DE2025819A1 - alpha-aminopenicillin compounds and processes for their preparation - Google Patents

Description

BEECHAM GROUP LIMITED, Brentford, Middlesex / Great Britain

Aminopeniciliin compounds and processes for their preparation

Priorities: May 28, 1969, April 7, 1970, both Great Britain 26898/69 and I6292 / 70

The present invention relates to new < ε-aminopenicillin compounds and processes for their preparation. In particular, the invention relates to acyloxymethyl esters of certain d -Aminopenicilline and condensation products of such d -Aminopenieilline with ketones relates. The new compounds are of particular value as antibacterial agents, as additives to animal feed, and as agents for treating mastitis in livestock. The new compounds are also suitable as therapeutic agents for the treatment, in particular, of infectious diseases which are caused by gram-positive and gram-negative bacteria in poultry, animals and humans.

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The compounds according to the invention are antibiotics with a broad spectrum, but they have the advantage over the iX-aminopenicillins from which they are derived that they are particularly well absorbed when administered orally and that they are hydrated after absorption, resulting in very high levels Blood levels of the relevant (A -aminopenicillins) can be achieved.

The c ^ aminopenicillin compounds according to the invention have the general formulas

^ y ~ _CH-CO. NH. CH CH C- OL.

V = / I 111

N CH. CO ₂ CH ₂ O. CO.R

(ID

O. CO.R

in which R is an optionally substituted alkyl, cyclo-alkyl, Is aralkyl, aryl or heterocyclic group and X is an amino group optionally present in the form of an acid addition salt or a protected amino group of the general formula

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ΪΙ ¹

or

(III)

or a tautomeric modification thereof, the dotted Connecting lines represent hydrogen bonds, R a Is Cj-Cg-alkyl group, R is either hydrogen or together ir.it R forms a carbocyclic ring, R * a C.-Cg-alkyl or a Cj-Cß-alkoxy group and Z is the remainder of an optionally substituted benzene or naphthalene ring means.

According to a preferred embodiment. R in compounds of the formulas I and II has the meaning of a tert-butyl group. The compounds in question, ie the pivaloyloxymethyl are of particular value because they have a very good oral absorption and therefore high because using such compounds blood levels of the respective <* ■ -Aminopenic ill inen be obtained.

In the context of the invention, the special position of the hydroxyl group in the benzene ring is of no importance. Preference is given, however, encryption \ compounds, wherein the hydroxyl group occupies the para position in the benzene ring. The compounds according to the invention can occur in epimeric forms and epimeric modifications are preferred in which the side chain is derived from the levorotatory (-) PC -amino-p-hydroxyphenylacetic acid.

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In the compounds of the formulas I and II according to the invention can the group R denotes an alkyl, cycloalkyl, aralkyl, aryl or heterocyclic group »Suitable alkyl groups can be saturated or unsaturated, branched or unbranched. For example, it can be the methyl, ethyl, isopropyl, n-butyl, act sec-butyl, tert-butyl, pentyl or hexyl group. Suitable cycloalkyl groups, which are also saturated or unsaturated are, for example, the cyclopentyl, cyclohexyl, 1-adamant'yl, Cyclopentenyl, cyclohexenyl, cycloheptyl and cyclohexylmethyl groups.

Aralkyl groups suitable for the purposes of the compounds according to the invention are the benzyl, phenylethyl and phenylpropyl groups. Suitable aryl groups are the phenyl or a substituted one Phenyl group, the 1- or 2-naphthyl group or the corresponding substituted Naphthyl groups. Suitable heterocyclic groups are the pyridyl, pyrazinyl, pyrimidinyl, thienyl, furyl or isoxazoly group *

The process according to the invention for the preparation of «£ -aminopenicillin compounds of the formulas I and II is characterized in that one

a) a salt of a penicillin compound of the general formulas

CH-CO.N.CH • -CH ^N C CH ₃

η CO - N CH. COOH

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NH k -CH-CH

β fco — N —— CH. COOH

_CH -pH -C-CH * (VI)

C (

in which X has the meaning given above, with a compound of the general formula

Y.CHgO.CO.R. .

in which Y is chlorine or bromine, brings about the implementation,
or
b) a compound of the general formula

■ H ₂ N ₁ CH - CH

/ \ / ^c S

CO-N CH. CO ₂ . CH ₂ . 0. CO. R.

in which R has the meaning given above, with a Derivative of the general formula

CH. COOH

J ₁ - (ix)

which has an activated carboxyl group, M being an amino group, a protected amino group, in particular
a protected amino group of the general formula III or IV, or a group which is then converted into an amino group or a protected amino group of the formula III or IV
can convert.

A suitable salt for procedure a) is, for example

Sodium or potassium salt. The implementation is expedient in one

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organic solvents such as acetone or dimethylformamide, carried out, the solvent may also contain a small amount of water if desired.

In procedure b), the phenolic hydroxyl group can during the acylation stage also be protected, for example in Form of an O ~ benzyl group or a Q-benzyloxycarbonyl group, which is removed after the implementation. In general however, protection of this hydroxyl group is not essential to the feasibility of the manufacturing process.

for the protection of the amino group ₊ .

