FI81104C - FOR EXAMINATION OF ANTIBIOTIC ACTIVE CRYSTALLINE 7- / D-AMINO- - (3-CHLORO-4-HYDROXYPHENYL) ACETAMIDO / -3-METHYL-3-CEFEM-4-CARBOXYL SYRAMONOHYDRATE. - Google Patents

Description

1 81104

The present invention relates to a process for the preparation of crystalline cephalosporin monohydrate. The present invention relates to a process for the preparation of an antibiotic-active crystalline 7- [Da-amino-.alpha. for the preparation of a monohydrate having the general antibiotic properties of a class of antibacterial agents and which is particularly useful in pharmaceutical formulations for the treatment of bacterial infections by oral administration.

The cephalosporin compound 7- [Da-amino-α- (3-chloro-4-hydroxyphenyl) -acetamido] -3-methyl-3-cephem-4-carboxylic acid is described and claimed in U.S. Patent 3,489,751. the compound, hereinafter commonly referred to as chlorocefadroxil, has the structural formula 20

HO ft -CH — C — NH —.- r ^ S N

C1 0 ^ NV ^ CH3

25 I

COOH

Chlorocefadroxil is an active broad-spectrum anti-30 active agent in the control of diseases caused by various gram-positive and gram-negative microorganisms. It is of particular interest as an oral cephalosporin antibiotic.

U.S. Patent 3,489,751 discloses the preparation of chlorocefadroxil by the acylation of 7-aminodesacetoxycephalos-2,8104 ranoic acid (7-ADCA) D (-) - α-amino-α- (3-chloro-4-hydroxyphenyl) acetic acid amino acid. protected derivative. Of the various amino-protected acylating agents described, the highest yields were obtained with D (-) - α- (3-chloro-4-hydroxyphen-5-yl) -α- (t-butoxycarbonylamino) acetic acid using the so-called t-BOC method. However, the yields in this method were not as high as is desirable for technical production, and the reagent used in the t-BOC method is very expensive.

U.S. Patent 3,985,741 discloses the preparation of chlorocefadroxil by acylation of 7-ADCA with a mixed anhydride of D (-) - α- (3-chloro-4-hydroxyphenyl) glycine with the latter α-amino group protected by a β-keto compound. such as methyl acetoacetate. Again, this method, although it has certain advantages over the t-BOC method, is not as efficient as is desirable for a technically viable production method. This patent also describes a crystalline chlorocefadroxil dimethylformamide solvate having 1.5 moles of dimethylformamide per mole of chlorocefadroxil.

The dimethylformamide solvate is slurried in boiling methanol until the solvate dissociates and the resulting suspension is then cooled to give the purified form of chlorocefadroxil. However, there is no indication in the publication that chlorocefadroxil prepared according to the process of this patent is in the form of a crystalline hydrate.

U.S. Patent 3,781,282 discloses in Example Example (Example 7) the preparation of chlorocefadroxil by dissolving a chlorocefadroxil * DMF solvate in acidified water, followed by neutralization with triethylamine. There is no indication in this reference that the chlorocefadroxil product is in the form of a crystalline monohydrate or that it is indeed in the form of a crystalline form.

U.S. Patent No. 3,810,104 discloses 7- [Da-amino-α- (p-hydroxyphenyl) -acetamido] -3-methyl-3-cefam-4-carboxylic acid (also referred to as cefadroxil). ) crystalline monohydrate prepared in the same manner as chlorocefadroxil monohydrate prepared according to the present invention.

Given the many significant advantages of chlorocefadroxil, it is desirable to have a technically feasible method for preparing this antibiotic 10 in higher yields and lower production costs than has been possible with previously known methods. In addition, it would be desirable to obtain chlor-richefadroxil in a stable crystalline form such as a crystalline hydrate, which would allow the antibiotic to be prepared into suitable pharmaceutical compositions for use as an antibacterial agent, e.g. aqueous suspensions.

This invention relates to a process for the preparation of a novel crystalline chlorocefadroxil monohydrate, i.e. 7- [D-α-amino-α- (3-20 chloro-4-hydroxyphenyl) acetamido] -3-methyl-3-cephem-4-carboxylic acid monohydrate. This crystalline chlorocefadroxil monohydrate is characterized by the following X-ray diffraction properties:

Line Distance d (A) Relative intensity 25 1 8.63 100 2 7.03 23 3 6.68 56 4 6.42 71 5 5.47 39 30 6 5.25 7 7 4.76 51 8 4.60 29 9 4.48 13 10 4.32 39 35 11 4.03 82 4 81104 12 3.96 47 13 3.87 52 14 3.70 32 15 3.53 36 5 16 3.28 30 17 3.07 23 18 2.98 10 19 2.87 13 20 2.81 21 10 21 2.72 19 22 2.69 46 23 2.63 15 24 2.53 8 25 2.50 9 15 26 2.44 13 27 2.31 21 28 2.25 10 29 2.19 9 30 2.14 6 20 31 2.09 6 The details of this determination of X-ray diffraction properties are as follows:

In the case of an automatic X-ray powder diffractometer 25 (Phillips PW 1050-70-source CuKa (1.54178Ä)), 2 cm2, 1 mm thick flat samples were used. Temperature = 22 ° C.

