KR920001769B1 - A process for preparing chlorocefadroxil monohydrate - Google Patents

Abstract

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Description

Method for preparing chlorocepadoxyl monohydrate

Figure 1 shows the infrared spectral absorption characteristics of chlorocepadoxyl monohydrate (KBr pellets) obtained according to the present invention.

The present invention relates to crystalline cephalosporin monohydrate having general use properties as an antimicrobial agent and to pharmaceutical compositions for the treatment of bacterial infections, in particular by oral administration.

7- [D-α-amino acids-α- (3-chloro-4-hydroxyphenyl) acetamido] -3-methyl-3-cepem-4-carboxylic acid cephalosporin compounds are described in US Pat. It is. This compound is generally referred to as chlorocepadoxyl as follows and has the following structural formula.

Chlorocepadroxyl has a broad spectrum antimicrobial effect against diseases caused by a wide variety of Gram-positive and Gram-negative bacteria, and is particularly useful as an oral cephalosporin antimicrobial agent.

U.S. Pat.No.3489751 discloses the amino protective derivatives of 7-aminodesacetoxycephalosporinic acid (7-ADCA) and D (-)-α-amino-α- (3-chloro-4-hydroxyphenyl) acetic acid. For the preparation of chlorocepadroxyl by acylation. Various aminoprotective acylating agents are described and the t-BOC method as high yields are obtained with D-(-)-α- (3-chloro-4-hydroxyphenyl) -α- (t-butoxycarbonylamino) acetic acid. It is called. However, the yield of this method is not as high as required for commercial production and the drugs used in the t-BOC method are too expensive.

U.S. Pat.No. 3,85,741 describes that acylated mixed anhydrides of 7-ADCA and D-(-)-α-amino-α- (3-chloro-4-hydroxyphenyl) glycine result in the formation of chlorocepadroxyl. And the latter α-amino group is combined with β-keto compounds such as methyl acetoacetate. This method has some obvious achievements over the t-BOC method, but it is not yet sufficient as a commercial production method. The patent also provides crystalline dimethyl of chlorosepadoxyl containing 1.5 moles of dimethylformamide per mole of chlorosepadoxyl. Formamide solvates are described. This dimethylformamide solvate is slurried in boiling methanol until the solvate dissociates and a suspension is formed which is then cooled to give the pure product of chlorocepadroxyl. However, the chlorocepadoxyl produced by this method is in the form of crystalline hydrates.

U. S. Patent No. 3781282 discloses chlorosepadoxyl in Example 7 by acidifying and dissolving solvate in water and neutralizing with triethylamine. The data do not even indicate that the chlorosepadoxyl product is in crystalline monohydrate form or crystalline form.

U.S. Pat.No. 4160863 discloses 7- [D-α-amino-α- (P-hydroxyphenyl) acetamido] -3- which produces chlorocepadoxyl monohydrate in a manner similar to that described and claimed herein. The crystalline monohydrate of methyl-3-cepem-4-carboxylic acid (also referred to as cephdoxy) is described.

In view of the many significant improvements of chlorocepadroxyl, there is a need for a commercially useful process for preparing this antibiotic with higher yields and lower production costs than that obtained by prior art processes. Furthermore, there is a need for obtaining chlorocepadroxyl in a stable crystalline form, such as a crystalline hydrate in which antibiotics can be produced, for example, as a pharmaceutical composition suitable for antibacterial use.

The present invention provides a novel chlorocepadoxyl crystalline monohydrate and a process for preparing the monohydrate. It also provides an improved acylation process for the preparation of chlorocepadroxyl, which is produced with better yields and lower production costs compared to the prior art.

The present invention, on the one hand, presents an advanced process for the preparation of chlorocepadoxyl or a pharmaceutically acceptable salt thereof, which process comprises: (a) inactivating 7-aminodes acetoxy cephalosporranic acid and Silylation in a substantially anhydrous neutral solvent, and (b) the silylated 7-aminodes acetoxy cephalosporranic acid so produced is D-(-)-α-amino-α- (3-chloro-4 Acylation of the hydroxyphenyl) acetyl chloride hydrochloride in an inert anhydrous neutral solvent in the presence of an acid acceptor, (c) the silyl group of the acylation product by hydrolysis or alcohol decomposition, and (d) the desired cephalo Recovery of sporanic acid or a pharmaceutically acceptable salt thereof.

