DE2164195A1 - Process for the production of N-acyl-benzyl-penicillins and the N-acyl-benzyl-penicillins produced by this process - Google Patents

Description

PATENT LAWYERS

DR. MAX SCHNEIDER

DR. ALFRED EITEL ERNST CZOWALLA DlPL ING. - DIPL. LDW. NUREMBERG

Telephone collective no. 20 39 31

Bank accounts: Deutsche Bank A.G. Nuremberg No. 330.688 Hypobank Nuremberg No. 156/274 500

Postal check Konlo: Nuremberg Office No. 383 Wire address: Norispatenr this no. 24 509 / Ma-Rl

22. »2.-71

NUREMBERG C, the

Pick-up box, Königsfraße 1 (Mute | Knsbrüctau> ·

Alfa farmaceuticl S.p.A., Via Ragazzi del '99, η.5, Bologna / Italy

»Process for the production of N-aoyl-benzyl-penicillins and the N-acyl-benzylpenioillins produced by this process "

The present invention "relates to the manufacture of semi-synthetic Penicillins, especially the synthesis of F-aoyl-benzylpenicillins of the general formula

CH OH

CO-i

01

CH,

I — COOH (!)

209830 / 11.6

ORIGINAL INSPECTED

as well as their salts and esters, where R is either a D <-Aminobenzyl-, (X-Garboxybenzyl-, 2 or 3 Thienylmethyl-, 2 or 3 ihienylaminomethyl, O (-amino-p-hydroxybenzyl-, or an isoxazole group of the general formula

ι υ

in which R ₁ denotes a phenyl, 2-chlorophenyl or 2,6 dichlorophenyl group, or _{ for a group of the general formula

in which R ₂ denotes an aryl group or an O <- or β-ihienyl group, an ortho, meta or paraoxyaryl group, an aryloxy group or an aryl mercapto group (which may be substituted by one or more halogen atoms); R, for hydrogen or a C ^ -0. ₀ alkyl group, GjO-jq alkoxy group, amino group, G ₁ -Gg monoalkylamino group, O ₁ -Cg dialkylamine group, Garboxy-

209830/1169

group, G ₁ -G ₈ carboxyalkyl group, carboxymethylacyloxy group, Carbqxybenzylgruppe and as a special case R « ^and R_ together belong to the same Gc-C ^ cycloaliphatic ring, while R. stands for hydrogen or in the special case mentioned above," with Rp and R, together form a G ₁ - ■ Or, cycloaliphatic ring, R represents an amino group, a Gj-Cg monobalkylamino group or a C ^ -Cg dialkylamino group.

The invention also includes the preparation of salts and esters of penicillins according to formula I.

The mentioned salts of penicillins according to formula I contain the salts with sodium, potassium, calcium, magnesium, aluminum, ammonium and substituted ammonium, as well as those used at "the reaction with amines such as triethylamine, procaine, dibenzylamine, 3J-Benzyl-ß - phenylethylamine, N, F'-dibenzylethylenediamine, M-alkylpiperidine, and others commonly used to form Salts obtained with amines used with benzyl penicillins will. As esters of the penicillins of the formula I, the the following are named: G.Gg Alkyl, G. ^ - Gg Acyloxymethyl, p-Methoxybenzyl, p-Nitrobenzyl, Benzhydryl, Phenacyl, p-Broin-Phena "oyl, p-bromo-phenacyl, trimethylsilyl, benzyl.

The process for the preparation of the N-acyl penicillins of the • Above formula I or its salts and esters, is characterized according to the present invention,

209830/1169

ORIGINAL INSPECTED

that an alkali metal or a derivative thereof Alkali metals in an inert medium with an ester of penicillin G- the general formula

GO

• GH GH '

GO Ή

■ GH

GH ₅

.COORr

(II)

is reacted (where R ₁ - is a Garboicylschutzgruppe, which can be eliminated in the simplest way by a suitable chemical reaction without decomposition or change in the penicillin structure) to the alkali derivative of the protected penicillin of the following'For me 1 j

OH ₂ GO M GH GH

M CO-

"ΧΟΗ,
• OH — COORr

(HD

(where R _n - has the same meaning as above and M is the alkali metal. The compound according to formula III, which is obtained as above _f . is then treated with an acid halide of the following formula:

R-

■ CO-

■ X

(IV)

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BATH ORIGINAL

(where R has the same meaning as mentioned above and X stands for an Ilalogenatom) reacted to form the ester of iT-acyl-benzyl-penicillin of the formula

(V)

to obtain (where R and R ₁ - have the same meaning given above). The desired H-acyl-benzyl-penicillins are obtained from the esters according to formula (V) by removing the protective group with the aid of a suitable chemical reaction.

