LU85670A1 - CHLOROCEFADROXIL MONOHYDRATE - Google Patents

Description

i *

Chlorocefadroxil monohydrate TECHNICAL BACKGROUND 1. Field of the invention

The crystalline cephalosporin monohydrate of the invention generally manifests the usual properties of antibacterial agents of this class and is particularly useful, in the form of pharmaceutical compositions, for the treatment of bac terial infections by oral administration.

ψ ii 2. Known state of the art 7- [D - "- amino-ol- (3-chloro-4-hydro-xyphenyl) acetamido] -3-methyl-3-cephem-4-carboxylic acid which is a cephalosporin derivative is the subject of EUA patent 3,489,751. This compound, generally referred to below as chlorocefadroxil, corresponds to the formula:

/ f ~ \ H

HO - (/ ') - CH- C- NH -1-f ^ 1 H - t £ X, - cl o T ό

COOH

Chlorocefadroxil is a broad spectrum antibiotic effective in the control of diseases caused by various Gram-positive and Gram-negative microorganisms. It is of particular interest as an antibiotic cephalosporin for oral use.

EUA patent 3,489,751 describes the preparation of chlorocefadroxil by acylation of 7-aminodeacetoxycephalosporanic acid (7-ADCA) using "an amino-protected derivative of D (-) -c (-amino-o acid) (- (3-chloro-4-hydroxyphenyl) acetic. Among the various amino-protected acylating agents mentioned, D (-) -c acid (- (3-chloro-4-hydroxyphenyl) - <X- ( t-butoxy-carbonylamino) acetic gives the highest yields by the so-called t-BOC process, but the yields of this process leave something to be desired for industrial production and the reactant used in the t-BOC process is very expensive.

Patent USA 3,985,741 describes the preparation of chlorocefadroxil by acylation of 7-ADCA using the mixed anhydride of D (-) -o (- (3-chloro-4-hydroxyphenyl) glycine when the radical o <-amino of this last- »i.

Was blocked by a ketone compound such as methyl acetoacetate. This process offers certain advantages defined over the t-BOC process, but is not yet as efficient as would be desirable for industrial production. This patent also describes a crystalline dimethylformamide solvate of chloro-cefadroxil containing 1.5 moles of dimethylformamide r per mode of chlorocefadroxil. The dimethyl dimethyl solvate is dispersed in boiling methanol until dissociation of the solvate and the resulting suspension is then cooled to give a purified form of chlorocefadroxil. There is, however, no indication that the chlorocefadroxil obtained by the process of this patent is in the form of a crystalline hydrate.

The patent EUA 3,781,282 describes in an example (Example 7) the preparation of chlorocefadroxil by dissolving the dimethylformamide solvate of chlorocef adroxil in acidified water, then by neutralization by means of triethylamine. There is no indication that the chlorocefadroxil obtained would be in the form of a crystalline monohydrate or even in a crystalline form.

The patent EUA 4,160,863 describes a crystalline monohydrate of 7- [DW-amino-C (- (p-hydroxyphenyl) -acetamido] -3-methyl-3-cephem-4-carboxylic acid (also called cefadroxil) which is prepared according to a technique analogous to that applied to chlorocefadroxil monohydrate and forming the subject of the present invention.

Because of the many important advantages of chlorocefadroxil, it would be desirable to have an industrially useful process for preparing this antibiotic with higher yields and lower manufacturing costs than by the already known processes. It would also be desirable to obtain chlorocefadroxil in a stable crystalline form, for example a crystalline hydrate, making it possible to present the antibiotic in the form of pharmaceutical compositions suitable for antibacterial use, for example aqueous suspensions.

OVERVIEW OF THE INVENTION

The present invention relates to a new crystalline monohydrate of chlorocéf adroxil and d.es processes for preparing this monohydrate. It also relates to an improved acylation process for the preparation of chlorocefadroxil with an excellent yield and at a lower manufacturing cost than in known processes.

DESCRIPTION OF THE DRAWING

The figure in the drawing is the infrared absorption spectrum characteristic of chlorocefadroxil monohydrate (KBr pellet) recorded using the techniques described below.

DETAILED DESCRIPTION OF THE INVENTION

According to one aspect, the subject of the invention is an improved process for the preparation of chlorocefa-droxil or a pharmaceutically acceptable salt thereof, which comprises (a) the silylation of 7-aminodeacetoxy-cephalosporanic acid in a solvent inert aprotic, substantially anhydrous; (b) acylation of the resulting silylated 7-aminodeacetoxy-cephalosporanic acid using D (-) -o (-amino-o (- (3-chloro-4-hydroxyphenyl) acetyl) chloride hydrochloride inert aprotic, substantially anhydrous in the presence of an acid acceptor; (c) elimination by hydrolysis or alcoholysis of all silyl radicals of the acylation product, and (d) isolation of the desired cephalosporanic acid or d '' a pharmaceutically acceptable salt of

. X

> this one.

The pharmaceutically acceptable salts contemplated above are, for example, (1) the non-toxic pharmaceutically acceptable salts of the carboxylic acid radical, such as the sodium, potassium, calcium, aluminum and ammonium salts and the salts of non-toxic substituted ammonium formed with amines such as trialkyl (lower) amines, procaine, dibenzylamine, N-benzyl-y3-phenethyl-amine, 1-ephenamine, N, N'-dibenzylethylenediami-ne, dehydroabietylamine, N, N'-bisdehydroabiétyl- * ethylenediamine, N-alkyl (lower) piperidines "such as N-ethylpiperidine and other amines which have already been used to form benzyl penicillin salts; and (2) pharmaceutically acceptable non-toxic acid addition salts (i.e., basic nitrogen salts), such as (a) mineral acid addition salts such as the hydrochloride , hydrobromide, hydroiodide, sulfate, sulfamate, sulfonate, phosphate etc. and (b) the addition salts of organic acids such as maleate, acetate, citrate, tartrate, oxalate, succinate, ^ benzoate, fumarate, malate, mandelate, ascorbate, leyl-naphthalenesulfonate and p-toluene- = sulfonate. For the purposes of the invention, by "lower alkyl radical" is meant a saturated straight or branched chain hydrocarbon radical of 1 to 10 carbon atoms inclusive.

