WO1997003990A1

WO1997003990A1 - Isomer separation

Info

Publication number: WO1997003990A1
Application number: PCT/EP1996/003176
Authority: WO
Inventors: Johannes Ludescher; Hubert Sturm
Original assignee: Biochemie Gesellschaft Mbh
Priority date: 1995-07-19
Filing date: 1996-07-18
Publication date: 1997-02-06
Also published as: AU6734596A; AT403161B; ATA123095A

Abstract

A process for the production of 7-trialkylsilylamino-3(E)-3-(acetoxy-1-propen-1-yl)-3-cephem-4-carboxylic acid trialkylsilyl esters and their use in the production of highly active vinyl-cephalosporin antibiotics, such as cefluprenam of formula (V).

Description

Isomer Separation

This invention relates to a process for the production of 3'(E)-substituted 7-trialkyl- silylamino 3-propenyl-3-cephem-4-carboxylic acid trialkylsilyl esters and their use in the production of highly active vinyl-cephalosporin antibiotics.

Vinyl-cephalosporins have a broad spectrum of activity, β-lactamase stability and advantageous pharmacokinetics and are valuable cephalosporin antibiotics. Examples thereof are, inter alia, cefluprenam of formula

and a compound of similar structure, for example a compound as disclosed in US 5 075 298, US 5 455 238, DE 4 212 840, US 4 751 295, or US 5 143 911.

In the type of substitution as is present for example in cefluprenam, i.e. a 3-(E)-quaternary ammonium- 1 -propenyl group, it has been proved that the E-configuration is a more active principle than the Z-configuration, as far as both the gram-positive and the gram-negative range is concerned (for example J. Antibiotics, Vol. 45, No. 6, page 998, 1992 or J. Antibiotics Vol. 47, No. 12, page 1507, 1994). Accordingly, an antibiotic of this type having no Z-content or as little Z-content as possible is desirable.

7-trialkyl-silylamino-2-(E)-3-(iodo-l-propen-l-yl)-3-cephem-4-carboxylic acid trialkylsilyl esters, which are useful intermediates in the production of highly active vinyl- cephalosporins, may be obtained, e.g. as described in EPA 528 343, which is introduced herein by reference, in accordance with the following reaction scheme:

Iodination

In this reaction scheme, R₂ denotes a silyl protecting group, alkyl, aryl or acyl and R, are the same or different and independently of each other denote alkyl. A compound of formula III may, be obtained by a Wittig-type reaction as known, for example in a similar manner as described in EP 503 453, according to the following reaction scheme:

+ OHC — CHr 2- OR^ix2

Compound of formula III optionally after splitting off protecting groups and bissilylation.

In this reaction scheme, R₃ and R₄ are the same or different and each signify a protecting group.

It was now found that in the reaction of a compound of formula III with, for example an trialkyl iodosilane to give a compound of formula I, the 3-(E)-isomer of formula III reacts much more rapidly than the corresponding 3-(Z-)isomer. The corresponding 3-(Z)-isomer of formula III reacts slowly, whilst maintaining the double bond geometry, to form the 7-trialkylsilylamino-3-(Z)-3-(iodo-l-propen-l-yl)-3-cephem-4-carboxylic acid trialkylsilyl- ester, which is then further isomerized slowly to form the compound of formula I. Owing to the slow reaction times of the 3-(Z)-isomer and the instability of the compounds of formula I, losses in yield may occur, if a 3-(Z)-isomer is used compared with an 3-(E)- isomer. Consequently, it is desirable that the compound of formula III should be the pure 3-(E)-isomer or should at least contain the 3-(E)-isomer in a ratio as high as possible.

In J. Antibiotics, Vol. 45, No. 6, page 998 there is described the thermic isomerisation of (Z)-7-tert.butoxycarbonyl-3-(3-acetoxypropen-l -yl)-3-cephem-4-carboxylic acid diphenylmethyl ester to give the corresponding (E)-compound . The reaction is carried out at the boiling point of toluene (ca. 110°C). The yield is only 51% and the product has to be recrystallised.