JM-acyl-benzyl-penicillins of the formula I are intermediates, in the manufacture of semi-synthetic penicillins can by an enzymatic process according to the earlier German patent application of the applicant P 21 55 042.5 in can be easily dephenylated.

In order to obtain the iJ-acyl-penicillins of the formula I, according to the invention used as raw material penicillin G-, which has been obtained by fermentation, in the form of an ester, as shown in the formula II and by introducing a protective group into the molecule of benzylpenicillin has been formed. To the protected derivative

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BATH ORIGINAL

of benzyl penicillin, a salt of penicillin G (for example with sodium, potassium, triethylamine, N-ethylpiperidine etc.) reacted with a reagent, as is usually the case for protection of carboxyl groups and is fully described in connection with peptide chemistry.

As protective groups to be introduced into the penicillin G molecule the following can be named in the context of the present invention: p-methoxybenzyl, benzyl, p-nitrobenzyl, Benzhydryl, phenacyl, p-bromo-phenacyl, trimethylsilyl and acyloxymethyl. Proceeding from this, forms the last stage of the process according to the invention Removal of the protective group, the selection of the protective group being based on how easily the respective protective group is can be removed again without causing secondary reactions in the penicillin molecule. As special According to the invention, the use of one of the following protective groups has proven advantageous; Acetoxymethyl and trimethylsilyl, which are easily removable by hydrolysis with a weak acid, benzyl, p-nitrobenzyl and benzhydryl, which can be removed by catalytic hydrogenation or finally phenacyl or P-Bcomphenacyl obtained by treatment with sodium thiophenate can be removed under conditions appropriate to penicillin

^209830/1169

- Ί -
structure of the molecule are harmless.

According to the process of the invention, the ester is des Benzyl penicillins, according to formula II, with an alkali metal or derivative of the same alkali metal reacted to form the protected benzyl penicillin of the general formula III. This reaction is characteristic of N-substituted amides, however until ödzt not yet been used for penicillins, has been described as suitable for this. In the context of the present invention, it is not critical whether as the alkali metal Lithium, sodium or potassium is used. This alkali metal can either be in its elemental form, finely divided, or used as a derivative, e.g. alkali metal naphthyls, alkali (C ^ -C ^) alkoxides, alkali hydrides or the like will.

The reaction of the esters of benzyl penicillin and the alkali metal or its derivatives takes place in an inert, anhydrous organic solution. It is advantageous that a solvent is selected in which all components are soluble in the reaction. Examples of such solvents include: benzene, toluene, xylene, Tetrahydrofuran, dioxane, or alkyl ethers, such as ethyl ether, isopropyl ether, ethylene glycol dimethyl ether, etc.

2098307 1 1 69

2164185

The ratio of the reagents (ie the ester of benzyl penicillin and the alkali metal) can range from the stoichiometric ratio to a large excess (up to 100 ^c ; 0 of one of the reagents to be used in approximately equimolar proportions.

The reaction temperature to be maintained varies depending on the alkali metal used and the form in which this alkali metal is used. In general, the advantageous temperature is zvd.schen -20 ° C and 7O -I- ⁰ G, preferably between ⁰ G and 4O ⁰ C.

The alkali derivatives of the protected benzyl penicillin according to formula III are unstable. They decompose very quickly in water or other compounds with moving parts Hydrogen departments. Within the scope of the present invention however, these connections do not need to be isolated, but can be used directly for production of M-acyl-benzyl-penicillins can be used.

The alkali derivatives of the protected penicillins according to formula III, which have been obtained as described above, are acid halides of the formula IV reacted to form protected .N-acyl-benzyl-

2 09830/1169

BATH ORIGINAL

Get formula Y penloillirie. This reaction is carried out in the medium in which the alkali derivative of the protected penicillin was produced. Are added, only the acid halide to the reaction mixture, keeping the l ^l emperature at about O ⁰ G. Theore table tenötigt to an equimolar amount of acid halide "with respect to the proportion of the alkali derivative of the protected .Benzyl-penicillin. Nevertheless it is advantageous, but not necessarily It is necessary to use a small excess of acyl halide over the stoichiometric equilibrium. If the acid halide according to formula IV is a solid, it is advantageous in an embodiment of the invention, but not essential, to use it in dissolved or dispersed form in an anhydrous inert solvent .

