FR2555989A1 - CHLOROCEPHADROXYL MONOHYDRATE - Google Patents

Abstract

A NEW 7-DA-AMINO-A- (3-CHLORO-4-HYDROXYPHENYL) ACETAMIDO-3-METHYL-3-CEPHEM-4-CARBOXYLIC ACID MONOHYDRATE CRYSTALLINE IS PREPARED AND IS FOUND IN A STABLE USABLE FORM OF THE ANTIBIOTIC BASED ON CEPHALOSPORIN ESPECIALLY ADVANTAGEOUS FOR PHARMACEUTICAL FORMULATIONS.

Description

CHLOROCEPHADROXYL MONOHYDRATE

  Crystalline cephalosporin monohydrate according to the present invention.

  In general, this composition has the usual attributes of this family of antibacterial agents and is particularly useful in pharmaceutical formulations for the treatment of bacterial infections by oral administration.

  The cephalosporin compound, 7- {D-α-amino-α- (3-chloro-4-)

  hydroxyphenyl) acetamido} -3-methyl-3-cephem-4-carboxylic acid is described and

  claimed in United States Patent No. 3,489,751.

  which is usually referred to below as chlorocephalogenesis.

  xyl, has the structural formula: Cl'o CH3 COOH Chlorocephradroxyl is active as a broad-spectrum antibiotic

  effective spectrum for the control of diseases caused by a wide range of

  rIty of gram-positive and gram-negative microorganisms. He is of a

  of particular interest, as a cephalosporin phase antibiotic

oral ble.

  U.S. Patent No. 3,489,751 discloses the preparation of

  chlorocêphadroxyl by acylation of 7-aminodesacetoxy-

  phalosporanic acid (7-ADCA) with an amino-protected derivative of D (-) - a-

  amino-u- (3-chloro-4-hydroxyphenyl) acetic acid. Among the various acylating agents

  the amino-protecting agents described, the highest yields have been

  obtained with D (-) - a- (2-chloro-4-hydroxyphenyl) -α- (t-butoxycarbonyl)

  nylainiino) by the so-called t-BOC method. However, yields in this process were not as high as desired for commercial production and the reagent used in the t-BOC method is

very expensive.

  U.S. Patent No. 3,985,741 describes the preparation of

  chlorocéphadroxyl by acylation of 7-ADCA with the mixed anhydride of D (-) - c- (3-chloro-4-hydroxyphenyl) glycine when the aamino group

  of the latter was blocked with an e-ketone compound such as

  methyl acetate. This process, while having some definite advantages over the t-BOC method, is not yet as effective

  desired for a commercially feasible production process.

  corn. Also disclosed in this patent is a chlorocéphadroxyl crystalline dimethylformamide solvate containing 1.5 moles of

  dimethylformamide per mole of chlorocephadroxyl. The product of solva-

  dimethylformamide is boiled in boiling methanol until the solvate dissociates and the suspension

  The result is then refoidie to give a purified form of chloro-

  céphadroxyle. However, there is no indication that chlorocrephadro-

  xyl produced by the method of this patent in the form of a crystalline hydrate. U.S. Patent No. 3,781,282 discloses and teaches in its example 7 the preparation of chloroecephadroxyl by dissolving a chloroecephadroxyl-DMF solvate in acidified water.

  and then by neutralization with triethylamine. There is no

  in this reference that the chlorocêphadroxyle produced either in the form of a crystalline monohydrate or even simply that it is under

the crystalline form.

  U.S. Patent No. 4,160,863 discloses a mono-

  crystalline hydrate of 7- {D-α-amino-α- (p-hydroxyphenyl) acetamido} -3-

  methyl-3-cephem-4-carboxylic acid (also called cephadroxyl), which is

  similarly to chloroephadroxyl monohydrate

  and claimed in this application.

  Given the many important benefits of chlorocephadroxyl,

  it is desirable to have a commercially usable process for preparing

  this antibiotic with higher yields and lower production costs than those of the prior art processes. In addition,

  it is desirable to produce chlorocéphadroxyle in a crys-

  stable tallin such as a crystalline hydrate which allows the antibiotic to be prepared in the form of pharmaceutical formulations suitable for antibacterial use, for example in the form of aqueous suspensions. The present invention provides a novel chlorocéphadroxyl crystalline monohydrate and processes for the preparation of this monohydrate. Also disclosed is an improved acylation process for the preparation of chloroecephadroxyl which gives the product with excellent yields and lower production costs compared to the prior art processes. The accompanying drawing, FIG. 1, illustrates the characteristic infrared absorption spectrum of chlorocephadroxyl monohydrate (KBr pellet) as obtained by the procedures described in FIG.

this request.

  In one of these aspects, the present invention provides a

  improved process for the preparation of chlorocéphadroxyl or a pharmaceutically

  it is acceptable that the method is characterized in that

  (a) silylation of 7-aminodesacetoxycephalosporic acid is carried out

  in a substantially anhydrous inert aprotic solvent;

  (b) acylation of 7-aminodesacetoxycephalosporic acid is carried out

  silylated ranic acid thus produced with D (-) - camino -: - (3-chloro-4-hydroxyphenyl) acetyl chloride hydrochloride in a substantially anhydrous inert aprotic solvent in the presence of an acid acceptor;

  (c) cleavage of all the silyl groups of the acyl

  hydrolysis or alcoholysis; and,

  (d) recovering the desired cephalosporanic acid or a pharmaceutically acceptable salt thereof

just acceptable.

