NO772396L - PROCEDURES FOR PREPARING PENAM AND CEFEM DERIVATIVES - Google Patents

Description

The present invention relates to a method for the production of penam and cephem derivatives by reacting a phosphitamide with the general formula:

where X denotes a group with the general formula: where the carbon atom adjacent to the group with the general formula -COOR is linked to the nitrogen atom, R denotes optionally substituted alkyl, optionally substituted aralkyl or an organometallic group, R 2 denotes hydrogen, acetoxy or a group with the general formula -S-Het, where Het denotes a heterocyclic group, and Z denotes a group of the general formula: 3 4 5 where R denotes alkyl, R and R are the same or different and each denotes alkyl, n denotes 1 or 2, and m represents 0, 1 or 2, with an acyl halide in an aprotic solvent. In Belgian patent document no. 809,110 and the corresponding .,, British patent applications no. 12788/75 and oa 26826/75 a'-^^° » method for the production of penam and cephem derivatives by v conversion of a phosphitamide of 6- aminopenicillanic acid or 7-aminocephalosporanic acid with an acyl halide in an aprotic solvent. With this turnover, penam or céfem derivatives are obtained in high yields. The reaction is proton-catalysed, and the reaction rate can be regulated by varying the proton concentration in the reaction medium, e.g. in that varying amounts of an acid addition salt of a weakly basic tertiary amine are added as a proton source, possibly in a mixture with the weakly basic tertiary amine itself. Examples of such amines are pyridine and N,N-dimethylaniline, and examples of acid addition salts are hydrochlorides. The total reaction proceeds with the release of a phosphite halide, which is exemplified in the following reaction scheme relating to the production of the trimethylsilyl ester of ampicillin:

Phosphite halides, such as the compound of formula A which of course

are completely stable, under aprotic conditions, react with hydroxy compounds such as water and alcohols. Therefore, hydroxy groups and corresponding substituents must be appropriately protected during the reaction. Problems may also arise when, as a step in the preparation of compounds as sensitive as penicillins and cephalosporins, there is a hydrolytic step, unless the vigorous reaction between the phosphite halide and water is sufficiently controlled. It has now surprisingly been shown that these obstacles can be overcome by adding a phosphite halide removing agent to the reaction

the mixture.

According to the present invention, the reaction between the phosphite amide of the general formula I and the acyl halide is therefore carried out in an aprotic solvent in the presence of a phosphite halide removing agent.

As indicated above can be a substituted alkyl or aralkyl group. Examples of substituted alkyl groups' are 2,2,2-trichloroethyl, p-bromophenacyl, pivaloyloxymethyl and phthalidyl. Examples of substituted aralkyl groups are benzhydryl and benzyl, which are optionally substituted with a nitro group in the benzene ring. Examples of an organometallic group are trialkylsilyl, preferably trimethylsilyl. In the present description and in the claims, the term alkyl, when used alone or in combination with other groups, denotes a linear or branched•alkyl group which preferably contains at most 6 carbon atoms, more preferably at most 4 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl and tert.butyl. Examples of groups with the general formula A3 are 1,3,2-dioxaphosfolan-2-yl, and groups with the general formula A4 are those where R 4 and R 5 each denote ethyl.

It is preferred that the acyl halide used in the method according to the present invention has the general formula:

where R<6> denotes naphthyl, cycloalkyl which is substituted with amino, and which is optionally interrupted by oxygen or sulphur, phenyl which is substituted with one or more . alkoxy groups, substituted heterocyclyl, methyl substituted with one or two of the following substituents: phenoxy, amino, cyclohexyl containing one or two unsaturated bonds, triazo, optionally substituted phenoxycarbonyl, optionally substituted phenyl, alkyl, thienyl, cyano, hydroxy or optionally with halogen substituted pyridylthio, or the corresponding groups containing a hydroxy or amino protecting group on an optionally present hydroxy or amino group, and Hal denotes halogen. Preferably R denotes 1-aminocyclohexyl, 4-aminotetrahydropyran-4-yl, 4-aminotetrahydrothiopyran-4-yl, 1-amino-cyclopentyl, phenoxymethyl, 1-(1,4-cyclohexadienyl)aminomethyl, a-triazobenzyl, a- (2,3-dihydro-inden-5-yloxycarbonyl)benzyl, α-aminobenzyl or 3-phenyl-5-methyl-

