NL8403670A - CHLOROCEFADROXIL MONOHYDRATE. - Google Patents

Description

t c ^ «/

Ai VO 6620 *

Reg .: Chl arocefadroxil monohydrate.

The crystal cephalososparin monohydrate of the present invention possesses. it generally has the usual attributes of that fanril of antibacterial agents and is particularly useful in pharmaceutical preparations for treating bacteria! e? infections 5 by oral administration *

The cephalosporin compound 7-CD-amino-3- (3-chloro-4-hydroxy-phenyl) acetanridi-3-phenyl-3-cephem-carbon-2 hours is described in and protected by U.S. Pat. No. 3,489. 751. This compound, which is generally referred to below as. chlorocefadrox.il ». ia has formula t from the formula sheet *

SfrTorocefadroxiT is active as a broad-spectrum antibiotic that provides effective control of diseases caused by a wide variety of gram-positive and gram-negative microorganisms. It is of particular importance as an oral cephalosporin-15 antibiotic *

U.S. Patent 3,489,751 shows the preparation of chlorocefadroxil by acylation of 7-amine nodesacetoxycephal osporanic acid (7-ADCA) with an amino-protected derivative of D (-} - cc-amino- <* :-( 3-ch 1 oro- 4-hydroxyphenyT Acetic acid * Of the various amino-protected 2Q acylating agents shown, the highest yields were obtained with D (-) - <* - (3-chToro-4-hydroxyphenyl) -Gc- (t-butoxycarbonyTanrino) acetic acid via the so-called t-BQC Method * However, the yields in this process were not as high as desired for commercial production and the reagent used in the t-BQC process is very expensive.

US patent 3,985 * 74-1 describes the preparation of chlorocefadroxil by acylation of 7-ADCA with the mixed anhydride of D (-) - oc- (3-chloro-4-hydroxyphenyT) glycine, where the <* - amino group of the latter compound is blocked with a 3-3-keto compound such as methyl acetoacetate. While this method has certain real advantages over the t-BQC procedure, it is not yet as efficient as 8403670 -2-1 *. for a commercially applicable production process is desired. Also disclosed in this patent is a crystalline dimethylformamidesolvate of chlorocefadroxil. that 1.5. mole of dimethylformamide per mole of chlorocefadroxil. The direthyformamide solvate is suspended in boiling methanol until dissolved. solvate dissociates and then the resulting suspension is cooled to give a purified form of chlorocefadroxiT. However, there is no indication that the chlorocefadroxil produced by the method of this patent is in the form of a crystalline hydrate.

10 'U.S. Pat. No. 3,781,282 shows in a teaching. Example, (Example 7) Preparation of Chlorocefadroxil by Dissolving a Chlorocefadroxil.DMF Solvent in Acidified Water, followed by Neutralization with Triethylamine. There is no indication from this publication that the chlorocefadroxil product is in the form of. a CRIS-15 TATIN: monohydrate would be or5 even that it is in a crystal! fine shape.

U.S. Pat. No. 4T6Q..865 discloses a crystalline monohydrate of 7- (T-β-amino-amino) (β-hydroxyphenyl-acetanridide), 3-methyl-3-cephem-4-carboxylic acid, Cook, cefadrox. named il), which is prepared in a similar manner to the chlorocefadroxi 1 monohydrate described and protected in the • present application *

In connection with the many important benefits of chlorocefadroxiT * would. it is desirable to have a commercially useful method of incorporating this antibiotic. higher yields and with cleaner pro-25. preparation costs than is possible with the known methods. In addition, it would be desirable to provide chlorocefadroxil in a stable, crystalline form such as a crystalline hydrate. It would be useful to present the antibiotic in the form of suitable pharmaceutical preparations for antibacterial use, e.g.

30 aqueous suspensions ..

The present invention provides a new crystalline monohydrate of chlorocefadroxil as well as methods of preparing date monohydrate. An improved acylation process is also provided for the. prepare, from. chlorocefadroxil, which results in excellent product yields and lower production costs compared to known processes.

The accompanying drawing »Fig. 1 * shows the characteristic infrared absorption spectrunr of chlorocef adroxi monohydrate (KBr grain) as obtained not the procedures described herein.

In one aspect, the present invention provides an improved method for preparing chlorocefadroxite or a pharmaceutically acceptable salt thereof, which method comprises; , (a) silylating 7-aminodesacetoxycephalosporanic acid in an inert »substantially anhydrous aprotic solvent · 10 (h) acylating the thus produced silylated 7-arainadesacetoxycephalosporanic acid with D (-) - <» c-anrino - <** - (3-chloro-4-hydroxyphenyljacetyl chloride hydrochloride in an inert, substantially anhydrous aprotic solvent in the presence of an acid acceptor) (c) cleavage of any silyl groups from the acylation product by hydrolysis or alcoholysis » and - recovering the desired cephalosporanic acid or a pharmaceutically acceptable salt thereof.

The pharmaceutically acceptable salts. ” referred to above ... include, for example, "Cf) non-toxic * pharmaceutically acceptable salts of the acidic carboxylic acid group such as the sodium" potassium "calcium" aluminum: and ammonium salts and non-toxic substituted ammonium salts with amines such as tri (lower) alkyl amines. » procaine »di benzyl amine, N-benzyT - / 3-phenethyl amine» t-phenamine * N, N '-di benzyl ethyl duck diamine, dehydroabiethylamine »N, N'-bisdehydroabethyl ethylene diamine, N- (low) -25 alkylpiperidines such as N-ethylpiperidine and other amines used to form salts of benzyl penicillin; and (2) non-toxic pharmaceutically acceptable acid addition salts (ie basic nitrogen salts) such as (a) the mineral acid addition salts such as hydrochloride »hydrobromide» hydroiodide, sulfate »sulfamate, sulfonate» phosphate »etc. and ( b) the addition salts with organic acid such as the maTeate, acetate, citrate, tartrate, oxalate, succinate, benzoate, fumarate, malate, mandate, ascorbate, 3-naphtha sulfonate and proton sulfonate. The term "(lower) alkyl" as used herein is defined to include straight chained branched saturated hydrocarbon radicals having 1 to 10 carbon atoms.