Pharmaceutically acceptable salts relating to the above include, for example, (1) non-toxic pharmaceutically acceptable salts of acidic carboxylic acid groups such as sodium, potassium, calcium, aluminum and ammonium salts and tri (lower) alkylamines, procaine, dibenzylamine , N-benzyl-beta-phenethylamine, 1-ephenamine, N, N'-dibenzyl ethylenediamine dihydro abiethylamine, N, N-bisdihydroabiethylethylene diami. Amines used in the form of non-toxic substituted ammonium salts and salts of carbon benzyl-phenylsilin with amines such as N- (lower) alkylpiperidine such as N-ethyl piperidine. (2) a) Inorganic acid addition salts such as hydrochloric acid addition salts, bromic acid addition salts, iodic acid addition salts, sulfates, sulfamate, sulfonates, phosphates, and the like. b) addition of organic acids such as maleate, acetate, citrate, tartarate, oxalate, succinate, benzoate, fumarate, succinate, mandelate, ascorbate, β-naphthalenesulfonate and P-toluenesulfonate Non-toxic pharmaceutically acceptable acid addition salts such as salts (ie salts of basic nitrogen). As used herein, "(lower) alkyl" refers to a linear and branched saturated hydrocarbon group having 1 to 10 carbon atoms.

In this process, 7-ADCA is silylated by first reacting with a silicide in an inert, anhydrous neutral solvent.

Suitable solvents for the silylation reaction are inert anhydrous solvents such as methylene chloride, tetra hydrofuran, chloroform, terachloroethane, nitromethane benzene and diethyl ether, with a preferred solvent being methylene chloride.

Silicing agents useful in such processes are technically described (e.g., U.S. Pat.Nos. 3,654,266; 3,575,970; 3,499,909; 3,349,622; 3,595,855; 3,249,622; 1,008,468), and any known silylating agent may be used, but it is preferable to use a medicine selected from those of the following structural formulas.

Wherein R ² , R ³ and R ⁴ are hydrogen, halogen, (lower) alkyl, halo (lower) alkyl, phenyl, benzyl, tolyl or dimethylamino phenyl and at least one R ² , R3 and R ⁴ group is Other than halogen or hydrogen; R ¹ is (lower) alkyl; m is a number from 1 to 2, X is halogen or,

Where R5 is hydrogen or (lower) alkyl and R6 is (lower) alkyl or R2, R3 and R4 as defined above

Examples of suitable silylating agents include trimethylchlorosilane, hexamethyldisilazane, triethylchlorosilane, methyltrichlorosilane, dimethyldichlorosilane, triethylbromosilane, tri-n-propylchlorosilane, bromomethyldimethylchlorosilane, Tri-n-butylchlorosilane, methyldiethylchlorosilane, dimethylethylchlorosilane, phenyldimethylbromosilane, benzylmethylethylchlorosilane, phenylethylmethylchlorosilane, triphenylchlorosilane, triphenylfluorosilane, tri-O Tolylchlorosilane, tri-P-dimethylaminophenylchlorosilane, N-ethyltriethylsilylamine, hexaethyldisilazane, triphenylsilylamine, tri-n-propyl-silamine, tetraethyldimethyldisilazane, Tetramethyldiethyldisilazane, tetramethyldiphenyldisilazane, hexaphenyldisilazane, hexa-P-tolyldisilazane and the like. Other suitable silylating agents include hexaalkylcyclotrisilazane or octaalkylcyclotetrasilazane and silylamides such as trialkylsilylacetamide and bis-trialkylsilylacetamide and silyluraides. Most suitable silylating agents are trimethylchlorosilane and hexamethyldisilazane and the like.

When used as a silyl halide silylating agent such as, for example, trimethylchlorosilane, the silylation step can be carried out using a suitable acid (halogen) such as a nitrogen base or propylene oxide such as triethylamine, trimethylamine, dimethylaniline, quinoline, lutidine or pyridine. Hydrogen) in the presence of an inert, substantially anhydride, neutral solvent. As the acid acceptor, propylene oxide, triethylamine or a mixture of triethylamine and dimethylaniline is suitable.

For example, when a silazane such as hexamethyldisilazane is adopted, the silylation step is usually carried out by heating the silazane and 7-ADCA to distill off the ammonia or amine derivative formed as a reaction byproduct.

In preparing the silylated 7-ADCA in this process, one or two molar equivalents of silylating agent per mole of 7-ADCA can theoretically be used to obtain mono or dissilylated 7-ADCA or mixtures thereof. Thus, when 7-ADCA reacts with about 1 equivalent of silylating agent, mono-silylated 7-ADCA is produced. When trimethyl chlorosilane or hexamethyl silazane is used, for example, the product has the following structural formula.

Disilyl derivatives of 7-ADCA are prepared using at least 2 equivalents of silylating agent per mole of 7-ADCA in the silylation step. Preferably, when trimethylchlorosilane or hexamethyldisilazane is used, the silylated 7-ADCA is produced having the following structural formula.

