of the present invention to provide a process for the preparation of the present active ingredient, a process which is easier to perform and industrially more advantageous, more particularly a process for the preparation of bacampicillin from an enamine of ampicillin, which involves considerable simplifying the process and enabling a high degree of purity of the desired product to be obtained.

The process according to the invention is characterized by the characterizing part of claim 1, since it has surprisingly been found that α-bromo diethyl carbonate can be used with great advantage as a reactant in the esterification process because a-bromo-diethyl carbonate leads to particularly high yield and high purity of 15. the end product bacampicillin.

The esterification reaction between Compounds II and III can be carried out in the presence of an esterification catalyst, adding a catalyst at this stage substantially shortens the reaction time and yields higher yields of the product with higher purity than usual.

The following substances can be used as catalysts: quaternary ammonium salts, bromides or iodides of alkali metals and cyclic ethers; According to the invention, it is preferred to use tetrabutylammonium bromide.

The catalyst can be used in an amount ranging from 0.005-0.10 moles per mole of Compound III to amounts equimolar with Compound III. In a preferred embodiment, tetrabutylammonium bromide is used in an amount of from 0.01 to 0.10 moles per mole of compound III.

Particular examples of the groups R, R and R are: alkyl: CHg, CH2, n_C3H7 / i_C3H7 'n "' C4H9 * alkoxy (RS only): OCH3, OC2, OCH2CH2CH3, OCH (CH3) 2, 0 (CH2) 3CH3 ·

The radical X is selected from those well known in the art, for example, alkali metals such as sodium and potassium, and alkaline earth metals such as calcium and magnesium, as well as organic bases of the species well known in the synthesis of penicillins, e.g.

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In the preferred embodiment of the process according to the invention, the group protecting the amino group of the ampicillin is a 1-methoxycarbonylpropen-2-yl group or a 1-ethoxycarbonylpropen-2-yl group, the preferred intermediate being the sodium or potassium salt of N- (1-methoxycarbonylpropen-2-yl) -penicillanic acid and N- (1-ethoxycarbonylpropen-2-yl) -penicillanic acid of formula 12, respectively (R = methyl; R = methyl; R = methoxy or ethoxy and X = sodium or potassium).

The intermediate IV is stable in neutral or alkaline medium, while in acidic medium it is possible to remove the amino protecting group simply, quickly and selectively.

The group protecting the amino group of the ampicillin can be selected, for example, from the groups mentioned in British Patent Specification No. 991586 and from other groups known in the art.

α-Bromo diethyl carbonate, compound III which is a novel compound, can be prepared by reacting the corresponding α-chloro diethyl carbonate with sodium bromide as 20 clet exemplified in Example 1 hereinafter.

According to a preferred embodiment of the process of the invention, the following steps comprise: 1) Conversion of ampicillin trihydrate in a polar solvent, e.g., Ν, Ν-dimethylformamide, to a salt thereof, e.g., the potassium salt, and then forming the corresponding enamine II by reaction with a derivative of acetoacetic acid, for example methyl acetoacetate.

2) Addition of an esterification catalyst, preferably tetrabutylammonium bromide.

3) Adding α-bromo diethyl carbonate to the reaction mixture to form the 1-ethoxycarbonyloxyethyl ester of am-picillin in the form of the one amine IV.

4) Hydrolysis of the protecting group with HCl diluted in an organic solvent, eg n-butyl acetate / water.

5) Extraction of bacampicillin hydrochloride by aqueous phase saturation, for example with sodium chloride and extraction with a suitable solvent such as n-butyl acetate.

6) Concentrating the low pressure solution in n-butyl acetate to crystallize the high purity product, 4

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whereupon the product is isolated by filtration.

Among the main advantages of the process according to the invention, the most important is that in this process it is possible to recover bacampicillin hydrochloride practically in one operation and with a high degree of purity.

In fact, the impurities present in the product obtained by the process according to the invention are negligible in comparison with known processes according to the prior art.

Another important advantage is that ampicillin trihydrate is used as a starting material, which compound is a known antibiotic which can easily be obtained in pure form at low cost.