8403670-4 -; * ff I Ih de? The above method is first silylated by 7-ADCA by reaction with a sizing agent in an inert, substantially water free aprotic solvent.

Suitable solvents and for the silylation reaction include inert, substantially anhydrous organic solvents such as methylene chloride * tetrahydrofuran, chloroform, tetrachloroethane, nitrometharic, benzene and diethyl ether. A preferred solvent is methyl chloride.

In? the above-mentioned process refractable silylating agents? are known per se (see, e.g., U.S. Pat. Nos. 2,654v265, 2,575,975, 3,499-909, 3,349,622, 3,595,855, 3,249,622, and Brother Patents 1,339,605, 959,853, and 1,008,468). While any known styling nid can be used, it has. it is preferred to use an * agent selected from those of formulas 2 2 4 15 2 'er 3, wherein R, R and R are hydrogen, halogen, (Tage) alkyl, halogen (Tage) alkyl, phenyT, to represent benzyT, tolyl or dimethyTaminophenyl, 2 3 4 wherein at least one of the groups R, R and R differs from: halo. f * none or hydrogen R stands for (low) aTkyl. iïï. an integer from '1 5 <5 £ ......... t to 2., and £ stands for halogen or -NR R * where R is hydrogen or 20 (low) aTkyl and Rff (Tage) aTkyT or SiR% V preposition, wherein: R2, R2 4: and R are as defined above.

. Examples of suitable silicone agents include tri methyl chlorosilane, hexamethyldsilazane, triethyl chlorosilane, methyl trichlorosilane, dimethyl dichlorodilane, triethyl bromosilane, tri-n-propyl-1-chloromethyl-dimethyl-dimethyl-dimethyl-dimethyl methyl Tdiëthyl chlorosi lane, dimethylethyl chl oros i lane, fenyldimethyl -bromosilaan, benzylmethyTethylchlorosi1aan, fenyTethy1methylch1orosi-Ton * trifenylchlorosilaan, trifenylfluorosiTaan, tri-o-tolylchlorosi-Ton, tri-p-dimethyTaminafenylchlorosilaan, N-ethyltriëthylsilylamine, 30. hexaethyldisil Azaan, ly trifenylsi 1 amine * tri-n-propyl sil amine, tetraethyl dimethyldisilazane * tetramethyldiethydisilazane, tetramethyldi-phenydisilazane * hexaphenyldisilazane and hexa-p-tolyldisilazane. Other suitable silylating agents are hexa-alkylcyclotrisilazanes or octa-alkylcyclotetrasilazanes and silylamides and silylates such as trialkyl-silylacetamide and a bis-trialkylsilylacetamide. The most preferred silylating agents are trimethyl-Torosilane. and hexamethyl 1 -disilazane.

When a silythalide * e.g. trimethylchlorosilon * when the styling agent is used, the styling stage is conducted in an inert * substantially. anhydrous, aprotic solvent in the presence of an acid (hydrogen halide) acceptor, preferably propylene oxide or a nitrogen base such as triethyl amine * tri methyl amine * dimethyl anatin, quinoline * tutidine or pyridine. Preferred acid acceptors are propylene oxide, triethyl amine or a mixture of triethylanrine and dimethylaniline. When a SiTazan. ” e.g. hexa-methydisilazane is used * the silylation step is conveniently carried out by heating the silazane and 7-ADCA such that * ammonia-amine derivatives * which are formed as hi products of the reaction * are distilled off * 15 deη the preparation of silylated 7-ADCA In the above manner, the process * can theoretically be used from 1 to Z mpfafre equivalents of silylating agent per mof 7-ADCA to obtain mono- or disilyl-7-ADCA or mixtures thereof * Therefore, when T'-ADCA is reacted is brought to about t equivalent silyl eri ngsmiddeT ». mono-2 (T silyl-7-ADCA is formed.) In the case where trimethyl chlorasilane or hexamethyl disis azane is used, the product is of formula 4, for example.

The disilyl derivative of 7-ADCA can be prepared by using at least two equivalents of silylating agent per mole of 7-ADCA in the silylation step. When the preferred trimethyl chlorosilane 25 or hexamethyldphsilazane is used * disilyl-7-ADCA of formula 5 is formed.

The. silylation step can be performed over a wide temperature range * e.g. room temperature up to the reflux temperature of the solvent system. Good results are generally obtained at room temperature with the silyl halides (20-30 ° C) and at elevated temperatures * e.g. reflux temperature in the case of de-silazanes, which are generally obtained less actively.

Either the monosilyl or the disilyl-7-ADCA * or a mixture thereof may then be acylated with D (~) - <* - amino- <x- (3-35 chloro-4-hydroxyphenyl) acetyl chloride hydrochloride (preferably in the form 8403670 * Ψs - δ - · varT a dioxansalvate) to form in situ silylated chlorocefadroxi 1 intermediate: * Silyl groups present after acylation are then passed through. hydrolysis or alcoholysis is removed and the desired endocorphefadroxil product is recovered from the reaction medium, for example, by neutralization to the isoelectric point, after which the torchocefadroxil is removed. the. solution precipitates *

The fn the acylation of the. silylated 7-ADCA applied solvents have been defined above in connection with the silylation step (all Honor preferred temperature range for the acylation step ranges from about -2Q to about + 7Q0C * However, the temperature is not critical and higher or lower temperatures than the temperatures within the preferred limits can be used. * The most preferred acylation temperature is between about -1Q and 15> 11l ° Q ~

The activation procedure is preferably carried out in the presence of an acid acceptor which may be the same, or different from, when preparing the silylated 7-ADCA acid acceptor used. Best results are obtained when a weak 2D re (e. G. PKa ^ -7) tertiary arase base such as dimethylanfline * pyridine or chirioline is used. Preferably also a salt of a weak. tertiary amine and a mineral acid »e.g. *. the hydrochloric acid salt of dimethyl aniline incorporated to inactivate any excess amine (see, e.g., U.S. Patent 3,678,037).