  The pharmaceutically acceptable salts referred to hereinafter

  include, for example, (1) non-toxic pharmaceutically

  acids of the carboxylic acid group, such as sodium, potassium, calcium, aluminum and ammonium

  substituted ammonium compounds with amines such as tri (alkyl)

  lower) amine, procaine, dibenzylamine, N-benzyl-beta-phenethylamine,

  1-ephenamine, N, N'-dibenzylethylenediamine, dehydroabiethylamine, N, N'-

  bisdehydroabiethylethylenediamine, N- (lower alkyl) piperidines such as N-ethylpiperidine and other amines which have been used to form

  benzyl penicillin salts; and (2) Pharic acid addition salts

  maceutically acceptable and non-toxic (i.e., basic nitrogen salts) such as (a) the mineral acid addition salts such as

2555989;

  hydrochloride, hydrobromide, hydroiodide, sulfate, sulfamate, sulfonate, phosphate, etc .; and (b) organic acid addition salts such as

  maleate, acetate, citrate, tartrate, oxalate, succinate, benzoate, fumarate

  spleen, malate, mandelate, ascorbate, naphthalene sulphonate and p-toluene

  sulfonate. As used herein, the term "(lower) alkyl" is defined to include saturated linear chain hydrocarbon radicals.

  and branched having from 1 to 10 carbon atoms, inclusive.

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

substantially anhydrous.

  Suitable solvents for the silylation reaction include substantially anhydrous inert organic solvents such as chloride

  methylene, tetrahydrofuran, chloroform, tetrachloroethane, nitro-

  methane, benzene and diethyl ether. Methylene chloride is a

preferred solvents.

  The silylating agents useful in the above process are

  in the state of the art (see, for example, United States Patents 3,654,266, 3,575,970, 3,499,909, 3,349,622, 3,595,855,

  3,249,622 and British Patent Nos. 1,339,605, 959,853 and 1,008,568).

  While any known silylating agent may be used, it is preferred to use an agent selected from those having the formula:

R R

R-R R1 R or Ro _Si - X -b -si 14

R N H

  in which: R2, R3 and R4 represent hydrogen, halogen, (lower) alkyl,

  halo-lower alkyl, phenyl, benzyl, tolyl or dimethylamino-

  phenyl, at least one of R2, R3 and R4 being different from halogen or hydrogen; R 1 represents (lower) alkyl; m is an integer of 1 or 2; and X is halogen or R-NR 6 R 6 is: R 6 is hydrogen or (lower) alkyl; and R6 is (lower) alkyl or Ra R2-Si R4 o

  R2, R3 and R4 are as defined above.

  Suitable silylating agents include, for example, the

  trimethylchlorosilane, hexamethyldisilazane, triethylchlorosilane, methyl-

  trichlorozilane, dimethyldichlorosilane, triethylbromosilane, tri-n-

  propylchlorosilane, bromomethyldimethylchlorosilane, tri-n-butylchlorosiline

  lane, methyldiethylchlorosilane, dimethylethylchlorosilane, phenyldimethyl

  bromosilane, benzylmethylethylchlorosilane, phenylethymethylchlorosilane, triphenylchlorosilane, triphenylfluorosilane, tri-o-tolylchlorosilane,

  tri-p-dimethylaminophenylchlorosilane, N-ethyltriethylsilylamine, hexamethyl

  ethyldisilazane, triphenylsilylamine, tri-n-propylsilamine, tetraethyl-

  dimethyldisilazane, tetramethyldiethyldisilazane, tetramethyldiphenyl-

  disilazane, hexaphenyldisilazane and hexa-p-tolylsisilazane. Other suitable silylating agents are hexaalkylcyclotrisilazanes or octaalkylcyclotetrasilazanes and silylamides and silylureas

  such as trialkylsilylacetamide and a bis-trialkylsilylacetamide.

  The most preferred silylating agents are trimethyl chloride.

  rosilane and hexamethyldisilazane.

  When a silyl halide, for example

  methylchlorosilane as a silylating agent, the silylation step is carried out in a substantially anhydrous inert aprotic solvent in the presence of an acid acceptor (hydrogen halide), preferably

  Propylene oxide or a nitrogen base such as triethylamine,

  thylamine, dimethylaniline, quinoline, lutidine or pyridine. The acceptors

  Preferred acid donors are propylene oxide, triethylamine or a mixture of triethylamine and dimethylaniline. When a silazane, for example hexamethylthisilazane, is used, the silylation step is conveniently carried out by heating the silazane and 7-ADCA such that ammonia or amine derivatives are distilled off. who

  form as a by-product of the reaction.

  By preparing the silylated 7-ADCA according to the above method, it is possible to

  theoretically employing from 1 to 2 molar equivalents of silyla-

  + per mole of 7-ADCA to give mono- or disilylated 7-ADCA or mixtures thereof. Thus, when reacting 7-ADCA with approximately

  1 equivalent of silylating agent, monosilylated 7-ADCA is formed.

  In the case where, for example, trimethylchlorosilane or hexamethyldisilazane is used, the product has the formula: s H2

N CH3

  COOSi (CH3) 3 The disilylated derivative of 7-ADCA can be prepared by employing in the silylating step at least 2 equivalents of the silylating agent per

  mole of 7-ADCA. When using trimethylchlorosilane or hexamines

  methyldisilazane, the disilylated 7-ADCA which is formed

  The silylation step can be carried out over a wide range of temperatures, for example from room temperature to room temperature.

  reflux of the solvent system. Advantageous results are generally

  obtained at room temperature with silyl halides (20 to 30 C) and at elevated temperatures, eg temperature

  reflux, in the case of silazanes which are generally less active.

  Either the mono- or disilylated 7-ADCA, or a mixture of these,

  can then be acylated with the hydrochloride of D (-) - aamino chloride

  a- (3-chloro-4-hydroxyphenyl) acetyl (preferably especially in the form of

  of a solvate in dioxane) to form an in situ

  silyl mediated chlorocéphadroxyle. All the silyl groups present after acylation are then removed by hydrolyl or alcoholysis and the chlorocéphadroxyle, the desired final product, is recovered from

  reaction medium for example by neutralization to the isoelectric point

  chlorhephadroxyl precipitates from the solution.

