CS251087B2 - Method of 6-(d-/-/alpha-amino-alpha-phenylacetamido)penicillic acid's ethoxycarbonyloxyethylester production - Google Patents

Abstract

The present invention relates to a new method of manufacture 1-ethoxycarbonyloxyethyl ester 6- [D- (-) - N -amino-α-phenylacetamido-penicillanic acid of Formula I

Description

This invention relates to a novel process for preparing 1-ethoxycarbonyloxyethyl kyseli2 NY 6- [D- (-) - «- amino-phenylacetamido penicillanic af formula I OCH CO-NW-COCH Cp-COO-CH ~ O H COOC _{of £}

CH (I)

The compound of formula I is an ampicillin ester which is extremely important from a therapeutic point of view since it is well absorbed 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 give 6-β-minopeniciphilaic acid 1-ethoxycarbonyloxyethyl ester which is isolated as the hydrochloride.

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

Β)

6- [D- (-) -. Alpha.-azido-.alpha.-phenylacetamide] -penicillanic acid is esterified with alpha-chlorodiethyl carbonate in a polar solvent.

Subsequent catalytic hydrogenation of 6- [D - (-) -. Alpha.-azido-.alpha.-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.

A first 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. A specific object of the present invention is to provide a process for the preparation of bacampicillin using ampicillin as a starting material, thereby greatly simplifying said process and obtaining the desired product with a high degree of purity.

The first object of the present invention, namely the preparation of 6- [D- (-) -. Alpha.-amino-.alpha.-phenylacetamide] -penicillanic acid 1-ethoxycarbonyloxyethyl ester according to the invention, is achieved by

a) reacting ampicillin, preferably in the form of an alkali salt, with a reactive acetoacetic acid derivative to form the corresponding enamine of formula II

r

- CH — C («I

CO-N CH-COOX (H) where

R ¹ represents a C 1 -C 4 alkyl group, an optionally substituted aryl or aralkyl group,

R ² represents hydrogen, alkyl with 1 to 4 carbon atoms, optionally substituted aryl or aralkyl group,

R ³ is C 1 -C 4 alkyl, optionally substituted aryl or aralkyl, C 1 -C 4 alkoxy, aryloxy or amino, and

X is an alkali metal, alkaline earth metal or organic base residue, in an aprotic polar solvent at 0 to 60 ° C for 2 to 8 hours, in the presence of an organic base or an alkali metal carbonate, the resulting intermediate is reacted with α-halodiethyl carbonate of formula III

From —CH — O — COOC2H5

CH3 (IIIJ where

Z is chlorine or iodine, in the presence of 0.005 to 0.10 molar, preferably 0.01 to 0.10 molar, catalyst selected from the group consisting of quaternary ammonium salts, alkali metal bromides, alkali metal iodides, and cyclic ethers based on 1; molar part of compound III to form the corresponding ester of formula IV // \ ^ CH-CO-NH-CH-WIII And ^what ^ / Γ "• Sx | \ CH ₃

CH-CQO-CH-O-CQOC _o Ht;

CH - (iv) wherein

R ^1, R ² and R ³ are as defined above, and the obtained compound is hydrolyzed under mild acidic conditions to a compound of formula I.

The addition of the catalyst in step b) greatly shortens the reaction time and provides a higher yield of product with a higher degree of purity.

The catalyst may be used in an amount that varies from 0.005 to 0.10 parts by molar to 1 part by molar of the compound of formula III to an amount equal to the compound of formula III. In a preferred embodiment, tetrabutylammonium bromide is used in an amount of from 0.01 to 0.10 parts by mole per part by mole of the compound of formula III.

Examples of the groups R ¹ , R ² and R ³ are: alkyl:

CH3, C2H5, n-C3H7, i-C3H7, C4H9-11, an alkoxy ^(R3 only):

OCH 3, OC 2 H 5, OCH 2 CH 2 CH 3, OCH (CH 3) 2,

O (CH 2) 3 CH 3.