Of the protected if-acyl- ^ penicillins of the formula V, the obtained according to the description above, result the H-acyl-benzyl-penicillins, optionally in the form their salts, by removing the protective group by means of an " known procedures. Benzyl, p-ifitrobenzyl, and Benzhydryl groups are formed by catalytic reduction, Phenacyl and p-bromo-phenacyl by treatment with sodium thiopenate and irimethylsilyl and acyloxymethyl weak acid hydrolysis removed. The removal of the protective

2098307 11 69 ^: ^ a

BATH ORIGINAL

group by catalytic hydrogenation takes place in an - '■ inert organic solvent, such as ethyl or butyl acetate, chloroform, dichloromethane, benzene, toluene or ethyl ether, in the presence of platinum or palladium as a catalyst, which can be dispersed on an inert carrier. The reaction proceeds rapidly at atmospheric pressure and room temperature.

After the catalytic reduction described above, lies N-acyl-benzyl-penicillin of the formula I as a free acid im Reaction medium before and can be isolated from it, by precipitating them out of solution with Natoum-2-ethylhexanoate, for example as a water-soluble sodium salt. Alternatively, the free acid can also be extracted by an equivalent amount of aqueous alkaline solution.

The desired salts can be isolated from this aqueous phase by lyophilization, or else by Precipitation with an amine, with which penicillin forms a crystalline salt that is poorly soluble in water. For this purpose, amines such as procaine, N, N'-dibenzylethylenediamine and others commonly used to form salts with benzyl penicillin will.

209830/1169

If sodium thiophenate is used to remove the protective group, so. N-acyl penicillins of the formula I are obtained directly in, SOrm. of the sodium salt. To this end can use one of the methods described in the technical literature. (e.g. Shoehau et al, J -, .- 0rg-.Chem. 29, 2006, 1964) »whereby the organic solution with two Equivalents of sodium thiophenate treated in a inert solution such as dimethylformamide, tetrahydrofuran or dioxane are dissolved. The sodium salt formed of N-acyl-benzyl-penicillin is made from this medium precipitated by adding a solvent in which this salt is insoluble, for example acetone.

Using the following exemplary embodiments, however To restrict the scope of the invention in any way, the invention is to be explained in more detail below.

example 1

Production of the p-nitrobenzyl ester of benzyl penicillin,

The production described under this example is not claimed in the context of the present invention and serves only to illustrate a method for protecting benzyl penicillin

209 8 30/1169

39 g of p-nitrobenzyl bromide are added to a mixture of 74.5 g of potassium benzyl penicillin and 500 ml of dimethylformamide. The mixture is kept at a temperature of 55-6O ⁰ O for five hours with stirring. They are then allowed to cool and diluted with 300 ml of benzine oil. The solution is then poured into 500 ml of water and the organic phase is separated off, washed three times with water in order to remove unreacted benzylpenicillin and dried with anhydrous sodium sulfate. After evaporation of the solvent, 70.8 g of protected benzyl penicillin are obtained.

Example 2

Production of the acetoxymethyl ester of benzyl penicillin.

The following manufacturing process is also not claimed within the scope of the present invention, but rather again serves only to illustrate a method for protecting benzyl penicillin.

A mixture of 45.6 g of the ethyl piperidine salt of benzylpenicillin and 79 ml of bromomethyl acetate in 200 ml of dimethylformamide is kept at room temperature for 16 hours with stirring. Then the solution is diluted with 500 ml of chloroform and poured into 500 ml of water. The organic phase which separates is repeated with

209830/11 β9

Washed water to remove all traces of benzyl penicillin remove the one that did not respond. The washed solution is dried using anhydrous sodium sulfate, the solvent is evaporated and 33.6 g of protected benzyl penicillin are obtained.

Example 3

Preparation of the trimethylsilyl ester of benzyl penicillin.

This manufacturing process is also not the subject of the protection request of the present application and serves again only to illustrate a method for protecting benzyl penicillins.