  The solvents employed in the acylation of silylated 7-ADCA are defined

  above in connection with the silylation step (a).

  The preferred temperature range for the acylation step is

  However, the temperature is not critical and higher or lower temperatures than those within the preferred range can be used. The most preferred acylation temperature is between about -10 C and about

+10 C.

  The acylation is preferably carried out in the presence of an acid acceptor which may be the same or which may be different from that employed in the preparation of silylated 7-ADCA. The best results are

  obtained if a lower tertiary amine base is used (ie

  say PKaE 7) such as dimethylaniline, pyridine or quinoline. Preferably

  In addition, a salt of a mineral acid or a tertiary amine is also incorporated.

  such as dimethylaniline hydrochloride to inactivate

  any excess amine (see for example the US patent

of America No. 3,678,037).

  While a reaction can occur regardless of the proportion

  molar ratio of the reagents used, it is preferred, in order to obtain

  maximum deactions in the acylation step, use approximately 1 mole of

  acylation or a slight molar excess thereof per mole of 7-ADCA if

  LYLE. The acylation product of silylated chlorocephadroxyl is treated

  by hydrolysis or alcoholysis to detach the protective silyl groups.

  Thus, the silylated intermediate can be hydrolysed by the addition of water or

  alcoholysis is preferably carried out by addition of an alcohol

  suitable, preferably a C1-C4 alkanol such as methanol, ethanol, n-propanol, isopropanol, n-butanol, etc. It is also possible to use a mixture of water and a lower alkanol (C1 to C4) in the detachment step

protective groups.

  Chloroecephadroxyl can be recovered from the reaction solution

  by methods usually used to isolate cephalospheres.

  analogous porins. Thus, the product can be recovered in its neutral molecule form by adjusting the pH of the reaction mixture upwards.

  until the desired acid precipitates from the solution. Preferably

  For example, a non-aqueous amine base such as triethylamine is used.

  Chlorocephadroxyl in the free acid form can be converted to a carboxylic acid or a pharmaceutically acid addition salt

  acceptable by reaction with a suitable base or acid.

  According to a preferred embodiment of the implementation of the present invention,

  7-aminodésacétoxyc & phalosporanique acid is silylated by the hexa-

  ethyldisilazane in a substantially anhydrous aprotic solvent of 2555989 t

  preferably methylene chloride, with external heating, preferably

  at the reflux temperature of the solvent, to form disilylated 7ADCA in situ of the formula: (CH 3) 3 Si-N H 3 O H 3 COOSi (CH 3) 3

  The disilylated 7-ADCA is then acylated directly in the same solution.

  (preferably at a temperature of -10 ° C. to + 10 ° C.) with the hydrochloride

  D (-) - α-amino-α- (3-chloro-4-hydroxyphenyl) acetyl chloride, preferably

  in the form of a solvate with dioxane, in the presence of an acid acceptor, preferably a tertiary amine base having a pKa <7 such as dimethylaniline, pyridine or quinoline. Following acylation, the silylated acylation product of chlorocéphadroxyle is

  treated with a C1 to C4 alkanol, preferably methanol or n-

  butanol, to remove all the silyl groups and the product is recovered (possibly after a filtration step) by neutralization until

  isoelectric point with a tertiary amine base, preferably

  thylamine, to carry out the precipitation.

  The use of hexamethyldisilazane as a silylating agent in place of the usual silyl halides such as trimethylchlorosilane, eliminates the formation of an acid halide as a by-product and therefore the need to employ an acceptor of acid in the stage

  silylation. Without the presence in the reaction medium of this accept-

  acid, a less insoluble salt, for example triethylamine-HCl,

  is present to interfere with subsequent recovery steps.

  By using hexamethyldisilazane, it is possible to obtain

  chlorocéphadroxyle yields higher than the classical silylation

  with trimethylchlorosilane.

  In another aspect, the present invention provides a novel form of chlorocéphadroxyl crystalline monohydrate which has been found to be a stable and useful form of the antibiotic

  cephalosporin particularly suitable for pharmaceutical formulations.

  Crystalline chlorocéphadroxyl monohydrate according to the invention

  essentially presents the following properties of powder diffraction

  X-ray: o Ray Spacing d (A) Relative Intensity

1 8.63 100

2 7.03 23

3 6.68 56

4 6.42 71

5.47 39

6 5.25 7

7 4.76 51

8 4.60 29

9 4.48 13

4.32 39

11 4.03 82

12 3.96 47

13 3.87 52

14 3.70 32

3.53 36

16 3.28 30

17 3.07 23

18 2.98 10

19 2.87 13

2.81 21

21 2.72 19

22 2.69 46

23 2.63 15

24 2.53 8

2.50 9

26 2.44 13

27 2.31 21

28 2.25 10

29 2.19 9

2.14 6

31 2.09 6

  The details of this determination of the X-ray diffraction properties are as follows:

  Flat samples of 2 cm 2 and 1 mm in thickness are used.

  with an automatic X-ray powder diffractometer (Phillips

  PW 1050-70-source CuKc (1.5A178A). Temperature = 22 C.

  A very small amount of crystalline sodium fluoride is

  mixed with some samples to provide internal calibration. In addition, for the same purpose, the complete procedure is carried out at a minimum.

pure NaF sample.

  The films are read on a Debye-Scherrer Norelco film player recording the positions of the nearest 0.05 mm diffraction circles. The data are corrected due to film shrinkage and interplanar spacings (d-spacing) are calculated from the corrected data. A computer program (X-ray, by P. Zugenmaier) is used for all calculations. Precision in the spacings-d

  resulting from it is approximately 1%.