Examples / are the protonated amino group (M = NH,), which is converted into the free amino group by simple neutralization after the reaction. _{The benzyloxycarbonylamino group (M = NH.CO 2} .CH ₂ * Ph) or substituted benzyloxycarbonylamino groups, which are then converted into the free amino group by catalytic hydrogenation, are also suitable for the purposes of the invention. In addition, a wide variety of other known groups are suitable as protective groups for the amino group, which groups can be converted into the free amino group following the reaction by mildly acidic or mildly alkaline hydrolysis.

Examples of groups M, which are then characterized by a mildly acidic Let hydrolysis convert into the free amino group, are the enamine groups of the general formulas III and IV.

Groups M, which are then characterized by mildly alkaline Let hydrolysis be converted into the free amino group, are in 2-

the
Position by ^ sulphonyl group substituted Xthoxycarbonylamino-

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groups of the formula R.SO ₃ .CH ₂ -CH ₂ .O.CO.NH-, in which R is an optionally substituted alkyl, aralkyl or aryl group.

The group M can, however, also be an azido group and in this case the conversion into the free amino group takes place either through catalytic hydrogenation or by electrolytic reduction instead.

When carrying out the reaction between the acid of the formula IX and the starting compound of the formula VIII, the choice of the activating group for the carboxyl group is also determined by the chemical The nature of the substituent M in the * C position is influenced. If M is an acid-stable group, for example the protonated amino group NH, or the azido group, it is often useful to convert the acid in question into an acid halide, by treating them with, for example, thionyl chloride or phosphorus pentachloride treated.

On the other hand, such reaction components should be avoided if M has an acid-unstable group of the enamine group type the formula III or IV and in this case it is often special expedient to use a mixed anhydride. Particularly suitable mixed anhydrides are obtained by adding an alkali metal salt or the salt of a tertiary amine of the acid having the formula IX in an anhydrous medium at room temperature or below treated with an appropriate alkyl chloroformate. On the other hand, the carboxyl group can also be activated by adding the acid with the formula IX with a carbodiimide to a reactive O-acyl, thiourea or by reaction with carbonyldiimidazole to one

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reactive imidazolide converts. Since the last-mentioned acylating agents, like the mixed anhydrides, are relatively unstable substances, they are usually not isolated, but the reaction with the 6-aminopenicillanic acid is carried out in situ. If <i> -amino-p-hydroxyphenylacetic acid is used for the preparation of the compounds according to the invention, this can also be used in the form of an anhydride from Leuch's. In such an anhydride, the same group serves both to activate the carboxyl group and to protect the amino group.

Compounds of the general formula I in which X is a free amino group can be prepared by reaction with acetone, which is preferably is present in excess, under neutral or basic conditions in the corresponding imidazolidino of the formula II be convicted. For example, you can make a corresponding connection of the formula I leave to stand overnight with acetone, which contains triethylamine as a catalyst. This reaction with acetone is reversible, so that the compound of formula II in the bloodstream Acetone loses again, which then takes a detour through a compound of the formula VI either a compound of the formula V or directly a compound of the formula I is formed.

example 1

Acetoxymethyl-6-L (~) N- (l-methoxycarbonyIpropen-2-yl) ~ <£ -amino- «^ (p-hydroxyphenyl) acetamidoy penicillanate

a) Redissolution of the compound ^ .- Benyloxycaiionylamino - ^ - Cphydroxyphenyl) acetic acid

22 ¹ I g of the above acid and 285 g of quinine trihydrate.

are dissolved in 2.5 liters of boiling ethanol and then the

00985 0/216 8

Cool the solution. The crystals which separate out are collected and recrystallized twice from ethanol. The quinine salt of the levorotatory acid is thus obtained in a yield of 7β% ² °

I) -158.5 ° < ^{c = 1} »° ⁱⁿ methanol). The free levorotatory acid is obtained by treating 68 g of the quinine salt with dilute sodium hydroxide, separating the released quinine by extraction with ether and acidifying the aqueous solution. This is recrystallized twice from aqueous ethanol and 28 g (yield of 8'5 %) of the (-) £ -Benzyloxycarbonylamino- «£ - - (p-hydroxyphenyl) acetic acid are obtained, mp 159-161 ° C., [c <] * ⁸ -12O, 0 ° (C = 1.0 in methanol).

Analysis for Cp ₁₁ H ₂₁ NO ₇

found C; 64.1 H: 5.2 N: 4.7 % <

Theory 63.9 4.9 4.7 %

The mother liquor from which the crude quinine salt has been separated is evaporated to dryness in vacuo to give a syrupy substance which is treated with aqueous sodium hydroxide. The released quinine is separated by extraction with ether. Acidification of the aqueous layer gives 108 g of the crude dextrorotatory acid, which is collected, dried and treated with 63 g of ephedrine in 450 ml of boiling ethanol. When the solution cools, the ephedrine salt of the turning acid separates out, is collected and recrystallized from ethanol. The yield is 111 g [«*] ²¹ ₊ I ₁₆₈ ⁰ (C = 1.0 in H ₀ O).