isoxazol-4-yl, which is optionally substituted with halogen in the 2- and 6-position of the phenyl group, 2,6-dimethoxyphenyl, p-hydroxy-ct-aminobenzyl, 1-phenoxypropyl, thien-2-ylmethyl, 1-naphthyl , 1-(thien-3-yl)aminomethyl, 1H-tetrazol-1-ylmethyl, pyrid-4-ylthiomethyl,

which is optionally substituted with halogen in the 2- and 6-position, cyanomethyl, α-hydroxybenzyl or p-(3,4,5,6-tetrahydropyrimidin-2-yl)phenylmethyl or similar groups containing a hydroxy or amino protecting group on an optionally hydroxy or amino group present.

As indicated above, R 2 may be a group of the general formula S-Het,. where Het denotes a heterocyclic group.

Examples of such heterocyclic groups are tetrazole, 1,2,3-triazole and 1,3,4-thiadiazole, each of which may be substituted with alkyl or carboxyalkyl, e.g. methyltetrazole, carboxymethyltetrazole and 2-methyl-1,3,4-thiadiazole.

In the present description and in the claims, the term halogen, when used alone or together with other groups, denotes bromine, chlorine and fluorine, preferably chlorine.

An example of a compound containing an amino protecting group is a compound of the general formula II, where R denotes a group containing a group of the general formula -NH^<+>Z , where HZ denotes an organic or inorganic acid. HZ preferably denotes HC1. An example of a hydroxy protecting group is trialkylsilyl. preferably trimethylsilyl, i.e. R g is a group containing p-trialkylsilyloxy,

■ preferably p-trimethylsilyloxy. It is also possible to use other compounds containing a protective group, provided that the protective group in question can then be easily cleaved to form the desired penam or cephem compound.

Examples of phosphite halide removing agents which are suitable for use in the method according to the present invention,

are epoxides and vinyl ethers which can react quantitatively or almost quantitatively with the phosphite halide, which is illustrated in example 1, where 2-chloro-1,3,2-dioxaphospholane and propylene oxide are used as reaction components in a control experiment. The turnover can be illustrated using the following reaction nucleus:

which, however, is only illustrative, but not limiting with regard to the scope of the invention.

As the phosphite halide removing agent does not interfere with the amide-forming reaction specified in reaction core 1, the presence of a phosphite halide removing agent such as a spoxide or a vinyl ether enables the reaction to also be carried out with a reaction component bearing an unprotected hydroxy group such as D-(-)- p-Hydroxyphenylglycyl chloride hydrochloride used in the manufacture of p-hydroxyampicillin.

A preferred subgroup of phosphite halide removing agents which are suitable for use in the method according to the present invention are compounds of the general formula: where Q denotes a residue of the formula -CH=CH-0- or

and R and R are the same or different and each represents hydrogen, substituted or unsubstituted alkyl or aryl, or R 7 and R<8> together with Q form a heterocyclic ring, with the proviso

7 8

that any symbol R or R which is attached to the oxygen atom of the residue Q with the formula -CH=CH-0-, does not denote hydrogen.

A preferred subgroup of compounds of the general formula III are compounds of the general formula:

where R 9 denotes hydrogen, substituted or unsubstituted alkyl or aryl, and preferably compounds where R 9 denotes methyl,

chloromethyl or phenyl.

A further preferred subgroup of compounds of the general formula III are compounds of the general formula:

where R"1"1 denotes hydrogen or alkyl, and R<10>- denotes alkyl, or R and R together with the residue -CH=CH-0- form a heterocyclic ring, and preferably compounds where R^ denotes hydrogen, and R "^° denotes ethyl or butyl, or R^° and R"^ together denote trimethylene.

