GB2086880A - Process for Preparing beta -Lactam Antibiotics and Intermediates Therefor - Google Patents

Abstract

A process for the preparation of a compound of the formula: <IMAGE> wherein R<3> is hydrogen or a lower alkyl, aryl or aralkyl group; R<6> is chlorine, bromine or iodine and Q is a leaving group, such as a halogen atom, or a group of the formula R- CO2-, where R-CO2H represents a beta -lactam antibiotic containing a carboxy group, or a protected derivative or precursor thereof, which process comprises reacting the corresponding 6 alpha - perhaloalkylsulphonyloxy-substituted compound with chloride, bromide or iodide ion in a reaction inert organic solvent and, if desired, removing any protecting groups.

Description

SPECIFICATION Process for Preparing p-Lactam Antibiotics and Intermediates Therefor This invention relates to the preparation of p-lactam antibiotics and in particular to a process for the preparation of methylene bis-esters of penicillins (and other ,B-lactam antibiotics) with 6-p- halopenicillanic acids and to novel intermediates for use in the process.

According to U.K. patent applications No. 2044255A and 2045746A there are disclosed penicillin derivatives of the formula:

wherein R3 is a hydrogen atom or a lower alkyl, aryl or aralkyl group; B is the side chain of a penicillin antibiotic and may be either: (a) a group of the formula.

where R1 is a phenyl, 4-hydroxyphenyl, 1 ,4-cyclohexadienyl or a 3-thienyl group and R2 is a primary amino or carboxy group, or (b) a group of the formula: R4 rH=N-- (b) where R4 is azacycloalkyl or azabicycloalkyl of from 5 to 10 carbon atoms attached by the nitrogen atom and optionally substituted with one or two lower alkyl groups which may be the same or different; and A is the radical of a p-lactamase inhibitor containing a p-lactam ring and a carboxy group including, in particular, the residue of a 6-p-halo-penicillanic acid of the formula

wherein R6 is halogen.

Such compounds are stated to be of value since they contain the moiety of an antibacterially highly active penicillin and the moiety of a potent p-lactamase inhibitor in the same molecule and the compounds are thus valuable pro-drugs of both the penicillin and the p-lactamase inhibitor having advantages in antibacterial efficacy and in oral absorption.

The present invention is concerned with a novel process for the preparation of the compounds of formula (I) in which A is the residue of a 6-p-halopenicillanic acid of the formula (II), and related compounds, via a 6-a-perhaloalkylsulphonyloxy derivative and provides novel intermediates for use in the process.

Thus according to the present invention, there is provided a process for the preparation of a compound of the formula:

wherein R3 is as previously defined; R6 is chlorine, bromine or iodine and Q is a leaving group, such as a halogen atom, or a group of the formula RO2-, where R--CO,H represents a p-lactam antibiotic containing a carboxy group, or a protected derivative or precursor thereof, which process comprises reacting a compound of the formula

(wherein R7 is a perchloro or perfluoroalkyl group of from 1 to 4 carbon atoms and R3 and Q are as previously defined, and, in the case where Q is R-C02-, wherein any reactive group in R may optionally be protected) with chloride, bromide or iodide ion in a reaction inert organic solvent and, if desired, removing any protecting groups.

The compounds of formula (IV) are novel intermediates according to the invention.

The term lower alkyl as used herein means a C-1 to C-6 straight or branched chain alkyl radical, and aryl stands for an aromatic monocyclic or bicyclic carbocyclic radical. Compounds containing chiral centres in the group R, or when R3 is other than hydrogen, give rise to diastereomeric forms and the invention includes all such diastereomers as well as mixtures thereof.

In the formulae a broken line indicates that the substituent is below the, plane of the bicyclic nucleus. Such a substituent is said to be in the a-configuration. Conversely wedge attachment of a substituent indicates that it is above the plane of the nucleus and is in the p-configuration.

In the compounds of formulae (III) and (IV) when Q is R-C02- RCO2- may be derived from any je-lactam antibiotic containing a carboxyl group, such as a penicillin or cephalosporin, or a precursor therefor (e.g. 6-amino-penicillanic acid) or a protected derivative thereof (e.g. a penicillin or cephalosporin or precursor therefor containing one or more protected amino or carboxy groups). R3 is preferably hydrogen or a methyl, phenyl, or benzyl group, hydrogen being particularly preferred. R6 is preferably iodine.