In the above process, 7-ADCA is first silylated by reaction with a silylating agent in a substantially anhydrous inert aprotic solvent.

Solvents suitable for silylation are in particular inert organic solvents which are substantially anhydrous such as methylene chloride, tetrahydrofuran, chloroform, tetrachloroethane, MT _ K _> "" nitromethane, benzene and diethyl ether.

Methylene chloride is a preferred solvent.

Silylating agents useful for the above process are known [see, for example, US Patents 3,654,266, 3,575,970, 3,499,909, 3,349,622, 3,595,855, 3,249,622 and English patents 1.339.605, 959.853 and 1.008.468]. Although any known silylating agent can be used, preference is given to an agent chosen from those of the formulas r1 y

VS1X 2 F

1 1 \ and R —Si — X

R1 NH ’7nH RX \ £ 4 jLs /)

I \ VA

: where R ^, and R4 represent hydrogen or halogen atoms or lower alkyl, lower alkyl-, phenyl, benzyl, tolyl or di-methylaminophenyl radicals, at least one of R, R and R4 not representing a halogen or hydrogen atom; R "* · represents a lower alkyl radical; m represents 1 or 2 and X represents a halogen atom or radical

- NOT

VF6 5 where R represents a hydrogen atom or lower alkyl radical and R represents a lower alkyl radical or R3 R2— Si OO Λ where R, R · 3 and R ’are as defined above.

Examples of suitable silylating agents which are used are, in particular, trimethylchlorosilane, hexa-methyldisilazane, triethylchlorosilane, methyl-trichlorosilane, dimethyldichlorosilane, tri * -thylbromosilane, tri-n-propylchlorosilane, -methyldimethylchlorosilane, tri-n-butylchlorosi-lane, methyldiethylchlorosilane # dimethylethyl-chlorosilane, phenyldimethylbromosilane, benzyl-methylethylchlorosilane, phenylethylmethylchlorosi-lane, triphenylchlorosilane triphenylchlorosilane triphenylchlorosilane -p-dimethylami-s nophenylchlorosilane, N-ethyltriethylsilylamine, 1 1 heocaethyldisilazane, triphenylsilylamine, tri-n-propylsilylamine, tetraethyldimethyldisilazane and tetramethyldiethyldisilazan, tetramethyldiethyazyldi-tilan-disl-tetane lyldisilazane. Other suitable silylating agents are hexa-alkylcyclotrisilazanes or octa-alkylcyclotetrazilazanes and silylamides and silyl- ureides such as a trialkylsilylacetamide and a bis-triaalcoylsilylacetamide. Especially preferred silylating agents c are trimethylchlorosilane and hexamethyldisilazane.

- When a silyl halide, for example trimethylchlorosilane, is used as a silylation agent, the silylation reaction is carried out in an inert aprotic solvent which is substantially anhydrous in the presence of an acid acceptor (hydrogen halide ), which is preferably propylene oxide OR- a nitrogenous base such as triethylamine, tri-methylamine, dimethylaniline, quinoline, lu- * tidine or pyridine. The preferred acid acceptors are propylene oxide, triethylamine or a mixture of triethylamine and dimethylaniline. When using a silazane, for example hexa-methyldisilazane, the silylation reaction is exe rn m.t _ 7 -

T

cut with advantage by heating the silazane and the 7-ADCA so that the ammonia or the amine formed as reaction by-products are distilled off.

To prepare the silylated 7-ADCA by the above method, it is theoretically possible to use one to two molar equivalents of silylating agent per mole of 7-ADCA to obtain the mono- or disilylated 7-ADCA or a mixture of those -this. Thus, when 7-ADCA is reacted with approximately one equivalent of silylating agent, monosilylated 7-ADCA is formed. When using trimethylchlorosilane or hexa- »methyldisilazane, for example, the product is of formula

¥ -τγ! NOT

COOSi (CH3) 3

The disilylated derivative of 7-ADCA can be obtained using at least two equivalents of silylating agent per mole of 7-ADCA for the silylation reaction. When using trimethylchlorosilane or hexa-methyldisilazane which are preferred, disilylated 7-ADCA of the formula:

If (CH-,), H-N - ^ ^ o Y ch3 COOSi (CH3) 3

Silylation can be performed in a large

MT Q

9 'm ”temperature range, for example from room temperature to the reflux temperature of the solvent system. Advantageous results are generally obtained at room temperature (20-30 ° C.) with silyl halides and at high temperatures, for example at reflux, with the silazanes which are generally less active.

The mono- or disilylated 7-ADCA or a mixture of the two can then be acylated using D (-) -oi-amino-o (- (3-chloro-4-hy-droxyphenyl) acetyl chloride hydrochloride preferably in the form of a dioxane solvate) giving in situ an intermediate silylated chloroefadro-xil All the silyl radicals present after acylation are then eliminated by hydrolysis or alcoholysis and the desired chlorocefadroxil is isolated from the reaction mixture, for example by neutralization up to the isoelectric point at which chlorocef adroxil precipitates out of the solution.

The solvents used for the acylation of silylated 7-ADCA are defined above with regard to the silylation stage (a).

A preferred temperature range for acylation ranges from about -20 ° C to about + 70 ° C.