The enamine II can be readily prepared, for example, as described in British Patent No. 991586 in a yield of over 95% by reaction of ampicillin trihydrate with methyl or ethyl acetoacetate in 10-50% more than the stoichiometric ratio and in the presence of a organic base or an alkali metal carbonate, e.g., potassium carbonate.

The Enamine II can be isolated and added to the esterification reaction in solid form. Alternatively, without the isolation of intermediate II, the esterification reaction can be carried out in the same solvent as that in which the reaction to form the enamine II took place.

The reaction to form the ampicillin enamine II according to the invention can be carried out in an aprotic polar solvent, for example Ν, Ν-dimethylformamide, dimethoxyethane, dimethylsulfoxide, tetrahydrofuran, dioxane or preferably Ν, dim-dimethylacetamide.

In order to complete the reaction, it is sufficient to keep the components of the mixture in contact at a temperature between 0 ° C and 60 ° C, preferably between 20 ° C and 30 ° C, for 2-8 hours, preferably 3 hours.

The esterification reaction after adding the α-bromo diethyl carbonate to the mixture takes place at a temperature between 15 ° C and 80 ° C for a period of 1-24 hours, according to the invention preferably at 25-42 ° C for 10-18 hours.

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The esterification reaction is conveniently carried out in an organic solvent such as methylene chloride or acetone, dimethylacetamide, dimethylformamide or dimethylsulfoxide, or in a mixture of organic solvents. It is also possible to use an organic solvent containing water.

Under the lightest and most convenient conditions for industrial purposes, the esterified enamine IV is isolated by diluting the reaction mixture with water and subsequent extraction with a suitable solvent which is immiscible with water, e.g. n-butyl acetate.

According to the invention, the acetate phase can conveniently be stirred with a thin solution (0.2-0.3N) of HCl until the protecting group is completely hydrolyzed. This requires a contact time of 2-8 hours, preferably 4-5 hours, at normal temperatures.

By the addition of sodium chloride, the compound I separates from the aqueous phase in the form of the hydrochloride, which is extracted with a suitable solvent such as n-butyl acetate.

By concentrating the organic phase at low pressure 20 at a temperature of 40 ° C until a small volume is present, crystallization of the product of formula I takes place.

The crystalline product is isolated by filtration, washing and vacuum drying.

The following examples serve to illustrate the invention.

Example A

g-Bromo diethyl carbonate (starting material) 30 acetone

NaBr + Cl- <j: H-OCOOC2H5-> Br-CjH-OCOOC ^ Hg + NaCl ch3 ch3 102.9 g of sodium bromide dissolved in 600 ml of acetone was reacted for 2-3 hours at room temperature (20-25 ° C) with 152.6 g of o-chloro-diethyl carbonate dissolved in 100 ml of acetone. Then the mixture was concentrated in vacuo at low temperature, at most 35 ° C until a semi-solid mass was obtained. Then it was distributed

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G

the reaction mixture between H 2 O and ethyl ether. The aqueous phase was separated and then extracted with 2 x 400 ml ethyl ether.

The combined organic phases containing the o-bromo diethyl carbonate were washed with first 800 ml H 2 O, then with 1000 ml 1% s aqueous sodium metabisulphate solution and then 1000 ml saturated solution of NaCl.

The organic phase was dried over magnesium sulfate and then concentrated in vacuo at low temperature, at most 35 ° C, to give the title product 10 (60%) in the form of a liquid that was initially colorless or slightly yellowish brown.

This product was used directly in the esterification step of Example 1 below.

Example 1 25.08 g (0.18 µM) of finely ground anhydrous potassium carbonate was suspended in 200 ml of Ν, Ν-dimethylacetamide and 32.4 ml (0.3M) of methyl acetoacetate and 60.4 g (0.15M) of ampicillin-20 were added. trihydrate.

The mixture was kept under rapid stirring for 5 hours at 20-25 ° C to which was added 46.1 g (0.234 mole) of bromo diethyl carbonate, 6 g (0.02 mole) of tetrabutylammonium bromide and 100 ml of Ν, Ν-dimethylacetamide.