When Q is a leaving group it may be a halogen atom e.g. chlorine, bromine or iodine or an alkylsulphonyloxy, arylsulphonyloxy, or chlorosulphonyloxy group.

In the compound of formula (IV) the group R7 includes the trifluoromethyl, the trichloromethyl and the nonafluorobutyl groups, the trifluoromethyl group being generally preferred.

The process for the preparation of compounds of the formula (III) is generally performed with the compound of formula (iv) dissolved in a reaction inert organic solvent, for example acetone, tetrahydrofuran or N,N-dimethylformamide, and excess of the appropriate halide ion is added, generally as an alkali metal or organic halide, for example as sodium iodide, The reaction mixture is conveniently stirred at room temperature and progress of the reaction may be monitored by thin-layer chromatography. When the reaction is judged to be substantially complete, generally within a period of one or two days, the reaction mixture is worked up in a conventional manner, for example by filtering and evaporation of the solvent. The product may be further purified, if desired, by solvent extraction, chromatography or crystallization as appropriate.

Naturally in the case where Q is RO2- and R contains one or more reactive groups such as free amino or carboxyl groups, it will be advantageous to protect these during the course of the reaction. Appropriate protecting groups are well known to those skilled in the art as are conditions for their introduction and removal. Thus as a final step in the process any protecting group which is initially present in the compound of formula (IV) may be removed, if desired.

Particular protecting groups which may be of value for the protection of amino groups, if present in R, include the triphenylmethyl, the t-butoxycarbonyl, the 1 -methoxycarbonylpropen-2-yl and 1-N,Ndimethylaminocarbonylpropen-2-yl groups, the t-butoxycarbonyl and 1-N,Ndimethylaminocarbonylpropen-2-yl groups being preferred because of their ease of removal under mild acidic conditions. In the case where R contains a carboxyl group, particular protecting groups which may be employed include the benzhydryl, t-butyl and 4-methoxybenzyl groups. Such protecting groups are removed under conditions appropriate to the nature of the particular protecting group employed and will be well known to those skilled in the art.Such conditions include reduction of acid or base hydrolysis, thus for example the dimethylaminocarbonylpropen-2-yl group, when present, may be removed by hydrolysis of the protected product of formula (III) with dilute hydrochloric acid at room temperature. Compounds of the formula (III) in which Q is R02- and R-C02- is derived from a precursor of a p-lactam antibiotic serve as intermediates for the corresponding compounds in which RO2- is derived from the antibiotic itself. For example compounds in which R-CO2- contains an azido group e.g. when Rq02 is derived from azidocillin, may serve as intermediates for the corresponding amino-containing compound, e.g. where RCO2 is derived from ampicillin, the conversion being readily achieved by catalytic reduction, e.g. using palladium on charcoal catalyst.

Similarly compounds in which R-CO2- is derived from 6-amino-penicillanic acid serve as useful intermediates, introduction of various side chains being effected by conventional techniques, as a subsequent step in the process, for example, by using techniques employed for the acylation of the amino group in 6-amino-peniciílanic acid.

In the case of compounds of the formula (IV) wherein Q is a leaving group, this may also be displaced by the halide ion during the course of the reaction if Q is a better leaving group than the particular halide ion employed. The product in this case will be a compound of the formula (Ill) wherein R6 and Q are the same and are both a halogen atom. Thus, for example in the case where R7 is a trifluoromethyl group and Q is a chlorine atom, reaction with sodium iodide yields the compound of formula (III) wherein R6 and Q are iodine. Products of this type are of value as they may be reacted with a p-lactam antibiotic of the formula RCO2H to yield a compound of the formula (Ill) in which 0 is R CO2-.

As mentioned above, the intermediates of formula (IV) are novel compounds according to the invention. They are prepared by a number of different processes according to further aspects of the invention.

Thus in one process the compounds of formula (IV) wherein 0 is R-C02- are prepared from the corresponding salt of the p-lactam antibiotic of formula: R--CO,-M+ (V) wherein any reactive group in R may optionally be protected and M+ is a cation, for example Na+, K+or tetralkylammonium ion; by reacting with a compound of the formula

wherein R3, R7 are as defined above and X is a leaving group, for example a halogen atom.