The temperature is however not critical and higher or lower temperatures than those falling between the preferred limits may be used. The especially preferred acylation temperature is about -10 to +10 ° C.

The acylation is preferably carried out in the presence of an acid acceptor which may or may not be the same as that used to prepare the silylated 7-ADCA. The best results are obtained with a relatively weak tertiary amine (that is to say of a pK 4 7) a 'such as dimethylaniline, pyridine or quinoline. Preferably, the mixture also comprises a salt of mineral ψ •> acid of a weak tertiary amine, for example dimethylaniline hydrochloride, in order to inactivate a possible excess of amine (see, for example, patent EUA 3.678 .037).

The reaction progresses to some extent regardless of the molar ratio between the reactants, but for maximum yield it is preferable to perform the acylation with about one mole of acylating agent or a small molar excess thereof by mole of silylated 7-ADCA.

Silylated chloroefadroxil, which is the acylation product, is subjected to hydrolysis or al-coolyse to remove protective silylated radicals. Thus, the silylated intermediate can be hydrolyzed by the addition of water or, more advantageously, alcoholized by the addition of a suitable alcohol, preferably a C 1 -C 4 alkanol such as methanol, ethanol, n-propanol. , Isopropanol, n-butanol etc.

A mixture of water and a lower C 1 -C 4 alkanol can also be used for this operation.

Chlorocefadroxil can be isolated from the reaction solution according to methods usually applied to the isolation of similar cephalosporins. Thus, the product can be isolated as a neutral molecule by adjusting the pH of the reaction mixture upwards until the desired acid precipitates from the solution. It is preferable to use a non-aqueous amino base such as triethylamine. Chlorocefadroxil in the form of the free acid can be converted to a pharmaceutically acceptable salt of carboxylic acid or acid addition by reaction with a base or an appropriate acid.

According to a preferred embodiment of the invention, 7-aminodeacetoxycephalosporospanic acid is silylated by means of hexamethyldisilazane *, "in a substantially anhydrous aprotic solvent, preferably methylene chloride, by external heating, preferably at the reflux temperature of the solvent, so that disilylated 7-ADCA of the formula: rs ^ / "Νγν coosi (ch3) 2 is formed in situ

The disilylated 7-ADCA is then acylated directly in the same solution (preferably between -10 and + 10 ° C) using D (-) -rt-amino chloride hydrochloride ** - (3-chloro-4 -hydroxyphenyl) acetyl, preferably in the form of a dioxane solvate, in the presence of an acid acceptor, preferably a tertiary amine of a pK ^ 7 such as dimethylaniline, pyridine or quinolein. After the acylation, the silylated ch lorocefadroxil which is the acylation product is reacted with a C 1 -C 4 alkanol, preferably methanol or n-butanol, for the elimination of all the silyl radicals and the product is collected (optionally after filtration) by neutralization to the isoelectric point using a tertiary amine, preferably triethylamine, for precipitation.

The use of hexamethyldisilazane as a silylating agent instead of the usual silyl halides such as trimethylchlorosilane eliminates the formation of an acid halide as a by-product and, therefore, the need for an acceptor acid for silylation. In the absence of this acid acceptor in the reaction medium, the quantity of insoluble salt, for example of chlorhy- ηη.Μ, τ - 11 - triethylamine drate, which may interfere with the subsequent isolation is lower. Consequently, hexamé-thyldisilazane makes it possible to obtain higher yields in chloroéfadroxil than those reached by conventional silylat-ion by means of trimethylchlorosilane.

According to another aspect, the invention relates to a new crystalline monohydrate form of chlorocefadroxil which has been found to be a useful stable form of this antibiotic cephalosporin which is especially suitable for pharmaceutical compositions.

The crystalline chloroefadroxil monohydrate of the invention essentially presents the X-ray diffraction diagram below noted according to the powder technique.

O

Line Equidistance d (A) Relative intensity 1 8.63 100 2 7.03 23 3 6.68 56 4 6.42 71 5 5.47 39 6 5.25 7 - 7 4.76 51 8 4.60 29 9 4.48 13 10 4.32 39 11 4.03 82 12 3.96 47 13 3.87 52 14 3.70 32 15 3.53 36 16 3.28 30 17 3.07 23 18 2.98 10 19 2.87 13 or »ht 10. * 20 2.81 21 21 2.72 19 22 2.69 46 23 2.63 15 24 - 2.53 8 25 2.50 9 26 2.44 13 27 2.31 21 28 2.25 10 29 2, 19 9 30 2.14 6 31 2.09 6

The details for the determination of this X-ray diffraction diagram are given below:, 2 Flat samples of 2 cm and a thickness of 1 mm are used, mounted in an automatic X-ray diffractometer for powders (Phillips PW 1050-70, o

CuK "(1.54178A)). Temperature = 22 ° C.

A very small amount of crystalline sodium fluoride is mixed with some of the samples to form an internal standard. For the same purpose, the full spectrum of a sample of pure NaF is likewise recorded.

The films are examined on a Norbyco Debye-Scherrer film reader by recording the positions of the diffraction rings to the nearest 0.05 mm. The corrected values are calculated taking into account the shrinkage of the film and the equidistances (equidistances d) are deduced from the corrected values. The calculations are carried out using a computer program (XRAY, by P. Zugenmaier). The accuracy of the equidistance calculation is around 1%.

Intensities are measured on all films using a Joyce-Loeble Mark IIIC recording microdensitometer (5: 1 scan ratio, 0.1 optical density wedge). Relative intensities are assigned on a scale of 1 to 100 to all identifiable diffraction rings, taking into account the continuous background to calculate the corrected intensity corresponding to the peak.