It was now suφrisingly found, that the yields in the iodination reaction of a compound of formula III to give a compound of formula I may be improved drastically. This was found to be due to the conversion of the Z-isomer of formula III into the corresponding E-isomer of formula III before iodination caused by a sulphur-radical.

In one aspect the present invention provides therefore a process for the production of a compound of formula

wherein R_j denote alkyl, characterized in that a compound of formula

R,

wherein R₂ denotes a silyl protecting group, alkyl, aryl or acyl, and R, is as defined above, is reacted with a iodinating agent in the presence of a source of a sulphur-radical and in the presence of a compound which is able to form a sulphur-radical from a source of a sulphur-radical.

Iodinating agent may be e.g. trialkyliodosilanes, for example trimethyliodosilane. The iodinating agent may be used in a stoichimetric quantity in respect to a compound of formula III, or in excess.

A source of a sulphur-radical which may be used include, for example, thiols such as a compound of formula R₅-SH, wherein R₅ denotes alkyl, aryl, heterocyclyl or a trialkylsilyl group; and disulphides or sulphides, such as a compound of formulae R₅-S-S-R₅ or R₅-S-R₅, wherein each R₅ is independently of each another as defined above. A source of a sulphur-radical preferably may be a thiol or a disulphide. If a substituted aryl or heterocyclyl is used, it is preferable to have substituents which are electron- donators, such as alkyl, which, as was found, accelerate the reaction, so that, even at reaction temperatures of around 40° C, the isomerization reaction may progress very rapidly and practically quantitatively.

In another aspect the present invention provides a process as described above, characterized in that the source of a sulphur-radical is a compound of formulae R₅-SH, R₅-S-S-R₅ or R₅-S-R₅ wherein R₅ are the same or different and independently of each another denote alkyl, aryl, heterocyclyl or a trialkylsilyl group; for example a compound of formula R₅-SH, wherein R₅ denotes unsubstituted phenyl or mono- or polysubstituted phenyl by alkyl or a compound of formula R₅-S-S-R₅, wherein R₅ denotes thiazolyl or benzothiazolyl.

Preferably R₅ denotes a sulphide, for example a compound of formula R₅-SH, wherein R₅ denotes phenyl, preferably mono- or polysubstituted, preferably mono substituted, by C,_.6alkyl, more preferably C,.₄alkyl; or a disulphide, for example of formula R₅-S-S-R₅, wherein R₅, preferably both R₅, denotes heterocyclyl, for example, thiazolyl or benzothiazolyl.

Compounds which are able to form a sulphur-radical from a source of a sulphur-radical include, for example, radical starters, such as azo compounds, for example 2,2a-azo- isobutyronitrile or l,l-azo-bis(cyclohexanecarbonitrile); and compounds of the peroxide type, for example tert.butyl hydroperoxide or dibenzoyl peroxide and peroxy acid esters, for example peroxybenzoic acid tert.butyl ester, tert.butyl peroxy(3,3,5-trimethyl)hexa- noate.

In another aspect the present invention provides a process as described above, characterized in that a compound which is able to form a sulphur-radical from a source of a sulphur-radical is a radical starter, selected, for example from an azo compound, a compound of the peroxide type, or a percarboxylic acid ester. If not otherwise defined herein, any carbon containing radical contains up to 10 carbon atoms; alkyl includes straight chain or branched C,.,₂alkyl, preferably C,.₆alkyl, more preferably C_M alkyl. Aryl includes unsubstituted aryl or substituted aryl, preferably phenyl or, mono- or polysubstituted phenyl, more preferably C_Mmonoalkyl substituted phenyl. Heterocyclyl includes unsubstituted heterocyclyl or substituted heterocyclyl; for example thiazolyl oder benzothiazolyl. Substituents of the aryl group and of the heterocyclyl group include for example alkyl, alkoxy, aryloxy, alkylthio or arylthio, preferably alkyl. Alkyl in any trialkylsilyl group is preferably C,.₄alkyl, more preferably methyl. Preferably the alkyl groups in the trialkylsilyl group are identical. Acyl includes alkylcarbonyl of altogether 2 to 6 carbon atoms, and arylcarbonyl, for example phenylcarbonyl and naphthy Icarbony 1; preferably alkylcarbonyl, for example acetyl. A silyl protecting group includes a trialkylsilyl group. A protecting group includes amine and carboxylic acid protecting groups, for example amine and carboxylic acid groups which are well known in the art.

