NO772018L - - Google Patents

Description

Intermediate for use in the production of phthalidyl esters of penicillins.

The invention relates to intermediate products for use in the production of phthalidyl esters of penicillins. These intermediates are phthalidyl esters of either benzylpenicillin or phenoxymethylpenicillin.

The main application, no. 1952/72, relates to the production of esters of penicillins and cephalosporins which, when administered orally, are absorbed into the bloodstream where they are split by enzymatic action to release the antibacterially active parent penicillin or cephalosporin.

By the aforementioned method, a class of compounds of formula I is provided:

where X and Y are the same or different and each represents oxygen or sulfur;

Z represents the residue of a lactone, thiolactone or dithiolactone ring system;

R represents hydrogen or an alkyl, alkenyl, alkynyl, aryl or aralkyl group or a functional substituent;

A represents a group of formula II or (III):

where B represents hydrogen, an acetoxy group or a pyridinium group, and is an organic acylamino group, a group of formula IV: or a group of formula (V):

where R 2 and R 3 each represent a lower alkyl group, or

2 3

R and R together with the nitrogen atom to which they are attached form a monocyclic ring.

For example, Z in formula (I) above can be a straight-chain or branched, saturated or unsaturated divalent hydrocarbon radical, and two or more carbon atoms in the radical can be connected in a carboxycyclic or heterocyclic ring system. The radical Z can also be one or more functional substituents, e.g. hydroxy, alkoxy, halogen, nitro, amino and carboxyl groups. Specifically, Z may be a 1,2-phenylene^ group which may be one or more substituents, e.g. alkoxy, nitro or halogen substituents.

Furthermore, for example, the group R in formula (I) above can be lower alkyl, e.g. methyl or ethyl; lower alkenyl, e.g. vinyl or allyl; lower alkynyl, e.g. ethynyl; aryl, e.g. phenyl; or aralkyl, e.g. benzyl. R can also be a functional group, e.g. a hydroxyl, alkoxy, halogen, amino or carboxyl group.

The radical A in formula (I) is a 6-substituted penam-3 or 7-substituted cephem-4 radical. When R?~ is an organic acylamino group, any of the acylamino side chains found in known antibacterially active penicillins and cephalosporins are suitable. E.g. can R"<*>" in formula II or III be phenyl-aeetamido; 2- or 3- thienylacetamido; phenoxyacetamido, amino-phenylacetamido; <yi -amino-2 (or 3-thienylacetamido, c^carboxyphenylacetamido; o^-sulfophenylacetamido; c<-azidophenylacetamido or o<-guanidinophenylacetamido, but other examples of suitable acylamino groups shall be given later in the description in the specific examples .

in

It will be clear that when the acylamino group R"<1>" contains an asymmetric carbon atom, the compounds according to the invention can exist in two optically active forms. The invention includes the pure epimers and also mixtures of epimers.

In formulas (II) and (III), R"*" can also be a group of formula (V). Preferably R 2 and R 3 in formula (V) are both methyl or together represent the divalent radical - CR^(CH^) ^ CH2-.

In the presence of human and animal serum, the esters are cleaved according to the invention to release the parent penicillin

or -cephalosporanic acid. Although the invention is not limited by any theory with regard to mechanism, it is believed that non-specific esterases in the serum cleave the molecule and give an unstable intermediate (VI):

The intermediate (VI) then undergoes spontaneous cleavage as follows:

The esters according to the invention can be prepared by esterification of the carboxyl group in the corresponding penicillanic acid or cephalosporanic acid.

Thus, the invention also provides a process for the production of compounds (I), and the process comprises reacting a compound of formula (IX)

or a reactive esterification derivative thereof, in which formula A is as defined with respect to formula (I), with a compound of formula (X). or a reactive esterification derivative thereof, in which formula X, Y, Z and R are as defined in formula (I). By the term "reactive esterification derivative" with regard to the compounds (IX) and (X) above, is meant derivatives of (IX) and (X) which, when reacted together, take part in a condensation reaction with the consequent formation of an ester bond

Many esterification methods that make use of different combinations of reactive esterification derivative are known from the literature. For example, the esterification reaction defined above can be carried out by reacting a compound of formula

(1 X A)

where A is as defined with respect to formula (r) above, with a compound of formula (XA)

wherein R, X, Y and Z are as defined with respect to formula (I), under conditions which effect the elimination of the elements from compound UV with the consequent formation of the ester of formula (I); the symbols U and V in the formulas (1 X A) and (XA) are such that U represents hydrogen or a salt-forming ion, and V represents a hydroxyl group, an alkylsulfonyloxy group, an arylsulfonyloxy group or a halogen atom; or U represents an organic acyl group, and V represents a hydroxyl group.

When the group R"<*>" in the radical A in compound (IX) contains a free amino group, it is preferable that the amino group is protected before the esterification reaction. More will be said about specific protecting groups that can be used, later.

The esterification methods discussed above are all specific applications of esterification methods known in the literature. Usually it will prove satisfactory to react compound (IXA) where U is a sodium or potassium ion, with compound (XA) where V is a halogen atom, especially bromine or chlorine.