  A recording of the intensity of all films is obtained using a Joyce-Loeble Mark IIIC recording microdensitometer

  (5/1 exploration ratio, 0.1 D on the edge). Intensities

  on a scale of 1 to 100 are assigned to all recognizable diffraction rings using corrected peak intensities

  because of the reading of the background.

  A sample of the crystalline monohydrate product is subjected to infrared analysis and the specimen spectrum (in disk form

  KBr) is shown in Figure 1.

  The present invention further relates to a process for the preparation of crystalline chlorocéphadroxyl monohydrate described above, which method is characterized in that:

  (a) silylation of 7-aminodesacetoxycephalosporic acid is carried out

  in a substantially anhydrous inert aprotic solvent;

  (b) acylation of 7-aminodesacetoxycephalosporic acid is carried out

  silylated ranic acid thus produced with D (-) - amino-α- (3-chloro-4-hydroxyphenyl) acetyl chloride hydrochloride in a substantially anhydrous inert aprotic solvent; (c) isolating all silyl groups from the acylation product by hydrolysis or alcoholysis; and (d) forming the desired monohydrate product by a method selected from: 1. Upward adjustment of the pH of the solution from step (c) in the presence of an excess of dimethylformamide or acetonitrile for form the solvate by the

  dimethylformamide or lacetonitrile of 7- {D-L-amino-α-

  (3-chloro-4-hydroxyphenyl) acetamido} -3-methyl-3-cephem-4-

  carboxylic acid; a dissolution of this solvate in

  acidified water or a mixture of acidified water and

  nitrile and the pH of this acidified solution is adjusted upwards to precipitate the crystalline monohydrate which one desires; 2. an upward adjustment of the pH of the solution from step (c) to an excess of dimethylformamide or acetonitrile to form the solvate by

  dimethylformamide or acetonitrile of 7- {D-α-amino-α-

  (3-chloro-4-hydroxyphenyl) acetamido} -3-methyl-3-cephem-4-

  carboxylic acid and contacting this solvate

  with water or a partially aqueous medium to

  piter the crystalline monohydrate desired; or 3. an upward adjustment of the pH of the solution from

  step (c) to form 7- {D-α-amino-α- (3-chloro-4-)

  hydroxyphenyl) acetamido} -3-methyl-3-cephem-4-carboxylic acid and contacting this acid with water or with a medium

  partially aqueous to crystallize the mono-

hydrate as one desires.

In the preparation of crystalline chlorocephalroxyl monohydrate according to the above method, the silylation, acylation and silyl group detachment steps are carried out as described above in connection with the improved acylation procedure for preparing chlorocéphadroxyle. The crystalline monohydrate desired can then be prepared

  according to any one of various variants.

  According to one of these methods, the chlorocéphadroxyle solution obtains

  after the solvolysis step is neutralized with a basic substance, for example a tertiary amine base such as triethylamine, in the presence of an excess of dimethylformamide or acetonitrile until

  that the solvate of chlorocephadroxyl by dimethylforma-

  mide or acetonitrile precipitates from the solution. The product of solva-

  tation can then be collected and washed (preferably not dried) for

  give a crystalline material. The solvate of chlorocepha-

  The dimethylformamide or acetonitrile can be converted to the desired chlorocephaloxyl monohydrate by dissolving the solvate in acidified water or a mixture of acidified water and acetonitrile and then neutralizing the acidified solution to precipitate the acid.

monohydrate product.

  Dissolving the solvate of chlorocephadroxyl with dimethylformamide or acetonitrile occurs at a pH of about 2 to 2.4 which can be obtained by adding a mineral acid, for example HCl, to a mixture of solvate either in water or in an acetonitrile-water mixture. Solid impurities can be removed during this process step by filtering the acid solution after treatment with activated charcoal and / or filter aid. The acidified solution is then neutralized, preferably with stirring and with heating to about 35 to 60 C, by addition of a base

  suitable, for example an aliphatic tertiary amine such as

  thylamine to raise the pH of the solution to the point where the chlorocephalic

  Droxyl monohydrate crystallizes from the solution.

  Acetonitrile is preferably added to the solution as an antisolvent (precipitating agent) during neutralization to achieve maximum recovery of the desired product. The yields are

  also improved by seeding the solution with crys-

  the level of the desired monohydrate before and / or during the final neutralization step

  tion. Another method for the preparation of crystalline chloroecephadroxyl monohydrate in the above process involves the preparation of the product

  solvation of chlorocephadroxyl with dimethylformamide or

  nitrile as described above and contacting this solvate with water or a partially aqueous medium until

  that the desired monohydrate crystallizes from the solvent system.

  The solvate of chlorocéphadroxyle by dimethylfor-

  mamide or acetonitrile is dissolved in water or a mixture of water and an organic solvent such as acetonitrile, acetone, a C1 alkanol

  to C5 (methanol, ethanol, n-propanol, isopropanol, n-butanol, amyl alcohol,

  lique, etc.) or a mixture thereof. It is preferred to use systems

  partially aqueous organic solvents since the organic solvents

  They absorb most impurities and give a purer final product. When mixtures of water and organic solvents are used,

  the ratios of the solvent components may vary in-wide

  mites without serious harm. The solvent ratios that we

  have been determined for several partial solvent systems.

  aqueous solution and these are: water / acetone (1/3) (v / v) water / isopropanol (1/3) (v / v) water / acetonitrile (1/3) (v / v) water / n -butanol (1/1) (v / v) With the water-acetonitrile system, it is preferred to add n-butanol

  (preferably after solubilization of the solvate) to ensure

  ensure that the solvent system remains in the form of a single homogeneous phase during crystallization. Preferably, enough is added

  n-butanol to this crystallization system so as to obtain a

  port of final solvent water-acetonitrile / n-butanol (1/2/1) (v / v).