One would expect that when the acylation of a phosphitamide with an acyl halide containing a free hydroxy group (e.g. when R g denotes p-hydroxy-α-aminobenzyl) is carried out in the presence of an excess of a weakly basic tertiary amine, there would occur a reaction with the unprotected hydroxy group to form a tertiary phosphite ester. The efficiency of the phosphite halide scavenger in blocking this reaction, in the presence of a weak base, e.g. N,N-dimethylaniline is illustrated in example 9 below.

The method according to the invention is explained in more detail by the following examples:

Example 1

0.9 ml (0.1 mmol) of 2-chloro-1,3,2-dioxaphospholane is dissolved at room temperature in 5.6 ml of dry methylene chloride, and 3.5 ml (50 mmol) of propylene oxide is added. A weakly exothermic reaction takes place during the formation of a mixture of two compounds, which can be ascertained by gas-liquid chromatography.<31>P-NMR spectra of the reaction mixture show 2 signals at 6 = 143 ppm and 134 ppm and indicate that the two compounds formed have formulas VI and VII. No signals can be detected from the output connection (6 = 168 ppm). The spectra are recorded at 36.43 MHz and 85% phosphoric acid is used as an external standard.

After adding water to the reaction mixture, when a silver nitrate solution is added, no chloride ions can be detected, but precipitation of metallic silver is observed.

By gas-liquid chromatography, it is established that the two propylene chlorohydrins with the formulas VI and VII are formed in a ratio of approx. 2:1.

Example 2

p-hydroxyampicillin

84 ml (0.6 mol) of diisopropylamine dissolved in 400 ml of dry methylene chloride is cooled to 0°C, and at this temperature 27 ml (0.3 mol) of 2-chloro-1,3,2-dioxaphospholane are added dropwise. After 30 minutes, the temperature is allowed to rise to room temperature, and 64.8 g (0.3 mol) of 6-aminopenicillanic acid and 38 ml (0.3 mol) of trimethylchlorosilane are added. When the slightly exothermic reaction has subsided, the mixture is stirred for 3 hours, cooled to 0°C and filtered to remove precipitated amine hydrochloride. 2.32 g are added to the cooled filtrate with vigorous stirring

(20 mmol) pyridine hydrochloride, 70 ml (1 mol) propylene oxide and

54.5 g (0.2 mol) D-(-)-p-hydroxyphenylglycyl chloride hydrochloride. Trading has ended after 40 minutes have elapsed. The yield is determined by titration after hydrolysis with the aid of Bacillus cereus

31

penicillinase to 94%. P-NMR spectra of this solution show the two signals indicated in example 1 at δ = 143 ppm and 134 ppm.

The reaction mixture is poured into ice water with vigorous stirring, while the pH value of the mixture is adjusted to 2 with a sodium hydroxide solution. After stirring for 30 minutes, the organic phase is removed, the aqueous phase is washed twice with methylene chloride, and the product is precipitated by setting the pH value to 4.9 with an aqueous ammonia solution. After 2 hours, the product is insulated with wood. filtration, and the filter is washed with water. The yield is 69.2 g (82.5%) raw material with a purity of 83%

(determined biologically against Sarcina lutea). Further purification can be carried out in a known manner.

Example 3

A reaction mixture is prepared in an analogous manner as described in example 2 from 3.18 g (15 mmol) 6-aminopenicillanic acid, 2.72 g (10 mmol) D-(-)-p-hydroxyphenylglycyl chloride hydrochloride and 3.5 ml ( 50 mmol) of propylene oxide, the addition of pyridine hydrochloride being omitted, however. This reaction is called reaction A.

In an analogous way, another reaction mixture is prepared,

adding 116 mg (1 mmol) of pyridine hydrochloride. This reaction is called reaction B.