74.5 g Kaliurnbenzyl penicillin are dissolved in 75 ml dry chloroform and added gradually 32.6 ml Trimethylehlorsilan, wherein the 'temperature at 26 ⁰ O is held iiach completion of this addition, the mixture is under stirring for one hour on a! Temperature held from 25-27 ⁰ G. After filtration, the piltrate is concentrated under reduced pressure until an oily consistency is achieved. The remainder (79.6 g) is dissolved in benzene and used directly in the next steps for the production of N-aeyl-benzyl-penicillins.

20 98 30/1169

- 14 " example 4

Process for the preparation of N-jp (-) ai-amino-phenylacetyl] benzyl-penicillin.

20.4 g of the acetoxyraethyl ester of benzyl penicillin, which is dissolved in 250 ml of dry benzene, are mixed with a tetrahydrofuran solution (50 ml) of sodium naphthalene (prepared from 1.15 g of sodium) at ⁰ ° C. with stirring and in a stream ^ treated by nitrogen; First 7 ml of triethylamine and then 10.8 g of D-oC -phenylglycylchloride-hydrochloride are added in small portions to the solution, which immediately takes on a yellow-brown color. After a reaction time of one hour at ⁰ ° G, the sodium chloride and the triethylamine hydrochloride that have formed are filtered off and the ITiltrate is treated ^{with a 1: 1 dilute hydrochloric acid at 0} : 1 until a pH of 1 is reached is.

After stirring for 30 minutes, the pH value is adjusted with! PrI- * ethylamine brought to the value 5 and the N-JD (-) <x-phenylacetyl-benzyl-penicillin separated as a white precipitate, which is filtered, washed with ice water and dried under vacuum is obtained, 23.2 g of the substance represented by the following formula?

209 830/1169

.15 -

! H GO

GH GH

CH _n -GO

GO N

with the following properties j analysis

CH GOOH

Calculated
G ₂₄ H ₂₅ N ₅ O for
5 ^S H ₂ O 59. 32 5 .56 ' 8th .66 6th 59 Found 59. 12th 5 .41 ' 8th .73 6th 42

enzymatic dephenylacetylation gives this Product ampicillin.

example 5

Process for the preparation of N-jjX -) (X ~ amine »ö ^ φ-oxyphenyl) -.- benzyl-penicillin.

By proceeding as in Example 1 and adding 11.1 g of D (-) CX- (p-oxyphenyl ^ G-lyeyl chloride hydrochloride is used, 20.5 g of a product of the following formula are obtained

209 830/1169.

HO - / % - CH-OO

'CH,

^ W ^/ I « ³

< ^{7 x} > CH * -CO CO N CH COOH

that by enzymatic dephenylacetylation (p (-) Q £ -.amino) -p-oxybenzyl-penicillin results.

Example 6

Process for the production of N- \ 0C -carboxy- (X-phenyl-

aeetyl | Benzyl penicillin.

100 ml of tetrahydrofuran solution of sodium naphthalene (prepared from 1.15 g of sodium) are added to a solution, cooled to ^{0 ° C., of 21.5 g of benzyl penicillin benzyl ester in 250 ml of dry benzene.} After 20 minutes of reaction at ⁰ ° C., 16.5 g of Oc-carboxybenzyl-phenylacetyl chloride, which are dissolved in 100 ml of dry benzene, are added. The mixture is kept at ⁰ ° C. for two hours while stirring and then poured into 150 ml of biswater. The organic phase is separated off, washed twice with water, dried with anhydrous sodium sulfate and the solvent is then evaporated off under vacuum.

20 9830/1 169

The residue consisting of the di-benzyl ester of IT acyl penicillin is dissolved in 250 ml of methanol. 40 g of a 10 $ palladium catalyst on activated charcoal are added to this methanol solution and the hydrogenation is carried out over a reaction time of five hours at room temperature and At the end of the reaction, the catalyst is filtered off, the filtrate is ^{evaporated at 0} ° G and the residue is dissolved in 250 ml of methyl isobutyl ketone jS-i NaOH adjusted to 7.8, with continuous stirring and external cooling. The aqueous phase is then separated off, treated with 5 g of active charcoal and filtered. By lyophilizing the filtrate

This gives 18.1 g of the sodium salt of the following formula;

COONa

N O

H C

(/ \). OH ₂ GO GO N ■ CH GOONa

from which one obtains OC-carboxybenzyl-penicillin (carbenicillin) duroh enzymatic dephenylaoetylation.