The mixture is heated under stirring for 10 hours to 40-42 ° C; the reaction mass is poured into a mixture of 1200 ml of water and 400 ml of n-butyl acetate.

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

The combined organic phases were washed with 2 x 100 ml water. 150 ml of N HCl and 370 ml of water were added to the organic phase, which was then stirred and allowed to stir at 22-23 ° C for 4 hours.

The aqueous phase was collected and the organic phase was extracted with 100 ml of water. The reunited aqueous phases were brought to pH 4 with 10% aqueous Na 2 O 3 solution, then bleached and filtered.

300 ml of n-butyl acetate and 80 g of sodium chloride 7 were added

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to the aqueous filtrate.

The organic phase was separated and the aqueous phase extracted with 200 ml of n-butyl acetate.

The reunited phases in n-butyl acetate were concentrated 5 at low pressure and 40 ° C to a volume of ca. 300 ml. The product was allowed to crystallize for 15 hours at + 5 ° C.

It was then filtered, washed with 100 ml of n-butyl acetate and 100 ml of ethyl acetate and vacuum dried at 40 ° C for 24 hours.

Yield 54.2 g (72%) of the 1-ethoxycarbonyloxyethyl ester of 6- (D - (-) - α-amino-α-phenylacetamido) -penicillanic acid, m.p. 160-162 ° C. The values for (d) and other characteristics were consistent with the authentic hydrochloride sample.

Claims (6)

8 DK 159821 B A process for the preparation of the 1-ethoxycarbonyloxy-5 ethyl ester of 6- (D - (-) - α-amino-α-phenylacetamido) -penicillanic acid of the formula CEL r-η ς 3 / V-ch -CH-CH ^ C> ^ CH_ I \ = J l III 3 NH0 CO -N CH-COO-CH-O-COOC ^ Ht- in I 2. S 1. ch3 by reaction of ampicillin, preferably in the form of a alkali salt, with a reactive derivative of acetoacetic acid to give the corresponding enamine of the formula CH3 <^ L-CH-CO-NH- (j: H-CH ^ SNpCcH3 ^ | CO-N-CH-COOX 'tr' '? K-20 | 3 R 1 2 3 2 2 where R is an alkyl group with 1-4 carbon atoms, R is hydrogen or an alkyl group of 1-4 carbon atoms, R is an alkyl group of 1-4 carbon atoms, an alkoxy group of 1-4 carbon atoms or an amino group and X is an alkali metal, an alkaline earth metal or organic base, characterized by reacting the resulting intermediate of formula II with α-bromo diethyl carbonate of formula 30 Br-CH-O-COOC..EL III I CH3 in the presence of a catalyst to form the corresponding ester of formula CH3 9 DK 159821 B // V-CH-CO-NH-CH-CH''S "C <- ~ CH, \ -JIIII 3 Wherein R, R and R have the above meanings and then perform mild hydrolysis in an acidic medium to form the compound of formula I. Process according to claim 1, characterized in that the alkali salt of ampicillin is formed by conversion of ampicillin trihydrate in a manner known per se in a polar solvent, preferably N, N-dimethylformamide. Process according to claim 1, characterized in that the formation of the enamine II is carried out by reacting the alkaline salt of ampicillin with an alkyl acetoacetate, preferably methyl or ethyl acetoacetate in an amount of 10-50% more than the stoichiometric calculated, in an aprotic polar solvent at a temperature between 0 ° C and 60 ° C and over a period of between 2 and 8 hours, and preferably in the presence of an organic base or an alkali carbonate. Process according to claim 1, characterized in that the esterification reaction of the enamine II is carried out by adding to the reaction mixture of α-bromo diethyl carbonate, the reaction being carried out at a temperature of 25-42 ° C and over a period of 10-18 hours. Process according to claim 1, characterized in that the esterification is carried out in the presence of tetr ^ butylammonium bromide as catalyst. Process according to claim 1, characterized in that the hydrolysis is carried out with associated hydrochloric acid after isolation of the ester IV. 2