DK167807B1 - METHOD FOR PREPARING THE 1-ETHOXYCARBONYLOXYETHYL ESTER OF 6- (D - (-) - ALFA-AMINO-ALFA-PHENYLACETAMIDO) -PENICILLANIC ACID - Google Patents

Description

5 in DK 167807 B1

The present invention relates to a particular process for the preparation of the 1-ethoxycarbonyloxyethyl ester of 6- (D - (-) - α-amino-α-phenylacetamido) -penicillanic acid of formula I

CH0 y 3 / ~ Y_CH-CO-NH-CH-C ^ S ^ - CH3 ^ nh2 co-n— ch-coo-ch-o-cooc2h5 ch3

The compound of formula I is an ampicillin nester which is highly significant from a therapeutic point of view because it is well absorbed by oral administration and provides much 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 bacampi ci11 in n-hydrochlori d.

Based on previously known methods (see, for example, BE Patent No. 772723), bacampicillin hydrochloride can be synthesized by the following two methods: A) Reaction of potassium benzylpenicillin with an α-chlorodiethyl carbonate in an organic solution or in an organic solution. aqueous solution of 70% dioxane 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 isolated as the hydrochloride.

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

B) Esterification reaction of 6- (D - (-) - α-azido-α-phenylacetamido) -35 penicillanic acid with α-chlorodiethyl 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-phenylacetamidoj-penicillanic acid.

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

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SUMMARY OF THE INVENTION It is an object of the present invention to prepare the present active substance by a process which is easier to carry out and industrially more advantageous. In particular, there is provided a process for preparing bacampicillin using 10 ampicillin as a starting material, which involves significantly simplifying the process and enabling a high degree of purity of the desired product to be obtained.

Said preparation of the 1-ethoxycarbonyloxyethyl esters of 6- (D - (-) - 15 α-amino-α-phenylacetamido) -penicillanic acid of the formula CH

V-CH-CO-NH-CH-Cl 2 N 2 - CH 3 I

NH3 CO-n CH-C00-CH-O-C00C2H5 L3 is characterized by the following steps: a) ampicillin is reacted, preferably in the form of an alkali salt thereof, with a reactive derivative of acetacetic acid to give the corresponding enamine of the formula: 30. CH3

“CO-il-CH-COOX

II

R2-M

R 3 wherein R 1 represents an alkyl group of 1-4 carbon atoms, B 1 R represents a hydrogen atom or an alkyl group of 1-4 carbon atoms, 3 R represents an alkyl group of 1-4 carbon atoms, an alkoxy group of 5 to 1 carbon atoms. 4 represents carbon atoms or an amino group and X represents an alkali metal, an alkaline earth metal or an organic base, b) reacting the resulting intermediate with α-chlorodiethyl carbonate of the formula: ci-ch-o-cooc2h5 in the presence of CH3 a catalyst to form the corresponding ester of the formula: ch3 20 / - - CH-CO-NH-CH-CH'-S'X - CH-j I co-n-ch-coo-ch-o-cooc2h5

R1-C2 NnH CH-IV

R 2 - <LC * 0 R 3 or 3 wherein R, R and R have the meanings given above, and c) hydrolysis in an acidic medium to form the compound of formula I.

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Addition of a catalyst in step b) substantially shortens the reaction times and yields higher yields of the higher purity product.

For this purpose, the following substances can be used as catalysts: quaternary ammonium salts such as e.g. tetrabutylammonium bromide, bromides or iodides of alkali metals and cyclic ethers.

The catalyst can be used in an amount ranging from 0.005-0.10. moles 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 mol per liter. mol of compound III.

Particular examples of groups R, R and R are:

Alkyl: CH3, C2H5, n-C3H7, i-C3H7, n-C4H9.

