IE50135B1 - Process for the preparation of a(d-a-amino-(p-hydroxyphenyl)-acetamido)cephalosporanic acid derivatives - Google Patents

Description

The invention relates to a process for the preparation of a £D-&(-amino-(p-hydroxyphenyl)Jacetamido group containing cephalosporanic acid derivatives, and more specifical ly of 7-£D-p(-amino-(p-hydroxyphenyl)acetamIdoJ-3-methyl-3cephem-4-carboxy lie acid (commonly named cefadroxil), 7- amino-(p-hydroxyphenyl) acetamido^-S-acetoxymethyl-3-cephem-4carboxylic acid, 7- £p-s(-amino - ( p-hy d r oxy pheny l)ace t amido Ύ-3-£(1Η)-1, 2,3-triazol-5-y1-thiomethylj-3-cephem-4-carboxylic acid (commonly named cefatrizine) and similar cephalosporanic acid derivatives, with - instead of the (1H)-1,2,3-triazol-5-yl-group other heterocyclic residues, which may be optionally substituted oy a lower alkyl group, and non-toxic, pharmaceutically acceptable salts thereof.

The invention relates to a process for the preparation of cephalosporanic acid derivatives containing a £D-e( — amino-(p-hydroxyphenyl)acetamidoj group, by the acylation of derivatives of 7-amino-cephalosporanic acid, wherein the 3acetoxymethyl substituent has been optionally replaced by other substituents, with an acylating agent derived from phydroxyphenylglycine . More specifically the invention relates to a process for the preparation of cefadroxil, cefatrizine and similar derivatives by the acylation of a compound having the following formula (D and/or *.s.

NH-QH— c.u, (II) C Ss ο cOo-Sikf \ *·ι Λ wherein Rj, R2 and &3 represent the same or different alkyl groups of 1-3 carbon atoms, and each preferably a methyl group, and wherein X represents a residue selected from the group consisting of hydrogen, acetoxy or a five membered heterocyclic ring, containing one or more heteroatoms selected from nitrogen, oxygen and/or sulphur and optionally substituted by Ci_3 alkyl, this ring being attached to the 3-CH2 group via a sulphur atom, and wherein an endocyclic -NH-radical, if present, has optionally been silylated, with an acylating agent according to the general formula wherein R4 represents alkyl containing 1-3 carbon atoms and preferably methyl, R5 represents hydrogen or alkyl containing 1-3 carbon atoms and preferably methyl, r6 represe nts lower alkoxy containing 1-3 carbon . 50135 atoms and preferably methoxy and K7 represents lower alkoxy containing 1-2 carbon atoms and preferably methoxy.

A process for the preparation of 6-^D-o(-amino—p(hydroxypheny1)acetamidoTJ-penicillanic acid is generally known from e.g. British Patent Specification no. 1,339,605 disclosing indeed the preparation of this compound according but in economically non-interesting yields (Example 1: 43% of a purity of 80%} Example 3: 20% of a purity of 16%; Example 4: 37% of a purity of 93%, while the final parts of Examples 2 and 5 only indicate the presence of the desired compound amoxycillin.

On the other hand, a process which comprises the acylation of a previously silylated cephalosporanic acid derivative according to the formula I and/or 11 with a mixed anhydride according to the general formula III, is generally known from e.g. the published Dutch application HL 6912811, the British Patent Specification no. 1073530 and more particularly from 'Irish Patent Specification No. 2332/73.

However, especially from e.g. examples 3 and 13 of the latter specification, a person skilled in the art cannot derive with sufficient clarity, that an acylation of e.g. 7-amino-3-((lH)15 1,2,3—triaxol-5-yl)-thiomethyl—3—cephem-4—carboxylic acid, or its trimethylsilyl derivative, by means of e.g. ethoxycarbonyl D-a-(lcarbomethoxy-propen-2-yl)amino-p-hydroxyphenyl acetate, could be carried out with economically attractive yields.

More particularly in example 13, page 21, the conversion of 0.02 mol of 7-amino-3-(l,2,3-triazol-5-yl)-thiomethyl-3-cephem4-carbosylic acid, which has previously been converted with 0.06 mol trimethylchlorosilane in the presence of 0.06 mol of an about 2:1 mixture of triethylamine and Ν,Ν-dimethylaniline, with a reaction mixture prepared in the usual way in acetonitrile from 0.05 mol of the Dane salt and ethylchloroformate, seems to lead only to rather unattractive yields (see e.g. page 21 line 38 in connection with lines 5-10 of the same page).

Also other patent literature relating to the preparation of this type of cephalosporanic acid derivatives showed only economically unattractive processes, e.g. US patent B 516.047, example 1, column 7, line 44, example 5A, line 52 and example 6, US patent 3,946,003, example 1 (column 11, line 65) and example 3 (column 12, line 62).

Moreover, according to column 4, lines 1-5 and example 1 (column 10), it seems necessary to silylate the phenolic P-hydroxy group first in order to obtain practical results, which necessity, moreover, also appears from example 1 on pages 13 and 14 of the Ge man application DT-2600880 and from the examples 1-5 of German application DT-2626280. 50133 Therefore, it was less attractive for people skilled in the art to develop the method described in e.g. the British specification 1.339.605 or similar methods for the preparation of cephalosporanic acids carrying the same p-hydroxy-phenylglycyl residue, than to look for alternative acylation methods in the search for a new and improved method for the preparation of the desired compounds with an economically attractive yield and a relatively high purity. An additional modern requirement for a process to be used on a technical scale is , moreover, that inevi10 tably occuring impurities can be removed in a cheap and simple manner so as to achieve the conditions of purity dictated by health authorities.