The group X is selected from the groups well known in the art, for example: alkali metal:

potassium, sodium, alkaline earth metal:

calcium, magnesium, organic base residue:

residues which are well known in the synthesis of penicillin, for example a tertiary amino group or a residue of triethylamine, ethylpiperidine and methyl morpholine.

In a preferred embodiment of the invention, the protecting group for the respective ampicillin group is 1-methoxycarbonylpropen-2-yl or 1-ethoxycarbonylpropen-2-yl, for which the preferred intermediate is the sodium or potassium salt of N- (1-methoxycarbonyopropen-2-yl) - penicillanic or Nkarbonylpropen-2-yl) -penicilanové or N- (l-ethoxycarbonylpropen-2-yl J-penicillanic acid of the formula II (R ¹ is methyl, R ² is methyl, R ³ is methoxy or ethoxy and X is sodium or potassium ).

The intermediate of formula (IV) is stable in a neutral or alkaline medium, while in an acidic medium, the amino-protecting group can be removed simply, rapidly and selectively.

The amine protecting group of ampicillin may be selected, for example, from those mentioned in British Patent No. 991,566 and other groups known in the art.

The production method according to a preferred embodiment of the invention comprises the following steps:

Converting ampicillin trlhydrate in a polar solvent such as N, N-dimethylformamide to its salt such as potassium and then forming the corresponding enamine of formula II by reaction with an acetic acid derivative such as methyl acetoacetate, adding an esterification catalyst preferably tetrabutylammonium bromide N-chloro- or α-iodo-diethyl carbonate to the reaction mixture to form ampicillin 1-ethoxycarbonyloxyethyl ester of the amine of formula IV, hydrolysis of the protecting group by dilute hydrochloric acid in an organic solvent, e.g. phase, for example sodium chloride and extraction with a suitable solvent, for example n-butyl acetate, evaporation of the solution under low pressure in n-butyl acetate to crystallize the product of high purity, whereupon the product is isolated by filtration rací.

Among the main advantages of the process according to the invention, the most important advantage is that by this process it is possible to obtain bacampicillin hydrochloride in virtually a single operation and with a high degree of purity.

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

Another equally important advantage is that ampicillin trihydrate, a known antibiotic, is easy to obtain in pure form and at low cost as a starting material.

The intermediate of formula (II) can be readily prepared, as described, for example, in British Patent No. 991,586 in a yield exceeding 95%, by reacting ampicillin trihydrate with methylacetoacetate or ethyl acetoacetate in an amount exceeding 10-50% stoichiometric ratio in the presence of an organic base or carbonate an alkali metal such as potassium carbonate.

The intermediate of formula (II) may be isolated and added in solid form in the esterification reaction. This intermediate can be used without isolation to the esterificael in the same solvent as the enamine-forming reaction of formula II.

The reaction to form the ampicillin enamine II is carried out in an aprotic polar solvent such as N, N-dimethylacetamide, N, N-dimethylformamide, dimethoxyethane, dimethylsulfoxide, tetrahydrofuran or dioxane.

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

The compound of formula II can be prepared by acylating the 6-aminopenicillanic acid with the corresponding enamine derivative of phenylglycine to give a compound of formula II, which can then be directly esterified and converted to bacampicillin.

The esterification reaction after addition of α-chloro or α-iodo dimethyl carbonate to said mixture proceeds at a temperature between 15 and 80 ° C, preferably between 45 and 55 ° C, for 1 to 24 hours, preferably 5 to 10 hours.

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

For the easiest and most convenient industrial conditions, the esterified enamine of formula (IV) is isolated by diluting the reaction mixture with water and then extracting with a suitable water-insoluble solvent such as n-butyl acetate.

The acetate phase is stirred with a dilute 0.2-0.3 N hydrochloric acid solution until the protecting group is completely hydrolyzed. This is achieved for a contact time of 2 to 8 hours, preferably 4 to 5 hours, at ambient temperature.