10 Alkoxy (R3 only): 0CH3, 0C2H5, 0CH2CH2CH3, 0CH (CH3) 2, 0 (CH2) 3CH3.

The radical X is preferably selected from all known potassium metals such as sodium and potassium, and terrestrial potassium metals, such as calcium and magnesium, as well as organic bases of the species well known for use in the synthesis of penicillins, e.g. tertiary ammonium groups, triethylamine, ethyl piperidine and methyl morpholine.

In the preferred embodiment of the process according to the invention, the group protecting the amino group of the amino is a 1-methoxycarbonylpropen-2-yl group or a 1-ethoxycarbonylprop-2-yl group, the the preferred intermediate is the sodium or potassium salt of N- (1-methoxycarbonyl-propen-2-yl) -penic acid and N- (1-ethoxycarbonylpropen-2-yl) -penicillanic acid of formula II (R1 = methyl, respectively). R 2 = methyl; R 3 = 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 group protecting the 5 ° amino group in a simple manner, quickly and selectively. ·

The group protecting the amino group of the ampicillin may be selected e.g. among the groups mentioned in 6B Patent No. 991586 and among other groups known in the art in this type of technique.

The hydrolysis of the protecting group can take place with HCl diluted in an organic solvent, e.g. n-butyl acetate / water.

5 DK 167807 B1

Extraction of bacampicillin hydrochloride can occur by aqueous phase saturation, e.g. with sodium chloride, and extraction with a suitable solvent such as n-butyl acetate.

Concentration of the solution can take place at low pressure in n-butyl acetate to crystallize the product of high purity and 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 in practically one operation and with a high degree of purity.

In fact, the impurities present in the product obtained by the process 1® according to the invention are negligible in comparison with known processes according to the prior art.

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

The intermediate II can be readily prepared, e.g. as described in GB Patent No. 991586, in a yield of over 95% by reaction of ampicillin trihydrate with methyl or ethyl acetate in an amount 25-1050% greater than the stoichiometric amount and in the presence of a organic base or an alkali metal carbonate, e.g.

potassium carbonate.

The intermediate II can be isolated and added to the esterification reaction 30 in solid form. Also, 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 is carried out in a 33 aprot polar solvent, e.g. Ν, Ν-dimethylacetamide, N, N-dimethylformamide, dimethoxyethane, dimethyl sulfoxide, tetrahydrofuran or dioxane.

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.

Compound II can be prepared via acylation of 6-aminopenicillanic acid with a corresponding enamine derivative of phenylglycine to form compound II, which can then be directly esterified and converted to bacampicillin under isolation of compound II.

The esterification reaction after adding the α-chlorodiethyl carbonate to said mixture takes place at a temperature between 15 ° C and 80 ° C, preferably between 45 ° C and 55 ° C, for a period of 1-24 hours, preferably 5-10 hours.

The esterification reaction is conveniently carried out in an organic solvent such as methylene chloride or acetone, dimethylacetamide, dimethyl formamide or dimethylsulfoxide, or in a mixture of organic solvents. It is also possible to use an organic solvent containing water. The use of an esterification catalyst is particularly necessary when using acetone as a solvent in the esterification reaction.

Under the lightest and most convenient conditions for industrial applications, 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.

The acetate phase is stirred with a thin solution (0.2-0.3 N) of HCl until the protecting group is completely hydrolyzed, requiring a contact time of 2-8 hours, preferably 4-5 hours, at ordinary temperatures.

By adding sodium chloride, the compound separates itself from the aqueous phase in the form of the hydrochloride, which is extracted with a suitable solvent, e.g. n-butyl acetate.

Crystallization of the product of formula I takes place by concentrating the organic phase at low pressure at a temperature of 40 ° C until a small volume remains.

7 DK 167807 B1

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

The following examples illustrate the described aspects of the invention.

Example 1 36.4 g (0.075 mole) of Potassium N- (1-methoxycarbonylpropen-2-yl) -6- [D - (-) - α-amino-ar-phenylacetamido] penicillinate are added to a solution of 17, 8 g (0.116 mol) of α-chlorodiethyl carbonate and 3 g (0.01 mol) of tetrabutylammonium bromide in 150 ml of N, N-di methyl formamide. With stirring, the temperature is raised to 45 ° C and kept at 45-50 ° C for 5 hours.