A very small amount of crystalline sodium fluoride was mixed with a few samples to obtain internal calibration. In addition, a pure NaF sample was run through a complete treatment process for the same purpose.

The membranes were read on a Norelco Debye-Scherrer membrane reader, which marked the positions of the diffraction rings to the nearest 0.05 mm. Values were corrected for film 35 shrinkage, and plane spacings (d-spacings)

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5 81104 were calculated from the corrected values. A computer program (XRAY, P. Zugenmaier) was used for all calculations. The accuracy of the d-spacing values obtained was 11%.

The intensity value of all membranes was obtained using a Jouce-Loeble Mark IIIC Recording microdensity meter (run ratio 5: 1, 0.1 O.D. wedge). Relative intensities on a scale of 1-100 were interpreted for all identified diffraction rings using background-corrected peak intensities.

An infrared analysis of a crystalline monohydrate product sample was performed and the spectrum of the sample (as a KBr plate) is shown in Figure 1.

This crystalline monohydrate is prepared according to the invention by (a) silylating 7-aminodesacetoxycephalosporanic acid in an inert, substantially anhydrous aprotic solvent; (b) acylating the silylated 7-amino-deacetoxycephalosporanic acid thus prepared with D (-) - α-amino-α- (3-chloro-4-hydroxyphenyl) acetyl chloride hydrochloride in an inert, substantially anhydrous aprotic solvent in the presence of an acid scavenger; (c) all silyl groups of the acylation product are cleaved by hydrolysis or alcoholization; and (d) forming the desired monohydrate product by any of the following methods: (1) adjusting the pH of the solution obtained in step (c) in the presence of excess dimethylformamide or acetonitrile to 7- [Da-amino-α- (3-chloro-4- hydroxyphenyl) acetamido] -3-methyl-3-cephem-4-carboxylic acid to form dimethylformamide or acetonitrile solvate; said solvate is dissolved in acidified water or a mixture of acidified water and acetonitrile, and the pH of said acidified solution is adjusted to precipitate the desired crystalline monohydrate; 6 81104 (2) The pH of the solution obtained in step (c) is adjusted higher in the presence of excess dimethylformamide or acetonitrile 7- [Da-amino-α- (3-chloro-4-hydroxyphenyl) acetamido] -3-methyl-3- to form a dimethylformamide or acetonitrile solvate of cephem-4-carboxylic acid or to precipitate the desired crystalline monohydrate, contacting said solvate with water and a partially aqueous medium; or (3) adjusting the pH of the solution obtained in step (c) to 10 to give 7- [Da-amino-α- (3-chloro-4-hydroxyphenyl) -acetamido] -3-methyl-3-cephem-4-carboxylic acid and the desired to cause crystallization of the monohydrate, said acid is contacted with water or a partially aqueous medium.

In the above process, 7-aminodesacetoxycephalosporanic acid, or 7-ADCA, is first silylated by reacting it with a silylating agent in an inert substantially anhydrous aprotic solvent.

Suitable solvents for the silylation reaction include inert, predominantly anhydrous organic solvents such as methylene chloride, tetrahydrofuran, chloroform, tetrachloroethane, nitromethane, benzene and diethyl ether. The preferred solvent is methylene chloride.

Silylating agents useful in the above process are known in the art [see, for example, U.S. Patents 3,554,266, 3,575,970, 3,499,909, 3,349,622, 3,595,855, 3,249,622, and GB Patents 1,339,605, 959,853. and 1,008,468]. Although any known silylating agent may be used, it is preferable to use an agent of the formula R1 R1 ^ 3

_ ------- T ^ NH _l \ _ I

-'- i. Dr Λ ... -Hr V- 7 81104 wherein R 2, R 3 and R 4 are hydrogen, halogen, (lower) alkyl, halogens lower) alkyl, phenyl, benzyl, tolyl or dimethylaminophenyl, at least one of said groups R 2, R 3 and R 4 being other than halogen or hydrogen; R 1 is 5 (lower) alkyl; m is 1 or 2 and X is halogen or R 5 -N 2 R 6 wherein R 5 is hydrogen or (lower) alkyl and R 6 is (lower) alkyl or R 3 R 2 -S 1 * wherein R 2, R 3 and R 4 are as defined above defined.

Examples of suitable silylating agents are tri-methylchlorosilane, hexamethyldisilazane, triethylchlorosilane, methyltrichlorosilane, dimethyldi-chlorosilane, triethylbromosilanyl, dimethylidilanyl, tri-n-propylchlorosilane, bromomethyldimethylchlorosilane, bentsyylimetyylietyylikloorisilaani, fenyylietyylimetyy-likloorisilaani, triphenylchlorosilane, trifenyylifluo-silane, tri-o-tolyylikloorisilaani, tri-p-dimethyl-aminofenyylikloorisilaani, n-etyylitrietyylisilyyliamii-30 Ni, heksaetyylidisilatsaani, trifenyylisilyyliamiini, tri-n-propyylisilamiini, tetraetyylidimetyylidisilatsaa-diamine, tetrametyylidietyylidisilatsaani, tetrametyylidife -nyldisilazane, hexaphenyldisilazane and hexa-p-tolyldisilazane. Other suitable silylating agents include hexaalkylcyclotrisilazanes or octaalkylcyclotetrazilazanes and silylamides and silylurides such as 8,810,104 trialkylsilylacetamide and bis-trialkylsilylacetamide. The most preferred silylating agents are trimethylchlorosilane and hexamethyldisilazane.