Although some reaction will take place regardless of the molar ratio of the reactants used, it is preferred in connection with. obtaining maximum yields in the acylation step using about 1 mole of acylating agent or a small molar excess thereof per mole of silylated 7-ADCA.

The silylated chlorocepadroxil acylation product is treated by hydrolysis or alcoholysis to cleave the protective silyl groups. The silylated intermediate may e.g. be hydrolyzed by the addition of water or, rather, alcoholysed by the addition. of a suitable alcohol, preferably a C 1 -C 2 -alkano! such as methanol, ethanol, n-propanol, isopropanol, n-butanol etc. A mixture of 8403670 j- -i -7- of water and honors Tags canoe! (C ^ -C ^) can also be used in the cleavage step.

Chlorocef adroxi 1 can be recovered from the reaction solution by methods customary for the isolation of similar cephalasporins. The product can be recovered as the neutral molecule by adjusting the pH of the reaction mixture upwards until the desired acid precipitates from solution. Bee. a non-aqueous amine base such as triethyl amine is preferably used. Chlo-rocefadroxil. in the form of the free acid, it can be converted into a pharmaceutically acceptable acid carboxylic acid or acid addition salt by reaction with an appropriate base or suitable acid.

According to a preferred embodiment of the invention, 7-aminodesacetoxycephosporanic acid is silylated with hexamethyldisilazane in a substantially anhydrous aprotic solvent, preferably methylene chloride, while heat is supplied from the outside, preferably at the reflux temperature. the solvent, which is formed in sitit-7-ADC & with formttl e-. The di si 1 yl-7-ADGAr is then directly put in? the same solution (preferably preferred to + tQoC) acylated with the D (-) - - - amina- © c- (3-chlQca-4-hydraxy.phenyT) acetyl-20 chloride hydrochloride "preferably in the form of a dioxan salvate, in the presence of an acid acceptor, preferably a tertiary amine base with a pK 7 7 such as dimethyl aniline, pyridine or quinine.

After acylation, the silylated chlorocefadroxyl tacylation product is treated with a C 1-6 alkanoate, preferably methanol or n-butanol, to cleave optional silyl groups and the product is recovered (after an optional filtration step) by neutralization to the isoelectric point using of a tertiary amine base, preferably triethyl amine, through which precipitation is effected.

Use of hexamethyldisilazane as a silylating agent in place of the usual silyl halides such as trimethyl chlorosilane eliminates the formation of an acid halide by-product and therefore the need to use an acid acceptor in the silylation step. Without the presence in the reaction medium. of this acid acceptor is less insoluble salt, e.g. triethylamine.HCI, present which can disrupt the late-35 recovery steps. Hence, by using hexamethyldisilazane 8403670 / - 8 '- higher yields of chTorocefadro-xil can be achieved than with the conventional trimethyl chlorosilon 1 tirol.

In? Another aspect provides the invention: a novel crystalline monohydrate form of chTorocefadroxil which has been found to be a stable useful form of the cephalosporin antibiotic, which is particularly suitable for pharmaceutical preparations.

The crystal chlorocefadroxil monohydrate of the present invention essentially exhibits the following X-ray powder diffraction property 10. Line Distance. d (ft) Relative intensity:

f 8.63. 10Q

. Z 7.03 23 3 6.68 56 4 "6.43 71 T5. S ·.. 5JT> 39

6 6.25- 'T

T-: · '.-1'. Φ.76. 51 * at .... .29? .. ·; - -. 9¼ .. · ....—- c -.-: 4.43 -.- - .... .... "... .. 4.

2d 16 4.32 39 tr '4.03: 82 13. . . 3.96 47 13 3.87 52 14 3.70: 32 25 15 3.53 36 16 3.28 30 17 3.07 23 18 2.98 10 19: 2.87 13 30 20 2.81 21 21 2 72: 19 22 2.69 46 23 2.63; 15 24 2.53 8 35 25 2.50 9 8403 670 • * 9 m - 9 - 26 2.44- 13 27 2.31 21 28 2 * 25- 10 29 2.19 9 5 30 2.14- 6 31 2.09 6

The details for this determination, of the X-ray diffraction elongations, are as follows:

Flat samples of 2. cm2 and with. a thickness of 1 mm, TCT was used on an automatic powder X-ray diffractometer (Phillips PW 105ff-7Q source (1.54478 ft). Temperature »22 ° C.

A very small amount of crystalline sodium fluoride was mixed with a few samples to give an internal calibration. In addition, a sample of pure NaF was subjected to the full procedure for the same purpose. on a Norelco-Oebye-Scherrer fiTm-. Λ reader, where the positions from the diffraction rings to the closest. ,, near Q5 imr were noted * The data was corrected for film shrinkage. With the layer distances (d-distances), were calculated, from the corrected data * A computer program (XRAY by P. Zugenmaier) was used for all calculations * The accuracy in the resulting d-distance data was about 1%.

Intensity recording was obtained from aTle films using a Joyce-Loeble Mark IIIC Recording; microdensitometer 25 (scan ratio 5: 1, 0.1 external diameter wedge). Relative intensities on a scale of 1 - 100 were assigned to all recognizable diffraction rings, using peak intensities corrected for the background reading.

A sample of the crystalline monohydrate product was subjected to infrared analysis and the spectrum of the sample (in the form of a KBr disc) is shown in Figure 1.