The process according to the present invention may be canied out as follows:

A compound of formula III, wherein R, and R₂ are as defined above and wherein the group -CH₂OR₂ has the cis [(Z)] -configuration in respect to the double bond where it is attached, or, preferably, a Z E mixture of a compound of formula III having, for example, an E-content of ca. 10%, suspended or dissolved in a solvent, for example an organic solvent, such as hydrocarbons, for example toluene; halogenated hydrocarbons, preferably dichloromethane; nitriles, e.g. acetonitrile; or mixtures of such solvents; preferably a hydrocarbon which is optionally halogenated; is treated with a iodinating agent and a source of a sulphur-radical in the presence of a compound which is able to form a sulphur-radical from a source of a sulphur-radical. The amount of the source of sulphur- radical employed is not critical and may, for example, range from catalytical quantities to molar excesses based on the compound of formula III to be isomerized, preferably from 0.5 to 0.7 molar equivalents based on the compound of formula III to be isomerized. The amount of a compound which is able to form a sulphur-radical from a source of a sulphur radical, for example a radical starter, may, for example, be in a range in which a radical starter is conventionally used, for example in the range of a few molar percent based on the compound of formula III to be isomerized. The reaction temperature may be from about 0° C, preferably from room temperature up to the boiling point of the reaction mixture. Preferably the reaction mixture is heated, preferably at the boiling point, preferably under N₂, for example under a stream of N₂. Termination of the iodination reaction may be detected, for example, by chromatography. A compound of formula I obtained may be isolated as conventional.

The yields of a process according to the present invention are extremely high, since suφrisingly neither decomposition nor secondary reactions take place to any notable extent. In particular, there are no or almost no 3-substituted S-compounds formed. High yields are even more suφrising in view of, for example, Flynn, Cephalosporins and

Penicillins, Academic Press (1972), p.151 , wherein is described that the exchange of the 3- acetoxy group in 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid (7-ACA) may take place very easily and a compound of formula III wherein R denotes acyl represents a vinyl-like 7-ACA or an analogue thereof. The isomerization reaction - and a subsequent iodination reaction - according to the present invention may be suφrisingly effected rapidly under moderate conditions, for example around 40° C. Suφrisingly practically no secondary reactions do occur, such as the formation of mercapto adducts, substitution of the 3-acetoxy group by an S-compound, or secondary reactions such as those that may readily occur during a photo-chemical reaction. The reaction may be carried out in short time and results in high yields.

Isomerization of a compound of formula III wherein the group -CH₂OR₂ has the cis [(Z)]- configuration in respect to the double bond where the group -CH₂OR₂ is attached, into a compound of formula HI wherein the group -CH₂OR₂ has the trans [(E)]-configuration in respect to the double bond where the group -CH₂OR₂ is attached, may be carried out in the same way as described for the iodination reaction, but without the presence of an iodinating agent. The Z-isomer of formula III may be isolated as conventional and may be used for further reaction, for example in an iodination reaction as described above, optionally after, for example conventional, splitting off protecting groups.

In another aspect the present invention provides therefore a process for the production of a compound of formula

wherein

Ri are the same or different and independently of each other denote alkyl,

R₂ denotes a silyl protecting group, alkyl, aryl or acyl, and wherein the group -CH₂OR₂ has the trans [(E)j-configuration in respect to the double bond where the group -CH₂OR₂ is attached, characterized in, that a compound of formula HI, wherein R, and R₂ are as defined above and wherein the group -CH₂OR₂ has the cis [(Z)] -configuration is reacted in the presence of a source of a sulphur-radical and in the presence of a compound which is able to form a sulphur-radical from a source of a sulphur-radical.

The practically quantitative degree of bissilylation of a compound of formula III may be maintained during the isomerization reaction according to the present invention. This is a great advantage and important, for example in a subsequent reaction, for example in an iodination reaction, wherein a compound of formula III is reacted with an iodinating agent to give a compound of formula I, because it was found that in case that a partially desilylated compound is used (preferably the amine group may be desilylated) excessive decomposition of the molecule may occur. An almost quantitative degree of bissilylation is thus essential to obtain high yields.

