DE2024359A1 - Penicillin esters and processes for their preparation - Google Patents

Description

Penicillin esters and process for their preparation ^^ "SS SS-Akw SSSS SS SS SS Sv SS SSi SS SS SS> SS SS SS S5 SS SS- SS SS SS SS SS SS SS SSt S3 SSf SS SS SS SS SS SS SS SS SS SJS SS SS SS SS SS SS SS S3

The present invention "relates to esters and, more particularly, to one new process for the preparation of esters of penicillin compounds.

The penicillin compounds referred to herein are corresponding to the penicillanic acid, which has the following structure has named.

CH

CH

COOH

(D

When transforming penicillin compounds, it is often necessary to the carboxyl group in the 3-position during the reactions to protect. The protecting group is a group that is in one can easily be removed later in the synthesis. Protecting groups that have these properties close a trichloroethyl, diphenylmethyl, p-methoxybenzyl, t-butyl, p-nitrobenzyl and p-methoxyphenyl groups.

00 984 8/196 9

Penicillinester are important intermediates "in the conversion of penicillins to cephalosporins, for. Example, in the method, as described in US Patent 3,275,626, 'that is, by heating a Penicillinoxydes under acidic conditions to a temperature of about 10O ⁰ C to about 175 ° C. In the course of the process, the 3-carboxy group of the penicillin is protected by esterification until the desired cephalosporin is produced and then the ester group is cleaved off This process creates an important route to cephalosporin antibiotics.

It is desirable that such protective ester groups can be introduced as efficiently as possible. When standard esterification procedures are unsatisfactory, a method often used to synthesize esters is to condense a haloformic acid ester with a carboxylic acid in the presence of a base to form the corresponding mixed anhydride and heat the latter in solution to effect decarboxylation. Thus, in the South African patent no. 67/1260, an esterification of 6 ~ / S- (2,2,2-tri ~ chloroethylcarbonyl) ™ D-2-amino-2-phenylacetamido7-penicillanic acid-1-oxide is described, the latter being is dissolved in dry tetrahydrofuran containing 2 molar equivalents of pyridine "The solution thus obtained is cooled and stirred in an ice / alcohol bath while a solution of chloroformic acid 2 _s 2 _$ 2 -trichloroethyl ester (1.5 molar equivalents) in tetrahydrofuran is added" The mixture is stirred for 2 hours in the cold and J hours at room temperature and is finally refluxed for 15 minutes. Hachdem the mixture was worked up in the usual manner, to obtain a yield of about 52% of the crude 2 _S) 2,2-Trichlorä tliylesters ^1, requires the further Umkristallisatiori for the preparation of the pure material.

It has now been found that the formation of the mixed anhydride of a penicillanic acid is satisfactory in the cold proceeds by reacting the chloroformic acid ester with a solution (or suspension) of the penicillin compound in an inert, essentially anhydrous organic solvent, the reaction being carried out in the presence of about 1 molar equivalent of a base

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to be led. The base can be present in the reaction mixture by using a penicillin salt of a base or when the penicillin compound used is not a "salt" of a base "By adding a" certain amount of a base to the reactants. Han gets lower overall yields when over-. shed base, ζ. B. 2 molar equivalents, during the formation of the mixed anhydride is present.

For the next stage of the process, i.e. the decomposition of the mixed anhydride by decarboxylation, it has been found that if a weak tertiary base such as pyridine (or pyridine-like bases such as picolines, lutidines or collidines) is added after the mixed anhydride has been formed, it is unnecessary to heat the mixture in order to effect the decarboxylation, since this proceeds satisfactorily and very quickly in the cold (e.g. Bi at ⁰ ° C. or even at lower temperatures). If desired, the reaction temperature can be increased; however, it appears that the effect of the heat treatment is that carbon dioxide which has been formed and which has dissolved in the reaction medium is released. It has been found that it is difficult to carry out the decarboxylation by heat treatment alone in the absence of an added base. Other bases such as pyridine or pyridine-like bases, especially strong organic bases such as N-ethylpiperidine or triethylamine, give poor yields when used in the decarboxylation reaction.

According to one embodiment of the process according to the invention, a process is provided for the preparation of an ester of a penicillin, which consists in that a penicillanic acid salt with a haloformic acid ester (z. B. chloroformic acid or bromoformic acid ester) of an alcohol or phenol in an inert, substantially anhydrous organic solvent relatively low temperature, e.g. B. contacted between -2O ⁰ C and +30 ⁰ C in the absence of a substantial amount of excess base until the desired mixed anhydride is obtained and the decarboxylation of the mixed anhydride is then effected by treating it with a weak tertiary base, preferably in the presence of a hydroxylic material, contacted,

009848/1969

whereby the ester of penicillanic acid with the corresponding Alcohol or phenol.