The silylation step is carried out over a wide temperature range, for example from room temperature to the reflux temperature of the solvent system. In general with silyl halides good results are obtained at room temperature (20-30 ° C.) and at high temperatures such as reflux when silazanes are generally less active.

The monona or silylated 7-ADCA or mixtures thereof can be converted to D-(-)-α-amino-α- (3-chloro-4-hydroxyphenyl) acetyl chloride hydrochloride (preferably in the form of a dioxane solvate Acylated to generate the silylated chlorosepadoxyl intermediate in situ. If any silyl groups remain after acylation, they are removed by hydrolysis or alcohol degradation, for example, by neutralization to the isoelectric point at which chlorocepadroxi precipitates in solution, thereby removing the desired chlorocepadoxyl end product from the reaction intermediate. Recover.

The solvent used for the acylation of the silylation 7-ADCA has been defined above in connection with the silylation step (a).

The preferred temperature range for the acylation step is about -20 ° C to about 70 ° C. This temperature is not critical but it is preferred to use a temperature that is not higher or lower than the temperature within the desired limits. Most preferred acylation temperature is between about -10 ° C and +10 ° C.

7) 3급 아민을 사용하므로서 얻어진다. 바람직하기로는 예를 들면 디메틸 아닐린의 염산염과 같은 약한 3급 아민의 무기산염과 혼합사용하므로서 약간 과잉의 아민을 불활성화시키는 것이다(예를 들면 미국특허 제3,678,037호를 참조할 것).The acylation process is carried out in the presence of the same or different acid acceptor as employed in the preparation of the silylated 7-ADCA. Best results are weaker (ie PK _a such as dimethyl aniline, pyridine or quinoline).

7) Obtained by using tertiary amines. Preferably, a slight excess of the amine is inactivated by mixing with an inorganic acid salt of a weak tertiary amine, such as hydrochloride salt of dimethyl aniline, for example (see US Pat. No. 3,678,037).

Regardless of the molar ratio or the reactants used, it is preferred that about 1 mole of acylating agent per mole of silylated 7-ADCA use slightly excess moles in order to obtain maximum yield in the acylation step.

The silylated chlorocepadoxyl acylation product undergoes hydrolysis or alcohol digestion to remove the silyl protecting group. The silylated intermediates are then hydrolyzed by the alcohol degradation by addition of water or suitable alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol. Also mixtures of water and lower alkanols (C ₁ -C ₄ ) may be used in the segmentation step.

Chlorocepadroxyl is recovered from the reaction solution by conventional methods applied to the isomerization of similar cephalosporins. The product may be recovered as a heavy component by raising the pH of the reaction mixture until a desired acid precipitate is produced from the solution. Preferred non-aqueous amine bases are those such as triethylamine. In the free acid form, chlorocepadoxyl may be substituted with pharmaceutically acceptable carboxylic acids or may be acid addition salts by reaction with a suitable base or acid.

Preferred specific examples of the present invention include silicidation of 7-aminodes acetoxy cephalosporanic acid by heating it externally at reflux temperature of the solvent in a substantially anhydrous neutral solvent such as methylene chloride at hexamethyldisilazane. At this position, the disilylated 7-ADCA of the structure

7를 가지는 3급 아민염기와 같은 산수용체의 존재하에서 바람직하기는 디옥산 용매화물의 형태로 D-(-)-α-아미노-α-(3-클로로-4-하이드록시페닐)아세틸로 클로라이드 염산염과 직접 반응시켜 아실화한다. 아실화한 다음 실릴화 클로로세파드록실 아실화 생성물을 메탄올 또는 n-부탄올과 같은 C₁-C₄알칸올로 처리하여 실릴그룹을 분절시키고 트리에틸아민과 같은 3급 아민염기와 함께 등전점까지 중화하므로서 침전물이 생기게 하여 생성물을 회수한다(원하면 임의로 여과 과정후에).The disilylated 7-ADCA is then in the same solution (preferably at -10 ° to + 10 ° C.), preferably PK _a such as dimethylaniline, pyridine or quinoline.

In the presence of an acid acceptor such as a tertiary amine base having 7 is preferably D-(-)-α-amino-α- (3-chloro-4-hydroxyphenyl) acetyl chloride in the form of a dioxane solvate Acylated by direct reaction with hydrochloride. After acylation, the silylated chlorosepadoxyl acylation product is treated with C ₁ -C ₄ alkanols such as methanol or n-butanol to segment the silyl group and neutralize to isoelectric point with a tertiary amine base such as triethylamine. The precipitate is thus formed to recover the product (optionally after filtration if desired).