When a silyl halogen-5 dia, e.g. trimethylchlorosilane, is used as the silylating agent, the silylation step is performed in the presence of an acid (hydrogen chloride) scavenger, preferably propylene oxide or a nitrogen base such as triethylamine, trimethylamine, dimethylaniline, quinoline, lutidine. The primary residual acid scavengers are propylene oxide, triethylamine or a mixture of triethylamine and dimethylaniline. When a silazane, e.g. hexamethyldisilazane, is used, the silylation step is conveniently performed by heating the silazane and 7-ADCA so that the ammonia or amine derivatives formed as by-products in the reaction are distilled off.

In the preparation of silylated 7-ADCA by the above-mentioned method, one to two molar equivalents of silylating agent per mole of 7-ADCA can theoretically be used to give mono- or disilylated 7-ADCA or mixtures thereof. Thus, when 7-ADCA is reacted with about one equivalent of a silylating agent, monosilylated 7-ADCA is formed. For example, in the case of using trimethylchlorosilane or hexamethyldisilazane, the product has the formula

h2n —I-f * N

30 o COOSi (CH3) 3.

The disilyl derivative of 7-ADCA can be prepared using at least two equivalents in the silylation step.

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9 81104 til of silylating agent per mole of 7-ADCA. When primary trimethylchlorosilane or hexamethyldisilazane is used, disilylated 7-ADCA of formula 5 is formed.

SitCBjJj H — N-10 COOSi (CH3) 3.

The silylation step can be performed over a wide range of temperatures, e.g., between room temperature and the boiling point of the solvent mixture. Preferred results are usually obtained at room temperature (20-30 ° C) when using silyl halides, and at higher than normal temperatures, e.g. boiling point, in the case of silazanes, which are generally less active.

Either mono- or disilylated 7-ADCA or a mixture thereof is then acylated with D (-) - α-amino-α- (3-chloro-4-hydroxyphenyl) acetyl chloride hydrochloride (preferably in the form of a dioxane solvate for 25 minutes), to form an in situ silylated chlorocefadroxil intermediate. Any silyl groups present after acylation are then removed by hydrolysis or alcoholization.

The solvents used to acylate the silylated 7-ADCA are the same as defined above for the silylation step (a).

The preferred temperature range in the acylation step is between about -20 ° C and about + 70 ° C. However, temperature is not critical and temperatures of 35 ° C or higher than those in the preferred ίο 81104 range may be used. The most preferred acylation temperature is between about -10 ° C and + 10 ° C.

The acylation treatment is performed in the presence of an acid scavenger, which may be the same or different from that used in the preparation of the 5 silylated 7-ADCA. The best results are obtained when using a weak (i.e. pK <7) tertiary amine base such as dimethyl

O

aniline, pyridine or quinoline. To inactivate the excess amine, a weak tertiary amine and a salt of an inorganic acid, e.g., the hydrochloride salt of dimethylaniline, are also preferably added to the mixture (see, e.g., U.S. Patent 3,678,037).

Although a particular reaction may occur regardless of the molar ratios or reagents used, it is preferred that about one mole or slightly excess of acylating agent, mole of silylated 7-ADCA, be used to obtain maximum yields in the acylation step. The silylated chlorocefadroxil acylation product is treated by hydrolysis or alcoholization to cleave off the silyl protecting groups. The silylated intermediate compound can then be hydrolyzed by the addition of water or, more preferably, alcoholized by the addition of a suitable alcohol, preferably a C 1 -C 4 alkanol such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, etc.

A mixture of water and lower alkanol (C 1 -C 3) can also be used in the cleavage step.

Chlorocefadroxil can be precipitated from the reaction solution by conventional methods used to isolate similar cephalosporins. This compound can thus be precipitated as a neutral molecule by adjusting the pH of the reaction mixture above until the desired acid precipitates from solution. Preferably, an anhydrous amine base such as triethylamine is used.

According to a preferred embodiment of the invention, 7-35 aminodesacetoxycephalosporanic acid is silylated with hexamethyldisilazane in a substantially anhydrous aprotic acid.

II

81104 in a solvent, preferably methylene chloride, using external heating, preferably at the boiling point of the solvent, to form in situ disilylated 7-ADCA of the formula 5 (CH3) 3Si-NH- | - ^ S \ COOSi (CH3) 3.

The disilylated 7-ADCA is then acylated directly in the same solution (preferably at -10 to + 10 ° C) with D - (-) - α-amino-α- (3-chloro-4-hydroxyphenyl) -acetyl chloride hydrochloride, preferably in the form of a dioxane solvate, in the presence of a tertiary amine base of the acid scavenger, preferably kP $ 7, such as dimethylaniline, pyridine-20 or quinoline. After acylation, the silylated chlorocefadroxil acylation product is treated with a C 1 -C 4 alkanol, preferably methanol or n-butanol to cleave off all the silyl groups, and the chlorocefadroxil formed (after the optional filtration step) is neutralized to amoelectric neutralization. primarily with triethylamine, to cause precipitation.