D / 2

The acid is released from this salt in the usual way and they are obtained after recrystallization from 50% aqueous ethanol

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in a yield of 96 % (m.p. 158-161 ° C., JVj ² J + 120.2 ° (C = 1.0 in methanol).

Analysis for C ^ H ^ NO ^

found C: 64.1 m 5.3 Nj 1.8 %

Theory 63.9 1.9 ² I, .7 *

b) Preparation of (-) "t-amino-" (, - (p-hydroxyphenyl) acetic acid A suspension of 21.8 g of (-) - ^ -Benzyloxycarbonylamino-. £ - (ρ-hydroxyphenyl) acetic acid in 180 ml of water is treated with so much dilute sodium hydroxide solution that a clear solution with a pH value of 8.7 is obtained, 2.2 g of a calcium carbonate catalyst with a palladium content of 5% are then added and this mixture is shaken with hydrogen at atmospheric pressure until no more gas is absorbed. The catalyst is then filtered off through a layer of kieselguhr and washed out with water. The filtrate and the washing water are combined, adjusted to a pH value of 5.0 and then the solution is concentrated in vacuo. The crude product, which separates out as a gelatinous precipitate, dissolves again when the mixture is boiled. On subsequent cooling, colorless, crystalline (-) - Ό -amino- <C - (p-hydroxyphenyl) acetic acid separates out. It is collected with a little cold Washed out water and dried in vacuo over phosphorus pentoxide. The yield is 10.1 g (83 %) mp 225-226 ° C £ X7 ² q -108 ° (C = 1.0 in H ₃ O). Analysis for C ₈ H ₉ NO,

found C: 57.2 H: 5.1 N * 8.3 % theory 57.5 5.1 8.1 %

The results of the nuclear magnetic resonance spectrum (D ₃ O + NaOD)

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are as follows: a multiplet centered around the line 3.15 (i »H, aromatic) and a singlet around the line 5.8 (IH N-CH) ..

c) Preparation of (-) - N- (l-methoxycarbonylpropen-2-yl) - «C -amino- «C - (p-hydroxyphenyl) sodium acetate

60 ml (0.32 ¹ 0.0195 IH or "oil) methanolic sodium hydroxide solution to be 3, ¹ * g (0.02 hol) (-) - 4-amino <L - (p-hydroxyphenyl) acetic acid added and washed in with 20 ml of methanol. As soon as the suspension is heated to about the boiling point, a clear solution forms. On further refluxing, however, the crystalline sodium salt of the amino acid in question separates out. In the course of 10 minutes, 2.4 ml (0.022 Λοί) methylacetoacetate in 20 ml of methanol are added to the stirred boiling suspension. After refluxing for a further 20 minutes, a clear solution has formed and heating is continued for a further 20 minutes. The methanol is then distilled off at a temperature of 130 ° C. and replaced to the same extent by dry toluene. As soon as 90 ml of toluene have been added, a white, crystalline solid separates out. This measure is continued until a distillation ^{temperature of 100 °} C. is reached and a total of 170 ml of toluene have been added. Then allowing the resulting suspension über'Nacht at 5 ⁰ C standing gathers then the precipitated product is washed with dry toluene and dried finally at HQ ⁰ C in vacuum over phosphorus pentoxide. The yield of the desired sodium salt is 0.5 g (95 %) . Analysis for C ^ H ^ NO ₅ Na.

found C: 5 ^, 35 Η; 4.9 N; 4.9 %
Theory 54.4 4.9 1.9 ί
IR (Nujol): 330OCm ^ (NH), 1655cm " ¹ (G ==== G-), 1560cm" ¹ (COO ").

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d) Preparation of the potassium salt of 6-aminopenicillanic acid

A solution of Ί, 32 g (0.02 Hol) 6-aminopenicillanic acid in 50 ml of water is prepared. Sufficient potassium hydroxide solution is then added until a pH value of 7> 8 is established. Then reacted 80 ml acetone are added and the mixture is cooled to -10 ⁰ C from. .

e) Preparation of the potassium salt of O-MJN-Cl-methoxycarbonylpropen-2-yl) - <L -amino- «L - (p-hydroxypheny-acetamido-penicillanic acid

50 ml of dry acetone maintained under stirring at a temperature of -10 ⁰ C to -8 ⁰ C while 2.0 ml (0.021 / jfol) Äthylchlorformat and then 3 ml of a l ^ solution of N-methylmorpholine in acetone will. Are then added 5.7 g ¹ I (0.02 Hol) (-) N- (l-Methoxycarbonylpropen-2-yl) -O6-amino- <^ - (p-hydroxyphenyl) of sodium acetate added, which according to the above procedure in section c) and wash this salt with 20 ml of ice-cold, dry acetone. This mixture is stirred for 30 minutes at -10 ⁰ C, then cooled to -25 ⁰ C \ and filtered through kieselguhr. To the FiItrat a cooled to -10 ⁰ C, stirred solution of the according to the above section d) of potassium salt prepared of 6-aminopenicillanic acid is added. The clear solution is stirred without further external cooling for 30 minutes and then evaporated under reduced pressure at a temperature below 20 ⁰ C to dryness. The residue is dried in vacuo over phosphorus pentoxide, then stirred with 70 ml of dry methanol and filtered through animal charcoal and kieselguhr to remove small amounts of solids. The piltrate obtained in this way is mixed with 250 ml of isopropanol and

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cooled to 5 ^° C., whereupon colorless crystals of the desired potassium salt separate. The precipitated product is collected, washed with dry ether and dried in vacuo. The yield is 3.5 g. .