Penicillanic acid salt

That in the production of the mixed anhydride according to the invention used penicillanic acid salt can have the following formula:

R ¹ CONH

II 2

COOR

1 p

where E CO is an acyl group and R is an alkali metal atom, e.g. sodium or potassium, or an organic ammonium group, e.g. B. tri (lower alkyl) ammonium (e.g. triethylammonium), Piperidinium, an N- (lower-alkyl) -piperidinium (e.g. N-ethylpiperidinium) or benzylammonium and Z means S, SO or

It is clear that Formula II does not include all penicillanic acid salts and that other such salts can be used in the methods of the invention.

Instead of a preformed Penicxllansauresalzes you can also use a free acid and a base in approximately equimolar amounts as described above. However, it is generally convenient to use a preformed salt and the reaction is described below with reference to such salts, it being clear is that the alternative method also applied if desired can be.

Certain salts, e.g. B. alkali metal salts may not have the required solubility in the selected reaction medium. In in some cases a small amount of an organic base, e.g. B. approx. 0 »2 molar equivalents, be exposed to lighten the solution »Πι»,

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Haloformic acid ester ■

The haloformic acid ester used is normally formed with an alcohol or a phenol, the ester residue being easily separated from the penicillin or cephalosporin compound can be, e.g. B. by hydrolysis, by reduction or by hydrogenolysis at any convenient stage in the process.

An alcohol residue that can easily be split off is the 2,2,2-Irihalogenäthylrest, z. B. the 2,2,2-trichloroethyl radical, which can be removed by zinc / acetic acid, zinc / formic acid, zinc / lower alcohol or zinc / pyridine.

Another method to split off the ester groups in the following, includes acid hydrolysis and one group that can be separated by acid hydrolysis is the tertiary butyl group.

Formation of the mixed species hydride

The reaction of the penicillanic acid salt with the haloformic acid ester is effected in an inert, essentially anhydrous organic solvent. Methylene chloride has been found to be a very useful solvent for this purpose, but other halogenated hydrocarbons such as chloroform and 1,2-dichloroethane can also be used. Other solvents that can be used are ketones, e.g. acetone, aromatic hydrocarbons e.g. B. benzene, and acyclic and cyclic ethers, e.g. B. tetrahydrofuran. Mixtures of solvents can be used if desired. Conveniently, the organic solvent should have a boiling point below 10O ⁰ C. It is not necessary that the reactants be completely dissolved.

It has further been found that, in order to obtain high yields of the ester, it is desirable to add the haloformic acid ester very rapidly (e.g., over a period of no more than 1 minute) to the solution (or suspension) of the penicillin salt in the organic solvent to be added. To overcome the difficulty of rapid addition in large-scale production, too

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However, it is beneficial to overcome the penicillin salt either as a solid or as a slurry to a solution of the. Add haloformic acid ester in the organic solvent. The haloformic acid ester and the penicillin salt can be used in equimolar amounts. However, there is excess Hai ο called is enoic acid ester in the following decarboxy » lation reaction takes part, it is desirable to 0.1 to 0.9 »preferably 0.3 to 0.5 molar equivalents of haloformic acid im To use excess in the formation of the mixed anhydride.

Although the formation of the mixed anhydride is a rapid reaction, in order to obtain optimal yields for these reactions it is very desirable to allow the reaction to proceed to completion before proceeding to the next step in the process. The speed of the reaction depends on at least two factors, the concentration of the penicillin salt and the temperature used. Using a concentration of about 10%, the reaction appears to take 5 to 10 minutes at a temperature of about -15 ° C after all of the penicillin salt has been added to the haloformic ester solution. However, at higher concentrations the reaction takes longer time. For example, are required at a concentration of 80% at -15 ⁰ C the reaction was complete 4-0 to 60 minutes, whereas one at ⁰ ° C for 20 minutes to JO needed.

Formation of the ester by decarboxylation

It is not necessary to recover the mixed anhydride from the reaction medium before effecting the decarboxylation and it is unnecessary to heat the mixture, ie the decarboxylation with the aid of the weak tertiary base can be effected at about the same temperature as it is Formation of the mixed anhydride was necessary. In general, temperatures of -10 ⁰ C prove of about -20 ⁰ C to +50 ⁰ C, preferably ⁰ to +30 C to be satisfactory.