When the heating is complete, the reaction mixture is poured into a mixture of 300 ml of 14% aqueous sodium chloride solution and 600 ml of n-butyl acetate. The mixture is stirred for 10 minutes, then the organic phase is separated and the aqueous phase is extracted with 100 ml of n-butyl acetate. The combined organic phases are concentrated after washing twice with 75 ml of 14% aqueous sodium chloride solution at low pressure until an oil is obtained.

The oil is mixed with 200 ml of tetrahydrofuran and 100 ml of water; the resulting solution (pH 4.8) is stirred to pH 1.5 by the addition of a total of 12 ml of 6N HCl over 1 hour.

After standing for an additional hour at ambient temperature, remove the tetrahydrofuran at low pressure and 40 ° C, add 150 ml of n-butyl acetate to the remaining aqueous phase (150 ml) and then add 15 g of sodium chloride.

The organic phase is separated and the aqueous phase is extracted with 100 ml of n-butyl acetate. 1

The combined organic phases are concentrated under vacuum at 40 ° C to a volume of 120 ml. The product is then allowed to crystallize for 15 hours at 5 ° C. Then filter and wash with 50 ml of n-butyl acetate and 50 ml of ethyl acetate. Finally, vacuum-dry at 40 ° C.

8 DK 167807 B1

25.2 g (66.9%) of 1-ethoxycarbonyloxyethyl ester of 6- (D - (-) - α-amino-α-phenylacetamido) -penicillanic acid hydrochloride are obtained by snip. 160-162 ° C.

5 Analytical provisions:

Titer: 97.82%

Optical rotatability: + 166.3 * (c = 1 in ethanol 95 °). pH: 4.05 (in 2% aqueous solution).

Moisture content: 0.82%.

Residual solvents: ethyl acetate 0.45% and n-butyl acetate 0.98%.

IR and NMR spectra are the standard for the compound.

Remaining amount of ampicillin: 0.06%.

Example 2 16.2 ml (0.15 mole) of methyl acetate acetate and 30.2 g (0.075 mole) of ampicillin trihydrate are added to a suspension of 12.54 g (0.0907 mole) of finely pulverized aqueous potassium carbonate in 100 ml. Ν, Ν-dimethylformamide.

The mixture is kept under stirring at 22-23 ° C for 3 hours, after which complete fluidization of the mixture can be observed.

17.8 g (0.117 mole) of α-chlorodiethyl carbonate, 3 g (0.01 mole) of tetrabutylammonium bromide and 50 ml of Ν, dim-dimethylformamide are added in that order.

The mixture is heated under stirring for 5 hours to 45-50 ° C and then left at + 5 ° C for 15 hours.

The reaction mass is poured into a mixture of 600 ml of water and 200 ml of n-butyl acetate and stirred until complete solution is obtained, whereupon the aqueous phase is collected and extracted with an additional 50 ml of n-butyl acetate.

The combined organic phases are washed with 2 x 50 ml of water. 75 ml of N HCl and 185 ml of water are added to the organic phase, which is subjected to stirring, and then it is allowed to stir at 22-23 ° C for 4 9 DK 167807 B1 hours.

Then the aqueous phase is collected and the organic phase is extracted with 50 ml of water. The combined aqueous phases are brought to pH 4 with a 10% 5 aqueous solution of 2 CO 2, then bleached and filtered.

150 ml of n-butyl acetate and 40 g of sodium chloride are added to the aqueous filtrate and the organic phase is separated and the aqueous phase is extracted with 100 ml of n-butyl acetate.

The combined phases in butyl acetate are concentrated at low pressure and 40 ° C to a volume of approx. 150 ml, whereupon the product is allowed to crystallize for 15 hours at + 5 ° C.