  The concentration of the solvate in the crys-

  Aqueous or partially aqueous solution is not critical. How-

  The best yields were obtained when concentrations between about 400 and 800 g / l of solution were used. The product

  solvation is preferably added to the solvent system incrementally.

  and with agitation over a period of time depending on the amount of solvate used, i.e.

many hours.

  The crystallization can be carried out over a wide temperature range, i.e. from room temperature to the boiling point of the solvent system. Good results are obtained in a temperature range of about 35 to 60 C, preferably

at 45 degrees C.

  Monohydrate yields are improved by seeding the solu-

  solvation with dimethylformamide or acetonitrile

  with chlorocéphadroxyl monohydrate crystal seeds.

  Another method of preparing the desired monohydrate in the

  However, the above-mentioned method consists of: (1) preparing the silylated chlorocephaloxyl and detaching the groups

  silyl protecting by hydrolysis or alcoholysis as described above.

  above; (2) to neutralize the solutions of the detachment step of the protecting groups to the isoelectric point of chlorocephadroxyl (<pH 5.7 to 5.8) with a suitable base, preferably an aliphatic tertiary amine such as triethylamine, to precipitate impure chlorocêphadroxyle or of lower quality; and, (3) bringing this impure chlorocephaloxyl into contact with water or

  a mixture of water with a suitable organic solvent, preferably

  acetonitrile, acetone, a C1 to C5 alkanol (eg methar ol, ethanol, n-propanol, isopropanol, n-butanol, alcohol

255598 9

  amyl, etc.) or mixtures thereof until the chlorine

  Rocephadroxyl monohydrate crystallizes from the solution.

  The chlorocephadroxyl solution can be conveniently neutralized to form impure or poorer chlorocéphadroxyl (amorphous) at room temperature by gradually adding the base to the stirred solution. The impure chlorocéphadroxyle can then be crystallized in the same manner as described above for the solvate of chlorocephadroxyl by dimethylformamide or

  acetonitrile. As in the case of the procedure of crystalliza-

  solvation with dimethylformamide or acetonitrile,

  the most preferred solvent system is water / acetonitrile / n-

butanol (1/2/1) (v / v).

  A preferred embodiment of the present invention

  The invention lies in the process for the preparation of mono-chlorocephadroxyl

  crystalline hydrate either from the chlorocene solvate

  phadroxyl with dimethylformamide or acetonitrile either from

  impure chlorocéphadroxyle (the lowest quality) by the following steps:

  (a) dissolving the solvate with dimethylformamide or acetonitrile of 7- {Da-amino-α- (3-chloro-4-hydroxyphenyl) acetamido} -3-methyl-3-cephem acid; -4-carboxylic acid in acidified water or a mixture of acidified water and acetonitrile; and adjusting the pH of this acidified solution upward until the desired monohydrate crystallizes from the solution; or

  (b) 7- {D-α-amino-α- (3-chloro-4-hydroxyphenyl) acetamido} is added

  3-methyl-3-cephem-4-carboxylic acid or the solvate thereof with dimethylformamide or acetonitrile in contact with water or a partially aqueous medium until the

  desired monohydrate crystallizes from the solution.

  The solvate with dimethylformamide or acetonitrile

  and chlorhephadroxyl as raw materials in the above process may be prepared by the methods described herein or by other known methods, for example the processes described in US Pat. Nos. 3,489,751 and US Pat.

3,985,741.

  The conditions which are preferred for forming the monohydrate of

  chloroephadroxyl in the above process are those described above.

  above in connection with the above-described overall reaction scheme, 2555989i that is, the combined steps of silylation, acylation and production

monohydrate.

  By employing the preferred reaction conditions described above

  above, the present invention makes possible the production of chlorhepha-

  primary quality droxyl with excellent yields and the subsequent conversion of this chlorocephadroxyl or its solvate

  dimethylformamide or acetonitrile to chlorocephalogen monohydrate

  xyl with effective yields up to about 85%.

  The crystalline monohydrate prepared according to any one of the

  above, can be recovered by conventional methods, for example

  by filtration, and then washed, dried and prepared into pharmaceutical formulations for use in antibiotic therapy for

  fight various bacterial diseases. These formulations are, for example,

  tablets or tablets, including doses and methods of

  chlorocéphadroxyl monohydrate and these pharmaceutical compositions.

  ticks are as described in United States Patents

  Nos. 3,489,751 and 3,985,741 for the amorphous form of chlorocephadroxyl.

  The invention therefore comprises a pharmaceutical composition, of

  especially a pharmaceutical composition suitable for oral administration comprising crystalline chlorocêphadroxyl monohydrate together with a pharmaceutically suitable carrier or inert diluent

acceptable.

  The invention further includes a method of treating humans or other animal species (eg, mammals) for diseases caused by gram-oemic or gram-negative bacteria, which method comprises administering to the host subject an effective dose crystalline chlorocêphadroxyl monohydrate as described herein, or

  a pharmaceutical composition as defined above.

  The following examples are given by way of illustration of the present invention. All temperatures are indicated in C. The 7-aminodésacétoxycaphalosporanic acid is abbreviated 7-ADCA, the

  triethylamine TEA, dimethylaniline DMA and dimethylformamide DMF.

  Preparation of raw materials Preparation 1

__ __L

  Preparation of D (-) chloro-3-hydroxy-4-phenylglycine / C-COCH 2 OH -COO

- NH2 -

2 2C

  Reagents -D (-) p-hydroxyphenylglycine ....... 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 at 400 g / l ..... 3 liters - acetone ......................... i15 liters Operating mode

  A suspension of 10 kg of D (-) p-hydroxyphenylglycine in 200

  very acetic acid is heated to 60 C. The hydrochloride is formed in

  bubbling bubbles of 6.25 kg of hydrochloric acid (during

  approximately 60 minutes); a solution of 8.1 kg of

  sulfuryl chloride in 28 liters of acetic acid to the solution obtained

  naked, maintained at 65 to 70 C for 90 minutes. The solution is degassed

  at low pressure, cooled to 20 ° C. and stirred overnight.