The present invention further provides a method for calculating the above-described crystalline chlorocefadroxil monohydrate, which method comprises (a) silylating 7-aminodesacetoxycephalosporanic acid in an 88403670 i-10-inert, anhydrous aprotic solvent; (b) the acylerr of the silylated 7-aminodesacetoxycephalosporanic acid thus produced with D (-) - oc-amino-oc - (3-chloro-4-hydro-xyphenyT) acetyl chloride hydrochloride in an inert, predominantly water-5 free aprotic solvent ;.

Cc), cleavage of any silyl groups. of the acylation product by hydrolysis or alcoholysis; and (dj. forming the desired monohydrate product by a method selected from IQ: (t) adjusting the pH of the solution upstream in an upward sense; (c) in the presence of excess dimethylformamide or acetonitrile to form of the dimethylformamide or acetonitrile salvate of 7-D-ec-amino-oc (3-chloro-4-hydroxyphenyl) acetamido J-3-methyl-3-cephem-4-carboxylic acid dissolving this sol vessel in acidified water or a mixture of acidified water and acetonitrile and adjusting in the upward direction the pH of said acidified solution to precipitate the desired crystalline monohydrate; adjusting the plf of the solution upwards (u: it step Cc), in the presence of excess dimethylformamide or acetonitrile to form the dimethyl 1 formamide or acetonitrile sal dishes of 7- & - ° t -ami no- <x- (3-chloro-4-hydroxyphenyl) acetamido. 7-3-methyl-3-cephem-4-carboxylic acid and contacting wash this sol with water on a partial aqueous medium to precipitate the desired crystalline monohydrate; or 25 (3j adjusting the pH of the solution of step (c) in the upward direction to form 7-D-oc-amina-oc- (3-chloro-4-hydroxy-phenyl) acetamido_T- 3-methyl-3-cephem-4-carboxylic acid and contacting this acid with water or a partial aqueous medium to process crystallization of the desired monohydrate * 30 deη the preparation of crystalline chlorocephalroxil monohydrate by the above process, the silylation, acylation err silyl group cleavage steps performed as previously described in connection with the improved acylation procedure for preparing chlorocefadroxil * 35. The desired crystalline monohydrate can subsequently be 8403670 ...... ..... ...... ___ I ......

- 11 *, t. i * one of several alternative routes are being prepared *

According to one method, the solution of chlorocefadroxil is neutralized after the solvalysis step with a basic substance, such as a tertiary amine base such as triethyl amine, in the presence of excess 5-dimethylformamide or acetonitrile until the dimethylpharmamide or acetonitrites-precipitate of chlorocefadroxil precipitates. * The solvate can then be collected and washed (preferably not dried) to give a crystalline material. * Chlorocefadroxil dimethylformamide or acetonitriTesolvate can be converted to the desired chlorocefa-1 (1-droxil monohydrate by dissolving it in. - acidic water or a mixture of acidified water and acetonitrile and then neutralize the acidified solution to precipitate the monohydrate product *

Dissolving the chlorocefadroxil dimethylfarmamide or acetoni-. TS trilesolvate takes place at a pH of about 2 - 2, 1 which can be realized by adding a mineral, acid tr * v * HCT to the 1 mixture of the water in either water or a AcetoMtrtle Water Mixture * Solid impurities can be removed at this stage of the process by filtration of the acidified solution after treatment with activated charcoal and / or filter aids.

The acidified solution is then neutralized at. preferably under agitation and with warmer to about 35-6 ° C "by adding an appropriate base" b * v. an aliphatic tertiary amine such as tri'ethylamine, thereby raising the pH of the solution to the point where chlorocefadroxyl monohydrate crystallizes from the solution *

Preferably, acetonitrile is added to the solution as an anti-solvent (precipitant) during neutralization to achieve maximum yield of the desired product. Yields are also improved by seeding the solution with seed crystals of the desired monohydrate before and / or during the final neutralization step.

An alternative method for preparing the crystalline chlorocefadroxil monohydrate in the above method involves preparing chlorocefadroxil dimethylformamide or acetonitri Tesol vessel as 8403670

•X

- 12 - described above and the. contacting this sol vessel with water or a partially aqueous medium until the desired monohydrate crystallizes from the solvent system.

The chlorocefadroxi dimethylformamide or acetonitrile solvate 5 is dissolved in water or a mixture of water and an organic solvent such as acetonitrile »acetone» a C 1 -alkanol (methanol »ethanol» rr-propanol »isopropanol» n-butanol »amyl alcohol etc.) or a mixture thereof. The use of partially aqueous organic solvent systems is preferred because the organic solvents absorb many of the impurities and lead to a purer final product.

When mixtures of water and organic solvents are used, the. ratios of the solvent components over a wide range are varied: without serious adverse influences. The preferred solvent ratios have been determined for several partially aqueous solvent systems and are as follows: water t acetone Cl: 2) Cv / v). "Γ.

.......... ...... water: isopropanol Ct: 3) (.v / v) ...................

2Q. water: acetonitrile (t: 2) (v / v water r n-butanol (1: 1) (v / v).

In the water-acetonitrile system, it is preferred that n-butanol (preferably after dissolving the sol dish) is added to ensure that the solvent system * remains present as a single homogeneous phase during crystallization. Preferably, sufficient n-butanol is added to this crystallization system to realize a final solvent ratio of water: acetonitrile: n-butanol of (I: 2: 1) (v / v).

The concentration of sol vessels in the aqueous or partially aqueous crystallization medium is not critical. However, the best yields are obtained when concentrations between about 400 and 800 g / liter of solution are used. The sol vessel is preferably added to the solvent system in periodic increments and with stirring over a period of time depending on the amount of sol vessel used, i.e. from a few minutes to several hours.