The use of hexamethyldisilazane as a silylating agent in which useful silyl halides such as trimethylchlorosilane are used excludes the formation of acid halide by-products and the need for the use of acid acceptors in the silylation step. Although not present in the reaction medium of these acid acceptors, less insoluble salts, such as, for example, triethylamine-HCI, are present to prevent later recovery steps. Hence, the use of hexamethyldiborazane yields higher yields of chlorocepadoxyl than by conventional trimethylchlorosilaneylation.

Another aspect of the present invention is to provide a crystalline monohydrate form of the novel chlorocepadoxyl which is known to be a stable and useful form of cephalosporin antibiotic which is particularly suitable for pharmaceutical composition.

The crystalline chlorocepadoxyl monohydrate of the present invention exhibits essentially the following X-ray powder diffraction properties.

The measurement of this X-ray diffraction characteristic is as follows.

An X-ray powder automatic diffractometer (Philips PW 1050-70-sourse Cuk ^- α (1,54 / 78 kPa)) was used for the 2 cm 2 piece specimen of thickness 1mm. Temperature +22 degreeC.

Mixing very small amounts of crystalline sodium fluoride with a few samples results in internal calibration. Pure NaF samples were also processed for the same purpose.

The films were decoded with a Norelco Debye-Scherrer film decoder that records the location of the diffraction ring to near 0.05 mm. This data was modified for film shrinkage and the lattice spacings (d-spacings) were calculated from the modified data. All calculations used a computer program (X-ray by p.Zugenmaier). The accuracy of the resulting d-spacing data was -1%,

Intensity records of all films were obtained using Joyce-Loeble Mark IIIC recording microphone rodentometa (scanning ratio 5: 1, 0.1 O.D. Wedge).

Relative intensities on scales 1-100 were represented by all recognizable diffraction rings using the modified peak intensity for background decoding.

The sample of the crystalline monohydrate product was subjected to infrared analysis and the spectrum (in KBr plates) of the sample was shown in FIG.

The present invention also includes a method for preparing the crystalline chlorocepadoxyl monohydrate described above, the process is as follows.

(a) silylating 7-aminodes acetoxy cephalosporranic acid in an inert substantially anhydrous neutral solvent, and (b) silylated 7-aminodes acetoxy cephalosporranic acid thus produced inert neutral Acylated with D-(-)-α-amino-α- (3-chloro-4-hydroxyphenyl) acetyl chloride hydrochloride in a solvent, (c) fragmenting the acylation product by hydrolysis or alcohol decomposition, (d) The desired monohydrate product is obtained by the method selected below.

(1) raising the pH of the solution from step (c) in the presence of excess dimethylformamide or acetonitrile to increase 7- [D-α-amino-α- (3-chloro-4-hydroxyphenyl) acet To form dimethylformamide or acetonitrile solvate of amido] -3-methyl-3-cepem-4-carboxylic acid, dissolving the solvate in aerated water or a mixture of acidates and acetonitrile and acidifying The pH of the solution is adjusted up to precipitate the desired crystalline mono-hydrate.

(2) raising the pH of the solution from step (c) in the presence of excess dimethylformamide or acetonitrile to obtain 7- [D-α-amino-α- (3-chloro-4-hydroxyphenyl) acet Form dimethylformamide or acetnatrile solvate of amido] -3-methyl-3-cepem-4-carboxylic acid and contact the solvate with water or a partially water soluble medium to precipitate the desired crystalline monohydrate. .

(3) The pH of the solution from step (c) was adjusted upward to adjust 7- [D-α-amino-α- (3-chloro-4-hydroxyphenyl) acetamido] -3-methyl-3-cepem. The 4-carboxylic acid is formed and contacted with this acid or water or a partially water soluble medium to crystallize the desired monohydrate.

The preparation of crystalline chlorocepadoxyl monohydrate based on the above process involves the silylation, acylation and silyl group removal steps described above in connection with the improved acylation process for the preparation of chlorocepadroxyl. Is carried out as follows.

The desired crystalline monohydrate can be prepared according to any one of several alternative routes.

In one way, a solution of chlorosepadoxyl, subjected to the solubilization step, in the presence of excess dimethylformamide or acetonitrile, e.g., until precipitated from a solution of dimethylformamide or acetonitrile solvate of chlorosepadoxyl, eg For example, neutralized with a tertiary amine base such as triethylamine. This solvate is collected and washed (preferably not dried) to obtain crystalline material. The chlorocepadoxyl dimethylformamide or acetonitrile solvate is solvated in acidic water or a mixture of acidic water and acetonitrile and converted to the desired chlorocepadoxyl monohydrate, followed by neutralization of the acidified solution to monohydrate. Precipitate the product.

Dissolution of chlorocepadoxyl dimethylformamide or acetonitrile solvate takes place in the vicinity of PH 2-2.4, which may be accomplished by addition of an inorganic acid such as HCI to water or a mixture of acetonitrile-water and solvate. In this process step solid impurities are removed by treating the acidified solution with activated carbon and / or a filtering aid followed by filtration.