Analysis for C ₂₁ H ₂ IjKN ₃ O ₇ S. 1/2 H ₂ O

found 0: ^ 9.3 H; 5.2 K: 7.6 Ni8.3 St 6, H% theory k9 ^ 4.9 7.7 8.3 6.3 %

f) Preparation of acetoxymethyl-6- £ "(-) N- (1-methoxycarbonylpropen-2-yl) * c -amino- <L (p-hydroxyphenyl) acetamido ^ penicillanate

The potassium salt prepared in accordance with section e) above is mixed with 20 ml of dry acetone and with an equivalent Amount (1.05 g) of bromomethyl acetate for 1 hour at room temperature touched. The mixture is then used to remove the released The potassium bromide is filtered through kieselguhr and the piltrate is poured into 120 ml of ice water. The separating The amorphous product is collected, washed with cold water and dried over phosphorus oxide in a vacuum; that way gets one the desired acetoxymethyl ester.

Example 2 .

Acetoxymethyl-6-Γ (-) <£ -amino- «£ - (p-hydroxy phenyl) ac et amidoj penicillanate

5 * 35 g (0.01. ^ F.ol) acetoxymethyl-6- r (-) N- (imethoxycarbonylpropen-2-yl) "C -amino- · £, - (p-hydroxy phenyl) ac et amidoJJ penicillanate, which according to the procedure of Example 1, section f) are mixed with * lo ml of water and Ao ml of methyl isobutyl ketone

. 009 850/2168

mixed and cooled to 5 ° C. The pH value is adjusted to 0.9 with vigorous stirring and ^{kept at this value at 5 °} C. for 75 minutes by adding further hydrochloric acid. The layers which form are then separated from one another and the aqueous layer is washed with 10 ml of methyl isobutyl ketone and then any remaining solvent is removed in vacuo. The aqueous solution is then cooled to 5 ⁰ C, adjusted with 10 jSiger sodium hydroxide to a pH value of 7.5 and extracted three times with 30 ml ethyl acetate. The combined organic extracts are dried over anhydrous magnesium sulphate and then under reduced temperature and reduced

ft

Pressure evaporated to give the desired penicillin ester.

Example 3

Acetoxymethyl-6- r2,2-dimethyl-5-oxo-4- (p-hydroxyphenyl) -l-imidazolidinylj penicillanate

a) A suspension of 5.0 g of 6- £ "(-) - Ί amino-p-hydroxyphenylacetamido / -penicillansäure in ¹ JO ₁ O mL of acetone is added 3.6 ml of triethylamine and this mixture is at 2H hours The supernatant solution is then decanted off from insoluble gummy substances and the solvent is distilled off in vacuo. The remaining glassy, solid product is dissolved in 10 ml of water. This solution is brought to a pH of The crystalline product which separates out is collected and dried in vacuo, giving 2 g of 6- / ^^ - dimethyl-il-ip-hydroxyphenyl) -5-oxo-1-imidazolinyl / penicillanic acid with a melting point of 198 ⁰ C (with decomposition).

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• Analysis for ^c ₁₉ ^ll ₂ 3 ^U J> ° 5 ^S

found -0: 56.0 H: 5.8 -Ni 10.1 %
Theory 56.3 5.7 10.4 %

b) 4.05 U (0.01 AoI) of the acid produced in this way are mixed with 25 ml dry acetone mixed and then rr.it 1.4 ml triethylamine as well then 1.53 g (0.01 / i | ol) bromomethyl acetate for one hour treated with stirring at room temperature. This mixture will then filtered through kieselguhr and the clear filtrate is dissolved in 150 ml Poured ice water. The amorphous product which separates out becomes collected, washed out well with water and over phosphorus pentoxide in. Vacuutr. dried. This way you get the one you want Ester.

Example 4

Pivaloyloxyn.ethyl-6- Γ (-) «C -amino- JL - (p-hydroxyphenyl) acetamido ^ -penicillanate hydrochloride

14.6 g (0.029 / <ol) crystalline pivaloyloxymethyl-6-aminopenicillanate-p-toluene sucphonate in 707 ml of ethyl acetate are treated with a 2 # solution of sodium bicarbonate (455 nil) while stirring. The organic layer which separates out is then separated off with Water washed over anhydrous. Magnesium sulphate dried and evaporated in vacuo to leave a residue oil .