The weak tertiary used in the decarboxylation stage Base can be used in an amount of about 0.5 molar equivalents upwards, calculated in relation to the penicillin conversion, can be used. The weak tertiary base ■ conveniently has a pKa (ge

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- 7 -
measure in water "at 25 ⁰ C) of 6.5 or less.

Conveniently, the weak tertiary base is pyridine, however, you can other aromatic heterocyclic bases are also used, such as quinoline, isoquinoline and homologues thereof, e.g. B. the alkyl-substituted Pyridines and quinolines, ζ. B. picolines, lutidines and methylquinolines.

For optimal yields during the decarboxylation reaction, it is highly desirable to use a hydroxylic material to be present, e.g. B. water, 2,2,2-trichloroethanol or methanol. Good yields have been obtained when 0.05 to 0.3 equivalents of water, based on the pencillin, in the solvent medium are present before adding the weak tertiary base.

In some solvents, e.g. B. methylene chloride, the necessary water can be associated with the solvent prior to the formation of the mixed anhydride, provided that the solvent is still essentially anhydrous, ie contains less than about 1 % water. It is believed that the hydroxylic material takes part in the reaction. It is also advantageous to have 0.1 to 0.9, preferably 0.3 to 0.5 molar equivalents of haloformic acid ester present with the hydroxylic material. The haloformic acid ester apparently takes part in the decarboxylation reaction. The haloformic acid ester can result from excess addition in the formation of the mixed anhydride or can be added before or during the decarboxylation reaction, e.g. B. as a complex with the weak tertiary base, as described below.

When using solutions containing 50 % or more of the mixed anhydride, the decarboxylation reaction becomes quite uncontrollable if the weak tertiary base is added to the mixed anhydride solution. For example, after about 0.3 mol of pyridine has been added to a 60% solution of 2,2,2-trichloroethyloxycarbonyl-Gß-phenylacetamidopenicillanate, a delayed reaction sets in and the temperature rises from -15 to 20 to even with external cooling 22 ° C, accompanied by extremely rapid development of carbon dioxide. This will be considerable

0 0 9 8 4 8/1 9% 9

Amount of solvent entrained. This is a disadvantage.

However, a more controllable system is obtained if the Lo ^ solution of the mixed anhydride is added to the weak tertiary base, e.g. B. in solution in an inert organic solvent, e.g. a halogenated hydrocarbon.

Not only is this process easier to control than adding the weak tertiary base to the mixed anhydride solution, but there is generally an increase in yield. This method is also effective at concentrations below 50 % (where the question of reaction control is not as important a factor), although the yield has been found to be somewhat reduced. So if you apply this process in conjunction with solutions of the mixed anhydride in the organic solvent in high concentrations, one achieves a number of advantages, which lead to an increased yield of the end product, ie to increased throughput of the production apparatus, to reduced amounts of solvent and greater control the decarboxylation reaction leads to consistently high yields.

A more controllable system can also be obtained, though the solution of the mixed anhydride to a suspension of a complex of the weak tertiary base with excess haloformate in an inert organic solvent such as a halogenated hydrocarbon.

The complex is obtained by mixing strong solutions of equimolar amounts of the haloformic acid ester and the tertiary base in a halogenated hydrocarbon, e.g. B. methylene chloride, the complex separating out as a white solid. It is thermally unstable, as can be seen from the discoloration at temperatures above ⁰ ° C., and extremely sensitive to moisture, whereby it decomposes violently.

The desired ester can then be recovered from the reaction mixture alternatively, further reactions can be caused in the solution be, e.g. conversion of a compound with the formula II,

009848/1969

where Z = S, to a penicillin oxide by the method of Chow, Hall and Hoover (J. Org. Chem. 1962, £ 7, 1381). Of the Penicillin ester is contacted with a suitable oxidizing agent in an amount such that at least one atom is active Oxygen is present per atom of thiazolidine sulfur. Suitable Oxidants include metaperiodic acid, peracetic acid, and permonophthalic acid. The resulting penicillin oxide can be obtained from the reaction mixture.

The penicillin salt of formula II suitably has an acyl group (E CO) in the 6β-position, which is obtained by a fermentation process of a penicillin, e.g. B. phenylacetyl or phenoxyacetyl. '

Alternatively, the acyl group can be in the 6β-position of the penicillin salt of formula II be the one found in the cephalosporin compound that one wishes when transforming the penicillin compound receives, e.g. B. a thienylacetyl or phenylglyoxylyl group or it can be a precursor for the desired acyl group be e.g. B. an acyl group which is a protected functional Ie Group contains such as a protected amino group. An example of such an acyl group is. protected <^ - aminophenylacetyl group.