The acidified solution is warmed at about 35-60 ° C. and neutralized by addition of a suitable base such as an aliphatic tertiary amine such as triethylamine with stirring, raising the solution PH to the point where the chlorocepadoxyl monohydrate crystallizes from the solution. .

Preferably, acetonitrile is added to the solution during neutralization as an antisolvent (precipitant) to achieve maximum recovery of the desired product. Yield is also improved by placing the desired monohydrate seed crystals in solution before and / or during the final neutralization step.

Another method for producing crystalline chlorocepadoxyl monohydrate in this process is to prepare chlorocepadoxyl dimethylformamide or acetonitrile solvate as described above, and then the solvate is obtained from the solvent system. Contact with water or an aqueous medium until

Add chlorocepadoxyl dimethylformamide or acetonitrile solvate to water or water and organic solvents such as acetonitrile, acetone C ₁ -C ₅ alkanols (methanol, ethanol, n-propanol, isopropanol, n-butanol, amyl alcohol, etc.) Or in a mixture with the mixture. The use of a partially water soluble organic solvent system is preferred because the organic solvent contains many impurities, resulting in a purer final product.

When using a mixture of water and organic solvent, the proportion of solvent components varies over a wide range without severe side effects.

Preferred solvent ratios for some partially water soluble solvent systems are as follows.

Water: Acetone (1: 3) (Volume Ratio)

Water: isopropanol (1: 3) (volume ratio)

Water: acetonitrile (1: 3) (volume ratio)

Water: n-butanol (1: 3) (volume ratio)

N-butanol (preferably after solubilization of the solvate) is added in the water-acetonitrile system so that the solvent system becomes a single homogeneous phase during crystallization. Preferably, sufficient n-butanol is added to this crystallization system so that the final solvent ratio is water-acetonitrile: n-butanol (1: 2: 1) (volume ratio).

The concentration of solvate in the water soluble or partially water soluble crystallization medium is not an important problem. However, the best yields are obtained at concentrations of about 400 to 8000 grams per liter of solution. The solvate is preferably added to the solvent system gradually with stirring depending on the amount of solvate used, ie, for several minutes to several hours. Crystallization is carried out over a wide temperature range, ie from room temperature to the boiling point of the solvent system, but good results are obtained in the temperature range of about 35-60 ° C., most preferably 40-45 ° C.

The yield of monohydrate is improved by putting seed crystals of chlorocepadoxyl monohydrate in a solution of dimethylformamide or acetonitrile solvate.

Other methods of preparing the desired monohydrate in the above process include the following.

(1) preparing a silylated chlorosepadoxyl as described above, and hydrolyzing or alcoholing to segment and remove the silyl protecting groups, and (2) the solution from the segmentation step is suitable as an aliphatic tertiary amine such as triethylamine. Neutralize base, preferably up to the isoelectric point of chlorosepadoxyl (-PH 5.7-5.8) to precipitate impure or primary chlorosepadoxyl, and (3) dispose of the impure chlorocepadoxyl with water or water. Chloro from solution in a mixture with an organic solvent, preferably acetonitrile, acetone, C ₁ -C ₅ alkanols (e.g. methanol, ethanol, n-propanol, isopropanol, n-butanol, amyl alcohol, etc.) or mixtures thereof. Contact is made until the cephadoxyl monohydrate crystallizes.

In order to neutralize the chlorocepadoxyl solution to form impure or primary chlorocepadroxyl (amorphous), it is usually carried out by slowly adding a base to the stirred solution at room temperature. Impure chlorocepadoxyl is then crystallized in the same manner as described above for chlorocepadoxyl dimethylformamide or acetonitrile solvate. As in the case of dimethyl formamide or acetonitrile solvate crystallization processes, the most suitable solvent system is water: acetonitrile: n-butanol (1: 2: 1) (volume ratio).

The most preferred embodiment of the present invention is to prepare crystalline chlorocepadoxy monohydrate from one of chlorocepadoxyl dimethylformamide or acetonitrile solvate or impure (primary) chlorocepadoxyl by the following steps. It is a process to do it.

(a) Dimethyl formamide or acetonitrile solvate of 7- [D-α-amino-α- (3-chloro-4-hydroxyphenyl) acetamido] -3-methyl-3-cepem-4-carboxylic acid Is dissolved in acidic acid or a mixture of acidified water and acetonitrile, and the pH of the acidified solution is adjusted upward until the desired monohydrate crystallizes from the solution, or (b) 7- [D-α-amino-α -(3-chloro-4-hydroxyphenyl) acetamido] -3-methyl-3-cepem-4-carboxylic acid or its dimethyl formamide or acetonitrile solvate in contact with water or a partially water-soluble medium to Crystallize the monohydrate.