8403670 - 13 -

Crystallization can be performed 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 - 60 ° C, preferably 4G - 45 ° C.

Monohydrate yields are improved by inoculating the dimethylpharmamide or acetorritrile solvate solution with seed crystals of chTorocefadroxil monohydrate *

Yet another method of preparing the desired monohydrate in the above process comprises (1) preparing the methylated dTlorocefadrox.il and cleaving off the protective silyl groups by hydrolysis or alcoholysis as described above, (2} neutralizing the solution from the cleavage step to the isoelectric point of chlorocefadroxiT (pH about 5.7-5.8) with a quenched base, preferably an aliphatic tertiary amine such as triethylamine, to give impure primary quality chlorocefadroxiT to precipitate, and (3) contacting this crude chloro-cafadroxil with water or a mixture of water with a suitable organ, niscit solvent, preferably acetonitrile, acetone, a C 1-4 alkanal ... (e.g. methanol, ethanol, nrpropanoT * isopropanoT, n-butanoT, amyfaTca-ZQ. hollow, enr.) or mixture thereof, until chlorocefadroxil monohydrate crystallizes from solution.

Neutralization of the chlorocefadroxi Top solution to form crude or primary grade chlorocefadroxiT (amorphous) can be conveniently performed at room temperature by adding the base gradually to the stirred solution. The crude chlorocefadroxiT can then be crystallized in the same manner as described above for the chlorocefadroxil dimethylformamide or acetonitrile solvate. As in the case of the dimethylformamide or acetonitrile solvate crystallization procedure, the most preferred solvent system is water; acetonitrile: n-butanol (1: Z: 1) (v / v).

A most preferred embodiment of the present invention is a process for preparing crystalline chlorocefadroxil monohydrate from chlorocefadroxildimethyoformamide or acetonitrile-35 solvate or crude (primary grade) chlorocefadroxil by dissolving 8403670-14 - (a) the dimethylformamide or acetonitrilesol dishes of 7- / rD - ^ - amino-e <- (3-chloro-4-hydroxyphenyl) acetamido_7-3-methyl-3-cephem-4-carboxylic acid in acidified water or a mixture of acidified water and acetonitrile; and adjusting the pH of the acidified solution in an upward direction until the desired monohydrate from solution is crystalized. or (b) contacting 7-D-O-C-amino (3-chloro-4-hydroxyphenyl) acetami do J-3-methyl-3-cephem-4-carboxylic acid or the dimethyl. thyl formamide? or acetonitrile solvate thereof with water or a partial aqueous medium until the desired monohydrate crystallizes from solution.

The dimethyformamide or acetonitrileso.l dishes and chTorocefadroxil contained in * the. The above method has been used as starting material, T5 can be prepared according to methods which. in the present application have been described by other known methods * e.g. the methods described are U.S. Pat. Nos. 3,489,751 and 3,435,354. ". . " -. Preferred conditions for forming chTarocefadraxilmono-20 hydrate in the above process are as described above in connection with the above-described overall reaction scheme *, i.e., the combined synthesis and moriohydrate formation steps.

Hear the preferred reaction conditions described above. The present invention allows the production of primary grade chlbrocefadroxil in excellent yields and a subsequent conversion of this chlorocefadroxil or its dimethyl formamide or acetonitrialsal dishes into chlorocefadroxil monohydrate in activity yields. about 85¾.

The crystal line monohydrate prepared by any of the above processes can be recovered by conventional methods, e.g. filtration, and then washed, dried and processed into pharmaceutical preparations for use in antibiotic therapy to combat various bacterial diseases. Examples of such preparations (e.g. capsules or tablets), doses and method of administration of chlorocefadroxil monohydrate and pharmaceutical preparation 8403670

* r W

-15- • thereof: are as described in U.S. Pat. Nos. 3,489,751 and -3,985.74-1 for the amorphous form of chlorocefadroxil.

The invention therefore encompasses a pharmaceutical composition, most preferably a pharmaceutical composition intended for oral administration, comprising crystalline chlorocefadroxil monohydrate with a suitable inert, pharmaceutically acceptable carrier or diluent.

The invention further encompasses a method of treating humans or other animal species (eg, mammals) for diseases caused by Gram-positive or Gram-negative bacteria, which method comprises the administration to the subject host of an effective dose of crystalline chlorocefadroxil monohydrate as defined herein or a pharmaceutical composition as defined herein.

The following examples are given to illustrate the present invention. All temperatures are in degrees Celsius.

7-aminodesacetoxycephalosporanic acid is abbreviated as 7-ADCA ». triethyl amine as TEA, dimethylant tine as DMA. and dimethylformamide as DMF. Preparation of starting materials:

Preparation t

Preparation of CTC -) - chTora-3-hydroxy-4-phenyTgTycfne according to reaction-2d scheme Ai

Reagents - - D (-) p-hydroxyphenyl glycine 10 kg (60 moT) -acetic acid 225 Titer - hydrogen chloride (gas) 6.25 kg 25 - sulfur chloride 8, t kg (60 moT) —No ethylene strength TOO Titer - sedêb solution 400 g / liter «3 Titer - acetone · *« 15 liters

Procedure 30 A suspension of 10 kg of D (-) p-hydroxyphenylglycine in 200 liters of acetic acid was heated to 60 ° C. The hydrochlorate was added. formed by bubbling 6.25 kg of hydrogen chloride (in about 60 minutes); then a solution of 8.1 kg of sulfuryl chloride in 28 liters of acetic acid was added to the resulting solution, which was kept at 65-70 ° C for 90 minutes. The solution was degassed under low pressure to 40 ° C. cooled and stirred overnight * The solid was collected, washed with two suspensions in methylene chloride ... It was. in. vacuum ... dried at 40 ° C *

Merr obtained 13 kg of chloro-3-hydroxy-4-phenylgycin hydrochloride.