  The solid is collected and washed with two resuspension in the

  methylene chloride. It is dried under vacuum at 40 C.

  Weight of chloro-3-hydroxy-4-phenylglycine hydrochloride obtained

= 13 kg.

  The hydrochloride is suspended in 130 liters of water and the

  The mixture is heated at 40 ° C. with stirring for 30 minutes. It is

  cooled to 20 C and the pH is adjusted to 1.4 by adding a sodium hydroxide solution at 400 g / l (approximately 3 liters). It is stirred for 2 hours at +5 ° C., filtered and the solid is washed three times with distilled water (absence of ionizable chlorine in the mother liquors), then with approximately 15 liters of acetone and dried at 600 ° C. . We mix on

  a Frewitt apparatus and dried to 0.1% H 2 O (KF).

  Weight of chloro-3-hydroxy-4-phenylglycine obtained = 8.1 kg (yield

= 67%).

Preparation 2

  Preparation of D (-) chloro-3-hydroxychloride hydrochloride

4-phenylglycine

O H -COOH COC12 OH CE-COOH

- NH2 dioxane L N-CC1j

/ _

C1l L Cl

--S I \ -:> OH H-COC1

HCl C NH2 dioxane II Cl

0

React fs

- D (-) chloro-3-hydroxy-4-

  phenylglycine .................. 50 g (0.248 moles) - dioxane ...............

  ....... 410 ml (+ wash) - phosgene ....................... 60 g (0.60 mol) - hydrochloric acid ( gas) ...... \ 190 g (5.2 moles) - methylene chloride .......... qs for the washing procedure 410 ml anhydrous dioxane (dried on a molecular sieve, KF <0.05%), then 50 g anhydrous D (-) chloro-3-hydroxy-4-phenylglycine (dried at 5 mmHg / 80, constant weight KF <0.1% and passing on a sieve with DTD: mesh size of 0.074 mm) are placed in a reactor of 1 liter.

  60.0 g of phosgene are passed over the course of 20 minutes while stirring, the initial temperature is increased to 35 at the beginning of the passage of the phosgene as long as the solid is transformed (more difficult stirring), after which the temperature tends to decrease}. When the necessary amount of phosgene has been added, the mixture is heated to 70 ° C.

  the temperature reaches 60 to 65 C, the crystallized mass goes into solution.

  The mixture is heated for 10 minutes at 70 ° C., after which time the heating is stopped and the solution is concentrated to a volume of 250 ml without external heating (elimination of excess phosgene); (the temperature is close to 'C at the end of the concentration). The solution is cooled to 8 to 10 ° C.

  and hydrochloric acid is passed through as quickly as possible.

  to maintain the temperature at 28 to 30 ° C. (the amount of hydrochloric acid used corresponds to a very large excess, the reaction is exothermic until the stoichiometric amount has been passed, that is, ie 2 moles, the temperature then tends to decrease and a temperature of 20 to 25 C is maintained). When approximately half of the hydrochloric acid is

  The solution is seeded and stirred overnight at 20 ° C.

  The chloride hydrochloride is filtered the next day, preventing contact with atmospheric air. It is washed once with anhydrous dioxane and twice with anhydrous methylene chloride. Dry at 2555989 ° C at room temperature giving 73 g (85%) of the product of

  title in the form of mono-solvation product by dioxane.

EXAMPLE 1

  Chlorocephadroxyl monohydrate A.- The solvate of chlorocephadroxyl with acetonitrile

H2N + HO CH-COC1

3 NH2HC1

COQOH

7-ADCA TMCS / CH2C12

  TEA / DMA / DMA HCl / Acetonitrile Cl HO CH --- CONH s h.N - /

- N CH 3CH CN

3:

OX COOH

  Solvate of chlorocephadroxyl with acetonitrile.

  Reactive - 7-ADCA ........................ 7.2 kg (33.6 moles) - methylene chloride (KF <0.1% ) 180.0 liters - trimethylchlorosilane (TMCS) ... 9.0 liters - N, N-dimethylaniline (DMA) ...... 4.35 liters (71.0 moles) triethylamine (TMA) .... ........ 23.4 liters

N, N-dimethylamine hydrochloride

  line (solution in 376 g / l methylene chloride) .................. 4.24 liters (10.1 moles) - solvate with dioxane hydrochloride

chloro-3-hydroxy-4- chloride

  phenylglycine (purity 53.8%) ... 17.0 kg (34.3 moles) - methanol ...........

  .......... 3.4 liters - acetonitrile ................... 107.0 liters - tap water ....... .......... 51.0 liters..DTD: 2555989;

  Procedure A 500 liter glass lined reactor was charged with 150 liters of anhydrous methylene chloride (KF <0.1%) and 7.2 kg of 7ADCA. To the

  stirred, 9.0 liters of TMCS and 4.35 L of DMA were added and

  Then 9.4 liters of TEA are added over a period of 15 minutes while maintaining the temperature at 20 to 250c. The mixture is stirred for 1 hour at 200C and cooled to -10 C. 4.24 liters of methylene chloride solution are then added to 376 g / l of DMA.HCI and then 17 kg of the product.

  dioxane solvation of D (-) chlorohydrochloride chloride

  3-hydroxy-4-phenylglycine (purity 53.8%) in ten portions over a period of one hour (the temperature is maintained between -120C and -80C). The mixture is stirred for 2 hours at -10 ° C. and 3.4 liters of methanol are added over a period of 10 minutes and then 48 liters of tap water (with efficient stirring). The mixture is stirred for 15 minutes (0 ° C.-5 ° C.) and the pH is adjusted to 2.3 by the addition of TEA- (9.0 liters). The aqueous solution is separated and washed twice with 15 liters of sodium chloride. methylene. 80 liters of acetonitrile are then added and the pH is adjusted to 5.0 by the addition of TEA (5.0 liters). The solution is seeded and stirred overnight at + 100C. The solid is collected, washed with 15 liters of acetonitrile-water (8/2) and 15 liters of acetonitrile and then dried at 400C to give 11.0 kg (74% yield from

7-ADCA) of the product in issue.