A sample of the resulting crystalline monohydrate is submitted to the infrared analysis, the spectrum of which (recorded on KBr disk) constitutes FIG. 1.

A subject of the invention is also a process for preparing the crystalline chlorocepadroxil monohydrate described above, which comprises (a) the silylation of 7-aminodesacetoxycephaloporanic acid in a substantially anhydrous inert aprotic solvent; (b) acylation of the resulting silylated 7-aminodeacetoxycephaloporanic acid by means of D (-) - o (-amino-o (- (3-chloro-4-hydroxyphenyl) - acetylchloride hydrochloride) an inert aprotic solvent which is substantially anhydrous; (c) the elimination by hydrolysis or alcoholysis of all silyl radicals of the acylation product, and (d) the formation of the desired monohydrate by a process chosen between "(1) adjust towards high the pH of the solution of stage (c) in the presence of an excess of dimethylformamide or acetonitrile to form the solvated dimethylformamide or acetonitrilic acid 7- [D - & - amino- ¢ (- (3 -chloro-4-hydroxyphenyl) acetamido] -3-methyl-3-cephem-4-carboxylic, dissolve this solvate in acidified water or a mixture of acidified water and a-ketonitrile and adjust upwards the pH of this acidified solution to precipitate the desired crystalline monohydrate; (2) adjust upwards the pH of the solution in stage (c) in the presence of an excess of dimethylformam ide or acetonitrile to form the solvate dimen Τι MT _ 1 A _ "t thylformamide or acetonitrilic acid 7- [D-0f-amino - <> M3-chloro-4-hydroxyphenyl) acetamido] -3 -methyl- 3-cephem-4-carboxylic acid and bring this solvate into contact with water or a partially aqueous medium to precipitate the desired crystalline monohydrate, and (3) adjust upwards the pH of the solution of stage ( c) to form 7- [D-of-amino-o (- (3-chlo-ro-4-hydroxyphenyl) acetamido) -3-methyl-3-cephem-4-car-boxylic acid and to put this acid in contact with water or a partially aqueous medium to cause crystallization of the desired monohydrate.

During the preparation of crystalline chlorocefadroxil monohydrate according to the above method, silylation, acylation and removal of silyl radicals are carried out as described above in connection with the improved acylation process for the synthesis of chlorocefadroxil.

The desired crystalline monohydrate can be prepared in any of several possible ways.

According to a process, the chlorocé-fadroxil solution, after solvolysis, is neutralized using a basic substance, for example a tertiary amine such as triethylamine, in the presence of an excess of dimethylformamide or acetonitrile up to 'that the dimethylformamide or acetonitrile solvate of chlorocefadroxil precipitates from the solution. The solvate can then be collected and washed (preferably without being dried) to give a crystalline material.

The dimethylformamide or acetonitrilic solvate of chlorocefadroxil can be converted into the desired chloro-cefadroxil monohydrate by dissolving the solvate in acidified water or in a mixture of acidified water and acetonitrile, then by neutralization. the acidified solution for the precipitation of the monohydrate.

The dissolution of the dimethylformamide or acetonitrile solvate of chlorocefadroxil takes place at a pH of about 2-2.4 which can be reached by adding a mineral acid, for example HCl, to a mixture of the solvate in water or in an acetonitrile-water mixture. The solid impurities can be separated at this stage by filtration of the acidified solution after treatment with activated carbon and / or "a filtration aid.

The acidified solution is then neutralized, preferably with stirring and heating to approximately 35-60 ° C, by addition of an appropriate base, for example a tertiary aliphatic amine such as triethylamine, for the purpose of raising the pH. from the solution to the point where the chlorocefadroxil mono-hydrate separates into crystals from the solution.

Acetonitrile is preferably added to the solution as an antisolvent (precipitating agent) during neutralization to ensure maximum collection of the desired product. The yields are also improved by seeding the solution with crystalline seeds of the desired monohydrate before and / or during the final neutralization.

According to a variant for the preparation of crystalline chlorocefadroxil monohydrate in the above process, the dimethylformamide or acetonitrile solvate of chlorocefadroxil is prepared as described above and is brought into contact with water or a partially aqueous medium until that the desired monohydrate separates into crystals from the solvent system.

The dimethylformamide or acetonitrile solvate of chlorocefadroxil is dissolved in water or a mixture of water and an organic solvent such as acetonitrile, acetone, a C 1 -C 4 alkanol. (metha-nol, ethanol, n-propanol, isopropanol, n-butanol, amyl alcohol, etc.) or a mixture of these. Partially aqueous organic solvents are preferred because organic solvents can cause many of the impurities and lead to a purer end product.

When using mixtures of water and organic solvents, the ratios between the components of the system can vary within a wide range without much adverse effect. The preferred ratios determined for various partially aqueous organic solvents are as follows: water: acetone (1: 3) (volume / volume) water: isopropanol (1: 3) (volume / volume) water: acetonitrile (1: 3) (volume / volume) water: n-butanol (1: 1) (volume / volume).

* With the water-acetonitrile system, it is preferable to add n-butanol (preferably after solubilization of the solvate) to ensure that the solvent system remains in the state of single homogeneous phase during »crystallization. Preferably, the amount of n-bu tanol added to this crystallization system is sufficient for the final water: acetonitrile: n-butanol ratio to be 1: 2: 1 by volume.

The concentration of the solvate in the aqueous or partially aqueous crystallization medium is not critical. However, the best yields have been obtained at concentrations of about 400 to 800 g / liter of solution. The solvate is preferably added little by little to the solvent system with stirring over a period which depends on the quantity of solvate which is used, namely from a few minutes to several hours.

Crystallization can be carried out over a wide range of temperatures, i.e. from room temperature to the boiling point of the solvent system. Good results are obtained at a temperature of about 35-60eC and more advantageously "40-45eC.