17 g (0.059 mol) of the (-) N- (1-methoxycarbonylpropen-2-yl) - «t -amino- Ji - (p-hydroxyphenyl) sodium acetate in 236 ml of ethyl acetate prepared according to Example 1, paragraph c) are stirred

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cooled to -15 ° C. and treated with 0.296 ml of N-methylmorpholine and with 5.66 ml (1 equivalent) of ethyl chloroformate. This mixture is stirred at -15 ° C. for 6 minutes. Then an ice-cold solution of the oily pivaloyloxymethyl-6-aminopenicillanate in 118 ml of ethyl acetate is added to the reaction mixture of the mixed anhydride and stirred for 10 minutes at -12 to -14 C and then for half an hour at room temperature. The reaction mixture is then washed with 59 ml of a 0.5 N sodium bicarbonate solution and then twice with 30 ml of water each time. The organic layer is clarified by filtering through kieselguhr, then dried over anhydrous magnesium sulphate and finally evaporated in vacuo to give a yellow colored foam. This foam is dissolved in a mixture of 18 ml of acetone and 10 6 ml of water and stirred at the same time, the pH value being kept at a value of 2.5 by the dropwise addition of 5η hydrochloric acid until no further acid is required . About 6.5 ml of acid is added over 20 minutes. The acetone is then evaporated off in vacuo and the aqueous phase that remains is extracted with 118 ml of ethyl acetate. The \ organic layer is diluted with 9 ¹ ImI petroleum ether (boiling range 40 to 60 ⁰ C) and then 30 ml of water extracted with * up to a pH-value of the third The aqueous extract is combined with the original aqueous solution and then treated with 28.4 g of solid sodium chloride with vigorous stirring. An oily organic layer separates and the remaining aqueous phase is extracted with 60 ml of ethyl acetate. The combined organic phases are dried over anhydrous magnesium sulphate and then evaporated in vacuo. The residue is taken up in 100 ml of isopropanol and again evaporated and

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- 1 / -

then the residue obtained in this way was redissolved in 100 ml of fresh isopropanol. The clear solution is poured into 750 ml of dry ether with stirring, the pesticide which separates out is filtered off, washed with dry ether and dried over phosphorus pentoxide in vacuo. This gives 13.37 g (yield 89.1 %) of a colorless, non-crystalline solid which is the desired penicillanate hydrochloride.

Example 5

Pivaloyloxymethyl-6- r2,2-dimethyl-5-oxo-4- (p-hydroxyphenyl) -limidazolidinylj penicillanate

16.20 g (0.04 mol) of the 6- r2,2-dimethyl-5-oxo-4- (p-hydrocyphenyl) -l-imidazolidinyl7 penicillanic acid prepared according to Example 2, section a) .in 120 ml of dimethylformamide are mixed with 5> 52 ml (1 equivalent) of triethylamine are treated with stirring for 5 minutes until everything has dissolved, and then 7 »8 g (1 equivalent) of bromomethyl pivalate in 20 ml of dimethylformamide are added. This solution is stirred for one hour at room temperature. Small amounts of deposited pesticide are filtered off and the clear piltrate is poured into 600 ml of ice water. The solid which separates out is filtered off, washed well with water and dried in vacuo over phosphorus pentoxide. 7.7 g (yield 37.1 %) of the desired penicillinate are thus obtained in the form of a pale yellow, non-crystalline pesticide.

Example 6

Pivaloyloxymethyl-6- £ (-) - N- (1-methoxycarbonylpropen-2-yl) <C -amino- 4 - (p-hydroxyphenyl) acetamido7 penicillanate

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¹ J, 85 g (0.01 mol) 6- f (-) ™ H- (l-methoxycarbonylpropen-2-yl) ί ^ -amino- * Ό - (p-hydroxyphenyl) acetamido7 sodium penicillanate in 30 ml dimethylformamide are with 1.95 g (1 equivalent) of bromo methyl pivalate in 5 ml of dimethylformamide for 1 hour with stirring at room temperature. The mixture is clarified by filtration and the piltrate is poured into 150 ml of ice water. The separated pesticide is filtered off, washed well with water and dried in vacuo over phosphorus pentoxide. This gives 4.03 g (yield 69.8 %) of the desired penicillanate in the form of a colorless, non-crystalline solid.

Example 7

The following experiments show that the concentrations of 6- [(~) ~ tC -amino- "C - (p-hydroxyphenyl) acetamidoy penicillanic acid, which is found in the serum of a small species of monkey (Marmoset, z Group belonging to the Hapalidae) are found and derived from the respective valoyloxymethyl ester, are greater than if equal amounts of the free acid are also administered orally Dose is equivalent to 100 mg of free acid per kg of live weight. After administration, serum samples are taken at certain time intervals and checked for their content of 6- f (~) ~ ⁰ L -amino- «i - (p-hydroxyphenyl) acetamidoj penicillanic acid Microbiologically tested against Sarcina Lutea Appropriate tests are carried out using α-aminobenzylpenicillin (ampicillin) and the corresponding pivaloyloxymethyleeter t and blood levels are each called

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Ampicillin concentrations given. The compounds used in the experiments have the following formula on, the meaning of which is indicated in Table I in each case the substituent X or the substituent R has.

fl »

C- / \ -CH. CO. MH. CH - CH "fc - -CH- (example 7)