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The product is filtered, washed with 50 ml of n-butyl acetate and 50 ml of ethyl acetate. Dry under a vacuum of 10 mm Hg in the presence of humidity at 25 ° C for 24 hours.

Yield 20.8 g (55%) of the 1-ethoxycarbonyloxyethyl ester of 6- (D - (-) - α-amino-no-ct-phenylacetamido) -peni-cyanic acid hydrochloride, m.p.

159-161 ° C and physical grades according to an authentic sample of the compound.

By reaction of the amino group in ampicillin with ethyl acetate (thereby forming a "Danes salt"), but otherwise as described in Example 2 above, the following results were obtained: 16.1 g White crystalline product, m.p. 144-148 ° C (Tottoli apparatus). IR and TLC were consistent with an authentic sample of the compound. Water content (Karl Fischer) 0.35%; pH 3.55 in 2% aqueous solution; titer 95.2%; residual solvents total 3.5%.

In one modification, the chlorodiethyl carbonate was added in two phases; in the first phase 9 g were immediately added and in the second phase an additional 9 g after 2 hours; heating was then made for 3 hours to 45 ° C. The following results were obtained:

Yield 13.7 g of crystalline beige product with m.p. 143-146 ° C

10 υκ ie / su / tn (Tottoli apparatus). IR and TLC were consistent with an authentic sample of the compound. Water content 0.2% (Karl Fischer); pH 3.43 in 2% aqueous solution; titer 94.8% in residual solvents total 2.6%.

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Claims (4)

A process for the preparation of the 1-ethoxycarbonyloxyethyl ester of 6- (D - (-) - α-aminO “-phenylacetamido) -penicillanic acid of the formula CH3 / -V-CH-CO-NH-CH-CIJ ^ j “NH? CO-N CH-C00-CH-O-C00CoHc 2, 25 io ch3 by reaction of ampicillin, preferably in the form of an alkali salt, with a reactive derivative of acetic acetic acid to give the corresponding enamine of the formula: ch 3 -NH-CH-CH 2 S's '- ~ - CH 3' CO-1-CH-COOX 20 R-fN 11 13 RJ 25 wherein R * represents an alkyl group of 1-4 carbon atoms, 2 R represents hydrogen or an alkyl group of 1-4 carbon atoms, 3 R represents an alkyl group of 1-4 carbon atoms, an alkoxy group of 1-4 carbon, or an amino group, and X represents an alkali metal, an alkaline earth metal or an organic base, characterized in that the intermediate of formula II formed is reacted with α-chlorodiethyl carbonate of the formula: DK-167807 B1 12 C1-CH-0-C00C2H5 III CH3 5. The presence of a catalyst to form the corresponding ester of the formula: CH3 / - \ CH-CO-NH-CH-CH 10. II 1 IJ '-' CO-N-CH ** C00-CH-O-COOC_Hc R1-C ^ Si Ah, IV R2-C, ci I3 15 12 3 wherein R, R and R have the meanings given above , in a manner known per se, 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 obtained by conversion of ampicillin trihydrate in a known manner in a polar solvent, preferably in Ν, Ν-dimethylformamide. 2® Process according to claim 1, characterized in that the formation of the enamine of formula II is carried out by reacting the alkali salt of ampicillin with an alkyl acetate, preferably methyl or ethyl acetate in an amount which is preferably 10-50% greater than the stoichiometric amount. in an aprotic, polar solvent at a temperature between 0 and 60 ° C for 2-8 hours, preferably in the presence of an organic base or an alkali carbonate. Process according to claim 1, characterized in that a quaternary ammonium salt, an al potassium metal bromide or iodide or a cyclic ether, preferably tetrabutyl ammonium bromide, is used as the catalyst. Process according to claim 1, characterized in that the hydrolysis is carried out using dilute hydrochloric acid after separation of the ester of formula IV. 10 15 20 25 30 35