These reactions are followed by enzymatic titration of. the penicillin content at different times:

Example 4

2 reaction mixtures are prepared in an analogous manner to that described in example 3B, however, the propylene oxide is replaced with 4.5 ml of dihydropyran, and the quantities of pyridine hydrochloride are as follows:

Reaction A: 116 mg (1 mmol)

Reaction B: 1.74 g (15 mmol)

The reactions are monitored titrimetrically:

Example 5

A reaction mixture is prepared in an analogous manner to that described in example 3 B, however, the addition of propylene oxide is omitted. The amount of pyridine hydrochloride is 116 mg (1 mmol). The reaction is monitored titrimetrically:

Example 6

A reaction mixture is prepared in an analogous manner to that described in example 3 B, however, the propylene oxide is replaced with 4.8 ml of ethyl vinyl ether. The yield is determined titrimetrically after 2 and 4 hours at 77%.

Example 7

In a reaction mixture described in example 2, the propylene oxide is replaced with 4 ml of epichlorohydrin (1-chloro-2,3-epoxypropane). The yield (by titration) of amoxicillin is 90% after 45 minutes.

Example 8

In a reaction mixture described in example 2, the propylene oxide is replaced with 10.5 ml of styrene oxide. The yield (by titration) of amoxicillin is 85% after 45 minutes.

Example 9

2.8 ml (20 mmol) of diisopropylamine dissolved in 15 ml of dry methylene chloride is cooled to 0°C, and 0.9 ml (10 mmol) of 2-chloro-1,3-dioxaphospholane dissolved in 5 ml methylene chloride. After stirring for 30 minutes, the temperature is raised to 20°C, and 2.16 g of 6-aminopenicillanic acid are added, followed by 1.2 ml (10 mmol) of trimethylchlorosilane. After stirring for 3 hours at room temperature, the mixture is cooled to 0°C, and the precipitated diisopropylamine hydrochloride is removed by filtration. The filtrate is cooled to -15°C, and 0.93 ml of a 2N solution of N,N-dimethylaniline hydrochloride in methylene chloride, 1.3 ml of N,N-dimethylaniline and 3.5 ml of propylene oxide are added, followed by 2.4 g (9 mmol) p-hydroxyphenylglycyl chloride hydrochloride. The cooling bath is removed, and

the temperature rises within 10 minutes to 15°C. After reaction for 30 minutes, the above-mentioned compounds with formulas VI and VII are identified in the reaction mixture by gas chromatography. The yield is 65%, calculated against a reference standard resolution. The yield of penicillin is 70%, calculated by enzymatic means

titration.

Claims (3)