It is known from literature to prepare penicillanic acid and cephalosporanic acid derivatives by acylating 6-APA or 7-A(d)CA and their derivatives with the hydrochloride of 2- phenylglycinechloride and derivatives thereof having a substituted phenyl group, whereby the said acid chloride is obtained by reacting the substituted phenylglycine with reagents like phosphorus pentachloride, thionyl chloride and phosgene. Although improved processes for the preparation of D-(-)-2-(p-hydroxyphenyl)glycylchloride.hydrochloride and the crystalline hemidioxane solvate thereof are known from Irish Patent Specification No. 39782 and British specification No. 1466637, the acylation of 6-APA or 7-A(d)CA or its 3- methyl modifications with the above mentioned acylating agent did not lead hitherto to results aimed at, mainly because either the product formed was too impure to make its recovery to the required quality meaningful, or the starting 0-2-(p-hydroxyphenyl) glycyl chloride.hydrochloride of the required quality (purity) is only available at economically unattractive prices, if at all.

The occurring impurities found, if an acid chloride.hydrochloride in economically necessary amounts for acceptable prices is used, appears to be in agreement with the indications about the accompanying impurities in the final products and the low yields of the rather similar acylation with the said j5 D-(-)-2-(p-hydroxyphenyl)glycyl chloride.hydrochloride of 7-amino-cephalosporanic acid derivatives according to Irish Patent Specification no. 2332/73 (viz. Examples 2, 4 and 9, especially page 17, lines 32-34 and Example 8 referring to further purification of the desired product) and Irish Patent Specification No. 2332/73 (viz. Examples 2, 5, 9 and 10). In German Application DT 2520647 page 2, lines 1-9 is also disclosed in this connection, that generally used acylating agents such as acid halides cannot be properly applied in the amoxicillin synthesis.

It is true that a process for the preparation of amoxicillintrihydrate was also known from the published German patent application DT 2611286, comprising the acylation of previously silylated 6-APA, with D-(-)-2-p-hydroxyphenylglycylchloride.hydrochloride and leading to yields which seem to approach to some extent at least present practical requirements.

However, for the preparation of this starting material according toe.g Irish Patent Specification No. 39782 and British Patent Specification No.. 1466637 phosgene is applied in a process relatively difficult to manage, in which a solid is reacted with a gas. Such an applica1 5 tion is extremely expensive in a large number of countries with very stringent safety regulations, if indeed it may be applied at all.

For the same reason the process described in Irish Patent Specification No. 32890 and British Specification No. 1 341 827, disclosing the 2C preparation of 6-isocyanatopenicillanic acid and 7-isocyanatocephalosporanic acid derivatives from 6-APA and 7-A(D)CA esters with phosgene and its subsequent reaction to form penicillins or cephalosporins, are left out of consideration for the preparation of amoxicillin and of cephalosporanic acid derivatives having the corresponding side chain in 7-position.

On the other hand, German Patent Application P 2520647, for example, discloses a process for the preparation of a- aminoacylpenicillanic acid derivatives and - inter alia - amoxicillin, in which (i) 6-APA is contacted with an excess of a strong tertiary amin base (e.g. triethylamine) in an inert, water-insoluble, organic solvent (e.g. methylene chloride or chloroform), resulting in a solution of a salt of 6-APA with the base in said solvent, (ii) the remaining strong tertiary amine base is neutra35 Used in the solvent, e.g, by addition of N,N-dimethylacetamide hydrochloride, (iii) the obtained neutralised solution is contacted with a solution of a mixed anhydride of a short chain alkoxyformic acid and a N-protected derivative of D-2-amino-p-hydroxyphenyl acetic S0135 acid, in which the N-protecting group is labile for acid, in a waterinsoluble, inert, organic solvent at a temperature of -50 to +30, preferably -30” to 0°C, resulting in a solution of a N-protected amoxicillin derivative, (iv) the solution so obtained is contacted with water and a strong acid (such as hydrochloric acid or p-toluene -sulphonic acid) at room temperature or cooled to, e.g. 0*C, in order to remove the acid-labile N-protecting group and (v) the thus obtained amoxicillin is isolated from the aqueous system.

Less attractive features of this process are, inter alia, that the process is carried out at low concentrations, that solvents become mixed so that recovery thereof becomes more difficult and that, uhen adding the dimethylacetamide hydrochloride, due to local high concentrations, 6-APA, 7-A(D)CA or 7-ACA and its derivatives sometimes crystallizes, so that a very accurate dosing scheme is required.

Furthermore, a number of patent specifications disclose preparation methods of a-aminoacyl penicillanic acid derivatives by acylating 6-APA with mixed anhydrides derived from modified Dane salts of D-2-amino-(p-hydroxyphenyl) acetic acid, e.g. those described in German patent applications nos. 1302847, 2020133 and 2065879 and British Patent Specifications nos 1327270 and 1347979· However, the yields resulting from the use of such Dane salts appeared to be unsatisfactory as well for the purpose of the present invention, and moreover, these Dane salts appeared not to be commercially available.

Dutch patent application no. 6401841 further discloses the protection of the carboxylic group of 6-APA, 7-ACA and other amino JO acids by reacting it with dihalogensilane derivatives. Those bifunctional silicon compounds are more easily accessible than the mono-functional trialkylhalogensilanes and the application thereof does lead to improved yields in a number of cases, as appears e.g. from British Patent Specification no. 1266544, disclosing the '5 preparation of intermediary organosilane penicillins by reaction of 6-ΑΓΑ with the aid of said bi-functional silicon compounds. The organosilanc derivatives are acylated to form, e.g. ampicillin. An expert, on account of the contents of this patent application would have expected that the application of the organosilane penicillins described therein, would lead to interesting yields in the preparations 50133 of amoxicillin too. However, very surprisingly this expectation could not be confirmed by the results of initial experiments .