Dimethylformamide or acetonitrile solvates and chlorocepadoxyl starting materials used in the process are prepared by this or other known methods, such as those disclosed in US Pat. Nos. 3,489,751 and 3,985,741.

Preferred conditions for the preparation of chlorocepadoxy monohydrate in the process are as described above in the overall reaction system described above, ie, silylation, acylation and monohydrate preparation steps.

By adopting the above preferred reaction conditions, the present invention enables the preparation of primary chlorocepadoxyl in excellent yield and converts the chlorocepadoxyl or its dimethylformamide or acetonitrile solvate to chlorocepadoxy monohydrate. The active yield in the case is up to about 85%.

The crystalline monohydrate prepared by the above process is recovered in a conventional manner such as filtration, washed and dried to prepare a pharmaceutical form for use in antibiotic therapy to treat various bacterial diseases. Examples of formulation forms (eg, capsules or tablets) doses, modes of administration, and pharmaceutical formulations of chlorocepadoxy monohydrate are described in US Pat. Nos. 3489751 and 3985741 for the amorphous form of chlorocepadroxyl.

The present invention encompasses pharmaceutical compositions containing crystalline chlorocepadoxyl monohydrate and suitable inert liquid-soluble carriers or diluents, with pharmaceutical compositions for oral administration being most preferred.

The present invention further encompasses methods for treating diseases caused by Gram-positive or Gram-negative bacteria of humans or other animal species (e.g., mammals), which methods include crystalline chlorocepadroxyl monohydrate or a medicament thereof. Administering an effective dose of the composition to the parasitic host.

In the following examples to illustrate the invention all temperatures are in degrees Celsius and 7-aminodesacetoxycephadrosporanic acid is abbreviated 7-ADCA, triethylamine is TEA, dimethylaniline is DMA and dimethyl formamide is abbreviated DMF. .

[Production of Starting Material]

[Manufacture 1]

Preparation of D (-)-chloro-3-hydroxy-4-phenylglycine

10 Kg of D (-)-P-hydroxyphenylglycine is suspended in 200 liters of acetic acid and warmed to 60 占 폚. Hydrochlorate is formed by bubbling (bubbling) about 6.25 Kg of hydrochloric acid. The solution obtained by adding a solution of 8.1 Kg of sulfuryl chloride to 20 liters of acetic acid is maintained at 65-70 ° C. for 90 minutes. The solution is defoamed at low pressure and stirred for 1 night, cooled to 20 ° C. The solids are collected and washed with a second suspension in methylene chloride. Dry in vacuo 40 ° C.

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

This hydrochlorate is suspended in 130 liters of water and the mixture is stirred at 40 ° C for 30 minutes. Cool to 20 ° C. and adjust to pH 1.4 by adding 400 g / liter of soda solution (about 3 liters). After stirring and filtering for 2 hours at + 5 ° C, the solid was washed three times with distilled water (the mother liquor was free of chlorine ions), washed once with about 15 liter of acetone and dried at 60 ° C. This was pulverized with a Frewitt apparatus and dried to H ₂ O (KF) ≦ 0.1%. Weight of obtained chloro-3-hydroxy-4-phenylglycine = 8.1Kg (yield 67%)

[Manufacture 2]

Preparation of D (-)-chloro-3-hydroxy-4-phenylglycinechloride hydrochloride

[process]

410 ml of anhydrous dioxane (molecular sieve, KF <0.05%, dried), followed by 50 g of anhydrous D (-) chloro-3-hydroxy-4-phenylglycine (dried at 5mmHg / 80 °, constant weight KF <0.1 % And 200 cc sieve) into a 1 liter reactor. Pass 60.0 g of phosgene in agitation for 20 minutes (the initial temperature 20 ° C. rises to 35 ° C. while the solid is being deformed (the stirring becomes more difficult) and then the temperature is lowered after passing the phosgene). The mixture is heated to 70 ° C. when the required amount of phosgene is added. When the temperature reaches 60-65 ° C., the crystallized mass passes through the solution. It is heated at 70 ° C. for 10 minutes, then the heating is stopped and the solution is concentrated to a 250 ml volume without external heating (eliminating excess phosgene) (fixing the temperature to 25 ° C. at the end of the concentration). The solution is cooled at 8-10 and passed through hydrochloric acid as quickly as possible to maintain the temperature at 28-30 ° C. (The amount of hydrochloric acid added is a very large excess; the reaction is almost stoichiometric until 2 moles have passed. Exothermic, then the temperature is lowered and then the temperature is maintained at 20-25 ° C.).