5. The hydrociflorate was: suspended in 130 liters of water and the mixture was brought to 40 ° C * with stirring for 30 minutes * It was cooled to 20 ° C and the pH was adjusted. 1.4 adjusted by addition of a 400 g / titer solution; of soda (about 3 Titer) *

Hid was stirred at: + 5 ° C for 2 hours, filtered and * the solid TO was washed twice with distilled water (absence of ionizable chlorine in the mother liquor) * then once with about 15: Titer acetone and dried at 60 ° C. It was mixed on a Frewitt equipment and dried to a H ^ Ck. (KF) ^ content of not more than 0, 1¾ ..

TS kg (67-. Yield) of chToro-3-hydroxy-4-phenyl- were obtained; glycine * ,.

Honor 2 *

Preparation of 0 (") ch: Torow3" "hydroxy-4-phenylglycine chlordehydrochloric acid. 1 ^ according to reaction scheme B. / ^. SO Reagents! - D (-) chloro-3-hydroxy-4-phenyglycine 50 g (0.248 moT) ) - dioxane 410 ml (+ washing oil) - phosgene 60 g (0.60 mol) «hydrogen chloride (gas)» 190 g (5.2 mol) Z5 * - methylene chloride qs for washing liquid

Procedure!

In; a T liter reactor were 410 ml anhydrous. dioxane (dried on a molecular sieve, KF <0.051), then 50 g of anhydrous D (-) - chToro-3-hydroxy-4-phenylglycine (dried 5 mm Hg / 8Q0C; constant weight KF <0, 11 and sieved: placed on a sieve with 74 ym mesh.

60.0 g of phosgene were added over the course of 20 minutes. pass through while stirring (the initial temperature of 20 ° C rose to 35 ° C at the beginning of the phosgene pass through while the solid was transformed. (stirring was more difficult), after which the temperature tended to decrease). When the necessary amount of phosgene was added, 8403670 * # * - π - the mixture was heated to 70 ° C. When the temperature reached 60 - 65 ° C *, the crystallized mass dissolved. He was heated at 70 ° C for 10 minutes, after which time the heating was stopped and the solution concentrated to a volume of 250 ml without external heating (elimination of the excess phosgene); (temperature at the end of the concentration was close to 25 ° C). The solution? was cooled to 8-10 ° C and hydrogen chloride was allowed to so quickly *

Passed through to keep the temperature at 28 DEG-30 DEG C. (the amount of hydrogen chloride added corresponded to a very large excess. The reaction was: exothermic until about the stoichiometric amount, i.e., ~ 2 moles, was passed through; the temperature then tended to decrease again, and then a temperature of 28 DEG-25 DEG C. was maintained. Then about half of. the hydrogen chloride was passed through, the solution was inoculated and left at 200C overnight. T5t stirred The chlordedehydrochlorate was filtered the following day, preventing contact with atmospheric air. It was made once with anhydrous dioxane and twice with anhydrous. methylene chloride washed. It was vacuum dried at room temperature where. .73: g (about 85%) of the title product was obtained as a. mono-dioxansoT-28 dishes.

Example I

Chl orocefadroxi Imonohydrate, A. ChlorocefadroxfTacetonitriTesolvate (see reaction scheme C) • 25 Reagents: - 7-ADCA 7.2 kg (33.8 mol)

- methyl chlorine (KF ¢, 1¾) 188.8 I.

- trimethylchlorosilane (TMCS) 9.8 1 (71.8 mol) - Ν, Ν-dimethylamine (DMA) 4.35 1 (34.3 mol) 38 - triethylamine (TEA) s 23.41 - ff »N -dfmethylaniline hydrochloride 4.24 1 (18.1 mol) (methylene chloride solution 376 g / 1) -chloro-3-hydroxy-4-phenylglycine chloride hydrochloride dioxansolvate 17.8 kg (34.3 mol) 8 (purity 53.8¾) 8403670 - 18 * - methanol 3.4 1 l - acetonitrile 107.0 1 tap water 51.01

Procedure: 5 In a 500 L glass lined reactor, 150 L anhydrous methylene chloride (KF ff »11) and 7.2 were added. kg 7-ADCA charged. To the stirred suspension, 8.0 liters of TMCS and 4.35 liters of DMA were added, followed by an addition of 8.4 liters of TEA over a 15 minute period while the temperature was at 20-25 ° C. kept. The mixed 10 seT was stirred at 20 ° C for 1 hour and cooled to -1 ° C. At that temperature, 4.24 liters of a 375 g / liter methyl-Torchoride solution of DMA.HCT was then added, followed by 17 kg of ((-) - ch'-Toro-3-hydroxy-4-phenyl-Torinhydrochloride-dioxansolvate (Purity 53.81)) in ten portions over a period of one hour (the tempe-TS nature was kept between -12 ° C and -8 ° C). The mixture was stirred at -ttt®C for 2 hours. In a period of time ttt minutes, 3.4 Titer of methanol was added followed by 48 liters of tap water (while stirring efficiently). The mixture was left for 15 minutes (at. - J ··. F · · _ ..

a. temperature of ff - 5 ° C) and the pH was adjusted to 2.3 by addition of TEA: (9, t liter). The aqueous solution was separated and washed twice with 15 liters of methylene chloride. Afterwards. 80 liters of acetonitrile were added and the pH was adjusted to 5, ff by adding TEA (5, ff liters). The solution was seeded and stirred at +10 ° C overnight. The solid was collected, washed with 15 liters of acetonitrile water (8: 2) and 15 liters of acetonitrile, and then dried at 40 ° C. 11.0 kg (74% yield] from 7-ADCA) of the title product were obtained.