The use of hexamethyldisilazane as a silylating agent in place of silyl halides such as trimethylchlorosilane eliminates the formation of an acid halide by-product, and therefore it is not necessary to use an acid scavenger in the silylation step. In the absence of this acid scavenger in the reaction medium, the mixture contains a more soluble salt, e.g. triethylamine HCl, which interferes with subsequent recovery steps. Using hexamethyldisilazane chlorocefadroxil can therefore be obtained in higher yields than conventionalization using trimethylchlorosilane silylation.

The desired crystalline monohydrate is prepared after cleavage of the silyl groups by one of the alternative routes mentioned above.

In one method, the pH of the chlorocefadroxil solution obtained in the hydrolysis or alcoholysis step is adjusted higher with a basic substance, e.g., a tertiary amine base such as triethylamine in the presence of excess dimethylformamide or acetonitrile. The solvate can then be collected and washed (primarily without drying) to give a crystalline material. Chlorocefadrox-15 silyl dimethylformamide or acetonitrile solvate is converted to the desired chlorocefadroxil monohydrate by dissolving the solvate in acidified water or a mixture of acidified water and acetonitrile and then neutralizing the acidified solution to yield the monohydrate product.

Dissolution of the chlorocefadroxil dimethylformamide or acetonitrile solvate occurs at a pH of about 2-2.4, which can be achieved by adding an inorganic acid, e.g. HCl, to the solvate mixture in either water or acetonitrile-water. Solid impurities can be removed at this stage of the process by filtering the acidified solution with activated carbon and / or a filter aid after treatment.

The acidified solution is then neutralized, preferably by stirring and heating at about 35-60 ° C, with the addition of a suitable base, e.g. an aliphatic tertiary amine such as triethylamine, to raise the pH of the solution to the point where chlorocefadroxil monohydrate crystallizes from solution.

Preferably, acetonitrile is added to the solution, which also acts as an antisolvent (precipitant) in neutral

II

13 81104 during recovery, to recover the desired product in maximum yields. Yields are also improved when seed crystals of the desired monohydrate are added to the solution before and / or during the final neutralization step.

An alternative process for preparing crystalline chlorocefadroxil monohydrate by the process of the invention involves preparing a dimethylformamide or acetonitrile solvate of chlorocefadroxil as described above and contacting said solvate with water or a partially aqueous medium until the desired monohydrate is obtained.

The dimethylformamide or acetonitrile solvate of chlorocefadroxil is dissolved in water or a mixture of water and an organic solvent such as acetonitrile, acetone, C 1 -C 5 alkanol (methanol, ethanol, n-propanol, isopropanol, n-butanol, amyl alcohol, etc.), or a mixture thereof. The use of partially aqueous organic solvent mixtures is recommended because organic solvents dissolve many impurities and result in a cleaner end product.

When mixtures of water and organic solvents are used, the ratios of the solvent parties can be varied within wide limits without serious side effects. Preferred solvent ratios for several partially aqueous solvent mixtures have been determined and are as follows: water: acetone (1: 3) (v / v) water: isopropanol (1: 3) (v / v) water: acetonitrile (1: 3) (v / v) 30 water: n-butanol (1: 1) (v / v)

When using an aqueous-acetonitrile mixture, it is recommended to add n-butanol (preferably after dissolution of the solvate) to ensure that the solvent mixture remains as one homogeneous phase during crystallization. Preferably, enough n-butanol is added to this crystallization mixture to provide a final water-acetone-1: 2: 1 (v / v) solvent ratio.

The concentration of the solvate in the aqueous or partially aqueous crystallization medium is not critical. However, the best yields have been obtained using concentrations ranging from about 400 to 800 grams / liter of solution. The solvate is preferably added to the solvent mixture gradually and with stirring for a period of time depending on the amount of solvate used, which is from a few minutes to several hours.

The crystallization can be performed over a wide temperature range, i. at a temperature between room temperature and the boiling point of the solvent mixture. Good results are obtained at a temperature in the range of about 35 to 60 ° C, most preferably about 40 to 45 ° C.

Monohydrate yields are improved when chlorocefadroxil monohydrate seed crystals are added to the dimethylformamide or acetonitrile solvate solution.

In a third process variant of the invention, the pH of the solution obtained in the cleavage step of silyl groups can be raised to the isoelectric point of chlorocefadroxil (pH 5.7-5.8) with a suitable base, preferably an aliphatic tertiary amine such as triethylamine, to impure or chlorosulfadhroxil is contacted with water or water and a suitable organic solvent, preferably acetonitrile, acetone, C 1 -C 5 alkanol (e.g. methanol, ethanol, n-propanol, isopropanol, n-butanol, amyl alcohol, etc.). ) or a mixture thereof until chlorocefadroxil monohydrate crystallizes from solution.