To further explain the present invention, the The following examples are given, which, however, are not intended to represent a restriction.

Example 1 ■

Methylene chloride (50 liters), which was washed twice with water and dried with sodium sulphate and its water content was adjusted to 0.1%, was cooled to -15 ⁰ C. 2,2,2-trichloroethyl chloroformate (2.15 liters) was added with stirring, then 6β-phenylacetamidopenicillanic acid N-ethylpiperidine salt (5 kg) was added over 10 minutes. After stirring for 5 minutes with all of the salt dissolved, 1.25 liters of pyridine was quickly added. Foaming occurred and the temperature rose to ⁰ ° C. The solution was diluted with dilute sulfuric acid solution, sodium bicarbonate solution.

.sung and water and each washing solution was then

re-extracted with methylene chloride. To the combined organic solvent layers, a solution of peracetic acid in acetic acid (2.32 liters, 4-0 %) was added with water cooling over 12 minutes. After stirring for an additional 30 minutes, the methylene chloride solution was washed with water, sodium bicarbonate and water, each detergent being re-extracted with methylene chloride. The combined organic layers were evaporated to a smaller volume (12.5 liters), methyl alcohol (26 liters) was added and the distillation was continued to a volume of 26 liters. After cooling to -5.degree. C. for 18 hours, the product was filtered off, washed with methyl alcohol, suspended in ether and again, filtered and dried at 40.degree. The 2,2,2-trichloroethyl-6β-phenylacetate-üidopenicillanat-1β-oxide weighed 4,788 kg. (89.07%). Mp 170-173 ° C; / dJjT = +179 »4 °. From the methylalk
another 2% of the product was kept.

jT = +179 »4 °. From the methyl alcoholic mother liquors he

Example 2

To a solution of öß-Phenylacetamidopenicillansäure-N-äthylpiperidinalz (22.4 g) in methylene chloride (250 ml), which with water. water was washed and contained 10% diethyl ether and 0.1 % water, which was stirred and cooled to 0 ° C., 2,2,2-trichloroethyl chloroformate (9> 8 ml) was quickly added and 5 ml were added two minutes later Add pyridine. After stirring for five minutes at ⁰ ° C., a 2% strength solution of sulfuric acid in water was added. The mixture was separated and the methylene chloride layer was washed with sodium bicarbonate solution and water. Each aqueous washing solution was re-extracted with methylene chloride. The combined organic layers were stirred and a solution of monoperphthalic acid in ether (40 ml, 1.5 M) was added over 10 minutes with water cooling. The solution was washed with sodium bicarbonate solution (twice) and water and the wash waters were then re-extracted with methylene chloride. The combined methylene chloride solution was evaporated to a smaller volume, methyl alcohol (120 ml) was added and the remaining methylene chloride was boiled off. The product 2,2,2-trichloroethyl-6ß-phenylacetamidopeni «= cillanate-1ß-oxide left. man-, crystallized out ^{overnight at 0 ° C}

it filtered and washed with methyl alcohol and ether, and dried at 4O ⁰ C. Yield: 19.61 g. (81.3 % I ¹ P. 169-171 ° 0).

Example 3 -

• To a solution of chloroformate ^^^ - trichloroethyl (9.8 ml) in methylene chloride (250 ml, 0.03% H ₂ O), which was stirred and cooled to 0 ⁰ C, was man'6ß ** ± Phenylacetam dopenicillanic acid N-ethylpiperidine salt (20.4 g) over 10 minutes followed by 0.1 ml of water (total water content = 0.07 %) * After stirring for 5 minutes, pyridine (5 ml) was added

.and the mixture was as described in Example 2, worked up and oxidized. Yield «20.54 g (85.3%) of 2,2,2-trichloroethyl-ß-phenylacetamidopenicillanate-iß-oxide.