The yields of monohydrate are improved by seeding the solution of the dimethylformamide or acetonitrile solvate by means of crystalline seeds of chlorocefadroxil monohydrate.

According to another variant to prepare the “monohydrate sought in the above process, (1) the silylated chloroefadroxil is prepared and the protective silyl radicals are eliminated by hydrolysis or alcoholysis, as described above, (2) the solution is neutralized resulting from the stage of elimination up to the isoelectric point of chlorocefadroxil (pH approximately 5.7-5.8) using an appropriate base, preferably a tertiary aliphatic amine such as triethylamine, to precipitate the impure or primary quality chlorocefadroxil and (3) this impure chlorocefadroxil is brought into contact with water or a mixture of water and a suitable organic solvent, preferably acetonitrile, acetone, a C ^ -C ^ alkanol (eg methanol, ethanol, n-propanol, isopropanol, n-butanol, • amyl alcohol etc.) or a mixture of these, until chlorocepadroxil monohydrate separates into crystals of the solution.

The neutralization of the chlorocé-fadroxil solution for the formation of impure or primary quality (amorphous) chlorocéfadroxil can be carried out with advantage at room temperature by gradual addition of the base to the stirred solution. The impure chlorocefadroxil can then be crystallized in the same way as described above with regard to the dimethylforma-midic or acetonitrile solvate of chlorocefadroxil. As rη MT _ 1 fl _,> for the crystallization of the dimethylformamide or acetonitrile solvate, the especially preferred solvent system is the water: acetonitrile: n-butanol 1: 2: 1 by volume system.

. According to a particularly preferred embodiment, the subject of the invention is a process for preparing crystalline chlorocepadroxil monohydrate from the dimethylformamide or aceto-nitrilic solvate of chloroefadroxil or from impure chlorocepadroxil (of primary quality), which comprises : * »Y.- (a) dissolution of the dimethylformamide or acetonitrilic solvate of 7- [Do (-amino-o (- (3-chlo-ro-4-hydroxyphenyl) acetamido) -3-methyl-3 acid - cephème-4-car-boxylic in acidified water or in a mixture of acidified water and acetonitrile and the adjustment upwards of the pH of the acidified solution until the desired monohydrate separates into crystals of the solution, or - (b) contacting the acid 7- [D-0 (-amino-0 (- (3-chloro-4-hydroxyphenyl) acetamido) -3-methyl-3-cephè-me -4-carboxylic acid or its dimethylformamide or acetonitrile solvate with water or a partially aqueous medium until the desired monohydrate separates in crista ux of the solution.

. The dimethylformamide or acetoni trilic solvate and the starting chlorocefadroxil for the above process can be obtained according to the processes described in this specification or according to other known processes, for example those described in EUA patents Nos. 3,489,751 and 3,985 .741.

The preferred conditions for the formation of chlorocefadroxil monohydrate in the above process are those described above with respect to the general reaction scheme already outlined, that is, the combination of silylation with acylation and CD. MJ - 19 - i> i »formation of the monohydrate.

Under the preferred reaction conditions described above, the present invention makes it possible to produce chlorocefadroxil of primary quality with an excellent yield and then to convert this chloro-cefadroxil or its dimethylformamide or acetonitrile solvate to chloroefadroxil monohydrate with a yield of activity up to around 85%.

"The crystalline monohydrate prepared according to one" or the other of the above methods can be isolated according to conventional techniques, for example filtration, and then be washed, dried and converted into pharmaceutical compositions suitable for antibiotic treatment of different bacterial conditions. Examples of these compositions (for example capsules or tablets), doses and modes of administration of chlorocé-fadroxil monohydrate and others of these pharmaceutical compositions are given in EU patents Nos. 3,489,751 and 3,985,741 in connection with the amorphous form of chlorocefadroxil.

The invention therefore also relates to a pharmaceutical composition, advantageously a pharmaceutical composition suitable for oral administration, which comprises crystalline chloroefadroxil monohydrate and a suitable pharmaceutically acceptable inert excipient or diluent.

The invention further relates to a method of treating humans or other animal species (for example mammals) affected by conditions caused by Gram-positive or Gram-negative bacteria, according to which the following are administered: the host reaches an effective dose of crystalline chloroefadroxil monohydrate as defined above or a pharmaceutical composition as defined above.

; The examples below illustrate the invention.

W ',%

All temperatures are given in Centigrade degrees. The abbreviations used are 7-ADCA for 7 - * - aminodeacetoxycephalosporanic acid, TEA for triethylamine, DMA for dimethylaniline and. DMF for dimethylformamide.

Preparation of starting compounds Preparation 1

Preparation of D (-) cbloro-3-hydroxy-4-phenylglycine? S ° 2C12

OH —ν 'y CH-COOH -OH— (' y- CH-COOH

\ - / nh2 Y = l / nh2

Cl

REACTANTS

- D (-) p-hydroxylphenylglucin 10 kg (60 moles) - Acetic acid 228 liters - Hydrochloric acid (gas) 6.25 kg - Sulfuryl chloride 8.1 kg (60 moles) - Methylene chloride 100 liters - Soda solution 400 g / liter - 3 liters - Acetone at 15 liters

OPERATING MODE

A suspension of 10 kg of ^ D (-) p-hydroxyphenylglycine in 200 liters of acetic acid is heated to 60 °. The hydrochloride is formed by bubbling 6.25 kg of hydrochloric acid (in about 60 minutes) and then a solution of 8.1 kg of sulfuryl chloride in 28 liters of acetic acid is then added to the resulting solution in 90 minutes maintained at 65-70 ". The solution is degassed under low pressure, cooled to 20 ° and stirred overnight. The solid is collected and washed by resuspending it twice in methylene chloride. It is dried under vacuum at 40 ”.