When U in compound (IXA) is hydrogen or a salt-forming ion, and V in compound (XA) is a hydroxyl group, the reaction is usually slow and unsuitable. In such cases, the hydroxyl group V in the compound (XA) is preferably best converted to an alkylsulfonyl or arylsulfonyl ester, as this gives a smoother reaction. In this case, the presence of a base is usually necessary to give high yields.

In the event that the group U in the reagent (IXA) is an organic acyl group, it will be clear that (IXA) is simply a mixed anhydride, the acyl group may be one of a wide variety of aliphatic or aromatic acyl groups, but generally . the alkoxycarbonyl groups (e.g. the C^H^OCO group) satisfactorily.

Another reactive esterification derivative of compound (IX) above is the acid halide, especially the acid chloride. This compound can be reacted with the hydroxyl compound (X) in the presence of an acid-binding agent to produce the desired ester according to the invention.

When the group R^" in radical A in compound (IX) or (IXA) contains a free amino group, this group should be protected before the esterification reaction.

Examples of protected amino groups include the protonated amino group (NH^<+>) which, after the acylation reaction, can be converted into a free amino group by simple neutralization; the benzyloxycarbonylamino group or the substituted benzyloxy-carbonylamino groups which are subsequently converted to NH^ by catalytic hydrogenation; and various groups which, after the acylation reaction, regenerate the amino group by mild acid hydrolysis.

(alkaline hydrolysis is not usually applicable, as hydrolysis of the ester group takes place under alkaline conditions.)

Examples of the group which can subsequently be converted to Nf^ by mild acid hydrolysis include anamine groups of the general formula (XI) or tautomeric modifications thereof, and (<-hydroxy - arylidene groups of the general formula (XII) or tautomeric modifications thereof:

In the structures (XI) and (XII), the dashed lines represent hydrogen bonds. In the structure (XI), R 3 is a lower one

4

alkyl group, R is either a hydrogen atom or forms together

3 5

with R a carbocyclic ring, and R is a lower alkyl, aryl or lower alkoxy group. In structure (XII), Z represents the residue of a substituted or unsubstituted benzene or naphthalene ring.

An example of a "protected amino group" that can be converted to NH^ after the esterification reaction is the azido group. In this case, the final conversion to Nt^ can be accomplished either by catalytic hydrogenation or electrolytic reduction.

An alternative method for producing compounds according to the invention of formula (E) where the R"^ group in the radical A is an acylamino group, is by N-acylation of the corresponding 6-aminopenam or 7-aminocephem.

Thus, in another of its embodiments, the invention provides a method for the preparation of compounds of formula (I), where the radical A is an acylamino group, and the method involves reacting a compound of formula (XIII)

or a silyl derivative thereof, in which formula H2NQ- represents a 6-aminopenam-3-radical or a 7-aminocep-3-em-4-radical, with a reactive N-acylation derivative of a compound of formula

(xiv)

where R 3.is an organic acyl group which may be a protected amino group, removal of the silyl group, if present, by

hydrolysis or alcoholysis, and, if a protected amino group is present, possibly converting this to a free amino group under acidic or neutral conditions.

The term "silyl derivative" of compound (XIII) means the reaction product between compound (XIII) and a silylating agent, e.g. a halotrialkyl silane, a dihalo-dialkyl silane, a halotrialkyl silane, a dihalo-dialkyl silane or a corresponding aryl or aralkyl silane and such compounds as hexamethyldisilazane. In general, halotrialkylsilanes, especially trimethylchlorosilane, are preferred. The silylated derivatives of the ester (XIII) are extremely sensitive to moisture and hydroxyl compounds, and after reaction with the reactive derivative of compound (XIV), the silyl group in the intermediate acylated compound can be removed by hydrolysis or alcoholysis.

A reactive N-acylation derivative of the acid (XIV) is used in the above process. The choice of reactive derivative will naturally be influenced by the chemical nature of the acyl group R"^. Thus, when R is acid-stable or carries an acid-stable group, e.g. the protonated amino group NH<*> or the azido group, it is often convenient to convert the acid (XIV) into an acid halide, eg by treating it with thionyl chloride or phosphorus pentachloride, so as to obtain the acid chloride.

However, such reagents would be avoided when R is an acid-labile group or carries an acid-labile group, e.g. of type (XI) or (XII). In such cases it is often convenient to use a mixed anhydride. For this purpose, particularly suitable mixing anhydrides are the alkoxy-formic anhydrides, which are conveniently prepared by treating an alkali metal or tertiary amine salt of the acid (XIV) with the appropriate alkyl chloroformate in an anhydrous medium at or below room temperature.

Other reactive N-acylation derivatives of the acid (XIV) include the reactive intermediate which is formed by reaction in situ with a carbodiimide or carbonyldiimidazole.

The ester (XIII) used in the above process can be prepared, albeit in poor yield, by direct coupling of 6-aminopenicillanic acid or 7-aminocephalosporanic acid with 3-bromophthalide in the presence of base. In this process, some epimerization occurs at C 6 or C_ I, and the method is therefore not fully

consistently satisfactory.