B .. Purification of chlorocefadroxilacetonitrilesol dishes Reagents:: 30 - chlorocefadroxilacetonitrilesOv (crude) 21.0 kg - tap water 115 1 - 33% HCl 5.2 1 - charcoal 1.5 kg - acetonitrile 250 1 35 - triethylamine (TEA) 8, 7 1 - Cell its q .s.

^ '* 8403670 * - 19 -

Procedure:

Raw chi orocefadroxi! acetoni tri leso.1 dishes (2.1 kg) were stirred in 1QG liter of tap water and the pH was adjusted to 0.8 - 0.9 by adding 5.2 liters of 33% HCl. To the solution, 1.5 kg of charcoal was added and the mixture was stirred and filtered through a Celite pad for 30 minutes. The solution and the washing water (10 Titer) were placed in a reactor fed with 250 Titer of ash, 200 liters of acetonitrile were added and the pH was adjusted to 2.5 by adding TEA (3.5 Titer). The solution was inoculation heated to 10 40'-45eC and the pH- was adjusted to 5.0 by addition of TEA (5.2

Titer) The mixture was stirred at 40 ° C * to 10 ° C for one hour. cooled and left overnight at 10 ° C while stirring * The solid rod was collected, washed with 30 liters of aceto-nitrile water (1: 2) and then. 30 liters of acetonitrile * and dried at 40 ° C. 16.5 kg (791) of purified title product * O * Cdl orocefadroxi Imonohydrate Reagents were obtained; - chlorocefadroxyl acetonitri Tesol vessel (purified) 5.85 kg.

.... ... .... - water. v ... .. ........... '^ 73 Jt T.

20 - 33¾. HCl 1 f, 7 T

- charcoal Q /, 7 kg

triethylamine (TEA) 2.5 T.

- CeTite g.s *

Procedure; Purified chlorocefadroxil acetonitrile solvate (5.85 kg) was stirred in 50 liters of water and the pH was adjusted to 0.8-0.9 by addition of 1.7 Titer 33% HCl. Charcoal (0.7 kg) was added and the mixture was stirred and filtered through a Celite pad for 30 minutes. The solution and wash water (5 liters) were transferred to a 100 liter glass lined reactor and heated to 40 ° C. The pH was adjusted to 1.5-1.8 by addition of TEA (1.24 liters) and the solution was inoculated with chlorocefadroxi monohydrate.

The mixture was added for half an hour. Stirred at 40 ° C and the pH was adjusted to 4.0 by adding TEA (1.55 liters). The suspension 35 was slowly cooled to 20 ° C and then at + 5 ° C for 8 hours 8403670 v

, V

Stirred. The solid was collected, washed three times with 6 liters of water and dried at 40 ° C to obtain 5.35 kg (86%) of the title product.

Example II

5 Chlorocefadroxil monohydrate (illustrates the preparation without grafting).

Purified chlorocefadroxil acetonitrile solvate (352 g) was suspended in 2.8 liters of water and then 36% HCl was added to obtain a pH of 0.9 (all material went into solution). The solution was stirred with 36.0 g of charcoal for half an hour and the mixture was filtered 10: 1 through a Celite pad. The resulting solution was heated to 40 ° C, and the pH was adjusted to 1.8 by addition of triethylamine. At this point crystals of chlorocefadroxil monohydrate began to form without the addition of inoculum. The mixture was stirred at 40 ° C for half an hour. The pH of the mixture was then adjusted to 4.0 using triethylamine and the suspension was stirred for an additional 2 hours at 5 ° C. The crystalline chlorocefadroxil monohydrate was collected, washed three times with water and dried at 45 ° C to obtain 295.5 g of the title product. H2 O (KF) = 3.74%. The IR spectrum was essentially as shown in Figure 1 and was identical to that obtained for the sample prepared according to Example I.

8403670

Claims (6)