From later patent specifications, e.g. British patent specification nos. 1356737, 1404846 and 1459999 it is known to employ trivalent phosphorous derivatives instead of the abovementioned silicon derivatives. Disadvantages of those phosphorous derivatives are certainly the coat prices being 10 to 20 times higher and this in combination with the toxicity and spontaneous inflammability of the di(lower alkyl/phosphorus derivatives as indicated in Inorganic Synthesis 15(1974) pages 191-3, makes the phosphorus compounds a poor substitute for the silicon compounds. See also Irish Specifications Nos. 36288 and 36816.

As a result of extensive research and development an improved process for the preparation of cephalosporanic acid derivatives containing a D-C(-amino-p-(hydroxyphenyl)acetamido group has surprisingly been found. This process is characterized in that a) a 7-amlnocephalosporanic acid derivative or a 3-methyl modification thereof is reacted in a dry, inert, organic solvent with a trialkylsilyl group supplying agent in approximately 2 equivalents with respect to 7-ADCA or 7-ACA and approximately 3 equivalents with respect to its 3-methyl modifications, whereby possibly present amounts of free trialkylhalosilane, containing 1-3 carbon atoms in the alkyl residues, and of tertiary amine in the reaction mixture have been mutually balanced by adjusting at the end of the reaction to an impirically determined signal value as defined in the specification, b) the obtained reaction mixture, containing a derivative of 7-aminocephalosporanic acid or 3-methyl modification thereof according to the formula S0135 and/or (I) Ο (II) wherein each of Rj, R2 and R3 represents the same or different alkyl group of 1-3 carbon atoms and each preferably represents a methyl group and X represents a residue selected from the group consisting of hydrogen, acetoxy or a five-membered heterocyclic thio ring, containing one or more heteroatoms selected from nitrogen, oxygen and/or sulphur and optionally substituted by alkyl containing 1-3 carbon atoms and is cooled and subsequently is rapidly mixed under anhydrous conditions with a cooled solution of at least an equimolecular amount of a mixed anhydride according to formula (III), which solution has been prepared by reacting the corresponding Dane salt with an alkyl chloroformate under anhydrous conditions in a water immiscible, inert, organic main solvent to which 0-25% by volume of an inert cosolvent has been added and in the presence of a catalytic amount of a tertiary amine, whereafter c) the acylation reaction is continued at a temperature below 0°C, followed by the recovery of the desired compound by methods known per se. The reaction is continued at a temperature of -10°C or lower and preferably from -20°C to -30°C during 0.25 to 3 hours and preferably one to 2.5 hours and the reaction mixture is poured out in water under exactly establishing the pH at a value below 2.5. Preferably the pH is established at a value between 0.8 and 1.2.

The dry, inert organic solvent for the silylation reaction is, preferably a water-immiscible solvent. The preferred dry, inert water-immiscible solvent is methylene chlor- and the silylating agent is preferably trimethylchlorosilane (TMCS), in the presence of a tertiary amine. However, good results may also be obtained with trimethylsilylacetamide, bis (trimethylsilyllacetamide, bis (trimethylsilyl)urea and hexamethyldisilazane.

The term mutually balanced”, as used under step (a) hereinbefore, can be clarified as indicated below.

It has been found, that optimal final yields can only be reached in a reproduceable manner by means of a very accurate balance between the amounts of agents employed to produce the silylated intermediate, especially in view of the desired optimal conversion with the prepared solution of the mixed Dane anhydride. It will be appreciated by persons skilled in the art, that - to point at just the main causes leading to undesirable deviation from the ideal balance - small errors In measuring out volumes of weighing out amounts are in practice inevitable, especially in experiments on very small scale (a few millimoles) or in production on large, industrial scale as well are impurities of technical reagents. What is needed then, is a tool whereby this necessary balance can be checked in situ and if necessary restored after completion of the silylation. The necessity and the advantage of measuring this mutual balance and its eventual restoration is a general feature of silylation procedures performed on 7-A(D)CA and the like, but is of preponderant importance when the silylation is carried out with the most economic agent combination, e.g. trimethylchlorosilane and triethyl amine, since such a combination - unlike single silylation agents like N,0-bistrimethylsilyl acetamide - does not provide for some sort of internal mutual balance by itself.

In the search for a suitable and at the same time simple method, by which this balance could be measured and if necessary corrected in situ, under technical conditions, it was surprisingly found, that for example the use of a good quality pH meter adequately fulfilled this demand. If for example a Radiometer pH meter type TTT2,C is employed in connection with a Radiometer GK 2401C electrode or an Ingold, socalled cold electrode at a temperature between 15 and 25°C, a pH scale value In the empirical range between 5.5 and 7.5 and preferably between 6.0 and 7.2 should prevail at the end of the sllylatlon reaction. If this is not the case a small additional amount of trimethylchlorosilane or e.g. triethylamine is added in order to effect an improved mutual balance.

It has appeared to be irrelevant whether or not the above indicated optimal pH scale interval does in fact correspond to an actual pH interval of the same order (6.0-7.2) to be measured after dissolution of the sllylatlon mixture in water, since scale interval readings on other suitable pHmeters can be gauged to the one obtained with the indicated pH meter type. A feature of the present invention therefore is recognition of the need to control the mutual balance of agents In the sllylatlon reaction as well as prescription of a simple method to solve this fundamental problem in situ.

The silylation is preferably carried out in dry methylene chloride containing 2 or 3 equivalents of a tertiary amine, such as triethylamine, and an equivalent amount of TMCS (about 2 equivalents for e.g. cefadroxil and about 3 equivalents for e.g. cefatrizine).