Addition of sodium chloride separates the compound of formula I from the aqueous phase in the form of the hydrochloride, which is extracted with a suitable solvent, for example n-butyl acetate.

Evaporation of the organic phase under reduced pressure at 40 ° C to a small volume of the residue and crystallization affords the compound of formula I.

The crystalline product is filtered off, washed and dried under reduced pressure.

The following examples illustrate the invention without limiting it.

He did

36.4 g (0.075 mol) of the potassium salt of N- (1-methoxycarbonyl-2-propenyl) -6- [1H-amino-α-phenylacetamide] penicillanic acid are added to a solution of 17.8 g (0.116 mol) and chlorodiethyl carbonate and 3g (0.01 mol) of tetrabutylammonium bromide in 150 ml of N, N-dimethylformamide, with stirring, the temperature rose to 45 ° C and maintained at 45-50 ° C for 5 hours.

When heating is complete, the reaction mixture is poured into a mixture of 200 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 were washed twice with 75 ml of 14% aqueous 'sodium chloride solution' under low pressure until an oil was obtained.

The oil was stirred with 200 ml of tetrahydrofuran and 100 ml of water, and the resulting solution of pH 4.8 was adjusted to pH 1.5 with stirring by adding a total of 12 ml of 6 N hydrochloric acid over an hour.

After the solution was allowed to stand for an additional hour at room temperature, tetrahydrofuran was removed at low pressure at 40 ° C, 150 ml of n-butyl acetate were added to the remaining 150 ml aqueous phase, and then 15 g of sodium chloride were added.

The organic phase is separated and the aqueous phase is extracted with 100 ml of n-butyl acetate. The combined organic phases were evaporated under reduced pressure at 40 ° C to a volume of 120 ml. The product was left to crystallize at 5 degrees Celsius for 15 hours. The product is then filtered, washed with 50 ml of n-butyl acetate and 50 ml of ethyl acetate. Drying is carried out under reduced pressure at 40 ° C.

6- [D- (-) -. alpha.-Amino-.alpha.-phenylacetamido] penicillanic acid 1-ethoxycarbonyloxyethyl ester, m.p. 160 DEG-162 DEG. Analytical determination:

Titr:

97,82%, optical rotation angle:

+166.3 ° (c = 1, C 2 H 5 OH 95 ° J, pH:

4.05 (2% aqueous solution), moisture content:

0.82%, residual solvents:

0.45% ethyl acetate, 0.98% n-butyl acetate,

IR and NMR spectra are standard, residual ampicillin:

0.06%.

Example 2

16.2 ml (0.15 mol) of methylacetoacetate a

30.2 (0.075 mol) of ampicillin trihydrate is added to a suspension of 12.54 g (0.0907 mol) of finely powdered anhydrous potassium carbonate in 100 ml of N, N-dimethylformamide.

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

17.8 g (0.117 mol) of α-chlorodiethyl carbonate, 3g (0.01 mol) of tetrabutylammonium bromide and 50 ml of Ν, Ν-dimethylformamide are then added, respectively.

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

The reaction mass is poured onto a mixture consisting of 600 ml of water and 200 ml of n-butyl acetate and stirred until a solution is obtained. The aqueous phase was separated and extracted with an additional 5-0 ml of n-butyl acetate.

The combined organic phases are washed twice with 50 ml of water each time. To the stirred organic phase was added 75 ml of 1N hydrochloric acid and 185 ml of water and allowed to stir at 22-23 ° C for 4 hours.

The aqueous phase is separated and the organic phase is extracted with 50 ml of water. The combined aqueous phases are adjusted to pH 4 with 10% aqueous sodium carbonate solution, then charcoal is added as a bleaching agent and filtration is performed.

150 ml of n-butyl acetate and 40 g of sodium chloride are added to the aqueous filtrate. The organic phase is separated and the aqueous phase is extracted with 100 ml of n-butyl acetate. The combined butyl acetate phases are evaporated at low pressure at 40 ° C to a volume of approximately 150 ml. The product is left to crystallize for 15 hours at +5 DEG C. then ^Q is filtrated and washed with 50 ml of n-butyl acetate and 50 ml of ethyl acetate.