In addition it was suφrisingly found, that a source of a sulphur-radical; or a compound which is able to form a sulphur-radical from a source of a sulphur-radical as used in the isomerization according to the present invention; or a product formed during isomerization by a sulphur-radical or by a compound which is able to form a sulphur-radical from a source of a sulphur-radical; do practically not disturbe a further reaction, for example, neither a reaction with trialkyliodosilane to give a compound of formula I, nor a subsequent reaction of a compound of formula I with a coπesponding nucleophile which replaces the iodo group. It was suφrisingly found that silylation of 7-amino-3-(3-acetoxy- l-propen-l-yl)-3-cephem-4-carboxylic acid, for example in the presence of trimethyliodosilane and hexamethyldisilane to give a compound of formula III, the isomerization of a compound of formula III according to the present invention, a subsequent reaction with iodoalkylsilane to give a compound of formula I and a nucleophilic exchange of the iodo group of a compound of formula I may be caπied out in a one-pot reaction. If the nucleophile used to replace the iodo group has a reactive group or groups which could react with the iodoalkylsilane used in the iodination step, the amount of iodotrialkylsilane should be increased to silylate this reactive group or groups. Otherwise the isomerized E-compound of formula III should be isolated before the reaction with the nucleophile is caπied out. Suitable solvents in the one-pot reaction include solvents as described above for the isomerization and/or iodination of a compound of formula III according to the present invention. Isolation of any intermediate, is not necessary. The reaction times may be very short and the process of the present invention is thus of high economical interest.

In another aspect the present invention therefore provides the use of a process according to claim 1 or according to claim 2 in the production of a 3'(E)-substituted 7-amino-3- propenyl-3-cephem-4-carboxylic acid.

A 3'(E)-substituted 7-amino-3-propenyl-3-cephem-4-carboxylic acid may be, for a example, a compound of formula I of EP 528 343, wherein R₀ is hydrogen and R, R, and X are as defined in EP 528 343.

Acylation of 3'(E)-substituted 7-amino-3-propenyl-3-cephem-4-carboxylic acid may result in a 3'(E)-substituted 7-acylamino-3-propenyl-3-cephem-4-carboxylic acid being an highly active cephalosporin antibiotic, for example cefluprenam, as already described above. Acylation may be caπied out as conventional in the field of cephalosporins. Acylation of a compound of formula IV to give cefluprenam is described, for example, in EP 333 154 which is introduced herein by reference.

In a further aspect the present invention provides the use of a process according to claim lor according to claim 2 in the production of a 3'(E)-substituted 7-acylamino-3-propenyl- 3-cephem-4-carboxylic acid.

A 3'(E)-substituted 7-acylamino-3-propenyl-3-cephem-4-carboxylic acid may be cefluprenam and a compound as described, for example, in US 5 075 298, US 5 455 238,

DE 4 212 840, US 4 751 295 and US 5 143 911 which are introduced herein by reference.

In a further aspect the present invention provides a process for the production of cefluprenam of formula

characterized in that a) a compound of formula

R, wherein

R₂ denotes a silyl protecting group, alkyl, aryl or acyl, and

R, are the same or different and independently of each other denote alkyl, is reacted with a iodination agent in the presence of a source of a sulphur-radical and in the presence of a compound which is able to form a sulphur-radical from a source of a sulphur-radical to give a compound of formula

wherein R, is as defined above, b) subjecting a compound of formula I to nucleophilic substitution of the iodo group to give a compound of formula

in free base form or in salt form, and, if desired, conversion of a salt form into the free base form or vice versa c) acylating a compound of formula IV to give a compound of formula V in free base form or in salt form, and, if desired, conversion of a compound of formula V into a pharmaceutically acceptable salt form.