The dry, water-insoluble main solvent used for the preparation of the so-called Dane anhydride may be dry methylene chloride to which dimethylformamide, sulfolane, tetrahydrofuran, N-methyl-pyrrolidone, 1,4-dioxane, acetonitrile, dimethylacetamide or tetramethylurea, or a mixture thereof, is added as a co-solvent to at most 25% by volume, or methyllsobutylketone as main solvent to which one or more co-solvents mentioned above optionally may be added up to 25% by volume. Preferably potassium or sodium D-o(-(lcarbomethoxy-propen-2-yl)-amino-p-hydroxy-phenyl-acetate is reacted with, preferably, methyl chloroformate In contrast with the opinions hitherto held for true, as may be evident from Houben-Weyl, Methoden der Organischen Chemie, 4th Edition (1974) Volume XVV2, Synthese von Peptiden, Part II, page 172. N-methylmorpholine Is preferably used as a catalyst. The chloroformate Is preferably added to the Dane salt, while the reaction is preferably carried out at a temperature of -10°C or lower, preferably at a temperature between -10°C and -35°C. Mixtures of methylene chloride and the indicated co-solvents, with to about % by volume and preferably up to 10% by volume of co-solvent in the starting mixture, are proposed as the optimal solvents for the preparation of the Dane mixed anhydride. Preferably, the concentrations of the co-solvent are selected so as to minimize mixing of solvents.

Preferably, tetrahydrofuran, N, H-dimethylacetamide, Ν,Ν-dimethylformamide, N-methylpyrrolidon and Ν,Ν,Ν·, N’-tetramethylurea are used as co-solvents.

According to a further preferred process the solution 10 of the anhydride is cooled to a temperature of -15“C or lower and a cooled solution of silylated 7-ACA or 3-methyl modifications thereof, is added rapidly with efficient stirring so that a temperature of -i5°C to -30°C is reached, whereafter the reaction mixture is stirred for a further 0.5 to 3 hours. A small excess of the Formula III compound is preferably employed, but the excess is dependent on the nature of the substituent at the 3-methyl group of the cephilosporanic nucleus.

For the preparation of e.g. cefatrizine, the initially prepared compound is preferably isolated from the reaction mixture in the form of the corresponding methanolate or propyleneglycolate. The solvates of cefatriziiie may be converted into non-toxic, pharmaceutically acceptable salts by known methods.

For the preparation of e.g. the methanolate of cefatrizine, the initially obtained reaction mixture is mixed with methanol and subsequently with a dilute aqueous solution of an inorganic acid such as hydrochloride acid, in such a way that finally a pH of 1.0 - 1.5 of the mixture was attained. From the mixture obtained, the methanalatc is prepared in the usual way, such as by adjusting the pH to 1 .7 - 2.4, concentration of the organic phase and addition of an inert organic solvent for a clear separation, extraction of the organic layer with ice water, concentration of the combined water layers, addition of an organic solvent such as ethyl acetate, concentration of the obtained solution, addition of methanol in large excess and adjustment of the pH to 5.5, collecting the precipitate and vashinj and drying it.

For the preparation of e.g. cefadroxil, this compound is preferably isolated from the initially obtained reaction mixture by mixing it with m aqueous solution of an inorganic acid in such .1 way that a Final pH oi about 1 is attained, purification, addition 135 of N,N —dimethyl!ormamide in large excess, adjustment o± pH to .5 at about 10 °C, collecting of solvate crystals, washing with UMF-water mixtures and drying.

The evfadroxll may be recovered from thia solvaLe by dissolving it In water and addition of seeding crystals of cefadroxil monohydrate.

However, the cefadroxil may also be recovered more directly from the initially obtained reaction mixture by the addition of seeding crystals of cefadroxil-monohydrate to the water phase, obtained after the hydrolysis and purification s teps .

A preferred process for the preparation of cefadroxil monohydrate after the cefadroxil is nearly quantitatively isolated from the initially obtained reaction mixture comprises the steps of mixing the cefadroxil with an aqueous solution of an inorganic acid in such a way that a final pH of about 1 is attained, subsequent purification, addition of Ν,Νdimethylf ormamide in large excess, adjustment to pH 5.5, collecting the cefadroxil N,N-dimethylformamide solvate crystals, washing them with Ν,Ν-dimethylformamide-water mixtures and optionally with other organic solvents, optionally followed by drying, dissolution of the obtained solvate crystals in water and addition of seeding crystals of cefadroxil monohydrate, collection of the crystalline precipitate by filtration, washing and drying and addition of N,N-dimethyl formamide in excess to the concentrated mother liquor and washings to recover again the cefadroxil-N,N-dimethylformamide solvate.

It will be appreciated that some of the most important advantages of the acylation process according to the invention are: - previous and selective silylation of the p-hydroxy group of p-hydroxyphenylglycine is being avoided. - the reaction is being carried out in a concentrated solution of the reactants; given the size of the equipment this will favourably influence the output in kilos per batch. - the use of a p-hydroxyphenylglycine chloro hydrochloride Is avoided which can only be prepared by a process SO 1 3 5 which is rather difficult to manage, which moreover is rather expensive in a number of countries due to very stringent saiety regulations, if indeed permission for its manufacture can be obtained at all. - the use of large amounts of other additional chemicals is avoided. - the desired final product can surprisingly be prepared in economically attractive initial yields in a quality acceptable under available health regulations while, at the same time, the number of purification steps can be reduced with attendant smaller losses of desired compound. - in many cases mixing of solvent is reduced advantageously, so that recovery of solvents used is rather simple and economically favourable, while moreover the starting solvent system can be dried fairly easily. - the chance of undesired and unexpected crystallization of 7-ACA or its 3-methyl modifications is practically nil, so that a reliable and rather trouble-free process is provided.