5 SM 39 10 ff 5.25 7 7 4 * 76 5i 8 4 * 56 29 9 4: * 48 12. : tO "4.32 39 15 tt" 4 * 02: 82. : ^ / 'ïZ'. . ... 47 "12 '2.87' .....’ * ™ 52 ...... "* ·. 14 3 * 76 32 15 '3 * 52 36 20 16 3.28 30 17 2 * 07 23 18 2 * 98 * 10 15 2.8T 13 20 2.81 21 25 21 2.72 19 22 2.69 46 22 2.63 15 24 2.53 8 25 2.50 9 '30 26 2.44 13 27 2.31 21 28 2.25' 10 8403 670 - 22 - * i Λ * V »29 * 2.19 9 3Q 2.14 g 31.09 g 2 · Guide to the. preparation of crystalline 7 -dc <-amino-c <~ 5 (3-chToro-4-hydroxypheny-Daceetami doV-3-methyl-3-cephem-4-carboxylic acid monohydrate which essentially has the following X-ray diffraction properties line low distance d (A) relative intensity t 8.52 100 1.0 2 7, Q2 23. 3 5.62 56 4 6.42 71 5 '5.47 32 6 5.25 7 15 7' 4.75 51; ; ·. 2 4, ea · 22 Γ; "'. 9r'." V · '4.42 ™ ..' / · /. \ V ;; tr '' - .. 3 ^ ...,., .rr '' 4.03 ”* .. 82 \ .. 20 12 3-, 95 & 12 2.87 52 14. 2.7a 32 15 3.52 36 16 3.28 30 25 17. 2.07 23 18. 2.98 10: 19- 2.87 13- 20 2.81 21 21 2.72 19 30 22 2.69- 46 22 2.62 15 24 2.53 8 25 2.50 9 26 2.44 13 35 27 2.21 21 8403570 * n - 23 - 28 2.25 10 29 2.19 9 30 2.14 6 31 2.09 6 5 which comprises Ca) the siteration of 7-aminodesacetoxycephalosporanic acid in an inert, irr essentially . aprotiscft anhydrous solvent; (ij) aylation of the silylated 7-amino-desacetoxycephalosporanic acid thus produced with D (<-amino-amino-(3-chloro-4-hydroxy-phenyl) -acetyl chloride hydrochloride in an inert, substantially aqueous j. aprotic solvent in the presence of an acid acceptor Cc) splitting off any Siyl groups from the acylation product by hydrolysis or alcoholysis and Cd) forming the desired monohydrate product by a me-T5. method selected from Ct) irr upwardly adjusting the ptf of the solution from step Cc) 5 in the presence of. excess of dimethylic amide or acetonitrile to dimethyformamide or acetonitrile. of 7'-CO - <- amina-oc- (3-chloro-4-hydroxy-phenyl) -acetami- to form 28-d-methyl-3-cephem-4-carphonic acid by dissolving the solvate in acidified water or a mixture of acidified water and acetonitrile, and. upwardly adjusting the ptf of the acidified solution to precipitate the desired crystalline monohydrate; 29 * (2) adjusting the pH of the solution from step (c) in the presence of excess dimethylformamide or acetonitrile to increase the dimethylformamide or acetonitrile solvate of 7-QX-amina-oc- (3) chloro-4-hydroxyphenyl) acetami-do, form 2-3-mathyT-3 'cefinin 4-carboxylic acid and contacting it. solvate with water or a partial aqueous medium to precipitate the desired crystalline monohydrate; or (3) adjusting the pH of the solution from step (c) upwardly to 7- (D- ° <- anrino-3-chloro-4-hydroxyphenyl) -35 acetamido J'-3-methyl -3-cefem-4-carboxylic acid and contacting the acid with water or a partial aqueous medium to crystallize the desired monohydrate in 8403670 η * * ^ «Μ Ί9 - 24. * 2 * Process according to claim 2, wherein the silylation step (a) is carried out by reacting 7-aminodesacetoxycephalosporanic acid with a silylating agent selected from those of formulas 2 Z 3 4 and: 3 * wherein. R * R and -R represent hydrogen, halogen, (lower) alkyl, halogen- (lower) alkyl * phenyl, benzyl, toTyT or dimethylaminophenyl, 2. 3 4 where: at least one of the groups R, R and R other than halo geen ld none or hydrogen: R stands for (lower) alkyl; m is an integer 5 6 5 from% to t and X represents halogen: or -NR R, where R represents hydrogen or ff 9 Q-Clage) alkyl and R (lower) alkyl or the group SiR R R, 2. L · wherein R, R and R are as defined above * 4 * Process according to claim 3, wherein the silylating agent in TS step? Ca) trimethylchlorositane or hexamethyldisilazane is -5-5. The method of claim 2 * wherein disiTyl-7-amimodesacetoxy-cephalosporanic acid is formed in step (a) by at least two equivalents; Tents STYLING AGENT to be used, per mold 7-amino-desacetoxycephalo- ...... "sporic acid * _ ........" 2CT 5 * Process according to claim 2, wherein step (a) is carried out Silylate 7-amine nodesacetoxycephalosporanic acid with trimethylchlorosilane in a substantially anhydrous aprotised solvent in the presence of an acid acceptor * The method of claim 6, wherein the silylation step is conducted in a main room anhydrous methylene chloride solvent system in the presence of an acid acceptor comprising triethyl amine or a mixture of triethylamina and dimethyl aniline at a temperature of about 20 - 3d0C * 51 8 * Process according to claim 2, wherein step (a) is carried out by silylating 7-ami nodesacetoxycephalosporanic acid with hexamethyldisilazane in a substantially anhydrous aprotic solvent with external heating * The method of claim 8, wherein the silylation step is conducted in a substantially anhydrous methylene chloride solvent at reflux temperature. 8403670 4. *. - 25 - Λ 10 * Process- according to claim 2 * wherein acylation step (b) is carried out in a substantially anhydrous methylene chloride solvent system at a temperature in the range of about -10 ° C to + 10 ° C in the presence of an acid acceptor * selected from a tertiary amine base with a pKa of less than or equal to 7. TT * Process according to claim 10 * wherein the acid acceptor is dimethylaniline * t2 * Process according to claim 2 * wherein silyl groups in step (c) cleaved by treatment with water or a C 1 -alkanal or Ta a mixture thereof * 13 * Process according to claim 2.v wherein im trap (c) silyl groups are cleaved off by treatment with a C 4 -alkanoT * 14 * Process according to claim 2 *. wherein step (d) comprises (T) adjusting the pH of the solution TS from step Cc) upwards with triethylamine in the presence of. excess of dimethylformamide or acetonitrile until the dimethylformamide or acetonephthylsalvate of Q-ed-anrin-oc-C-chloro-4-hydroxy-phenyl-acetyl-amide-3-methyl-3-cephenHf-carboxylic acid precipitates out of solution ^ C2) dissolving the solvate in acidified water. and 2Q (3) adjusting the pH of the solution in an upward direction by adding triethy Tanrine'om. precipitate the desired crystalline mono-hydrate. Method according to claim 14, wherein the final pH adjusting step for forming. the desired crystalline monohydrate is carried out at a temperature of about 35-60 ° C. 15 * Process according to claim 14, wherein acetonitrile is added as an anti-solvent during the final pH adjustment step * 17 * Process according to claim 14 * where graft crystall and the desired 7- / TD-c < -amino-oc- (3-chloro-4-hydroxyphenyl) acetamido J-3-methyl-3-cephem-4-carboxylic acid monohydrate are added before or during the final pH adjustment step. Pharmaceutical composition * comprising a compound according to claim 1, together with an inert pharmaceutically acceptable carrier or thinner. 8403670-26 Ί β '' tr * T9v A method of treating mammals against diseases caused by gram-positive or gram-negative bacteria, which comprises administering to the subject host an effective antibacterial dose of the compound of claim 1 or of a pharmaceutical preparation according to claim 18. t / - 8403670