The esters of the formula (XIII) are also new compounds,

and as they are valuable intermediates in the process according to the invention, they also form part of the invention. Much better yields of the compounds (XIII) can be obtained by coupling an N-protected derivative of 6-aminopenicillanic acid or 7-aminocephalosporanic acid (e.g. the triphenylmethyl derivative) with 3-bromophthalide and subsequent removal of the protecting group (e.g. by mild acid hydrolysis in the case of the triphenylmethyl derivative) .

Alternative types of N-protected 6-aminopenicillanic acid are the 6-acylaininopenicillanic acids. Techniques for removing the 6-acyl side chain from benzylpenicillin and phenoxymethylpenicillin, for example, are well documented (cf. British Patent No. 1,189,022)

and generally involves treating an ester of the 6-acylaminopenicillanic acid with PCl,_ to form an imino chloride bond on the 6-amido nitrogen atom, then treating the imino chloride with a. alcohol to form an imino ether and then hydrolysis of the imino bond to form the 6-aminopenicillanic acid ester. In the present case, it is possible to start from the phthalide ester of penicillin G or penicillin V (produced, for example, by reacting the sodium or potassium salt of penicillin with 3-bromophthalide) and to cleave the acyl side chain to produce the phthalide ester of 6 -aminopenicillanic acid.

Likewise, alternative types of N-protected 7-amino-cephalosporanic acid are the 7-acylaminocephalosporanic acids. Techniques for removing the 7-acyl side chain from cephalosporins are well known, and in the present case it is possible to start with the appropriate ester of a 7-acylaminocephem, e.g. Cephalosporin C, and remove the acyl side chain to form the ester of 7-aminocephalosporanic acid.

The following examples illustrate methods for preparing the compounds according to the invention.

Example 1

Benzylpenicillin phthalide esters

The potassium salt of benzylpenicillin (20.0 g, 0.054 mol)

was dissolved in 50 ml of dry dimethylformamide and cooled to 0°C.

To this stirred solution was added 3-bromophthalide (11.5 g, 0.054 mol)

in 20ml of dimethylformamide added in one portion. Reaction mixture-. The mixture was then poured into 600 ml of ice-cold water and stirred vigorously. The white solid precipitate that separated was collected and washed well with water. After drying, the material was recrystallized from hot isopropyl alcohol to give a white, crystalline product (21.0 g, 41.9%).

The I.R. spectrum (Nujol) contains i.a. strong ties by:

1770 cm"<1>1678 cm<7>"<1>1524 cm<-1>970 cm<-1>

N.M.R. [(CD3) 2SO/D20] contains peaks at:

8= 7.88 (4H.m.-phthalide aromatics) ; S = 7.61 (1H.s.CO.0CH-); 6 = 7.28 (5H. s.-aromatics) ; 6= 5.55 (2H .m./3-lactam) ; = 4.55 (lH.s. C3 proton) ; <$* = 3.56 (2H.s. PhCH 2 CO) ; 6 = 1.53 (6H.d.gem-dimethyls).

The purity was determined by hydroxylamine analysis and was 109.2%.

Found:

C: 61.55%; H: 4.90%»N: 5.87%; S: 6.72%; C24H22N2<S>°6 requires: C: 61.80%; H: 4.72%;. N: 6.02%; S: 6.86%.

Example 2

Phenoxymethylpenicillin phthalide esters

The potassium salt of phenoxymethylpenicillin (17.0 g, 0.038 mol) was dissolved in 50 mL of dry dimethylformamide and cooled to 0°C. To this stirred solution was added 3-bromophthalide (8.1 g; 0.038 mol) in

20 ral dimethylformamide added in one portion. The reaction mixture

was allowed to warm to room temperature and was then stirred for a further 2 hours. The mixture was then poured into 600 ml of ice-cold water and stirred vigorously. The sticky white solid that separated was collected and washed well with cold water. After drying, the material was recrystallized from hot isopropyl alcohol to give a white, crystalline solid (13.0 g, 70.8%).

The I.R. spectrum (Nujol) contains i.a. strong bands at: 1770 cm<-1>1678 cm"<1>1585 cm"<1>970 cm"<1>750 cm<-1>

N.M.R. [ (CD3)2S0/D20] contains peaks at:

S= 7.88 (4H.m.phthalide aromatics); S = 7.65 (1H.s.CO.0CH-); 5 = 7.10 (5H.m. aromatics); 6 = 5.60 (2H.m. /3-lactam) ;

δ= 4.68 (2H.s. PhOCH2CO) ; <$ = 1.58 (6H.s. gem-dimethyls) .

The purity, determined by hydroxylamine and cysteine analyses, was 84.3 and 100% respectively.

Found:

C: 59.62 H: 4.82%; N: 5.67%; S: 6.72%. C24H22N2°7S requires: C: 59.98%; H: 5.02%; N: 5.74%; S: 6.55%.

Claims (1)

Intermediate product for use in the production of phthalidyl esters of penicillins, characterized in that it is the phthalidyl ester of benzylpenicillin or phenoxymethylpenicillin.