It will be appreciated that at least two undesired side reactions always will be considered by skilled people, when acylating by means of a mixed anhydride: 1) acylation, whereby alkoxycarbonylamino cephalo- acid derivative. will L>·· formed; 2) partial racemisation Of the H-protected amino acid, e.g. during the conversion of the N-protected amino acid or salt thereof into the mixed anhydride.

The avoidance of the first side reaction by rather simple means will be regarded as rather impossible by skilled people, the more so as this side reaction at least often partially has a trivial nature, relating to the fact that mixed anhydrides naturally are more or less labile and are inclined to disproportionate into two symmetrical anhydrides. Hence the preparation of the mixed anhydride as well as the conversion of this anhydride with an amino acid will always be carried out at low temperatures.

The second undesired side reaction (racemisation) may be mainly avoided by trial and error methods.

Whereas, according to the literature, ethylchloroformate and - in the event of racemisation when using this reactant, in a somewhat lesser extent - isobutylchloroformate, pivaloylchloride and benzoylchloride were regarded as suitable reactants, while the use of metlylchloro formate could not be recommended, it now appeared surprisingly that use of the cheap methylchloroformate leads to significantly improved results.

For the preparation of the mixed anhydride and the subsequent acylation, preferably solvent systems are used, which will meet the requirements of economy (recovery, recycling) and/or ecology. A preferred solvent system for the preparation of e.g. cefadroxil is dichloromethane with a relatively small amount of a suitable co-solvent, such as N-methylpyrrolidon (preferred), tetramethylurea or N,N-dimethylacetamide.

These conditions could surprisingly be fulfilled by the certainly not predictable use of said solvent systems.

The applications of the solvent systems in the preparation of the mixed anhydride surprisingly lead to; a) an improved and moreover more reproduceable and reliable formation of the mixed anhydride and hence an improved conversion yield to the desired compound; b) an improved yield of the desired compound in combination with a simultaneous increase of the concentrations to an attractive level, in relation to the present economical requirements; c) the rather unexpected application of N,O-silylated 7-ACA or derivatives thereof for the reaction with the mixed anhydrides in the indicated yields; d) the improved conversion yields in the case of the application of co-solvents of the amide type for certain conversions of silylated 7-ACA derivatives; e) the possibility to carry out both the silylation reaction and the preparation of the mixed anhydride in one and the same vater-inmiscible main solvent, and more particularly dichloromethane, on account of which the presently required recovery of solvents is simplified drastically.

Moreover, it was found that in the preparation of the mixed anhydride, N-methyl morpholine or other similar (cyclo) aliphatic tertiary amines may be used as catalysts. The presence of catalysts may be avoided by the use of significant amounts - e.g. about one third of the total solvent volume - of co-solvents of the amide type.

As in industrial processes the application of thoroughly dried solvents and/or of Dane salts of very high purity is· an ideal that will never be realized completely, a slight excess of the starting Dane salts and of (lower) alkylchloroformates is preferably used.

The following examples illustrate the process according to the invention, however, without being considered to be restrictive in any respect.

Example I Preparation of ^D-a-amino-tp-hydroxyphenylJacetamido^3-2(lH9-1 ,2„3-triazol-4-yl-thiomethy^-3-cephem-4-carboxylic acid methanolate, a) Preparation of 0,N silylated 7-amino- 3<(1H)-1,2,3triazol-5-yl-thiomethyl7-3-cephem—4-carboxylic acid._ To a suspension of 4.173 g (13.33 mmol) of 7-amino-3(1H)—1,2,3—triazol—5—yl—thiomethyl -3-cephem-4-carboxylic acid, prepared by the conversion of 7-ACA uith a slight excess of sodium (1 H)—12,3—triazol—5—thiolate in water at elevated temperature and followed by recrystallization from water, in 50 ml of dry acetonitrile, purified by distillation and stored on weak acid aluminum oxyde (water content < 0.25 g/liter), 5.617 ml (40.29 mmol) of triethylamine were added at 3-5*C. While continuously passing nitrogen over the surface of the stirred mixture and at a temperature slightly below 5*C, 5.179 ml (40.99 mmol) of trimethyl chlorosilane were added. The cooling bath was removed and stirring was continued for 20 hours at room temperature (about 20*c) and hereafter for 3-4 hours at about 30 *C. The preparation vas cooled to -20*C. b) Preparation of methoxycarbonyl D-a»(l-carbomethoxy10 propen-2-yl)amino-p-hydroxyphenyl-acetate.

To a stirred and cooled (0*C) suspension of 11.478 g (37.88 mmol) of potassium D-α- 1-(carbomethoxypropen-2-yl)-2amino phenylacetate in a mixture of 50 ml of (from Redal) distilled tetrahydrofuran and 12 ml of tetramethylurea, 6 droplets (from a Pasteur pipette) of N-methyl-morpholine were added. While continuously passing nitrogen over the surface of the reaction mixture, the slurry was cooled to -10* - -12*C, whereupon a solution of 3 ml (38.8 mmol) of raethylchloroformate having a purity of 97% in 7 ml of distilled tetrahydrofuran was added dropwise, while a reaction temperature of -10’C up to -12’C was maintained.

The resulting mixture was additionaiiy stirred during 30 minutes at -10°C to -12°C. The mixture was subsequently cooled to -20 C. c) Preparation of 7-/D-a-amino-p-hydroxyphenylacetamido73-/( 1H )-1,2,3-triazol-5-yl-thiomethyl7-3-cephem-4-carboxylic acid25 methanolate.