The process is generally performed in a reaction-inert organic solvent, for example, N,Ndimethylformamide, using equimolar proportions of the reactants at a temperature of from 0 to 2O0C.

Progress of the reaction may be monitored by thin-layer chromatography and, when judged to be substantially complete, the reaction mixture is worked up in a conventional manner, i.e. by removal of the solvent followed by solvent extraction and washing as appropriate. Further purification may be carried out, if desired, by re-crystallization or by chromatography.

In an alternative process for the preparation of the compounds of formula (IV), according to a further aspect of the invention a compound of the formula:

wherein R7 and M+ are as previously defined, is reacted with a compound of the formula:

wherein R3, 0 and X are as previously defined and in the case where 0 is R-C02-, wherein any reactive group in R may optionally be protected, and with the proviso that, in the case where 0 is a leaving group, X is a better leaving group than 0.

Thus the compound of formula (VIII) may be, for example, a chloroiodoalkane and reaction with the compound of formula (VII) yields the corresponding compound of formula (lV) wherein Q is chloro.

This product may also be further reacted as previously described with a compound of the formula (V) to yield compounds of the formula (IV) wherein 0 is R-C02-.

The reaction between the compounds of formulae (VII) and (VIII) is performed under similar conditions to those described for the reaction of the compounds of formulae (V) and (VI).

In a further process according to the invention compounds of the formula (IV) may be prepared from the corresponding 6-p-amino derivative of formula

wherein R3 and Q are as previously defined and, in the case where Q is R--CO,,-, wherein any reactive group in R may optionally be protected; by a process which involves reacting the compound of formula (IX) with nitrous acid and treating the resulting diazo compound with a perhaloalkylsulphonic acid of formula R7SO3H wherein R7 is as previously defined. Alternatively the amine of formula (IX) may be reacted with nitrous acid followed by treatment with acid to yield the 6-sg-hydroxy derivative which may be sulphonated with an appropriate perhaloalkylsulphonic anhydride or acid chloride.

The starting materials of formula (VII) are described in our co-pending patent application No.

8015816. Compounds of the formula (VIII) wherein Q is RC 2, penicillin salts of formula (V) and compounds of formula (VIII) wherein Q is a leaving group are known compounds described in the literature. (See for example U.K. patent applications Nos. 2044255A and 2045746A and U.K. Patent Specification No. 1573614). Compounds of the formula (IX) may be prepared from 6-p-amino- penicillanic acid (or preferably an amino-protected derivative thereof) by reaotion with a compound of the formula (VIII) in a similar manner to that described for reaction of the compound of formula (VII).

Appropriate conditions for preparation of the various starting materials when not available from commercial sources will be obvious to those skilled in the art from the above references and standard text books, as will other variations and possibilities for their preparation. Selection of suitable protecting groups will be made as appropriate to the particular compound and bearing in mind the conditions employed in the particular reaction sequence for which the starting material is intended.

The process of the invention is illustrated by the following examples in which Examples 1, 3, 4, 6, 7, 9 and 10 are examples of preparation of the novel intermediates of formula (IV).

Example 1 Chloromethyl 6-a-trifluornmethanesulphonyloxy-penicillanate 6-a-Trifluoromethanesulphonyloxypenicilíanic acid (5 mmole) in N,N-dimethylformamide (7.5 ml) is treated dropwise with triethylamine (7 mmole) and chloroiodomethane (30 mmole), and the mixture stirred at room temperature for 4 hours, diluted with ethyl acetate (30 ml), and washed with water (3x 10 ml) then brine (5 ml), dried, and evaporated in vacuo to give the title compound. NMR (CDCl3) 1.33 (s, 3H), 1.41(s,- 3H), 4.69 (s, 1 H), 5.54 (s, 2H), 5.78 (ABq 2H, 6=5.72, 5.84, J=6.3).