Neutralization of the chlorocefadroxil solution to form impure or primary grade chlorocefadroxil (amorphous-35) can be conveniently performed at room temperature by gradually adding the base to the solution and

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is 81104 while stirring. The crude chlorocefadroxil can then be crystallized in the same manner as described above for chlorocefadroxil dimethylformamide or acetonitrile solvate. As with the crystallization method of dimethylformamide or ace-5-nitrile solvate, the most preferred solvent mixture is water: acetonitrile: n-butanol (1: 2: 1) (v / v).

According to a most preferred embodiment of the present invention, the crystalline chlorocefadroxil monohydrate is prepared from either chlorocefadroxil dimethylformamide or acetonitrile solvate or impure (primary) chlorocefadroxil by the steps of (a) 7- [Da-amino-α-4-hydroxy-4- (3-chloro) -acetamido] -3-methyl-3-cephem-4-carboxylic acid dimethyl-15-formamide or acetonitrile solvate is dissolved in acidified water or a mixture of acidified water and acetonitrile; and raising the pH of said acidified solution until the desired monohydrate crystallizes from solution; or (b) 7- [Da-amino-α- (3-chloro-4-hydroxyphenyl) acetamido] -3-methyl-3-cephem-4-carboxylic acid or its dimethylformamide or acetonitrile solvate is contacted with water or a partially aqueous solution. with the medium until the desired monohydrate crystallizes from solution. Using the preferred reaction conditions described above, primary grade cefadroxil can be obtained in maximum yields and said chlorocefadroxil or its dimethylformamide or acetonitrile solvates can then be converted to chlorocefadroxil monohydrate in activity yields of up to about 85%.

The crystalline monohydrate prepared according to any of the above process alternatives can be recovered by conventional methods, e.g., by filtration, and then washed, dried, and formulated therein into pharmaceutical formulations for use in antibiotic therapy for the control of various bacterial diseases. Examples of such formulations (e.g., capsules or tablets), dosages and modes of administration of chlorocefadroxil monohydrate and its pharmaceutical combinations are those described in U.S. Patents 3,489,751 and 3,985,741 for the amorphous form of chlorocefadroxil.

The crystalline chlorocefadroxil monohydrate prepared by the process of the invention is a new stable crystalline form of chlorocefadroxil, which is preferred in that it allows the preparation of the antibiotic into suitable pharmaceutical preparations.

Compared to the previously known cefadroxil monohydrate, chlorocefadroxil monohydrate is surprisingly very advantageous in that it provides a much more stable ready-to-use aqueous suspension than cefadroxil monohydrate. This is evident from the following stability test: 600 mg of Nipagin M (methyl paraben) and 0.112 mg of nipazole (propyl paraben) and 2.625 mg of tragacanth gum were dissolved in 500 ml of hot (80 ° C) distilled water with stirring. The solution was cooled to room temperature and 875 g of sucrose and 2.250 g of apricot-orange flavor (NFA-1800), 1.012 g of mandarin flavor (NF-1580) and 0.375 g of coconut flavor (GIV. 735 134) were added with stirring. To this masterbatch was then added 159.232 g of chlorocefadroxil monohydrate, first passed through a stainless steel screen (100 mesh). The mixture was then homogenized in a mixer for 15 minutes. Volume 30 was made up to 750 ml with distilled water and stirred for another 15 minutes. The resulting suspension was dispensed into clear 50 ml glass vials which were sealed.

Similar procedures were performed using 159.570 g of cefadroxil monohydrate instead of chloro-35 fadroxil monohydrate.

Il 17 81104

The stability of both solutions was tested by keeping them at 5 ° C and 30 ° C for 2 months. After this time, the following results were obtained, expressed in grams of activity per gram of suspension:

5 5 ° C 37 ° C

a) chlorocefadroxil monohydrate 0.163 0.158 b) cefadroxil monohydrate 0.163 0.135

The results show that the decrease in efficacy over two months at 37 ° C was only less than 2% with chloro-10 cefadrozil monohydrate, whereas the efficacy of cefadroxil-li monohydrate was reduced by about 20%.

This unexpected property of crystalline chlorocefadroxil monohydrate allows this oral cephalosporin to be formulated into a ready-to-use aqueous suspension instead of being used as a dry monohydrate powder that would have to be mixed with water just before use with cefadroxil.

The following examples illustrate this invention. 7-20 aminodesacetoxycephalosporanic acid is abbreviated 7-ADCA, triethylamine is abbreviated TEA, dimethylaniline is abbreviated DMA and dimethylformamide is abbreviated DMF.