Under a nitrogen atmosphere, the mixture, containing the mixed anhydride and in situ .prepared under b), was quickly added at -20*C to the reaction mixture, as obtained under a).

The resulting mixture was additionally stirred for 3 hours at -20 *C and thereafter stored overnight at -18*C. Under stirring, the mixture was gradually brought to 20 *C in about 45 minutes. Hereafter the mixture was filtered through a G-3 glass filter and the collected precipitate was repeatedly washed with in total 50 ml of dry methyl isobutylketone. Hereafter 5 ml of absolute methanol were added under ice cooling and stirring. The combined filtrate was poured out into 40 ml of vigorously stirred iced water. While cooling and stirring 4N. HCl vas added until the mixture had attained a pH of 1.5. The ice cold mixture was additionally stirred for 30 minutes, whereupon the pH was raised to 2.3 by means of the addition of triethylamine. Prior to the separation of the phases, the major part of the organic solvent was removed by evaporation in vacuo and subsequent addition of methyl isobutyl ketone until a clear tuo layer system was obtained. The layers were separated. The under™layer was stored in ice and the upper-layer was extracted twice with 25 ml volumes of iced water. The two washings were combined with the previously obtained under-layer and concentrated in vacuo to a small volume at temperatures below 20*C. 150 ml of ethyl acetate were added to the residue followed by almost complete evaporation in vacuo, again at temperatures below 20*C. While maintaining the temperature below 20“C, the residual, still somewhat moist oil was dissolved in 100 ml of dry (about 99%) methanol, followed by a slow introduction of triethylamine until a constant pH of 5.5 was reached. Precipitation of the desired cefatrizine methanolate started at pH 4. The mixture was additionally stirred under cooling during one hour. The precipitate was collected by filtration, washed with dry and cold methanol and dried in vacuo. Yield 4.640 g The PHR-spectrum of the product indicated an exactly 1:1 ratio between cefatrizine and methanol, while the crude yield of cefatrizine methanolate was 73.0%.

By careful calculation of integrals of various proton absorption signals in the PMR spectrum of a solution of the crude product in dedeuterio formic acid, it was found that the hydrochlo25 ric acid salt of triethylamine was present for about 1.0% by weight and tetramethylurea for about 0.6%. Since the crude product dit not contain detectable amounts of p-hydroxyphenylglycine nor of the starting ACA-derivative, the crude product seemed to have a purity of at least 98.4% by weight.

JO The slightly yellowish crude product could easily be converted into practically pure and stable solvates of cefatrizine, such as the sesqui hydrate.

Example ΙΓ Preparation of D-o-amino-(p-hydroxyphenyl)acetamido73-^~(ill )-1,2,3-triazol-5-yl-thiomethyl7-3-cephem-4-carboxylic acid methanolate. a) Preparation of silylated 7-amino-3-^'(lH)-1,2,3-triazol-5-y-l.-thi.omcthyl7-3-cephero-4-carboxylic acid._ S0135 To a suspension of 20.865 q of 7-amino-3-^-(l H)-1,2,3triazol-5-yl-thiomethyl7-3-cephem-4-carboxylic acid, in 200 ml of acetonitrile, 28.0 ml of triethylamine were added at -5*C to O’C, while continuously passing nitrogen over the surface of the mixture.

At a temperature of O’C to 7’C, 26.0 ml of trimethylchlorosilane were added and the reaction mixture was stirred for 3 hours at about 30’C.

The pH value measured with a Radiometer pH meter TTT2,C and a Radiometer GE 2401C electrode was kept constant between 6-0 and 6.5. b) Preparation of methoxycarbonyl D-a(l-carbomethyoxypropen-?-yl)amino-p-hydroxyphenylacetate._ To 57.390 g of potassium D-a-/”l-carbomethoxy-propen-2yj7amino-p-hydroxyphenylacetate, 200 ml of dry tetrahydrofuran were added and after cooling to O’C, 50 ml of N,N-dimethylacetamide were added. After addition of 30 Pasteur pipette drop3 of H-methylraorpholine, the mixture was cooled to -10’C to -15’C and 15 ml of methyl chloroformate were added. The reaction mixture was additionally stirred, for 30 minutes at -1 O’C to -1 5’C, whereafter the mixture was cooled to -20’C. c) Preparation of the cefatrizine methanolate.

Under a nitrogen atmosphere, the reaction mixture as obtained under b) and which contains the in situ prepared mixed anhydride, was added at -20’C at once to the mixture as obtained under a) at -20’C. The resulting mixture was additionally stirred for one hour at -20’C and stored in the refrigerator at -5’C overnight. The mixture was brought under stirring to 20’C in about 45 minutes. Hereafter the mixture was filtered by means of a G-3 glass filter and the collected material was repeatedly washed with dry methyl isobutyl ketone (about 200 ml). The combined filtrate was cooled in an ice-bath under a nitrogen atmosphere and subsequently treated with dry methanol (20 ml) and stirred for 5 minutes. Ice cold water (20 ml) was added and the pH was adjusted to 1.2 with 4N. HCl solution and the mixture was stirred for 30 minutes under ice bath cooling. The pH was raised to 1.8 with triethylamine and the reaction mixture was concentrated by evaporation under vacuo to 100-150 ml. Methyl isobutyl ketone (150 ml) was added and the layers were separated. The upper layer was extracted with (2x5 ml) and the extracts were combined with the under layer, (if separation is difficult a few ml of acetonitrile are added to improve the separation.) The combined water layers were added to cold methanol in such a way that finally a total volume of one liter was reached. By the addition of triethylamine the pH was adjusted to 5.5, while a solid precipitate was immediately formed. The mixture was additionally stirred for 3 hours and stored in the refrigerator overnight. The mixture was filtered, washed with methanol (95%) and dried over Ρ,,Ο^ vacuo at 30“C, giving a yield of 21,574 q (65.5%), having a purity of at least 98% by weight.