When almost half of the hydrochloric acid has passed, the solution gives off crystal seed and is stirred overnight at 20 ° C. This chloride hydrochlorate was filtered the next day while preventing contact with the atmosphere. Wash once with dioxane anhydride and twice with anhydrous methylene chloride. Vacuum drying at ambient temperature yields 73 g (= 85%) of the title product as mono-dioxane solvate.

Example 1

Chlorocepadoxy monohydrate

A. Chlorocepadoxyl Acetonitrile Solvate

[process]

150 L of anhydrous methylene chloride (KF <0.1%) and 7.2 Kg of 7-ADCA were charged to a 500 L glass lined reactor. Agitated to add 9.01 TMCS and 4.35 L of DMA as suspension and 9.4 L of TEA in 15 minutes while maintaining the temperature at 20-25 ° C. The mixture is stirred at 20 ° C. for 1 hour and cooled to −10 ° C. Then 4.24 L of 376 g / L DMA.HC1 methylene chloride solution was added and 17 Kg of D (-) chloro-3-hydroxy-4-phenylglycinechloride hydrochloride dioxane solvate (purity 53.8%) was added to 10 parts in one hour. Add in portions (temperature maintained between -12 ° C and -8 ° C). The mixture is stirred at -10 [deg.] C. for 2 hours, then 3.4 liters of methanol are added for 10 minutes and 48 liters of tap water (with sufficient stirring). The mixture is stirred for 15 minutes (temperature 0 ° -5 ° C.) and adjusted to pH 2.3 by addition of TEA (9.0 L). The aqueous solution is separated and washed twice with 15 L of methylene chloride. Then 80 L of acetonitrile was added and TEA (5.0 L) was added to adjust pH to 5.0. Seeds are formed in the solution and stirred for 1 night at + 10 ° C. The solids are collected and 15 l of acetonitrile-water (8: 2) and 15 l of acetonitrile are dried and dried at 40 ° C. to give 11.0 Kg (74% yield from 7-ADCA) of the title product.

B. Purification reagents for chlorocepadoxyl acetonitrile solvates:

Chlorocepadoxyl acetonitrile solvate (Crude) 21.0 Kg

115 liters of tap water

33% HCI 5.2 liters

Charcoal 1.5K

250 liters of acetonitrile

8.7 liters of triethylamine (TEA)

Sufficient amount of Celite

[process]

The crude chlorocepadoxyl acetonitrile solvate (21 Kg) is stirred in 100 l of tap water and adjusted to pH 0.8-0.9 by adding 5.2 L of 33% HCI. 1.5 Kg of charcoal is added to the solution and the mixture is stirred for 30 minutes and filtered through a CELITE pad. The solution and wash water (10 L) are charged to a 250 L glasslining reactor. 200 L of acetonitrile is added and TEA (3.5 L) is adjusted to pH 2.5. Seeds develop in solution. Heat to 40-45 ° C. and adjust pH to 5.0 by adding TEA (5.2 L). The mixture is stirred at 40 ° C for 1 hour, cooled to 10 ° C, and stirred at 10 ° C for 1 night. The solid is collected and washed with 30 L acetonitrile-water (1: 2) and with 30 L acetonitrile. Drying at 40 ° C. yields 16.6 Kg (79%) of pure title product.

C. Chloro Sephaxyl Monohydrate

reagent

Chlorocepadroxyl acetonitrile solvate (purified) 6.85 Kg

73.0 liters of water

33 liters of 33% HCl

Charcoal 0.7Kg

2.8 liters of triethylamine (TEA)

Enough cide

[process]

The purified chlorocepadoxyl acetonitrile solvate (6.85 Kg) was stirred in 50 L of water, and 1.7 L of 33% HCI was added to pH 0.8-0.9. Charcoal (0.7 Kg) is added and the mixture is stirred for 30 minutes and filtered through a pad of celite. The solution and wash water (5 L) are transferred to a 100 L glasslining reactor and heated to 40 ° C. TEA (1.24 L) is added and adjusted to pH 1.6-1.8, the solution is seeded with chlorocepadoxyl monohydrate, the mixture is stirred at 40 ° C. for 1 h and adjusted to pH 4.0 by addition of TEA (1.56 L) do. The suspension is cooled to 20 ° C. and then stirred at + 5 ° C. for 2 hours. The solid is collected, washed three times with 6 L of water and dried at 40 ° C. to give 5.35 Kg (79%) of the title product.