The weight of chloro-3-hydro-- xy-4-phenylglycine hydrochloride obtained is 13 kg.

i!

The hydrochloride is suspended in 130 liters of water and the mixture is brought to 40 ° in 30 minutes with stirring. It is cooled to 20 ° and the pH is adjusted to 1.4 by adding a sodium hydroxide solution at 400 g / liter (about 3 liters). The mixture is stirred for 2 hours at + 5 ° C., it is filtered and the solid is washed 3 times with distilled water (until there is no ionizable chlorine in mother liquors), then once with approximately 15 liters of acetone , after which it is dried at 60 ". The solid is stirred in a Frewitt apparatus and dried to a water content (KF) <0.1%.

The weight of chloro-3-hydroxy-4-phenylglycine obtained is 8.1 kg (yield of 67%).

Preparation 2

Preparation of D (-) chloro-3-hydroxy-4-phenylqlycine chloride hydrochloride coc12

OH —γ 'V-CH-COOH - = - ”OH — Y \ V-CH-COOH

; \ - / NH2 = dioxane \ - / NH-COC1 cr Cl f / \ HC1 OH— ('xVch — z' -> OH-v y- CH-COC1

0 "B2 diSL

Cl Nc / Cl

II

O

REACTANTS

- D (-) chloro-3-hydroxy-4-phenylglycine 50 g (0.248 mole) - Dioxane 410 ml (+ washing) - Phosgene 60 g (0.60 mole) V · - - Hydrochloric acid (gas) ûi 190 g (5.2 moles) - Methylene chloride qs for washing rn m.t _ ri>>

OPERATING MODE

410 ml of anhydrous dioxane (dried over molecular sieve, KF <0.05 $) are introduced into a 1 liter reactor, then 50 g of anhydrous D (-) chloro-3-hydroxy-4-phenylglycine (dried under 5 mm Hg at 80 ° at constant weight KF <$ 0.1 and sieved on a 0.075 mm sieve). 60.0 g of phosgene are passed therein in 20 minutes with stirring, [the initial temperature of 20 ° increases to 35 ° at the start of the passage of phosgene during the transformation of the solid (more difficult agitation), after which the temperature tends to drop]. After adding the necessary amount of phosgene, the mixture is heated to 70 °. When the temperature reaches 60-65 °, the crystallized mass dissolves. The solution is heated for 10 minutes at 70 °, after which the heating is stopped and the solution is concentrated to a volume of 250 ml without external heating (removal of excess phosgene); (the temperature is close to 25 ° at the end of the concentration). The solution is cooled to 8-10 ° and hydrochloric acid is passed through it as quickly as possible to maintain the temperature at 28-30 ° (the "amount of hydrochloric acid added corresponds to a very large excess; the reaction is exothermic until the stoichiometric amount, ie 2 moles, passes, and the temperature then tends to drop again, then a temperature of 20-25 ° is maintained). After passing approximately half of the hydrochloric acid, the solution is inoculated and stirred overnight at 20 °. The chloride hydrochloride is filtered the next day, preventing contact with atmospheric air. The hydrochloride is washed once with anhydrous dioxane and twice with anhydrous methylene chloride. It is dried under vacuum at room temperature to obtain in the form of the solvate.

L

- 71 - * monodioxane 73 g (approximately 85%) of the product advertised in the title.

EXAMPLE 1

Chlorocefadroxil monohydrate A. Chlorocefadroxil acetonitrilic solvate

Cl H 7 N —I-S S ^ // \ TMCS / CH-Cl- I I + HO - // \) - CH-COCl -----> · \ - / ÄH, .HCl 2 Acetomtnle

^ COOH

7-ADCA

Ci ^ HO — ff y-ÇH —CONH-j-f ^

^ H2] -NVs ^ J — CH3 * CH3CN

COOH

Chlorocefadroxil acetonitrilic solvent.

REACTANTS

- 7-ADCA 7.2 kg (33.6 moles) - Methylene chloride (KF <0.1%) 180 liters - Trimethylchlorosilane (TMCS) 9.0 liters (71.0 moles) - N, N-Dimethylaniline ( DMA) 4.35 liters (34.3 moles) 4 - Triethylamine (TEA) 23.4 liters - N, N-dimethylaniline hydrochloride 4.24 liters (10.1 moles) (solution in methylene chloride at 376 g / liter) - Dioxane hydrochloride solvent 17.0 kg (34.3 moles) of chloro-3-hydroxy-4-phenylglycine chloride (purity of 53.8%) - Methanol 3.4 liters - Acetonitrile 107, 0 liters - tap water 51.0 liters rn mt _ oa -, 4

OPERATING MODE

150 liters of anhydrous methylene chloride (KF <0.1%) and 7.2 kg of 7-ADCA are introduced into a 500-liter vitrified reactor. 9.0 liters of TMCS 'and 4.35 liters of DMA are added to the stirred suspension to which 9.4 liters of TEA are also added over 15 minutes while the temperature is maintained at 20-25 °.

The mixture is stirred for 1 hour at 20 ° and is re-cooled to -10 °. Then added 4.24 liters of a φ solution of DMA.HCl at 376 g / liter of methylene chloride, then 17 kg of dioxane solvate of hydrochloride of D (-) chloro-3-hydroxy chloride -4-phenylglycine (53.8% purity) in ten fractions in 1 hour (keeping the temperature between -12 and -8 °). The mixture is stirred for 2 hours at -10 ° and 3.4 liters of methanol are added thereto over 10 minutes, then 48 liters of tap water (with effective stirring). The mixture is stirred for 15 minutes (temperature 0 to 5 °) and the pH is adjusted to 2.3 by addition of TEA (9.0 liters).