Preparation of starting material 25 Preparation 1

Preparation of D (-) - chloro-3-hydroxy-4-phenylglycine 30 oa-fi V-CH-COOH_gl? C12> 0K-J V_C2.C00H

\ = y ™ 2 \ - / im-

Cl 35 ie 81104

Reagents -D (-) p-hydroxylphenylglycine 10 kg (60 moles) -acetic acid 228 liters -hydrochloride (gas) 6.25 kg 5-sulfuryl chloride 8.1 kg (60 moles) -methylene chloride 100 liters soda solution 400 g / liter 3 liters of acetone 15 liters 10 Method

A suspension of 10 kg of D (-) p-hydroxyphenylglycine in 200 liters of acetic acid was heated to 60 ° C. Hydrochlorate was formed by bubbling 6.25 kg of hydrogen chloride (about 60 minutes into ai-15 chicken) into the suspension; to the resulting solution was then added 8.1 kg of sulfuryl chloride in 28 liters of acetic acid over 90 minutes, maintaining the temperature at 65-70 ° C. The gases were removed from the solution in vacuo, cooled to 20 ° C and stirred overnight. The solid was collected and washed by resuspending it twice in methylene chloride. It was dried in vacuo at 40 ° C.

Weight of chloro-3-hydroxy-4-phenylglycine hydrochlorate obtained = 13 kg.

The hydrochlorate was suspended in 130 liters of water and the mixture was heated to 40 ° C with stirring for 30 minutes. It was cooled to 20 ° C and the pH was adjusted to 1.4 by adding a soda solution at a concentration of 400 g / l (about 3 liters). Stirred for 2 hours at + 5 ° C, filtered and the solid was washed 3 times with distilled water (no ionizable chlorine is present in the mother liquor solution), then once with about 15 liters of acetone, and dried at 60 ° C. Stirred in a Frewitt apparatus and dried until H 2 O (KF) was £ 0.1%.

Weight of chloro-3-hydroxy-4-phenylglycine obtained = 8.1 kg (yield 67%).

il 19 81104

Preparation 2 Preparation of D (-) chloro-3-hydroxy-4-phenylglycine chloride hydrochloride 50H-CH-COOH

\ _ / I - = - 55. OH- (- CK-COOH

C-iT- ”“ 2 dioxane \ - / iffl-COCl 10 C1 OH-f HCl / -λ 15 \ / I I ^ OH— ('') —CH-COC1

Cl 'V = / nh \ hc1 ·.

Il Dioxane O Ci 20

Reagents 25 -D (-) chloro-3-hydroxy-4-phenylglycine 50 g (0.248 mol) -dioxane 410 ml (+ washing liquid) -phosgene 60 g (0.60 30 mol) -hydrochloride (gas) = 190 g ( 5.2 moles) -methylene chloride sufficient for washing 35 ίο 81104

Method

A 1 liter reaction vessel was charged with 410 mL of dry dioxane (molecular sieve dried, KF <0.05%), then 50 g of dry D (-) chloro-3-hydroxy-4-phenylglycine 5 (dried, 5 mmHg / 80 ° C; constant weight). KF <0.1% and screened with a 200 mesh screen). 60.0 phosgene was introduced into the reactor for 20 minutes with stirring [the initial temperature of 20 ° C rises to 35 ° C when the introduction of phosgene starts as the solid changes shape (stirring more difficult), after which the temperature tends to decrease]. After adding the required amount of phosgene, the mixture was heated to 70 ° C. After the temperature rose to 60-65 ° C, the crystalline mass dissolved. The mixture was heated at 70 ° C for 10 minutes, after which time the heating was stopped and the solution was concentrated to a volume of 250 ml without external heating (removal of excess phosgene); (at the end of the concentration the temperature is around 25 ° C). The solution was cooled to 8-10 ° C and hydrogen chloride gas was bubbled through it as rapidly as possible to maintain a temperature between 28-30 ° C (the amount of hydrogen chloride added corresponds to a very large excess; the reaction is exothermic until approximately stoichiometric amount, i.e. 2 moles, the temperature then tends to decrease again and the temperature is then maintained between 20 and 25 ° C). After about half of the total amount of hydrogen chloride was added, seed crystals were placed in the solution and stirred overnight at 20 ° C. The chloride hydrochloride was filtered off the next day to prevent it from coming into contact with atmospheric air. It was washed with dry dioxane and twice with dry methylene chloride. Dry in vacuo at ambient temperature to give 73 g (= 85%) of the title product as a mono-dioxane solvate.

Il 21 81104

Example 1

Chlorocefadroxil acetonitrile solvate A. Chlorocefadroxil acetonitrile solvate 5 S CS_k 32N ~ j — f "// \ I I + HO- (f y — CH-COCl β CH3 \ - / NH - HCl O 2

COOH

10

7-ADCA

tmcs / ch2ci2 -> TEA / DMA / DMA · HCl / acetonitrile 15

Cl HO —C -CH — CONH ---- S ^

\ / 'h I

N- 'N 2 J_m A-OU: CH, CN

20 0 ^ 3

COOH

Reagents 7-ADCA 7.2 kg (33.6 moles) -methylene chloride (KF <0.1%) 180.0 1 25 -trimethylchlorosilane (TMCS) 9.0 1 (71.0 moles) -N, N-dimethylaniline (DMA) 4.35 L (34.3 moles) -triethylamine (TEA) 23.4 L -N, N-dimethylaniline hydrochloride 4.24 L (10.1 moles) (methylene chloride solution 376 g / l) 30 -chlorine -3-Hydroxy-4-phenylglycine chloride-hydrochloride-dioxane solvate 17.0 kg (34.3 moles) (purity 53.8%) -methanol 3,4'-acetonitrile 107.0,135 tap water 51, 0 1 22 81 1 04