The wet product is dried at low pressure of 1 330 Pa, then drying is continued at 25 ° C for 24 hours.

Yield: 20.8 g (55%) of 6- [D- (-) -. Alpha.-amino-.alpha.-phenylacetamido] penicillanic acid 1-ethoxycarbonyloxyethyl ester hydrochloride, m.p. 159-161 [deg.] C., and confirmed by an authentic sample.

Esterification of the ampicillin salt with ethyl acetoacetate affords a white crystalline product, m.p. 144-148 ° C. Infrared analysis and thin layer chromatography confirm the expected structure, a 2% aqueous solution having a pH of 3.55. The total solvent residue is 3.5%

The addition of chlorodiethyl carbonate, carried out in 2 portions of 2 hours each at a temperature of 45 ° C, resulted in a crystalline off-white product with a melting point of 143-146 ° C. Infrared analysis and thin layer chromatography confirm the expected structure. The 2% aqueous solution has a pH of 3.43. The total solvent residue was 2.6%.

Claims (5)

OBJECT OF THE INVENTION A process for the preparation of 6- [D- (-) -? - amino -? - phenylacetamidephenicillanic acid 1-ethoxycarbonyloxyethyl ester of the formula (I) -. ξ Λ- CH ~ C ON H - C / - / C NH- ^CU • CH r Ί 5 N — CH-COb-CH-O-COOCH, Cri (I) characterized in that ampicillin, preferably in the form of an alkali salt, is reacted with a reactive acetoacetic acid derivative to form the corresponding amine of formula II -NH CH ~ I coCH ' AND -N'S ₃ I ^x -CH 3 CH-COOX (») where R ¹ represents a C 1 -C 4 alkyl group, an optionally substituted aryl or alkyl group, R ² represents hydrogen, alkyl with 1 to 4 carbon atoms, optionally substituted aryl or aralkyl group, R ³ is C 1 -C 4 alkyl, optionally substituted aryl or aralkyl, C 1 -C 4 alkoxy, aryloxy or amino, and X is an alkali metal, an alkaline earth metal, or an arganic base residue, in an aprotic polar solvent at 0 to 60 ° C for 2 to 8 hours, in the presence of an organic base or an alkali metal carbonate, the resulting intermediate reacted with a-haloethylethyl carbonate of formula III Z - CH - O - COOC2 H5 AND AND GH3 (III) wherein Z is chlorine or iodine, in the presence of 0.005 to 0.10 molar, preferably 0.01 to 0.10 molar, catalyst selected from the group consisting of quaternary ammonium salts, alkali metal bromides, alkali metal iodides, and cyclic ethers, based on 1 mole of the compound of formula III to give the corresponding ester of formula IV rf-f. '' K.Cri <O - NH - CH - Cti 'A. ,, \., JIIII' - » ^{C0 N} X-i) and .0 CA CCI-CO-CH-O-CC I ch ₃ (IV) where R ^1, R ² and R ³ are as defined above, and the obtained compound is hydrolyzed under mild acidic conditions to a compound of formula I. 2. The process of claim 1 wherein the alkyl acetoacetate is methylacetoacetate or ethylacetoacetate in an amount 10 to 50% greater than the stoichiometric ratio. 3. The process of claim 1, wherein a polar aprotic solvent is selected from the group consisting of Ν, Ν-dimethylacetamide, N, N-dimethylformamide, dimethoxyethane, dimethylsulfoxide, tetrahydrofuran and dioxane. 4. The process of claim 1 wherein the reaction of ampicillin, optionally in the form of an alkali salt, with the reactive acetoacetic acid derivative is carried out at a temperature of 20-30 [deg.] C. for 3 hours. 5. The process of claim 1 wherein the catalyst is tetrabutylammonium bromide.