The aqueous solution is separated and washed twice with 15 liters of methylene chloride. 80 liters of acetonitrile are then added and the pH is adjusted to 5.0 by addition of TEA (5.0 liters). The solution is inoculated and stirred overnight at + 10 °. The solid is collected, washed with 15 liters of acetonitrile-water (8: 2) and 15 liters of acetonitrile, then it is dried at 40 ° to obtain 11.0 kg (yield of 74% based on 7 -ADCA) of the product announced in the title.

B. Purification of the acetonitrile chlorate-cefadroxil solvate REACTANTS:

Chlorocefadroxil acetonitrilic solvent (crude) 21.0 kg Tap water 115 liters 33% HCl 5.2 liters. Activated carbon 1.5 kg MT O Z.

'\

250 liter acetonitrile

Triethylamine (TEA) 8.7 liters Célite q.s.

OPERATING MODE

Stirred acetonitrilic solvate of chlo-rocefadroxil (21 kg) in 100 liters of tap water is adjusted and the pH is adjusted to 0.8-0.9 by addition of 5.2 liters of 33% HCl. 1.5 kg of activated carbon are added to the solution and the mixture is stirred for 30 minutes, then filtered through a layer of CELITE.

The solution and the washing water (10 liters) are introduced into a 250-liter vitrified reactor into which 200 liters of acetonitrile are introduced, then the pH is adjusted to 2.5 by addition of TEA (3.5 liters).

The solution is inoculated and heated to 40-45 ° and the pH is adjusted to 5.0 by addition of TEA (5.2 liters).

The mixture is stirred for 1 hour at 40 °, cooled to 10 ° and kept stirring overnight at 10 °. The solid is collected and washed with 30 liters of acetonitrile-water (1: 2), then with ^ 30 liters of acetonitrile and dried at 40 ° to collect 16.6 kg (79%) of the purified product announced in the title.

C. Chlorocefadroxil monohydrate REACTANTS:

Chlorocefadroxil 6.85 kg (purified)

Water 73.0 liters 33% HCl 1.7 liters

Activated carbon 0.7 kg

Triethylamine (TEA) 2.8 liters CELITE q.s.

PROCEDURE: w Stirred acetonitrilic solvate of purified chlo rocefadroxil (6.85 kg) in 50 liters of water and adjust the pH to 0.8-0.9 by adding 1.7 liters of HCl to 33 %. Activated charcoal (0.7 kg) is added and the mixture is stirred for 30 minutes, then filtered through a layer of CELITE. The solution and the washing water (5 liters) are introduced into a 100-liter vitrified reactor and the whole is heated to 40 °. The pH is adjusted to 1.6-1.8 by addition of TEA (1.24 liters) and the solution is inoculated with chlorocefa- droxil monohydrate. The mixture is stirred for 30 * minutes at 40 ° and the pH is adjusted to 4.0 by addition * of TEA (1.56 liters). The suspension is slowly cooled to 20 ° and then stirred for 2 hours at + 5 °. The solid is collected and washed three times with 6 liters of water and dried at 40 ° to obtain 5.35 kg (86%) of the product advertised in the title.

EXAMPLE 2

Chlorocefadroxil monohydrate (illustration of the preparation without seeding)

Acetonitrilic solvate of purified chlorocefadroxil (352 g) is suspended in 2.8 liters of water, then -T 36% HCl is added to establish a pH of 0.9 (all the substance dissolves). The solution is stirred for 30 minutes with 36.0 g of activated carbon, then the mixture is filtered through a layer of CELITE. The resulting solution is heated to 40 ° and its pH is adjusted to 1.8 by the addition of triethylamine. At this time, crystals of chlorocefadroxil monohydrate begin to form without seeding. The mixture is stirred for 30 minutes at 40 °. The pH of the mixture is adjusted to 4.0 with triethylamine and the suspension is stirred for a further 2 to 5 hours. The crystalline chlorocepadroxil monohydrate is collected, washed three times with water and dried at 45 ° to obtain 295.5 g of the title compound; H „0 (KF) = 3.74%.

The IR spectrum is substantially that illustrated in \

Fig. 1 and is identical to that noted on the sample prepared in accordance with Example 1.

v Λ

Claims (16)