Method A 500 L glass-coated reactor was charged with 150 L of dry methylene chloride (KF <0.1%) and 7.2 kg of 7-ADCA. To the stirred suspension was added 9.0 L of TMCS and 4.35 L of DMA, followed by 9.4 L of TEA over 15 minutes maintaining the temperature between 20-25 ° C. The mixture was stirred for 1 hour at 20 ° C and cooled to -10 ° C. Then 4.24 l of a solution of 376 g of DMA.HCl per liter of methylene chloride were added, followed by 17 kg of D (-) chloro-3-hydroxy-4-phenylglycine chloride-hydrochloride-dioxane solvate (purity 53 , 8%) in ten batches per hour (temperature maintained between -12 ° C and -8 ° C). The mixture was stirred for 2 hours at -10 ° C and 3.4 l of methanol-15 was added over 10 minutes, followed by 48 l of tap water (with efficient stirring). The mixture was stirred for 15 minutes (temperature 0 ° C to 5 ° C) and the pH was adjusted to 2.3 by the addition of TEA (9.0 L). The aqueous solution was separated and washed twice with 15 liters of methylene chloride. 80 L of aceto-20 nitrile was then added and the pH was adjusted to 5.0 by the addition of TEA (5.0 L). Seed crystals were placed in the solution and stirred overnight at + 10 ° C. The solid was collected, washed with 15 liters of acetonitrile-water (8: 2) and 15 liters of acetonitrile and then dried at 40 ° C to give 11.0 kg (74% yield of 7-ADCA) of the title product. .

B. Purification of chlorocefadroxil acetonitrile solvate Reagents: 30 chlorocefadroxil acetonitrile solvate (crude) 21.0 kg tap water 115 l HCl, 33% 5.2 l charcoal 1.5 kg 35 acetonitrile 250 l triethylamine (TEA) 8.7 1

Celite enough

II

23 81104

Method:

The crude chlorocefadroxil acetonitrile solvate (21 kg) was stirred in 100 liters of tap water and the pH was adjusted to 0.8-0.9 by the addition of 5.2 L of 33% HCl. To the solution was added 1.5 kg of charcoal and the mixture was stirred for 30 minutes and filtered through a pad of Celite. The solution and wash water (10 L) were placed in a 250 L glass-coated reactor, 200 L of acetonitrile was added, and the pH was adjusted to 2.5 by the addition of TEA 10 (3.5 L). Seed crystals were placed in the solution, heated to 40-45 ° C and the pH was adjusted to 5.0 by the addition of TEA (5.2 L). The mixture was stirred for 1 hour at 40 ° C, cooled to 10 ° C and allowed to stir overnight at 10 ° C. The solid was collected, washed with 30 liters of 15 acetonitrile-water (1: 2) and then with 30 liters of acetonitrile, and dried at 40 ° C to give 16.6 kg (79%) of purified title product.

C. Chlorocefadroxil monohydrate Reagents: 20 chlorocefadroxil acetonitrile solvate, (purified) 6.85 kg water 73.0 1 HCl, 33% 1.7 l charcoal 0.7 kg 25 triethylamine (TEA) 2.8 1

Celite enough

Method:

The purified chlorocefadroxil acetonitrile solvate (6.85 kg) was stirred in 50 liters of water and the pH was adjusted to 0.8-0.9 by the addition of 1.7 L of 33% HCl. Charcoal (0.7 kg) was added and the mixture was stirred for 30 minutes and filtered through a pad of Celite. The solution and wash water (5 L) were transferred to a 100 L glass-coated reactor and heated to 40 ° C. The pH was adjusted to 1.6-1.8 by the addition of TEA (1.24 L) and the solution was seeded with chlorocefadroxil monohydrate. The mixture was stirred for half an hour at 40 ° C and the pH was adjusted to 4.0 by the addition of TEA (1.56 L). The suspension was slowly cooled to 20 ° C and then stirred for two hours at + 5 ° C. The solid was collected in talc, washed three times with 6 liters of water and dried at 40 ° C to give 5.35 kg (86%) of the title product.

Example 2

Chlorocefadroxil monohydrate (prepared without the use of sie-10 menk crystals)

The purified chlorocefadroxil acetonitrile solvate (352 g) was suspended in 2.8 liters of water and then 36% HCl was added to adjust the pH to 0.9 (total soluble). The solution was stirred with 36.0 grams of charcoal for half an hour and the mixture was filtered through a pad of Celite. The resulting solution was warmed to 40 ° C and the pH was adjusted to 1.8 by the addition of triethylamine. At this point, chlorocefadroxil monohydrate crystals began to form without the use of seed crystals. The mixture was stirred for half an hour at 40 ° C. PH of the mixture

was then adjusted to 4.0 with triethylamine and the suspension was stirred for a further two hours at 5 ° C. The crystalline chlorocefadroxil monohydrate was collected, washed three times with water and dried at 45 ° C to give 295.5 g of the title product. H 2 O (KF) <3.74%. The IR spectrum was essentially as shown in Figure 1 and identical to the spectrum obtained from the sample prepared according to Example 1.