Examples 4 to 8

; The procedure was as in Example 1, but using 9.8 ml of chloroformic acid-2,2,2-trichloroethyl ester in different

J Solvents that add to the ß-phenylacetamidopenicillanic acid-N-ethylpiperidine salt (22.4 g) and pyridine (5 ml) at -15 ° C. The results are given in the following table. ■

example
No. solvent yield
(% Th.) Fp.
⁰ C r 7 ²⁰ ° 4th chloroform 71 166.7 ° ' 178.5 ° , 5 benzene 66.5 168.5-170 ° 180.5 ° 6th acetone 63.5 168.5-169.5 ° 181 ° 7th 1,2-dichloroethane 63.5 170.5-171 ° 177, .5 ° 8th Tetrahydrofuran 62.4 169-170 ° 178.5 °

Example 9

To a solution of öß-phenvlacetsmidopenicillanic acid-N-ethyl-

OR) OiK ¹ Ai

piperidine salt (22.4 g) in methylene chloride (250 ml, water content 0.06%), which was stirred and ^{cooled to 0} ° C., 2,2,2-trichloroethyl chloroformate (9 * 8 ml) was quickly added and 5 Minutes later, oV picoline (6 ml) was added. After stirring for 5 minutes, the mixture was refluxed for 15 minutes, cooled and, as described in Example 2, worked up and oxidized. Yield = 18.4 kg (76.3 %) of 2,2,2-trichloroethyleß-phenylacetamidopenicillanate-iß-oxide. Mp 167 -. 70 ^0C

Example 10

Using the procedure of Example 9 but with application of ß-picoline instead of ολ-picoline, 18.24 g are obtained (75 »6%) of the product.

Example 11

Using the procedure of Example 9 »However using of 2,4,6-collidine (8.3 ml) the yield is 17.94 g (74.4%).

Example 12

Using the procedure of Example 9 but using of quinoline (6.9 ml) »a yield of 14.91 g (61.8%).

Example 15

At -20 ⁰ C chilled methylene chloride (250ml; 0.09% water) were added chloroformic acid-2,2,2-trichloroethyl (9 »8 ml) followed by pyridine (0.7 ml). Potassium öß-phenylacetamidopenicillanate (18.7 g) was added at -15 ° C. over a period of 4 minutes. After a further 8 minutes, pyridine (5 ml) was added and the reaction mixture was worked up as described in Example 2. C. · 174 ⁰ - yield was obtained from 20.94 g (86.9%), mp 171st

Example 14 · ■

To ar "~ 20 ° C chilled methylene chloride (250 mlj 0.09% water) were added chloroformic acid 2,2 _$ 2-trichloroethyl (9.8 ml) and

Q09848 / 196 9

N-ethyl piperidine (1.2 ml). After stirring for 3 minutes, one was able to Potassium ß-phenylacetamidopenicillanate (18.7 g) added gradually 5 ml of pyridine for a further 5 minutes. The reaction mixture was like in Example 2, worked up and 20.26 g (84.3%) of des were obtained Product.

Example 15

Methylene chloride (150 ml; 0.08% H ₅ O), water (0.92 ml) and 2,2,2-trichloroethyl chloroformate (52.5 ml, 1.42 equiv.) Were mixed, stirred and brought to -15 ° C chilled. Was added in the course of 4 minutes OLS Phenylacetamidopenicillansäure-N-äthylpiperidinsalz (120 g, 0.268 mol) was added and the slurry was stirred for one hour at -15 ⁰ C. The resulting solution was then in the course of 14 minutes to a solution of pyridine ( .. 21.5 ml, 1 equiv) in methylene chloride (50 ml; 0.08% HPO) was added and at -15 ⁰ C 10-between. The reaction mixture was stirred at -15 ° C. for 15 minutes. With cooling it became 12% strength. Sulfuric acid (100 ml) was added and the phases separated. The methylene chloride solution was then washed with 10% NaHCO -, - solution (120 ml), the aqueous phase being back-extracted with methylene chloride. The combined organic solutions were (ml 57; 40% solution in acetic acid) with peracetic acid is oxidized, which was slowly added with stirring to keep the temperature below 2O ⁰ C. After stirring for a further 15 minutes, the reaction mixture was worked up by washing (twice 100 ml H ₂ O, once 120 ml 10% -N_aHCO, -Caution ^ and once 100 ml H ₂ O). The methylene chloride solution was concentrated and methanol (240 ml) and continued the distillation until the vapor temperature was 62 ⁰ G. After standing overnight in the cold room, the product was collected by filtration, washed with methanol, slurried in ether, dried in vacuo at 4O ⁰ C to give 122.7 g (95% of theory) of 2,2,2-trichloroethyl ESS-phenylacetamido-penicillanate-ISS-oxide (mp. I70 to 172 ⁰ C).