209830/1169

Example 7

Process for the preparation of Ii- [OC-Carboxy-OC (p-thienyl) -

AcetylJ benzyl penioillin.

Using an equivalent amount of flC-carboxybenzyl - (^ - thienyl) -acetylochloride when proceeding as in Example 6, 15.7 g of the sodium salt of the following are obtained Formula:

- CH - CO \ _ / - CH ^ - CO CO U

[j I \ S _v .CH,

CH-, COOEa

from which one by enzymatic ^ dephenylacetylation 6- [ÖC-Carboxy-OC (^ -Thienyl) -Acetamide] -penioillic acid

receives.

Example 8

Process for the preparation of N-joC-carboxy-cc ^ - thienyl) ·

Acetyl] benzyl penioillin.

209830/1169

Using 15.2 g of Ot-carboxybenzyl-OC-thienyl acetyl chloride one obtains, "when proceeding according to Example 6, 15.1 g of the double sodium salt of the following formula:

^b COONa ^N N — CH CH ' QZ ..

OH-

^GH 2- CO CO N-CH. COONa

from which one by enzymatic dephenylacetylation 6- [oil -0 ^ & - Thienyl) -Acetami <J -penicillic acid.

Example 9

Process for the preparation of the sodium salt of N-phenyl-acetyl-6 Jj3- (2-Chlorophenyl) -5 ~ methyl-isoacazolyl-4-Carbo3cyami ^ -Penicillic acid.

A tetrahydrofuran (70 ml) solution of lithium naphthalene (prepared from 0.7 g of lithium) of a solution is added dropwise, containing 41 g of benzyl penicillin trimethylsilyl iti 500 ml of dry benzene at a temperature of ⁰ C .0.

After a reaction time of one hour. O ⁰ C, 27 g of the chloride of 3- (2-chlorophenyl) -5-methyl-isoxazolyl-4-carboxylic acid in 100 ml of dry benzene are added to the solution.

209830/1 169

. ' Λ.
^{The mixture is initially kept at 0} ° C. for one hour and then at 10 ° C. for two hours while stirring. Then the solution is poured into ice water, brought to a pH of 1.5 with 1: 1 dilute hydrochloric acid and ^{stirred at 0} ° C. for 20 minutes. The aqueous phase is removed and the organic phase is washed three times with 250 ml of water and with anhydrous sodium sulfate

dried. '' '· ■

ν

The dried solution is mixed with 40 ml of 42 # lia-2-ethyl-hexanoate solution treated in n-butanol. The precipitating sodium salt is filtered, washed with ether and dried under vacuum.

The product obtained (38.5 g) has the following formula:

and delivers by ejacymatic dephenylacetylation Chloropheny ^ -S-methyl-isoxazolyl ^ -carboxyamidj-penicillic acid (Cloxacillin).

830 (1

ORIGINAL BATHROOM

Example 10

Process for the preparation of the sodium salt of N-phenyl-acetyl-6- ^ 3- (2,6-dichlorophenyl) -5-1

Carboxyamide / penicillic acid.

Using 30.5 g of the chloride of 3 (2,6-dichlorophenyl) -5-methyl-isoxazolyl-4-carboxylic acid, 41.2 g of the sodium salt of the following formula are obtained:

Cl

* C1

C "~" C """" CO ₁

N C - CH,

CH ₂ CO

N-CH CH

.CH.

CH.

CO N-

¹ CH-COONa

that by enzymatic dephenylacetylation β-Γ. Provides 5- (2,6-dichlorophenyl) -5-methyl-isoxazolyl-4-carboxamide / penicillic acid (dicloxacillin).

209830/1169

Claims (11)