  B. Purification of the solvate of chlorocephadroxyl with acetonitrile Reagents

- solvate of the chloro-

  cephadroxyl with acetonitrile (crude) ......................... 21.0 kg tap water .......... ....... 115 liters - HCI at 33% ....................

  5.2 liters - activated carbon .................. 1.5 kg acetonitrile ....... DTD: ........... 250 liters - triethylamine (TEA) ............ 8.7 liters..DTD: - celite .................... ..... qs

  Procedure The crude chlorocephadroxyl acetonitrile solvate (21 kg) is stirred in 100 liters of tap water and the pH is adjusted to 0.8 to 0.9 by the addition of 5.2 liters of HCl. at 33% To the solution, 2555989 i

  1.5 kg of activated carbon are added and the mixture is stirred for 30 minutes.

  and filtered through a pad of celite. The solution and wash water (10 liters) is charged to a 250 liter glass-lined reactor, 200 liters of acetonitrile are added and the pH is adjusted to 2.5 by addition of TEA (3.5 liters) . The solution is seeded, heated to 40-45 ° C and the pH is adjusted to 5.0 by addition of TEA (5.2 liters). The mixture is stirred for 1 hour at 40 ° C., cooled to 10 ° C. and allowed to stand overnight with stirring at 100 ° C. The solid is collected, washed with 30 liters of acetonitrile-water (1/2) and then 30 liters of acetonitrile and dried at 40 ° C. to give 16.6 kg (79%) purified title product. C.- Chlorocephadroxyl monohydrate Reagents - solvate of chlorocephadroxyl with acetonitrile (purified) ..... 6.85 kg water .................... ..... 73.0 liters - 33% HCl ................... 1.7 liters - activated carbon ..........

  ... 0.7 kg - triethylamine (TEA) ......... 2.8 liters..DTD: celite .................... .. qs

  Procedure The purified chlorocéphadroxyl acetonitrile solvate (6.85 kg) is stirred in 50 liters of water and the pH is adjusted to 0.8 to 0.9 by addition of 1.7 liters of HCl. 33%. Activated charcoal (0.7 kg) is added and the mixture is stirred for 30 minutes and then filtered through

  a pad of celite. The solution and washing water is

  very) in a reactor lined with glass of 100 liters and heated to 40 C.

  The pH is adjusted to 1.6 to 1.8 by addition of TEA (1.24 liters) and the solution

  It is inoculated with chlorocephaloxyl monohydrate. The mixture is stirred for 1/2 hour at 40 ° C and the pH is adjusted to 4.0 by addition of TEA (1.56 liters). The suspension is cooled slowly to 20 ° C. and then stirred for 2 hours at +5 ° C. The solid is collected, washed three times with 6 liters of water and dried at 40 ° C., which gives 5.35 kg (86%). ) of

title product.

EXAMPLE 2

  Chloroecephadroxyl monohydrate (illustration of the preparation without seeding)

  352 g of solvate are suspended in acetone.

  chlorocéphadroxyle nitrile purified in 2.8 liters of water and added

2Z555989.

  then 36% HCl to establish a pH of 0.9 (all the material passes

  in solution). The solution is stirred for 1/2 hour with 36.0 g of char-

  good active and the mixture is filtered on a pad of celite. The resulting solution is heated to 40 ° C. and the pH adjusted to 1.8 by addition of triethylamine. At this time, chlorocéphadroxyl monohydrate crystals begin to form without seeding. The mixture is stirred for 1/2 hour at 40 ° C. The pH of the mixture is then adjusted to 4.0 with triethylamine and the suspension is stirred for a further 2 hours at 5 ° C. Crystalline chlorocéphadroxyl monohydrate is collected. washed three times with water and dried at 45 ° C to give 295.5 g of title product. H20 (KF) = 3.74%. The IR spectrum is substantially that shown in FIG. 1 and is identical to that obtained for

  the sample prepared according to Example 1.

2555989X

22 -

Claims (18)