V = / ι ι ι i

ΜΙ _Λ · CO-N CH. COpR

TABLE I.

link 1/2 Concentration in
Aminopeniillin / Ug / ml
into the serum 6th H X R. 22 h lh 2 h Il h 2, 2 OH CH ₂ OGOCCH ₃ 17, 2 25, ¹ I 20.7 6.8 0, 31 OH H 2 '15.3 5.6 0.99

H CH ₂ OCOCCH ₃ 11 , 9 9 , 0 3 , 2 0 , 63 O , 15 H H 6th , 5 9 , * » 3 ,1 0 , * »5 0 , 07

Example 8

a) Benzoyloxymethyl-ö-aminopenicillanate-p-toluene sulphonate 27 g (0.125 WoI) of 6-aminopenicillanic acid in 17.3 ml of dry acetone are mixed with 17.3 ml of triethylamine and then stirred for half an hour at room temperature. The solution is then ^{cooled to 0 °} C. and then 26.9 g (0.125 mol) of bromine

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methyl benzoate in 5.5 ml of dry acetone and the mixture is stirred for 4 hours at 15 to 20 C. A further amount of 20 ml of dry acetone is then added and the mixture is then poured into 625 ml of dry ether and filtered. The clear Piltrat becomes 62.5. ml of saturated sodium bicarbonate solution and then washed with 62.5 ml of saturated sodium chloride solution. The solution thus obtained is treated with a solution of 15.9 g of p-toluenesulfonic acid in 250 ml of dry acetone. The mixture is stirred for half an hour, then the precipitated solid is filtered off, washed with dry ether and dried under vacuum. ) This gives 16.98 g (yield 25.9 %) of a colorless crystalline solid with a melting point of I ² IO to I ¹ Ml C (with decomposition). Recrystallization from an acetone-ether mixture gives a product with a melting point of 139-110 ° C. (with decomposition).

Analysis for ^C 23 ^H 26 ° 8 ^N 2 ^S 2

found C: 52.21 H: 5.02 N: 5.31 S: 12.71 % theory 52.85 5.02 5.36 12.28 %

The results of the nuclear magnetic resonance spectrum (CD,) pSO are as follows: S = 1, 1 * 3 and 1.62 (6H.d. gem-dimethyl), 6 = 2.30 (3H.S. p-methyl), S = 4.65 (IH.8.C ₅ proton), S = 5.15 (IH.d. C ₆ proton), S = 5.57 (IH.d. C proton), 3 = 6.10 (2H.s. methylene), δ = 7.15 and 7.58 ( ¹ IH.q. p-substit. Aromatic), S · - 7.78 (5H.m. Bonzoyl) ..

b) Benzoyloxymethyl] -6- [_ (- ') <-amino- I - (p-hydroxyphenyl) -acetamidoj pe'riicillanate hydrochloride < ^! """"'10, ^ 5 g (0.02 AoI) kriütalime3 ^& l3enzoyloxyinf: / thyl-6-aminopenici3 lanat-

DO !! 5 @ / 216Spr

p-toluenesulphonate are converted into the free base and then reacted with the mixed anhydride, which is obtained according to the procedure of Example 4 from 11.5 g (0.0 * 1 JVoI) (-) N- (1-methoxycarbonyl-propene-2 -yl) O -amino- -L - (p-hydroxyphenyl) sodium acetate has been produced.

The pesticide that eventually separates out is filtered off, washed out with dry ether and dried in a vacuum. This gives 5> 7 ^ g (yield 53.5 %) of the desired end product in the form of a colorless, "non-crystalline pesticide.

Example 9

a) Hexahydrobenzoyloxymethyl-ö-aminopenicillanate-p-toluclsulphonate 21.6 g (0.1 mol) of 6-aminopenicillanic acid are mixed with 22.1 g (0.1 / fol) of bromo-methylhexahydrobenzoate ( Boiling point 116 to 121 ⁰ C / 18-19 mmHg) implemented. The product which separates out is isolated in an amount of 8.36 g (yield 15.8 %) in the form of a colorless crystalline solid with a melting point of 1 ^ 9 to 151 ^{° C.}

Analysis for ^C 23 ^H 32 ° 8 ^N 2 ^S 2

Found C: 52.38 H: 6.16 Nj 5.10 Ss 12.63 V. Theory 52.26 6.10 5.30 12.13 V.

Nuclear Magnetic Resonance Spectrum (CD ^) ₂ SO results are as follows: £ = 2.30 (3H.s. p-methyl), S = 1.56 (1 Hs C ₃ proton), S = 5.11 (IH .d. Cg proton), ε = 5.52 (lH.d. C ₅ proton) ,: $. = 5.80 (2H.S. methylene), & - 7.11 and 7.53 (^ Hq p-substit.

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aromatic).

b) Hexahydrobenzoyloyymethyl-6- M-) ¹ C -amino- JL - (p-hydroxy-

phenyl) acetamido ^? penicillanate hydrochloride 8.99 g (0, ol7 WoI) crystalline hexahydrobenzoyloxymethyl-6-aminopenicillanate-p-toluene sulphonate are converted into the free base and then reacted with the mixed anhydride, which according to the procedure of Example 4 from 9.77 g ( 0.034 mol) (-) - N- (1-methoxycarbonylpropen-2-yl) <. -amino- <* L - (p-hydroxyphenyl) sodium acetate has been produced.