Example Hi Preparation of the monohydrate of D-a-amino1 5 (p-hydroxyphenylhcetamido7-3-methyl-3-cephem-4-carboxylic acid. a) Preparation of silylated 7-amino-3-methyl-3-cephem-4carboxylic acid (7-ADCA).

To 35.0 g (163 mmol) of 7-ADCA were subsequently added 400 ml of dichloromethane and 19.8 g (123 mmol) of hexamethyldi20 silazane (HMDS). After heating to 38*C, the mixture was refluxed under a dry nitrogen atmosphere for 7.5 hours. The amount of nitrogen, which was passed over per hour, was then about 20 1 (of standard conditions). The volume in the reactionflask was maintained on a constant value by the addition of small amounts of dichloromethane as far as necessary. The 7-ADCA was completely dissolved and after the titration of the starting IN. sulphuric acid solution in a washing bottle connected to the reactionvessel, 98% of the starting HMDS appeared to be catched as ammonia. b) Preparation of methoxycarbonyl D-u-(l-carbomethoxy30 propen-2-yl) amino-p-hydroxyphenylacetate,_ To 58.0 g of potassium D-a-(l-carbomethoxy-propen-2-yl)amino-p-hydroxyphenylacetate, 200 ml of dichloromethane were added. After coolino to -40’C 20 ml of dimethylacetamide were added, while the temperature raised to -33“C. After addition of 0.5 ml of N-methylmorpholine the mixture was cooled to -38*C and 16.0 ml of methylchloroformate were added in one charge. The temperature raised to about -30°C and the reaction mixture was stirred at this temperature for ?. hours, whereafter the mixture was cooled to -35*C. c) Preparation of the dimethylformaraidesolvate of 7-/“ l>-a-£unino-(p-hydroxyphenyl)acetamido7'-3-methyl-3-cephem4-carboxyiic acid (cefadroxil-DMF-solvate)._ The reaction Mixture as obtained under a) was cooled to 5 -30*C and added as quickly as possible to the solution of the mixed anhydride as obtained under b) under stirring and cooling, whereby a temperature of -25*C was attained. The reaction mixture was stirred for one hour at -25*C to -20*C. A mixture of 200 ml of distilled water and of 17 ml concentrated hydrochloric acid was added in such a way, that a temperature of 0*0 was attained. After 90 minutes stirring at 0*C, hydrolysis appeared to be completed and the pH was 1. The layers were separated and the waterlayer was washed with 100 ml of dichloromethane. The organic layer was washed with 50 ml of distilled water and after extraction of the washing water with the dichloromethane washings, the waterlayer was filtered and the filter was washed with the obtained water washings. Under cooling 1500 ml of dimethylformamide were added and the pH was adjusted to 5.5 at about 10*0 by addition of 25% ammonia solution, whereafter crystallization of the cefadroxil-DMF-solvate occurred. After about one hour the crystallization mixture was adjusted to pH 7 and cooled to 0*C. After cooling for one hour at this temperature, the needle-shaped crystals were filtered, washed with 150 ml of a 90% dimethylformamide-water mixture, washed with 300 ml of ethyl acetate and dried under vacuo at about 30*C. 73.2 g of a white preparation were obtained. The alleged structure was confirmed by IR and PMR spectra, showing a virtually pure product. Yield 08%. d) Preparation of pure crystalline 7-/*D-a-amino-phydroxypnenylacetamido7-3-methyl-3-ce?hem-4-carboxylic acid30 monohydrate (cefadroxil-monohydrate)._ The DMF-solvate as obtained under c) was added in portions and under stirring in about 10 minutes to 175 ml of distilled water of room temperature. After addition and dissolution of 5 g of the solvate, 1 g of seeding crystals of cefadroxil-monohydrate were added. After the complete addition stirring was continued for one hour. The pyramidal crystals were filtered and washed with water of 0*C and dried under vacuo at about 30*0, giving 35.4 g of a crystalline white product. The alleged structure of the obtained compound was confirmed by IR and PMR spectra, showing a high purity of the obtained product. The mother liquor was evaporated to 50 ml and after addition of 600 ml of DMF, 21.3 g of the same solvate were recovered, giving rise to an overall yield of 78% of cefadroxil, based on the starting 7-ADCA.

Example IV in exactly the same way as in Example III, a-c, a water layer was obtained as under c. This water layer was brought to crystallization without DMF, using 1 g of seeding crystals of the cefadroxil-monohydrate at pH 5. 21.7 g of the desired compound were obtained. After additional treatment of the mother liquor an overall yield of 78.3% could be attained.

Example V a) Preparation of silylated 7-amino—3—methyl—3—cephem—4— carboxylic acid.___________ To 35.0 g of 7-ADCA (l63 mmol), 400 ml of dichlororaethane and 45.3 ml (327 mmol) of triethylamine were added. Within some minutes 41.5 ml (327 mmol) of trimethylchlorosilan were dropwise added without cooling, while the temperature raised to 38*C. After refluxing for one hour at 38“ to 40“C, the reaction mixture was cooled to -30’C. Hereafter 82.2 g of cefadroxil-DMF-solvate were obtained by following the same additional steps b and c of Example III, representing a yield of 98.8%. The alleged structure could be confirmed by IR and PMR spectra, indicating a high purity of the obtained product. According to exactly the same process step d) of Example III, obtained cefadroxil-DMF-solvate was converted into 41.5 g of cefadroxil-monohydrate. The alleged structure of which could be confirmed by IR and PMR spectra, which were also indicating a high purity of the obtained product.