li

Claims (9)

25 81 1 04 A process for preparing an antibiotically active crystalline 7- [Da-amino-α- (3-chloro-4-hydroxyphenyl) acetamido] -3-5 methyl-3-cephem-4-carboxylic acid monohydrate, which essentially has the following X-ray f fractional properties. Line Distance d (A) Relative intensity 1 8.63 100 10 2 7.03 23 3 6.68 56 4 6.42 71 5 5.47 39 6 5.25 7 15 7 4.76 51 8 4.60 29 9 4.48 13 10 4.32 39 11 4.03 82 20 12 3.96 47 13 3.87 52 14 3.70 32 15 3.53 36 16 3.28 30 25 17 3.07 23 18 2, 98 10 19 2.87 13 20 2.81 21 21 2.72 19 30 22 2.69 46 23 2.63 15 24 2.53 8 25 2.50 9 26 2.44 13 35 27 2.31 21 28 2.25 10 26 81 1 04 29 2.19 9 30 2.14 6 31 2.09 6 5 characterized in that (a) 7-aminodesacetoxycephalosporanic acid is silylated in an inert, substantially anhydrous aprotic solvent; (b) acylating the silylated 7-amino-deacetoxycephalosporanic acid thus prepared with D (-) - α-amino-α- (3-chloro-4-hydroxyphenyl) acetyl chloride hydrochloride in an inert, substantially anhydrous aprotic solvent in the presence of an acid scavenger; (c) all silyl groups of the acylation product are cleaved by hydrolysis or alcoholization; and (d) forming the desired monohydrate product by one of the following methods: (1) adjusting the pH of the solution obtained in step (c) in the presence of excess dimethylformamide or acetonitrile to 7- [Da-amino-α- (3-chloro-4-hydroxy). - ciphenyl) acetamido] -3-methyl-3-cephem-4-carboxylic acid to form a dimethylformamide or acetonitrile solvate; said solvate is dissolved in acidified water or a mixture of acidified water and acetonitrile, and the pH of said acidified solution is adjusted to precipitate the desired crystalline monohydrate; (2) the pH of the solution obtained in step (c) is adjusted higher in the presence of excess dimethylformamide or acetonitrile 7- [Da-amino-α- (3-chloro-4-hydroxyphenyl) acetamido] -3-methyl-3-cephem To form a dimethylformamide or acetonitrile solvate of -4-carboxylic acid and to precipitate the desired crystalline monohydrate, said solvate is contacted with water or a partially aqueous medium; or II 27 81 1 04 (3) the pH of the solution obtained in step (c) is adjusted to higher 7- [Da-amino-α- (3-chloro-4-hydroxyphenyl) -acetamido] -3-methyl-3-cephem-4- to form a carboxylic acid and cause the desired monohydrate to crystallize, said acid being contacted with water or a partially aqueous medium. Process according to Claim 1, characterized in that the silylation step (a) is carried out by reacting 7-aminodesacetoxycephalosporanic acid with trimethylchlorosilane. Process according to Claim 1, characterized in that the disilylated 7-aminodesacetoxycephalosporanic acid is prepared in step (a) using at least two equivalents of silylating agent per 15 mol of 7-aminodesacetoxycephalosporanic acid. Process according to Claim 1, characterized in that step (a) is carried out by silylating 7-aminodesacetoxycephalosporanic acid with trimethylchlorosilane in a substantially anhydrous aprotic solvent in the presence of an acid scavenger. Process according to Claim 4, characterized in that the silylation step is carried out in a substantially anhydrous methylene chloride solvent mixture containing triethylamine or a mixture of triethylamine and dimethylaniline as acid-binding agent at a temperature of about 20 to 30 ° C. Process according to Claim 1, characterized in that the acylation step (b) is carried out in a substantially anhydrous methylene chloride solvent mixture at a temperature in the range from about -10 ° C to + 10 ° C in the presence of an acid scavenger having a tertiary amine base which kP S 7, preferably dimethyl-O lianiline. Process according to Claim 1, characterized in that in step (c) the silyl groups 28 81 104 are cleaved off by treatment with water or a C 1 -C 4 alkanol or a mixture thereof. Process according to Claim 1, characterized in that the pH of the solution obtained in step (c) in step (d) 5 (1) is adjusted with triethylamine in the presence of excess dimethylformamide or acetonitrile until 7- [Da-amino-α- (3) -chloro-4-hydroxyphenyl) acetamido] -3-methyl-3-cephem-4-carboxylic acid dimethylformamide or acetonitrile solvate precipitates from solution; (2) dissolving said solvate in acidified water; and (3) the pH of said solution is increased by adding triethylamine to precipitate the desired crystalline monohydrate, preferably at a temperature of about 35-60 ° C, and preferably adding acetonitrile as an insoluble solvent during the final pH adjustment step. Process according to Claim 8, characterized in that the seed crystals of the desired 7- [Da-amino-α- (3-chloro-4-hydroxyphenyl) acetamido] -3-methyl-3-cephem-4-carboxylic acid monohydrate are added before during or during the final pH adjustment step. Il 29 81 1 04