The deposited pesticide is filtered off, washed with dry ether and dried in vacuo. This gives 5-7 g (yield 61, 8 %) of the desired end product in the form of a pale yellow, non-crystalline pesticide.

Example 10

a) (3,5-Dimethylisoxazol- ⁱ l-carbonyl) oxymethyl-6-amino-penicillanate ^ p-toluene sulphonate

5.92 g (0.027 ¹ l mol) of 6-aminopenicillanic acid are reacted with 6.4 g (0.0274 Hol) of bromomethyl 3,5-dimethylisoxazole-4-earboxylate according to the procedure of Example 8, section a).

The result is a colorless, crystalline Peststoff in an amount of 2.95 g (yield 19.9%) having a melting point 142-146 ⁰ C (with decomposition).

Analysis for ^C 22 ^H 27 ° 9 ^N 3 ^S 2

found C: 48.10 H; 4.97 N; 7.52 S: 12, O4 % theory 48.78 5.02 7 * 7-6 11.84 %

009850/2168

The result of the nuclear magnetic resonance _{spectrum (CD,) 2} SO is as follows: 5 "= 1, i43 and 1.63 (6H.d. gem-dimethyl), 5" = 2.30 (511. see p-methyl) , Γ = 2.35 (5H.s. 3-methyl), «Γ = 2.63 (3H.s. 5-methyl), S =» 1/52 (IH. S. C, proton), £ = 3.14 (IH.d. Cg proton), S = 3.36 (IH.d. C _r proton) £ = 6.01 (2H.s. methylene), £ = 7.06, 7.20, 7 , 48 and 7.61 ( ¹ JH.q. p-substit. Aromatic).

b) (3,3-Diir.ethylisoxazol- ^J "carbonyl) oxymethyl-6 - (p-hydroxyphenyDacetamidoJpenicillanat-IIydrochlorid 2.71 ε (0.003 'Ol) of crystalline (3,3-rimethylisoxazol-Jj-carbonyl) oxymethyl o-aminopenicillanate-p-toluene sulphonate are converted into the free base and then reacted with the mixed anhydride which, according to the procedure of Example 4, is obtained from 2.87 g (0.01 mol) of (-OHd-methoxycarbonylpropene - ^ - yl ) «C-amino-« (.- (p-hydroxyphenyl) sodium acetate has been produced.

The precipitated solid is filtered off, washed with dry ether and dried in vacuo. The desired end product is thus obtained in an amount of 1.38 g (yield 49.7 %) as a colorless, non-crystalline solid.

Example 11

Propionyloxymethyl-6- Γ (-) «* -amino- <t (p-hydroophenyl) -acetamido] penicillanate hydrochloride is prepared according to the procedure of Example 8 but using bromomethyl propionate instead of bromomethyl likewiseate. Isobutyryloxymethyl-6 Γ (~) ■ <■ -amino- <Ί (p-hydroxyphenyl) -acetamidoj -penicillanate hydrochloride can be derived from bromomethyl isobutyrate, (2-ethylhexoyl) -oxymethyl-6-

0 09850/2 1 ba ^;

[(-) "<, - amino-Ό (p-hydroxyphenyl) -acetamidoj penicillanate hydrochloride from bromomethyl-2-ethylhexoate and phenylacetoxymethyl-6 Γ (-) <£ ~ amino- JL (p-hydroxyphenyl) -acetamido " J penicillanate hydrochloride can be obtained from bromomethylphenyl acetate.

Example 12

Pivaloyloxymethyl-6- £ "(-) ^ -amino- d (m-hydroxyphenyl) -acetamido ^ penicillanate hydrochloride is prepared according to the procedure of Example 4 using (-) N- (l-methoxycarbonylpropen-2-yl) ^ Obtain.-amino- ⁰ C - (m-hydroxyphenyl) sodium acetate instead of the p-hydroxy isomer.

Example 13

The average concentrations of 6 £ (-) «£ -Amino - d-

- (p-hydroxyphenyl) acetamidoj penicillanic acid and 6 / "(-)« £ - Aminophenylacetamidol penicillanic acid in the blood serum of two, different Investigated animal species following oral administration of the appropriate pivaloyloxymethyl ester and collaborate compared. The esters in question are administered orally to groups of rats (Sprague-Dawley CFY strain) and groups of sniffer dogs, a dose of 100 mg of the free aminopenicillin each 1 kg of weight corresponds to.

After administration, serum samples are taken at certain time intervals and tested microbiologically for Sarcina Lutea. The results listed below in Table II are obtained. In both animal species, the compound which contains the hydroxyl group in the ρ position generally gives higher serum levels than the corresponding unsubstituted analogous substances,

009850/2168

the difference being in particular several hours after administration becomes noticeable.