1. Process for the production of penam or cephem derivatives by reacting a phosphitamide with the general formula: where X denotes a group with the general formula: where the carbon atom in the neighboring position in relation to the group with the general formula -COOR <1> is linked to the nitrogen atom, R1 denotes optionally substituted alkyl, optionally substituted aralkyl or an organometallic group, R 2 denotes hydrogen, acetoxy or a group with the general formula - S-Het, where Het denotes a heterocyclic group, and Z denotes a group of the general formula: where R <3> denotes alkyl, R <4> and R <5> are the same or different and each denotes alkyl, n denotes 1 or 2, and m denotes 0, 1 or 2, with an acyl halide in an aprotic solvent, characterized in that the reaction is carried out in the presence of a phosphite halide removing agent. 2. Method according to claim 1, characterized in that R" <*> " denotes trialkylsilyl 1. '3. Method, according to claim 2, characterized in that R 1 denotes trimethylsilyl..;4. Method according to claim 3, characterized in that X denotes a group with the general formula Al, where R denotes trimethylsilyl, and Z denotes 1,3,2-dioxaphospholan-2-yl.; 5. Method according to claim 1, characterized v e 4 that the acyl halide has the general formula: R <6-> C0-Hal (II) where R^ denotes naphthyl, cycloalkyl which is substituted with amino, and which is optionally interrupted by oxygen or sulphur, phenyl which is substituted with one or more alkoxy groups, substituted heterocyclyl, methyl which is substituted with one or two of the following substituents : phenoxy, amino, cyclohexyl containing one or two unsaturated bonds, triazo, optionally substituted phenoxy-carbonyl, optionally substituted phenyl, - alkyl, thienyl, cyano, hydroxy or \optionally halogen-substituted pyridylthio, or the • corresponding groups containing a hydroxy- or amino protecting group on an optionally present hydroxy or amino group, and Hal denotes halogen.;6. Process according to claim 5, characterized in that R^ bete^F ^is 1-aminocyclohexyl, 4-aminotetrahydropyran-4-yl, 4-aminotetrahydrothiopyran-4-yl, 1-aminocyclopentyl, phenoxy- , methyl, 1-(1,4-cyclohexadienyl)aminomethyl-,α-triazobenzyl,α-(2,3-dihydroinden-5-yloxycarbonyl)benzyl,α-aminobenzyl or 3-phenyl-5-methylisoxazol-4-yl , which is optionally substituted' with halogen in the 2- and 6-position in the phenyl group, 2,6-dimethoxyphenyl, p-hydroxy-α-aminobenzyl, 1-phenoxypropyl, thien-2-ylmethyl 1', 1-naphthyl, 1 -(thien-3-yl)aminomethyl, 1H-tetrazol-1-ylmethyl, pyrid-4-ylthiomethyl which is optionally substituted with halogen in the 2- and 6-position, cyanomethyl, α-hydroxybenzyl or p-(3,4, 5,6-tetra- . hydropyrimidin-2-yl)phenylmethyl or similar groups containing a hydroxy or amino protecting group on an optionally present hydroxy or amino group, and Hal denotes halogen.;7. Method according to claim 5 or 6, characterized in that Hal denotes chlorine. .8. Method according to any one of claims 5-7, characterized in that R denotes a group containing a group of the formula -NH3+C1 .;9. Method according to claim 6, characterized in that R denotes α-aminobenzyl or substituted or unsubstituted β-hydroxy-α-aminobenzyl, and Hal denotes chlorine.; 10. Method according to any one of claims 1-9, characterized in that the phosphite halide removing agent is an epoxide or a vinyl ether.;11. Method according to claim 10, characterized in that the phosphite halide removing agent has the general formula: where Q denotes a residue of the formula -CH=CH-0- or ~ l o ;and R and R are the same or different and each represents hydrogen, substituted or unsubstituted alkyl or aryl, or R 7 and R <8> together with Q form a heterocyclic ring, with the proviso that any symbol R 7 or R 8 which is linked to the oxygen atom in the residue Q with the formula -CH=CH -0 -, does not denote hydrogen.;12. Method according to claim 11, characterized in that the phosphite halide removing agent has the general formula: ;where R 9 denotes hydrogen, substituted or unsubstituted alkyl or aryl.;1. 3. Method according to claim 12, characterized in that R 9 denotes methyl, chloromethyl or phenyl.; 14.. Method according to claim 11, characterized in that the phosphite halide removing agent has the general formula: ; where R <1> "^ denotes hydrogen or alkyl , and R"1"0 denotes alkyl, or R10 and R"1"1 together with the residue -CH=CH-0- form a heterocyclic ring.; 15. Method according to claim 14, characterized in that R ^ and R"^ together denote trimethylene.;16. Method according to claim 14, . characterized in that R"*""^ denotes hydrogen, and R^ denotes ethyl or butyl-. 17. Method according to which. preferably from claims 1-16, characterized in that a proton donor is added to the reaction mixture. 18. Method according to claim 17, characterized in that the proton donor is an acid addition salt of a weakly basic tertiary amine. 19. Method according to claim 17, characterized in that the proton donor is a mixture of an acid addition salt of a weakly basic tertiary amine and the weakly basic tertiary amine. 20. Process according to claim 18, characterized in that the amine is pyridine or N,N-dimethylaniline. 21. Method according to claim 18 or 19, characterized in that the acid addition salt is the hydrochloride.