  1.- 7- {D-α-Amino-α- (3-chloro-4-hydroxyphenyl) monohydrate   crystalline acetamido} -3-methyl-3-cephem-4-carboxylic acid having   the following X-ray diffraction properties: o Spacing Spacing 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 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 28 2.25 10 29 2.19 9 30 2.14 6 31 2.09 6   2.- Process for the preparation of 7- {D-α-amino-α-acid monohydrate   Crystalline (3-chloro-4-hydroxyphenyl) acetamido} -3-methyl-3-cephem-4-carboxylic acid having substantially the following properties of X-ray diffraction: o Radiation Spacing d (A) Relative Intensity 1 8.63 100 2 7.03 23 3 6.68 56 4 6.42 71 5.47 39 6 5.25 7 7 4.76 51 8 4.60 29 9 4.48 13 4.32 39 11 4.03 82 12 3.96 47 13 3.87 52 14 3.70 32 3.53 36 16 3.28 30 17 3.07 23 18 2.98 10 19 2.87 13 2.81 21 21 2.72 19 22 2.69 46 23 2.63 15 24 2.53 8 3.50 9 t6 2.44 13 27 2.31 21 28 2.25 10 29 2.19 9 2.14 6 31 2.09 6 characterized in that   (a) silylation of 7-aminodesacetoxycephalosporic acid is carried out   in a substantially anhydrous inert aprotic solvent;   (b) acylation of 7-aminodesacetoxycephalosporic acid is carried out   silylated ranic acid produced with chlorohydrochloride 2555989 '   D (-) -? -Amino-t- (3-chloro-4-hydroxyphenyl) acetyl in a substantially anhydrous inert aprotic solvent in the presence of an acid acceptor;   (c) all the silyl groups are detached from the acylation product by hydrolysis;   lysis or alcoholysis; and (d) forming the desired monohydrate product by a method selected from the following: 1. the pH of the solution from step (c) is adjusted upward in the presence of excess dimethylformamide or acetonitrile to form the solvate with dimethylformamide   or 7- {D-L-amino-α- (3-chloro-4-hydroxy) -acetonitrile   phenyl) acetamido} -3-methyl-3-cephem-4-carboxylic acid; this solvate is dissolved in acidified water or a mixture of acidified water and acetonitrile and the pH of this acidified solution is adjusted upward to precipitate the crystalline monohydrate desired; 2. the pH of the solution from step (c) is adjusted upward in the presence of dimethylformamide or excess acetonitrile to form the solvate with dimethylformamide   or acetonitrile of 7- {D-α-amino-α- (3-chloro-4-hydroxy)   phenyl) acetamido} -3-methyl-3-cephem-4-carboxylic acid and it is   this solvate in contact with water or a   essentially aqueous to precipitate the desired crystalline monohydrate; or 3. the pH of the solution from step (c) is adjusted upward to form 7- {α-amino-α- (3-chloro-4-hydroxyphenyl) acetamido} -3-methyl-3-acid -ephem-4-carboxylic acid and this acid is brought into contact with water or a partially aqueous medium   to effect crystallization of the desired monohydrate.   3. A process according to claim 2, characterized in that the step   silylation (a) is accomplished by reacting the 7-aminodesac-   toxycephalosporanic acid with a silylation agent chosen from those of formula: R1 R1 $ i R NH / R2   R1 kNHou R Sli-X 1 / 1x R4 in which:   R2, R3 and R4 represent hydrogen, halogen, alkyl (lower than   lower, phenyl, benzyl, tolyl or dimethylaminophenyl, at least one of R 2, R 3 and R 4 being different from halogen or hydrogen; R represents (lower) alkyl; m is an integer of 1 or 2; and X represents a halogen or RS -, R6: R5 represents hydrogen or (lower) alkyl; and, R6 represents (lower) alkyl or R3 R2 -Si R4 o:   R2, R3 and R4 are as defined above.   4. A process according to claim 3, characterized in that the silylating agent in step (a) is trimethylchlorosilane or hexamethyldisilazane. 5. A process according to claim 2, characterized in that the disilylated 7-aminodésacétoxycephalosporanic acid is produced in step (a) using at least 2 equivalents of silylating agent per mole of acid.   7-aminodesacetoxycephalosporanic.   6. A process according to claim 2, characterized in that the step   (a) is carried out by silylation of 7-aminodesacetoxycephalic acid.   losporanic with trimethylchlorosilane in an aprotic aprotic solvent.   Sibly anhydrous in the presence of an acid acceptor.   7. A process according to claim 6, characterized in that the silylation step is carried out in a chloride solvent system.   substantially anhydrous methylene in the presence of a common acid acceptor   taking triethylamine or a mixture of triethylamine and dimethyl-   aniline at a temperature of about 20 to 30 C.   8. A process according to claim 2, characterized in that the step   (a) is carried out by silylation of 7-aminodesacetoxycephalic acid.   losporanic with hexamethyldisilazane in an aprotic aprotic solvent.   Sibly anhydrous with external heating.   9. A process according to claim 8, characterized in that the silylation step is carried out in a methylene chloride solvent.   substantially anhydrous at the reflux temperature.   The process according to claim 2, characterized in that the acylation step (b) is carried out in a substantially anhydrous methylene chloride solvent system at a temperature in the range of about -10 ° C. at +10 ° C. in the presence of an acid acceptor chosen from   tertiary amine bases having pKa 7.   11. A process according to claim 10, characterized in that   the acid acceptor is dimethylaniline.   12. A process according to claim 2, characterized in that in step (c), the silyl groups are detached by treatment with water.   or a C1 to C4 alkanol or a mixture thereof.   13.- Method according to claim 2, characterized in that in step (c), the silyl groups are detached by treatment with an alkanol in CI to C4.   14. A process according to claim 2, characterized in that step (d) comprises: (1) adjusting the pH of the solution from step (c) upwards with triethylamine in the presence of dimethylformamide or excess acetonitrile until the solvate   dimethylformamide or acetonitrile of 7- {D-α-amino acid   a- (3-chloro-4-hydroxyphenyl) acetamido} -3-methyl-3-cephem-4-carboxylic   xylium rushes from the solution; (2) dissolving this solvate in acidified water; and (3) the pH of this solution is adjusted upward by the addition of   triethylamine to precipitate the desired crystalline monohydrate.   15. A process according to claim 14, characterized in that the   final pH adjustment step to produce crystalline monohydrate   desired is conducted at a temperature of about 35 to 60 C.   16. A process according to claim 14, characterized in that the acne   tonitrile is added as an anti-solvent during the final adjustment step pH.   17. The process as claimed in claim 14, characterized in that 7- {Da-amino-α- (3-chloro-4-hydroxyphenyl) acetamido} -3-naphthyl-3-cephem- 4-carboxylic monohydrate are added before   or during the final pH adjustment step.   18. A pharmaceutical composition characterized in that it comprises a compound according to claim i together with a vehicle or a   pharmaceutically acceptable inert diluent.