Example 16

Methylene chloride (200 ml; 0.08 % H ₂ O), water (0.9 ml) and 2,2,2-trichloroethyl chloroformate (40 ml; 1.1 equiv.) Were mixed, stirred and adjusted to -1 ' 5 ⁰ O cooled. One gave in the process

00984.871989

of 5 minutes öß-phenylacetamidopenicillanic acid-N-ethyl-piperi-'din salt (120 g) was added and the mixture was stirred for one hour. Pyridine (21.5 ml; 1 equiv.) Was then added dropwise to a stirred solution of 2,2,2-trichloroethyl chloroformate (12.5 ml; 0.32 equiv.) In methylene chloride (50 ml) at "-15 ⁰ O was added dropwise. the mixed anhydride was added to the suspension of the complex at -15 to -10 ⁰ C and after stirring for 15 minutes, the product after washing and oxidizing as described in example 15, isolated and there was obtained 2,2, 2-Trichloroethyl-ß-phenylacetamidopenicillanate-iß-oxide (12.05 g> 86.8 % of theory) mp. 171-175 ° C.

Example 17

Methylene chloride (150 ml; 0.08 % water) and chloroformic acid-2,2,2-trichloroethyl ester (52.5 ml; 1.42 equiv.) Were mixed and cooled to -15 ° O and added with stirring It takes minutes to add Sß-phenylacetamido-penicillanic acid-N-ethylpiperidine salt (120 g). After stirring for an additional hour, the solution was added to a solution of pyridine (21.5 ml / 1 equiv.) And water (0.92 ml) in methylene chloride (50 ml) while maintaining the temperature between 25 and 30 ° C. After stirring for 15 minutes, the product, after washing and oxidizing as described in Example 15, was isolated and 2,2,2-trichloroethyl-Gß-phenylacetamidopenicillanate-iß-oxide (121.7 65 94.2% of theory) was obtained. Pp. 171-173 ⁰ C.

Example 18

Methylene chloride (500 ml, which was washed beforehand with water, dried over sodium hydroxide chips to a water content of 0.02% w / v and filtered) containing 6β-phenylacetamide-penicillanic acid-N-ethyl-piperidyl salt (50 g), was stirred and cooled to -16 ⁰ C. To the stirred solution, 2,2,2-trichloroethyl chloroformate (21.5 ml) and 2,2,2-trichloroethanol (3 »3 ml) were quickly added, followed immediately by pyridine (12» 5 ml). The mixture was heated to reflux and refluxed for 15 minutes, cooled to room temperature and washed successively with dilute aqueous sulfuric acid, dilute aqueous sodium bicarbonate and water

00.9848 / 1 969

Wash waters were then back extracted with methylene chloride. The combined methylene chloride solutions were washed with water chilled while taking an essential solution of monoperphthalic acid (96 ml; 1.3 m) were added with stirring. The resulting mixture was twice with aqueous sodium bicarbonate and once

the

washed with water and / aqueous wash water were back extracted with methylene chloride. The combined methylene chloride solutions were evaporated to a smaller volume, meihanol (260 ml) was added and the remaining methylene chloride was boiled off. The product was allowed 2,2,2-trichloroethyl-6ß-phenylacetamidopenieillanat-1ß-oxide at -5 ⁰ C to crystallize for 3 hours it filtered, washed with methanol and ether, and dried in vacuo at 38 ⁰ O. Yield - 45 .00g (83.7%)

Example 19 . ,

Potassium oss-phenoxyacetamidopenicillanate (100 g; 258 mmol) was added to a solution of 2,2,2-trichloroethyl chloroformate (5 ml, 362 mmol, 1,4 equiv.) In dry methylene chloride (500 ml), the had cooled to -20 ^{0 C.} The temperature was allowed to rise to ⁰ ° C. over half an hour, water (1 ml; 55 »6 mmol, 0.215 equiv.) Was added and the mixture was cooled again to -20 ° C. Pyridine (20 mL; 248 mmol) was slowly added and the mixture was slowly heated to reflux over one and a half hours and held at reflux for 1 to 2 minutes. The solution was cooled to room temperature, washed with dilute hydrochloric washed, then acid-dried and cooled to 5 ⁰ C and treated with peracetic acid (68 ml in a solution in. Of glacial acetic acid containing 5 »57 mMl per ml, 379 mmol, 1.44 Iquiv treated.) over 15 minutes so that the temperature did not exceed 10 ⁰ C. The pale yellow solution was washed with water (twice 100 ml) and with dilute sodium bicarbonate solution (three times 100 ml), then dried (MgSO ^) and evaporated to a pale yellow syrup. Methanol (200 ml) was added and the solution was concentrated to about 100 ml, whereupon a white plague began to crystallize. After cooling overnight, the solid was separated off by filtration, washed with ether and dried in vacuo, and 2,2,2-trichloroethyl-6β-phenoxyacetamido * was obtained. penicillanate-i-oxide (111.8 g; 225 mmol, 87%). Fp. 14? up to 148.5 ° C, / α7§ ⁴ »+ 160.4 ° (c_ - 1.17, chloroform). The mother-.