In the following examples all temperatures are given in degrees Celsius. Example 1 7-amino-3-[(E)-3-carbamoyImethylethylmethylammonium)-l-propen-l-yl]-3-cephem-4- carboxylic acid iodide (one-pot reaction)

50 g of (Z)-7-amino-3-(3-acetoxy-l-propen-l-yl)-3-cephem-4-carboxylic acid (E-isomer content: 7.2%) are suspended in 1000 ml of absolute dichloromethane. 90 μl of trimethyl¬ silyl iodide and 62.7 ml of hexamethyldisilazane are added. The resultant solution is refluxed for 1 hour under N₂. 14.5 g of 4-methylthiophenol and 8.0 ml of perbenzoic acid tert.butyl ester are added, and the reaction mixture is refluxed for a further 3 hours. N,O-bissilylated (E)-7-amino-3-(3-acetoxy-l-propen-l-yl)-3-cephem-4-carboxylic acid is obtained. The reaction mixture is cooled to -10° and 66.5 ml of trimethylsilyl iodide are added. After stiπing for 3 hours at -10°, a solution of 23.4 g of N-methyl,N-ethyl- glycine-amide and 29.1 ml of hexamethyldisilazane in 7 ml of dichloromethane, which has been boiled for 24 hours, is added. 68.9 ml of N-ethyl-diisopropylamine are added dropwise. After stiπing for 3 hours at -10°, the reaction mixture is stirred into 1000 ml of isopropanol. A precipitate is obtained, filtered off, washed with isopropanol and dried.

67.5 g (74.7% of theory) of 7-amino-3-[(E)-3-carbamoylmethylethylmethylammonium)-l - propen-l-yl]-3-cephem-4-carboxylic acid iodide are obtained in the form of a light brown powder.

Z/E content: < 0.1/ > 99.9

Example 2 7-Amino-3-[(E)-3-(carbamoylmethyIethylmethylammonium)-l-propen- l-yl]-3-cephem-4-carboxyIic acid iodide (one-pot reaction) 100 g of (Z)-7-amino-3-(3-acetoxy-l-propen-l-yl)-3-cephem-4-carboxylic acid (E-isomer content: 6.4 %) are suspended in 2000 ml of absolute dichloromethane. 400 μl of trimethylsilyl iodide and 127 ml of hexamethyldisilazane are added. The resulting solution is refluxed for ca. one hour under N₂. A solution of 23.2 g of tert.-butylperoxy-(3,3,5- trimethyl)hexanoate and 20.8 g of 4-methylthiophenol in 100 ml absolute dichloromethane are added in 3 portions within ca. 2 hours. The reaction mixture is refluxed for one hour. A solution of N,O-bissilylated (E)-7-amino-3-(3-acetoxy-l-propen-l-yl)-3-cephem-4- carboxylic acid is obtained, which is cooled to -25°. At this temperature 133 ml of trimethylsilyljodide are added. The reaction mixture is stiπed for ca. 17 hours at -25°, a solution of 46.7 g of N-methyl,N-ethyl-glycine-amide and 58.2 ml of hexamethyldisilazane in 14 ml of dichloromethane, which has been boiled for 24 hours, is added. 137.6 ml of N-ethyl-diisopropylamine are added and the reaction mixture is wanned to 0° and stiπed for ca. 3.5 hours at this temperature. 24.1 ml of N-ethyl-diisopropylamine are added. After stiπing for ca. 4 hours at 0° the reaction mixture is stiπed into 99 ml of methanol within ca. 20 to 25 minutes. The temperature is kept at ca. 30 to 35°. A precipitate is obtained, filtered off , washed with dichloromethane and dried.

157.8 g of 7-Amino-3-[(E)-3-(carbamoylmethylethylmemylammonium)-l -propen- l -yl]-3- cephem-4-carboxylic acid iodide in the form of a light brown powder are obtained. Z/E- content: <0.1/>99.9

Example 3 7-Amino-3-[(E)-3-(carbamoylmethylethylmethylammonium)-l-propeι_- l-yl]-3-cephem-4-carboxylic acid iodide

a) (E)-7-Amino-3-(3-acetoxy-l -propen-1 -yl)-3-cephem-4-carboxylic acid

7.5 g of (Z)-7-amino-3-(3-acetoxy-l-propen-l -yl)-3-cephem-4-carboxylic acid (E-content:

7.2 %) are suspended in 150 ml of absolute dichloromethan. 14 μl of trimethylsilyliodide and 7.3 ml of hexamethyldisilazane are added. The resulting solution is refluxed for ca. one hour under N₂. 1.56 g of 4-methylthiophenol and 0.72 ml of perbenzoic acid tert.butylester are added and the reaction mixture is refluxed for ca. 2 hours, cooled to room temperature and stiπed into 150 ml of methanol. The pH is kept at 3.5 by addition of diluted HCl. The reaction mixture is stiπed for ca. 30 minutes, the precipitate separated, washed with methanol and dried.

7.07 g of (E)-7-amino-3-(3-acetoxy-l-propen-l-yl)-3-cephem-4-carboxylic acid in the form of a light yellow powder are obtained. ZE-ratio: 0.36/99.64

b} (E -7-Amino-3-(^'3-acetoxy- 1 -propen- 1 -y l)-3-cephem-4-carboxylic acid

7.5 g of (Z)-7-amino-3-(3-acetoxy-l -propen- l-yl)-3-cephem-4-carboxy lie acid (E-content:

7.2 %) are suspended in 150 ml of toluene. 14 μl of trimethylsilyliodid and 9.5 ml of hexamethyldisilazane are added. The resulting solution is stiπed under N₂ for ca. 2 hours at a inner temperature of the reaction vessel of ca. 70°. 2.93 g of mercaptobenzthiazol- disulfide and 1.2 ml of perbenzoic acid tert.butylester are added and the reaction mixture is stiπed for ca. 18 hours at this temperature and cooled. Precipitated mercaptobenz- thiazoldisulfide is filtered off. The resulting mother liquor is stiπed into 150 ml of methanol. The pH is kept at 3.5 by addition of diluted HCl. The reaction mixture is stiπed for ca. 30 minutes, the precipitate separated, washed with methanol and dried. 6.68 g of (E)-7-amino-3-(3-acetoxy-l -propen- 1 -yl)-3-cephem-4-carboxy lie acid are obtained. Z/E-ratio: 2.1/97.9

c}^' 7-Amino-3-r(EV3-(carbamoylmethylethylmethylammoniumVl -propen- l -yll-3- cephem-4-carboxylic acid iodide 71.6 g of (E)-7-amino-3-(3-acetoxy-l -propen- 1 -yl)-3-cephem-4-carboxy lie acid are suspended in 1430 ml of absolute dichloromethan. 130 μl trimethylsilyliodide and 112 ml of hexamethyldisilazane are added. The resulting solution is refluxed for ca. 7 hours under

N₂. N,O-bissilylated (E)-7-amino-3-(3-acetoxy-l -propen- 1 -yl)-3-cephem-4-carboxy lie acid is obtained. The reaction mixture is cooled to -20°. At this temperature 95 ml of trimethylsilyliodide are added dropwise. The reaction mixture is stiπed for ca. 17 hours at this temperature. A solution of 34.9 g of N-methyl,N-ethyl-glycinamide, 2.2 g of saccharine and 93 ml of hexamethyldisilazane in 10 ml of dichloromethan, boiled for 24 hours, is added. 98 ml of N-ethyl-diisopropylamine are added dropwise. The reaction mixture is stiπed for ca. 4 hours and stiπed into a mixture of 1440 ml of isopropanol and 15.6 ml of water at -10°. Precipitation occurs. The suspension is cooled to 5° and stiπed for ca. one hour at this temperature. The precipitate is filtered off, washed with isopropanol and dried.