Example 2 lodomethyl 6-p-iodopenicillanate Chloromethyl 6-a-trifluoromethanesulphonyloxypenicillanate (285 mg) in acetone (2.5 ml) was treated with sodium iodide (322 mg) at room temperature in the dark, until the reaction is complete by t.l.c. (2 days). The mixture was evaporated to dryness, and the residual oil re-dissolved in ethyl acetate (30 ml). The solution was washed with water (2 xl O ml), dried (MgSO4) and evaporated to 5 ml; purification by chromatography on silica, eluting with methylene chloride in petrol yields the title product (200 mg, 60%).

Example 3 6-cg-Trifluromethanesulphonyloxypenicillanoyloxymethyl 6ss-[N-(1- I - dimethylaminocarbonylpropene-2-yI)-D-a-amino-a-phenylacetamidoj penicillanate To potassium 6-cr-trifluoromethanesulphonyloxy-penicillanate (11 mmole) in N,Ndimethylformamide (25 ml) is added dropwise a solution of 10 mmole of iodomethyl 6-p-[N-(1- dimethylaminocarbonylpropene-2-yl)-D-a-amino-a-phenyl-acetamido] penicillanate in the minimum quantity of N,N-dimethylformamide, with stirring at 50C, over 30 minutes. The mixture is kept until t.l.c. confirms completion of the reaction. The mixture is diluted with ethyl acetate (100 ml), extracted with water, (4x25 ml) then brine, (25 ml). The organic layer is evaporated to dryness to give the title product.

Example 4 6-a-Trifluoromethanesulphonyloxypenicillanoyloxymethyl 6-p-(D-cr-amino-- phenylacetamido)penicillanate The product of Example 3 is stirred in 50 ml ethyl acetate plus 25 ml water, and hydrolysed by addition of 2N hydrochloric acid at such a rate as to maintain the pH of the aqueous phase at 2.5. The aqueous phase is freeze-dried to give the title compound as the hydrochloride salt.

Example 5 6-p-lodopenicillanoyloxymethyl 6-p-( D-a-a mino-a-phenylacetamido) penicillanate A. The product of Example 3 is dissolved in acetone (20 ml) and treated with sodium iodide (15 mmole) at room temperature until the reaction is complete by t.l.c. The mixture is evaporated to dryness, the residue re-dissolved in ethyl acetate, filtered and the filtrate re-evaporated yielding the N (1 -dimethylaminocarbonylpropene-2-yl) derivative of the desired compound.

B. The product of procedure 5A is hydrolysed and the reaction mixture worked up according to the procedure of Example 4, to give the desired compound as the hydrochloride salt.

Example 6 Chloromethyl 6-cz-trifluoromethanesulphonyloxypenicillanate Trimethylsilyl 6--trifluoromethanesulphonyloxypenicillanate (8.42 g, 20 mmole) in dichloromethane (140 ml) was treated with water (3 ml) and then tetrabutylammonium hydroxide (13 ml, to pH 8 in the aqueous phase); the organic layer was dried (20 g MgS04) and filtered and the MgSO4 washed with methylene chloride (2x20 ml). The combined organic extracts were evaporated to yield the tetrabutylammonium salt of the penicillin as a viscous oil (13.2 g) containing a little methylene chloride. To this residue was added chloroiodomethane (20 ml) and the mixture was stirred at room temperature for 24 hours, and evaporated in vacuo, yielding a residue (18.2 g).This product was diluted with diethyl ether (50 ml) and pentane (50 ml) was then added; the mixture was shaken hard and decanted. The insoluble residue was re-treated with ether (25 ml) and pentane (25 ml). The total decantate (ca. 1 50 ml) was evaporated to dryness yielding the product as a pale yellow viscous oil (4.1 g, 52% yield) of high purity by NMR, IR, and TLC (Rf 0.8 in ethylacetate/silica).