009-8487 1969.

alkalis were evaporated to low volume and cooled to give a second fraction which could be obtained by filtration was collected, washed in ether and dried in vacuo (3.084 g, 6.18 mmol, 2.4%), melting point 142-143 °, / oL / Jp = + 151.5 ° (c = 1.02, chloroform).

Example 20

Ethylene chloride (350 ml, 0.02 % w / v H ₂ O) and 6β-phenylacetamidopenicillanic acid-iß-oxide (137 §>) were slurried, stirred and cooled to ^{0 ° C.} Triethylamine (54.4 ml) was added over the course of 5 minutes, the reaction temperature being kept at 0.degree. The solution was stirred and cooled to -5 ° C over 10 minutes and then added over 15 minutes to a solution of 2,2,2-trichloroethyl chloroformate (75.25 ml) in methylene chloride (150 ml) -5 ° C, kept the temperature at -5 ° The reaction mixture was stirred at this temperature for 5 minutes and then added over minutes to a mixture of pyridine (43.7 ml) and water (1.75 ml) which was stirred at -9 ° C. During this addition, the temperature of the reaction mixture rose to + 2 ° C. and a white solid precipitated out (hydrochloride of the base). After stirring for 15 minutes, the reaction mixture was washed with aqueous sulfuric acid (200 ml), 29.5% aqueous sodium bicarbonate solution (200 ml, 7% w / v) and water (200 ml). The aqueous phases were back extracted successively with methylene chloride (80 ml). The combined organic phase was worked up as described in Example 1 and 170.5 g (90.5 % of theory) of 2,2,2-trichloroethyl-6β-phenylacetamidopenicillanate 1β-oxide were obtained.

Example 21

Methylene chloride (500 ml, moisture content 0.04%) and 2,2,2-trichloroethyl chloroformate (53.8 ml) were mixed, stirred and cooled to -5 ° C. Eß-phenylacetamidopenicillanic acid-N-ethylpiperidine salt (175 g) was added in the course of 30 minutes and the mixture was stirred at -5 ° C. for 10 minutes. The resulting solution was converted into a mixture of pyridine (34.3 ml) and 2,2,2-trichloroethanol (32.2 g) at -12 ⁰ C, maintaining the temperature at 4-1 ⁰ C increased. The reaction mixture

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The mixture was ^{stirred for 15 minutes at 0} ° C. and then washed, by shaking, successively with 7% sulfuric acid (200 ml) sodium bicarbonate solution (200 ml) and water (200 ml), each aqueous wash water being mixed with one volume of methylene chloride (80 ml ) was back extracted. The combined organic solutions were oxidized with peracetic acid (85 ml; 38.9% solution in acetic acid), which was added over the course of 15 minutes, with cooling in order to keep the temperature below 10 ^° C. After stirring an additional 15 minutes, the reaction mixture was worked up by washing successively with water (300 ml twice), 7 1/2% sodium bicarbonate solution (200 ml) and water (200 ml), each aqueous wash water being washed with one volume of methylene chloride ( 80 ml) was back extracted. The methylene chloride solution was evaporated to a small volume, was added methanol (910 mL) and led to the distillation continues until the temperature of the vapor was 62 ⁰ C. After 3 hours stirring at -5 ° C the product was collected by filtration, washed with methanol (105 ml), with ether (175 ml) slurried in ge ', dried in vacuo at 38 ⁰ C to give 160.6 g (85 »3% of theory) 2,2,2-trichloroethyl-6ß-phenylacetamidopenicillanate 1ß-oxide.

9-848 / 1969

Claims (1)