118.5 g (84% of theory) of 7-amino-3-[(E)-3-(carbamoylmethylethylmethylammonium)-l- propen-l-yl]-3-cephem-4-carboxylic acid iodide in the form of an orange coloured powder are obtained. Z/E-content: <1.0/>99.0 Example 4 7-amino-3-[(E)-3-(carbamoylmethyIethylmethylammonium)-l-propen-l-yI]-3-cephem- 4-carboxylic acid iodide (Comparison Example)

100 g of (Z)-7-amino-3-(3-acetoxy-l -propen- l-yl)-3-cephem-4-carboxy lie acid (E-content: 7.2%) are suspended in 2000 ml of absolute dichloromethane. 180 μl of trimethylsilyl iodide and 127 ml of hexamethyldisilazane are added. The resultant solution is refluxed for ca. 7 hours under N₂. N,O-bissilylated (Z)-7-amino-3-(3-acetoxy-l -propen- l-yl)-3- cephem-4-carboxylic acid is obtained. The reaction mixture is cooled to -10° and 133 ml of trimethylsilyl iodide and 300 ml of absolute sulpholane are added dropwise at this temperature. The reaction mixture is stiπed for ca. 40 hours at this temperature and a solution of 48.8 g of N-methyl,N-ethyl-glycine-amide, 230 μl of trimethyliodo silane and 61 ml of hexamethyldisilazane in 14 ml of dichloromethane, which has been boiled for 24 hours, is added. 137.6 ml N-ethyl-diisopropylamine are added dropwise. After stiπing for 4 hours at -10°, the reaction solution is stirred into 2000 ml of isopropanol. A precipitation is obtained. The precipitate is filtered off, washed with isopropanol and dried.

138.9 g (59.4% of theory) of 7-amino-3-[(E)-3-(carbamoylmethylethylmethylammonium)- l-propen-l-yl]-3-cephem-4-carboxylic acid iodide in the form of a brown coloured powder are obtained. Z/E-Gehalt: <l/>99

Claims

Patent Claims:

1. A process for the production of a compound of formula

wherein R_[ are the same or different and independently of each other denote alkyl, characterized in that a compound of formula

R,

2. A process for the production of a compound of formula

R,

wherein

R, are the same or different and independently of each other denote alkyl,

R₂ denotes a silyl protecting group, alkyl, aryl or acyl, and wherein the group -CH₂OR₂ has the trans [(E)J-configuration in respect to the double bond where the group -CH₂OR₂ is attached, characterized in, that a compound of formula III, wherein R, and R₂ are as defined above and wherein the group -CH₂OR₂ has the cis [(Z)]-configuration is reacted in the presence of a source of a sulphur-radical and in the presence of a compound which is able to form a sulphur-radical from a source of a sulphur-radical.

3. Process according to any one of claims 1 or 2, characterized in that the source of a sulphur-radical is a compound of formulae R₅-SH, R₅-S-S-R₅ or R₅-S-R₅ wherein R₅ are the same or different and independently of each another denote alkyl, aryl, heterocyclyl or a trialkylsilyl group.

4. Process according to claim 3, characterized in that the source of a sulphur-radical is a compound of formula R₅-SH, wherein R₅ denotes unsubstituted phenyl or mono- or polysubstituted phenyl by alkyl, or a compound of formula R₅-S-S-R₅, wherein R₅ denotes thiazolyl or benzothiazolyl.

5. Process according to any one of claims 1 to 4, characterized in that a compound which is able to form a sulphur-radical from a source of a sulphur-radical is a radical starter. - 18

6. Process according to claim 5, characterized in that the radical starter is selected from an azo compound, a compound of the peroxide type, or a percarboxylic acid ester.

7. Use of a process according to any one of claims 1 or 2 in the production of a 3 '(E)- substituted 7-amino-3-propenyl-4-cephem-carboxylic acid.

8. Use of a process according to any one of claim lor 2 in the production of a 3'(E)- substituted 7 -acylamino- 1 -propen- 1 -yl-3-cephem-4-carboxy lie acid.

9. A process for the production of cefluprenam of formula

characterized in that a) a compound of formula

wherein R₂ denotes a silyl protecting group, alkyl, aryl or acyl, and

10. A process for the production of 7-trialkylsilylamino-2-(E)-3-(iodo-l -propen- l-yl)-3- cephem-4-carboxylic acid trialkylsilyl-esters of formula

wherein R, signifies a lower alkyl group, characterized in that compounds of formula

wherein

R₂ denotes a silyl protecting group, alkyl, aryl or acyl, and

Rj is as defined above, are converted radically with an S-radical into the practically pure E-isomers of the compounds of formula III, and these are reacted with trialkyliodosilane to form the compounds of formula I.