Example 7 6-a-Trifluoromethanesulphonyloxypenicillanoyloxymethyl- 6p-N-(1 -methoxycarbonylpropene-2 yl)-D--am ino-a-phenylacetamidopenicillanate Chloromethyl 6-a-trifluoromethanesulphonyloxypenicillanate (0.64 g) and potassium 6p-N-(1- methoxycarbonylprnpene-2-yl)-D-a-amino--phenylacetamidopenicillanate (0.78 g) in N,N dimethylformamide (6 ml) were stirred at room temperature for 20 hours, partitioned between ethyl acetate (40 ml) and water (1 5 ml), and the organic layer washed with water (2 x 1 5 ml) then evaporated to low bulk and chromatographed over silica, eluting with a mixture of petrol/methylene chloride/methanol (gradient elution).Evaporation of the relevant fractions gives the title product as a yellow oil (20 mg). Rf 0.7 (methanol/chloroform 1:19, on silica). IR (film) 1790 cm-l (p-iactam). NMR (CDCl3) showed penam methyl absorption at ô 1.4-1.8 (12H), side chain methyl groups at a 2.25 and 3.74, a phenyl group at a 7.4 and other expected features consistent with the assigned structure.

Example 8 6-P-lodopenicillanoyloxymethyl-6P-N-( 1 -methoxy-carbonylpropen-2-yl )-D-cr- amino phenylacetamido-penicillanate The product of Example 7 (15 mg) in acetone (1 ml) (use of perdeuterated acetone enables the reaction to be followed by NMR) is treated with sodium iodide (58 mg) overnight at ambient temperature to give a solution of the title compound.

Example 9 6-a-Trifluoromethanesulphonyloxypenicillanoyloxymethyl GP-[(hexahydro-l H-azepin-1 - yl)methyleneamino]penicillanate The title compound is obtained as the trifluoromethanesulphonate salt by treating 6 diazopenicillanoyloxymethyl 6,B-[(hexahydro-1 H-azepin- 1 -yl)methyleneamino]penicillanate in methylene chloride or ethanol-free chloroform with two equivalents of trifluoromethanesulphonic acid, dropwise with stirring over 15 minutes at a temperature of O to 1 OOC, and stirring for a further 1 5 minutes. Preferably, a small amount (1 g per gram of acid) of powdered magnesium silicate is added to the reaction mixture to improve dispersal of the acid. The product is obtained by filtration and evaporation of the filtrate in vacuo.

Example 10 lodomethyl 6-a-trifluoromethanesulphonyloxypenicillanate lodomethyl 6p-triphenylmethylaminopenicillanate (1.19 g) in acetone (10 ml) was treated with 4-toluenesuiphonic acid hydrate (380 mg) at room temperature for 1 hour. The mixture was re dissolved in chloroform and the product was precipitated by adding this solution to pentane. The precipitate was dried to yield iodomethyl 6p-amino-peniciííanate as the tosylate salt (975 mg).

Sodium nitrite (193 mg) was added to a cold stirred solution of 4-toluenesulphonic acid hydrate (432 mg) in a stirred mixture of water (20 ml) and methylene chloride (20 ml) at 50C. The mixture was stirred for 10 minutes at 50C. lodomethyl 6,B-aminopenicillanate tosylate (925 mg) was added, and the mixture stirred vigorously at 5--7 OC for 25 minutes. The organic layer was separated, dried (Na2SO4) and filtered.Powdered magnesium silicate (290 mg) was added and the filtrate cooled to 5 C and stirred while trifluoromethanesulphonic acid (290 mg) was added dropwise over 1 minute, keeping the temperature below 1 OOC. After stirring for a further 1 5 minutes, the solution was filtered and the filtrate was evaporated to dryness under vacuum to yield 525 mg of a brown viscous oil which was chromatographed on silica, eluting with pentane to chloroform, giving the title compound (20 mg), rf 0.55 (chloroform/silica), NMR (CDCI3) ot 1.57 (s, 3H); 1.62 (s, 3H); 4.54 (s, 1 H); 5.50 (s, 2H); 5.93 and 5.96 (centre peaks of AB quartet, 2H); ; 1 R (film) jB-lactam at 1800 cm~1.

Claims (3)

Claims

1. A process for the preparation of compounds of the formula (III) from compounds of the formula (IV) as herein before described.

2. The novel compounds of formula (IV) as hereinbefore defined.

3. Processes for the preparation of the compounds of formula (IV) as hereinbefore described.

3. Processes for the preparation of the compounds of formula (IV) as hereinbefore described.

New Claims or Amendments to Claims filed on 9 November 1981 New or Amended Claims:

1. A process for the preparation of compounds of the formula (III) from compounds of the formula (IV) as hereinbefore described.

2. The novel compounds of formula (IV) as hereinbefore defined.