Claims ss: /1./ Process for the preparation of an ester of a penicillin, characterized in that a penicillan acid salt with a haloformic acid (chloroformic acid or bromoformic acid) ester of an alcohol or phenol in an inert, essentially anhydrous organic solvent at relatively low temperature in the absence of a substantial amount of excess base until one has the 3 mixed anhydride and the decarboxylation of the mixed anhydride is then effected by contacting the latter with a weak one tertiary base, whereby the ester of penicillanic acid with the alcohol or phenol is obtained. ■ 2. The method according to claim 1, characterized in that the mixed anhydride is formed at a temperature between -20 ⁰ C and +30 ⁰ C. 3. The method according to claim I. or 2, characterized in that that penicillanic acid has the general formula: R ¹ CONH COOR ² λ ο where E CO is an acyl group, R is an alkali metal atom or represents an organic ammonium group and Z represents S, SO or SOp. 4. The method according to claim 3, characterized in that R CO is a phenylacetyl or phenoxyacetyl group. 5 ". Method according to claim 3 or 4-, characterized in that that R sodium, potassium, triethylammonium, piperidinium, N-ethylpiperidinium or represents benzylammonium «, 6. The method according to any one of the preceding claims, characterized in that the alcohol is a 2.2 * .- xrihalogen ■ 009848/1969 is ethanol. 7. The method according to claim 6, characterized in that the 2,2,2-trihaloethanol is 2,2,2-trichloroethanol. 8. The method according to any one of the preceding claims, characterized in that the inert, substantially anhydrous organic solvent is a halogenated hydrocarbon, a ketone, an aromatic hydrocarbon or a
Ether is. · 9. The method according to claim 8, characterized in that the halogenated hydrocarbon is methylene chloride. 10. The method according to any one of the preceding claims, characterized in that the haloformic acid ester SGhnell
is added to a solution of a suspension of the penicillin salt in the organic solvent. 11. The method according to any one of claims 1 to 9, characterized in that the penicillin salt either as a solid or as a slurry to a solution of the haloformic acid ester
in the organic solvent is added. 12. The method according to any one of the preceding claims, characterized in that the decarboxylation is effected ^{at a temperature of -20 0} C to +50 ^{0 C.} '" A method according to claim 12, characterized in that the decarboxylation is effected at a temperature of -10 ⁰ C to +30 ⁰ C. Process according to any one of the preceding claims, characterized in that the weak tertiary base used in the decarboxylation step is used in an amount of about 0.25 molar equivalents upwards, based on the penicillin compound. Method according to one of the preceding claims, da-009848/1969 characterized in that the weak tertiary base is an aromatic one is heterocyclic base. 16. The method according to claim 15> characterized in that that the aromatic heterocyclic base is pyridine. 17. The method according to claim 15 »characterized in that the aromatic heterocyclic base is quinoline, isoquinoline, alkyl-substituted pyridine, or alkyl-substituted quinoline. 18. The method according to any one of the preceding claims, characterized in that a hydroxylic material during the decarboxylation reaction is present. 19. The method according to claim 18, characterized in that the hydroxyl material see water, 2,2,2-trichloroethanol or methanol is. 20. The method according to claim 19 »characterized in that from 0.03 to 0.3 equivalents of water based on the penicillin in the organic solvent are present prior to addition the weak tertiary base. 21. The method according to any one of claims 18 to 20, characterized characterized in that 0.1 to 0.9 molar equivalents of haloformic acid ester are present during the decarboxylation reaction. 22. The method according to claim 21, characterized in that 0.3 "to 0.5 molar equivalents of haloformate present are during the decarboxylation reaction. 23 · Process according to one of the preceding claims, characterized in that the decarboxylation reaction is effected is made by adding the mixed anhydride solution to the weak tertiary base or a 'solution thereof in an inert organic solvents. 24. The method according to any one of claims 1 to 22, characterized in that the decarboxylation reaction is effected 009848/1969 by adding a solution of the mixed anhydride to a suspension a complex of the weak tertiary base with the haloformic acid ester in an inert organic solvent. , 25 «The method according to any one of the preceding claims, characterized characterized in that, when Z is S, the resulting ester is oxidized to a corresponding compound, where Z £ 0 means before the ester is recovered from the reaction mixture. . 26. Penicillin esters obtained according to a method of the foregoing Expectations. ' 2 ?. Process for the preparation of a mixed anhydride of a penicillin, characterized in that a penicillin ! acid salt with a haloformic acid (e.g. chloroformic acid or bromo formic acid ester of an alcohol or phenol in an inert, substantially anhydrous organic solvent at a relatively low temperature in the absence contacted a substantial amount of excess base until the desired mixed anhydride is obtained. 28. Process for the preparation of an ester of a penicil " lins, characterized in that the Deearboxylissrung one mixed anhydride, formed from a penicilic acid and a haloformic acid (i.e. chloroformic acid or bromamic acid) sens acid) ester of an alcohol or phenol, whereby one first forms the mixed anhydride and then withfc one schwaenen tertiary bas © 29. The method according to claim J®, since & iir & h stan the Decarboxyiieruiig in ßegejiwart vsa o _r , 1 bis ^; © _s , f MoSM