Claims; γ Process for the preparation of N-acyrbenzyl-penioillins of the general formula ^ P. GH. GH CET NC ^ ^y / \ I ' ^GH 3 (/ \ _f OH ₂ GO GO IT -OH— GOOH (I) and their salts and esters, where R is either a (X -aminobenzyl-, OL -carboxybenzyl-, 2 or 3 ihienyl- "methyl-, 2 or 3 TM e nylami η ome thyl, öC-amino-p- Hydroxybenzyl or an isoxazole group of the general formula in which R ₁ denotes a phenyl, 2-chlorophenyl or 2,6-dichlorophenyl group ", or R denotes a group of the general formula ^L 4 209830/1 in which R _{2 is} an aryl group or an (X- or jS-thienyl group, an ortho-, meta- or paraoxyaryl group, an aryloxy group or an aryl mercapto group (which may be substituted by one or more halogen atoms); IU for hydrogen or a Cj- ¹ C ₁ O alkyl group, O ₁ -G ₁₀ alkoxy group, amino group, G ₁ -G ₆ monoalkylamino group, G ₁ -Gg dialkylamino group, carboxy group, O ₁ -Cq carboxyalkyl group, garboxymethylacyloxy group, garboxybenzyl group and ^J nd as a special case Rp and R are common belong to the same 0> -G ₇ cycloaliphatic ring, while R, stands for hydrogen or in the special case mentioned above, in which Rp and R, together form a Gc-O ₇ cycloaliphatic ring, an amino group, an O ₁ -G monoalkylamino group oder.eine G ₁ -Gg dialkylamino group, characterized in that an alkali metal or a derivative of such an alkali metal in an inert medium with an ester of benzylpenicillin of the general F ormel S ₂ _ GO MH CH-OH G GO — Ii GH GOORr is reacted (where R, - a carboxyl protecting group means that without decomposition or alteration 2 0 9 8 3 0/1169 2164795 the penicillin structure in a simple manner by a suitable one chemical reaction can be eliminated) to the alkali derivative of the protected penicillin of the following Formula:. . CO N GH GH M GO / λ / "" ³ CH, .GH-GOOR ₅ (III) (where R, - has the same meaning as above and M denotes the alkali metal "which is taken from the group lithium, sodium and potassium) which then with an acid halide of the following formula: CO -X (IV) (where R has the same meaning as mentioned above and X stands for a halogen atom) is reacted by the ester of the protected N-acyl-benzylpenicillin of Formula; R GO 2-CO -CH- GO- • N- GH-GOORr (V) 209830/1169 (where R and K have the same meaning given above have), which by removing the protective group with the help of a suitable chemical reaction, the N-acyl-benzyl-penicillin of formula I provides. 2. The method according to claim 1, characterized in that the alkali metal used in its elemental form or as a derivative is used in an inert solvent at a temperature between -2O ⁰ G and + 7O ⁰ G, preferably between ^{0 0} G and 40 ⁰ G. 3. The method according to claim 1 or 2, characterized in that metallic lithium, sodium or as alkali metal Potassium is used. 4. The method according to claim 1 or 2, characterized in that that as alkali derivative sodium naphthalene, sodium hydride, Lithium naphthalene, lithium hydride, potassium naphthalene, sodium triphenylmethyl, Lithium butyl or similar compounds can be used. 5. The method according to any one of claims 1 to 4, characterized in that that the preparation of the alkali derivatives of the protected benzyl penicillin in a dry inert Solvent is carried out. 2 09830/1169 6. The method according to one of the claims 1 to 5, characterized in that that the metal derivatives of the protected benzyl penicillin are not isolated, but directly to the reaction with acid halides' of formula IV can be used. 7. The method according to any one of claims 1 Ms 6, characterized in that that for the production of N-acylbenzyl penioillins of the formula I acid halides of the formula R-OD-X are used, in which R has the same meaning as in claim 1 and X represents a chlorine or bromine atom. 8. The method according to any one of claims 1 to 6, characterized in that that the penicillins according to formula I are produced in the form of their salts, such as the salts with sodium, Potassium, calcium, magnesium, aluminum, ammonium and substituted ammonium such as those produced by reaction with amines such as triethylamine, procaine, dibenzylamine ,, N-benzyl-p-phenylethylamine, !!, IT'-dibenzylethylenediamine and others Amines can be obtained as are usually used to form salts with benzyl penicillin. 9. The method naoh one of claims 1 "to 6, characterized in that the N-aoyl-benzyl-penicillins of the formula I are prepared in the form of their Bsterlier the following groups: O ₁ -O ₈ alkyl, O ₁ -O ₈ acyloxymethyl, p-methoxybenzyl, p-nitrobenzyl, benzhydryl, phenaoyl, p-bromophenaoyl, trimethylsilyl and benzyl. 209830/1169 10. Protected F-acyl penicillins of the general formula V, characterized in that they are manufactured according to the method according to any one of claims 1 to 7. 11. H-ayl penicillins of the formula I, or their salts or Esters, characterized in that they are produced according to the process according to one of Claims 1 to 7. 209830/1 169