2. Process for the preparation of 7- [D- <X-amino-ot- (3-chloro-4-hydroxyphenyl) acetamido 3-3-methyl- 3-cephem-4-carboxylic acid monohydrate having substantially the diagram X-ray diffraction below: o Equidistance line d (A) Relative intensity ^ 1 8.63 100 ^ 2 7.03 23 -, 3 6.68 56 4 6.42 71 5 5.47 39 6 5, 25 7 7 4.76 51 8 4.60 29 9 4.48 13 10 4.32 39 11 4.03 82 12 3.96 47 - 13 3.87 52 14 3.70 32 "* 15 3.53 36 16 3.28 30 17 3.07 23 18 2.98 10 19 2.87 13 20 2.81 21 21 2.72 19 22 2.69 46 23 2.63 15 24 2.53 8 25 2.50 9 26 2.44 13 ^ 27 2.31 21 ut in _ ♦ 28 2.25 10 29 2.19 9 30 2.14 6 31 2.09 5 characterized in that it comprises (a) the silylation of the 7-aminodeacetoxy-cephalosporanic acid in a substantially anhydrous inert aprotic solvent; ^ (b) acylation of the resulting silylated 7-aminodeacetoxycephalosporanic acid by means of D (-) -o (-amino-o (- (3-chloro-4-hydroxyphenyl) chloride) acetyl in a substantially anhydrous inert aprotic solvent in the presence of an acid acceptor; (c) removal by hydrolysis or alcoholysis of all silyl radicals of the acylation product, and "(d) formation of the monohydrate sought by a process chosen between (1) adjust the pH of the solution in stage (c) upwards in the presence of an excess of dimethylformamide or acetonitrile to form the solvate dimethylformamide or acetonitrile of acid 7- [Do (-amino- o (- (3-chloro-4-hydroxyphenyl) acetamido] -3-methyl-3-cephem-4-carboxylic, dissolve this solvate in acidified water or a mixture of acidified water and a-ketonitrile and adjust the pH of this acidified solution upwards to precipitate the desired crystalline monohydrate; (2) adjust the pH of the solut upwards ion of stage (c) in the presence of an excess of dimethylformamide or acetonitrile to form the dime-thylformamide or acetonitrilic solvate of 7- [Dc (-amino-o (- (3-chloro-4-hydroxyphenyl) acid ) acetamido] -3-methyl- 3-cephem-4-carboxylic acid and put this solvate in contact with water or a partially aqueous medium CD.MJ - 31 - * to precipitate the desired crystalline monohydrate, and (3) adjust the pH of the solution in step (c) upwards to form the acid 7- [Dc (-amino-o (- (3-chlo-ro-4-hydroxyphenyl) acetamido) -3-methyl -3-cepheme-4-car-boxylic and bring this acid into contact with water or a partially aqueous medium to cause crystallization of the desired monohydrate. "R 3 - Process according to claim 2, characterized in that the silylation stage (a) is carried out by reaction of the 7-aminodeacetoxycephalosporonic acid with a silylation agent chosen from those of the formulas: R1 R1 R3 \ / J If V and R2— Si— X RM R4 H ^ / m 2 3 4 where R, R "3 and R represent hydrogen or halogen atoms or lower alkyl, halo- alkyl radicals lower, phenyl, benzyl, tolyl or dimethylaminophenyl, at least one of R, R and ^ 4 R not representing a halogen or hydrogen atom; R "1" represents a lower alkyl radical; m represents 1 or 2 and X represents a halogen atom or radical N XR6 5 where R represents a hydrogen atom or lower alkyl radical and R ° represents a lower alkyl radical or F3 "R2- Si ^ 14 R -" 2 3 4 where R, R and R are as defined above. 4. Method according to claim 3, characterized in that the silylating agent in stage (a) is trimethylchlorosilane or hexamethyldisilazane. 5. Method according to claim 2, characterized in that disilylated 7-aminodeacetoxycepha-losporanic acid is produced in stage (a) by means of at least two equivalents of silylating agent per * - mole of acid 7 -aminodeacetoxycephalosporanic. 6. Method according to claim 2, cak. characterized in that stage (a) is carried out by sily lation of 7-aminodeacetoxycephalosporanic acid by means of trimethylchlorosilane in a substantially anhydrous aprotic solvent in the presence of an acid acceptor. 7. Method according to claim 6, characterized in that the silylation stage is carried out in a solvent system comprising substantially anhydrous methylene chloride in the presence of an acid acceptor comprising triethylamine or a mixture <= · of triethylamine and dimethylaniline, at a temperature of about 20-30 ° C. 8. Method according to claim 2, characterized in that stage (a) is carried out by silylation of the acid 7-aminodesacetoxycephalosporani-only by means of hexamethyldisilazane in a substantially anhydrous aprotic solvent with external heating. 9. Method according to claim 8, characterized in that the silylation stage is carried out in a solvent system comprising substantially anhydrous methylene chloride at the reflux temperature. 10. Process according to claim 2, characterized in that the acylation stage (b) is carried out in a solvent system comprising substantially anhydrous methylene chloride at a temperature of about -10 ° to + 10 ° in the presence of an acid acceptor which is a tertiary amine having a pK _ <7. 11. Method according to claim 10, characterized in that the acid acceptor is dimethyl-aniline. 12. Method according to claim 2, characterized in that in stage (c) the silyl radicals are removed by reaction with water or a C 1 -C 4 alkanol or a mixture of these. 13. The method of claim 2, ca acterized in that in step (c), the silyl radicals are removed by reaction with a C ^ -C ^ alkanol. 14. Method according to claim 2, characterized in that stage (d) comprises (1) the upward adjustment of the pH of the solution of stage (c) by means of triethylamine in the presence of an excess of dimethylformamide or acetonitrile until the dimethylformamide or acetonitrile solvate of 7- [D - "(- - amino-o (- (3-chloro-4-hydroxyphé-nyl) acétamido) -3- methyl-3-cephem-4-carboxylic precipitate out of the solution; ^ (2) dissolving the solvate in acidified water, and * (3) adjusting the pH of this up solution by addition of triethylamine to precipitate the desired crystalline monohydrate. 15. The method of claim 14, characterized in that the final adjustment of the pH to produce the desired crystalline monohydrate is carried out at a temperature of about 35-60 16. Method according to claim 14, characterized in that acetonitrile is added as an antisolvent during the final adjustment of the pH. ** 17 - Process according to claim 14, ca- 'ΓΤ \ MT * 5 A Λ characterized in that crystal seeds of 7- [D-OÎ-amino - ^ - (3-chloro-4-hydroxyphenyl) acid ) acetamido] - 3-methyl-3-cephem-4-carboxylic monohydrate sought are added before or during the final adjustment of the pH. 18. Pharmaceutical composition, characterized in that it comprises a compound according to claim 1 together with an inert pharmaceutically acceptable excipient or diluent. 19. A method of treating mammals suffering from diseases caused by Gram-positive or Gram-negative bacteria, characterized in that an effective antibacterial dose of the compound according to claim 1 or of a pharmaceutical composition is administered to the affected host according to claim 18. i- *