Tabel II Concentration in / tg / ml
of aminopenicillin in serum 2 h 4 h 6 h h 1 h 4.2
1.9 1.9
I, o4 1.37
0.65 Animal species Substituent im
Benzene ring 3.9
3.9 8.4
1.4 3.4
0.31 1.9
0.06
< 1/2 8.6
■ 3.9 Rats
Rats p-hydroxy
no substituent 2.2
4.3 dogs
Dogs" p-hydroxy
no substituent 6.1
4.0

00 98 50/2 168

Claims (18)

PATENT CLAIMS 1. oC aminopenicillin compounds of the general formula: ^ --_ CH-CO. NH. CH CH C — CH, CO N χ CO N CH. CO ₂ CH ₂ O. CO. R. NH N CH — CH 'C-CH ₃ ^ ¹¹ * -N CH. CO «. CH ₀ O. CO. R. CO-N CH. CO ₂ . CH ₂ in which R is an optionally substituted alkyl, cycloalkyl, Aralkyl, aryl or heterocyclic group and X denotes an amino group which is optionally present in the form of an acid addition salt or a protected amino group of the general formulas -CH (HI), (IV) or a tautomeric modification thereof, the dotted Connecting lines represent hydrogen bonds, R a 2
Is C ₁ -Cg -alkyl, R is either hydrogen or together with R forms a carbocyclic lling, R is a C ₁ -C, - alkyl or a C ^ -Cg -alkoxy group and % the remainder of one is optionally 009850/2168 substituted benzene or naphthalene ring means. 2. Ti- aminopenicillin compounds according to claim!., Characterized in that the phenolic hydroxyl group is in the p-position on the phenyl ring. 3. * C-aminopenicillin compounds according to claim 1, d a d u r c h characterized in that X is the 1-methoxycarbonylpropen-2-yl group is. k. »Ι -aminopenicillin compounds according to claims 1-3» characterized in that R is a Cj-Cg-alkyl group, preferably the methyl or tert-butyl group. 5. Pivaloyloxymethyl-6- Γ (~) ti -amino- ^ - (p-hydroxyphenyl) acetamide ^ penicillanate or a non-toxic acid addition salt. 6. Pivaloyloxymethyl-6- L2,2-dimethyl-5-oxo- ^/ 1- (p-hydroxyphenyl) -l-imidazolidinyl7 penicillanate or a non-toxic acid addition salt. , 7. Acetoxymethyl-6- | _ (-) * t -amino- «c- (p-hydroxyphenyl) aetamido") penicillanate or a non-toxic acid addition salt. 8. Acetoxymethyl-6- £ 2,2-dimethyl-5-oxo-ί ^ - (p-hydrocyphenyl) -iimidazolidinylJ penicillanate or a non-toxic acid addition salt, 9. Process for the preparation of * L -aminopenicillin compounds 009850/2168 according to claim 1-8, formula I and II, characterized draws that one a) a salt of a penicillin compound of the general formulas / V / CH-CO. N. CH CH C ^CH,: II ³ (ν) CO N - CII. COOH - P ⁰ S ^, CH ^ ίΐ — CH CH I ß to Ν— CH. COOH NH jj — CH — CH ^A C CH ₅ (VI) tN in which X has the meaning given in claim 1, with a Compound of the general formula Y.CH ₂ 0.C0.R. in which Y is chlorine or bromine, brings about the reaction b) a compound of the general formula . CH - CH C <- ~ CH, CO - N CH. CO ₂ . CH ₂ . 0. CO. R. in which R has the meaning given in claim 1, with a Derivative of the general formula H( 'CH.COOH I. (IX) 009850/2168 converts, which has an activated carboxyl group, wherein M is an amino group, a protected amino group, especially one protected amino group of the general formulas III or IV, or a group which is subsequently converted into an amino group Or convert a protected amino group of the formulas III or IV leaves. ■ 10. The method according to claim 9, characterized in that that the procedure a) is carried out in an organic solvent, which is optionally a small Contains amount of water. 11. The method according to claim 10, d a d u r c h characterized in that for the operation a) as a compound of Formula VII acetyloxymethyl bromide or chloride is used. 12. The method according to claim 9j d a d u r c h characterized that pivaloyloxymethyl bromide or chloride is used as the compound of formula VII for procedure a). 13. The method according to claim 9 » dadurchgeke η η indicates that in the procedure b) the phenolic hydroxyl group of the compound of formula IX is protected during the reaction and. That the protective group is then removed. 14. The method according to claim 9, characterized in that that in procedure b) pivaloyloxymethyl-o-aminopenicillanate is used as a compound of formula VIII. 15. The method according to claim 9, characterized in that in the mode of operation b) as a compound of Formula VIII acetyloxymethyl-6-aminopenicillanate is used. 16. The method according to claim 9, characterized that in procedure b) a compound of the formula IX is used in which the amino group is protonated or protected by a benzyloxycarbonyl group. 17. The method according to claim 9 »characterized that in procedure b) a compound of the formula IX is used in which M is the azido group. 18. The method according to claim 9 »d a d u r c h, that in the mode of operation b) a connection of the Formula IX is used in the form of an acid halide, acid anhydride or a mixed anhydride. 009850/2168