According to a Karl Fisher test the moist content seemed to be 5.5%. From the mother liquor an additional amount of 23 g of DMF-solvate could be obtained, in total representing an overall yield of 89.5% cefadroxil raonohydrate, based on the starting 7-ADCA

Claims (15)

Claims

1. Process for the preparation of a 7- -amino-phydroxyphenylacetamidojjgroup-containing cephalosporanic acid derivatives by acylation of a 7-aminocephalosporanic acid derivative or a 3-methyl modification thereof in a water immiscible, inert, organic main solvent with a solution of a mixed anhydride according to the general formula wherein R7 represents an alkoxy group containing 1-2 carbon atoms, Rg represents an alkoxy group containing 1-3 carbon atoms, R5 represents an alkyl group containing 1-3 carbon atoms or a hydrogen atom, and R4 represents an alkyl group containing 1-3 carbon atoms, which mixed anhydride solution has been previously prepared by reacting the corresponding Dane salt with an alkylchloroformate in an inert, organic main solvent and in the presence of a catalytic amount of a tertiary amine, characterized in that: a) a 7-aminocephalosporanic acid derivative or a 3-methyl modification thereof is reacted in a dry, inert, organic solvent with a trialkylsilyl group supplying agent in approximately 2 equivalents with respect to 7-ADCA or 7-ACA and approximately 3 equivalents with respect to its 3-methyl modifications, whereby possibly present amounts of free trialkylhalosilane, containing 1-3 carbon atoms in the alkyl residues, and of tertiary amine in the reaction mixture have been mutually balanced by adjusting at the end of the reaction to an empirically determined signal value as defined in the specification, b) the obtained reaction mixture, containing a derivative of 7-aminocephalosporanic acid or 3-methyl modification thereof according to the formula S0135 and/or ft, '\ ?/ CH R CGO-Si'-R (i) c// o cm—.<,£ I 1, (II) I z s, COO - Si c) the acylation reaction isycontinued at a temperature below 0°C, followed by the recovery of the desired compound by methods known per se.

2. Process according to claim 1, wherein R 1 , Rg and Rg each represents a methyl group.

3. Process according to claim 1, characterized in that the 7-aminocephaiosporanic acid derivative or a 3-methyl modification thereof is reacted in dry methylene chloride with trimethylchlorosilane in the presence of a tertiary amine.

4. Process according to claim 3, characterized in that the possibly present amounts of free trimethylchlorosilane and of tertiary amine have mutually been accurately compensated so that the signal recorded by a pH electrode is adjusted at the end of the reaction at a constant value of a pH scale value between 5.5 and 7.5 at a temperature between 15-25°C, of a Radiometer pH meter type TTT2, and a Radiometer GK 2401C electrode or an Ingold cold electrode.

5. Process according to claims 1-4, characterized in that the mixed anhydride is previously prepared from the corresponding Dane salt and methyl chloro formate under anhydrous conditions, in the presence of a tertiary amine as catalyst, for example N-methylmorpholine or N,N-dimethy1benzylamine, in dry methylene chloride mixed with a cosolvent or in methyl isobutyl ketone optionally mixed with a cosolvent .

6. Process according to claim 5, characterized in that the mixed anhydride is prepared in dry methylene chloride, to which dimethylformamide, sulfolane, tetrahydrofuran, N-methylpyrrolidone, 1,4-dioxane, acetonitrile, dimethylacetamide or tetramethylurea or a mixture thereof is added as a cosolvent, or in methyl isobutylketone as main solvent to which one or more of the said cosolvents may be added.

7. Process according to claim 6, characterized in that the solvent is dry methylene chloride, to which dimethylformamide, tetrahydrofuran, N-methylpyrrolidone, dimethylacetamide or tetramethylurea or a mixture thereof is added.

8. Process according to claim 7, characterized in that the cosolvent Is added in an amount of up to 10% by volume.

9. Process according to any one of claims 1-8, characterized In that the preparation of the Dane mixed anhydride is carried out at a temperature of -10°C to -35°C.

10. Process for preparing the Dane mixed anhydride according to any of claims 1-8, characterized in that sodium or potassium D-0(.-( 1-ca r bome thoxy p ropen-2-y 1 )-amino-p-hydr oxyphenylacetate is reacted with methylchloroformate.

11. Process according to any one of the claims 1-10, characterized in that cefadroxil is prepared.

12. Process for the preparation of cefadro.xll monohydrate according to claims 1-10,characterized in that the cefadroxil is nearly quantitatively isolated from the initially obtained reaction mixture by mixing it with an aqueous solution of an inorganic acid in such a way that a final pH of about 1 is attained, subsequent purification, addition of N,Ndimethylformamide in large excess, adjustment of pH 5.5, collecting the cefadroxil N,N-dimethylformamide solvate crystals, washing them with N,N-dimethylformamide-water mixtures and optionally with other organic solvents, optionally followed by drying, dissolution of the obtained solvate crystals in water and addition of seeding crystals of cefa— droxil monohydrate, collection of the crystalline precipitate by filtration, washing and drying and addition of N,N-dimethyl formamide in excess to the concentrated mother liquor and washings to recover again the cefadroxil-N,N-dimethylformamide s olvat e.

13. Process according to any one of the claims 1-10, characterized in that cefatrizine is prepared.

14. Process for preparing a 7 - [D-α- amino-p-hydroxyphenylacetamido] group-containing cephalosporanic acid derivative substantially as described herein with reference to the Examples.

15. 7 - [D - α-amino - p - hydroxyphenyl acetamido] group containing cephalosporanic acid derivatives whenever produced by a process according to any one of the preceding claims.