Example 2

Chlorocepadoxyl Monohydrate (Preparation without Seeding) Purified chlorocepadoxyl acetonitrile solvate (352 g) is suspended in 2.8 L of water and added to 36% CH1 to pH 0.9. Material becomes a solution). The solution is stirred for 1 hour and half with 36.0 g of charcoal and the mixture is filtered through a pad of celite. The resulting solution is heated to 40 ° C. and adjusted to pH 0.8 by addition of triethylamine. At this point, crystals of chlorosepadoxyl monohydrate begin to form without seeding. The mixture is stirred at 40 ° C. for 1 hour and a half. Triethylamine is added to the mixture to adjust to pH 4.0. The suspensions are stirred for another 2 hours at 5 ° C. Crystalline chlorocepadoxyl monohydrate is collected, washed three times with water and dried at 45 ° C. to obtain 295.5 g of the title product. H ₂ O (KF) = 3.74%. The IR spectrum is substantially the same as in FIG. 1 and is consistent with that obtained in the sample prepared according to Example 1.

Claims (18)

(a) silylating 7-aminodesacetoxycephalosporanic acid in an inert, nearly anhydrous, aprotic solvent; (b) The silylated 7-aminodesacetoxycephalosporanic acid thus produced was subjected to D-(-)-α-amino-α- ( Acylating with 3-chloro-4-hydroxyphenyl) acetylhydrochloride; (c) degrading the silyl group of the acylation product by hydrolysis or alcoholic decomposition; (d) the pH of the solution obtained from step (c) is adjusted in the presence of excess dimethylformamide or acetonitrile to give 7- [D-α-amino-α- (3-chloro-4-hydroxyphenyl) acet Generating dimethylformamide or acetonitrile solvate of amido] -3-methyl-3-cepem-4-carboxylic acid; Characterized in that the solvate is dissolved in acidified water or a mixture of acidified water and acetonitrile and the pH of the acidified solution is adjusted to precipitate the desired crystalline monohydrate to produce the desired monohydrate product. Crystalline 7- [D-α-amino-α- (3-chloro-4-hydroxyphenyl) acetamido] -3-methyl-3-cepem- essentially showing the following X-ray diffraction characteristics How to prepare 4-carboxylic acid monohydrate:

The process according to claim 1, wherein the silylation step (a) is carried out by reacting 7-aminodesacetoxy cephalosporanic acid with a silylating agent selected from compounds of the general formula:

Wherein R ² , R ³ and R ⁴ are hydrogen, halogen, (lower) alkyl, halo (lower) alkyl, phenyl, benzyl, tolyl or dimethylaminophenyl and at least one of R ² , R ³ and R ⁴ groups Is not halogen or hydrogen; R ¹ is (lower) alkyl; m is an integer from 1 to 2; X is halogen or

ego; Wherein R ⁵ is hydrogen or (lower) alkyl and R ⁶ is (lower) alkyl or

(R ² , R ³ and R ⁴ are as defined above). The process of claim 2 wherein the silylating agent in step (a) is trimethylchlorosilane or hexamethyldisilazane A process according to claim 1, wherein the disilylated 7-aminodesacetoxycephalosporanic acid is prepared in step (a) using at least 2 equivalents of silylating agent per mole of 7-aminodesacetoxycephalosporranic acid. The process according to claim 1, wherein step (a) is carried out by silylating 7-aminodesacetoxycephalosporranic acid with trimethylchlorosilane in the presence of an acid acceptor in a substantially anhydrous aprotic solvent. 6. The process according to claim 5, wherein the silylation step is carried out in the presence of an acid acceptor consisting of triethylamine or a mixture of triethylamine and dimethylaniline at a temperature of about 20-30 [deg.] C. in an almost anhydrous methylene chloride solvent system. The process according to claim 1, wherein step (a) is carried out by silylating 7-aminodesacetoxycephalosporanic acid by external heating with hexamethyldisilazane in an almost anhydrous aprotic solvent. 8. The process of claim 7, wherein the silylation step is carried out at reflux temperature in a substantially anhydrous methylene chloride solvent. Under the method, the acylation step (b) a substantially anhydrous methylene chloride sex temperature of about -10 ℃ to 10 ℃ range from the solvent system to _a 1 PK

The process is carried out in the presence of an acid acceptor selected from tertiary amine bases having 7. The method of claim 9, wherein the acid acceptor is dimethylaniline. The process of claim 1 wherein in step (c) the silyl group is decomposed by treatment with water or C ₁ -C ₄ alkanols or mixtures thereof. The process of claim 1 wherein in step (c) the silyl group is decomposed by treatment with water or C ₁ -C ₄ alkanol. The process according to claim 1, wherein step (d) is carried out by adjusting the pH of the solution obtained from step (1) (c) with triethylamine in the presence of excess dimethylformamide or acetonitrile to obtain 7- [D-α-amino dimethylformamide or acetonitrile solvate of -α- (3-chloro-4-hydroxyphenyl) acetamido] -3-methyl-3-cepem-4-carboxylic acid is precipitated in solution; (2) dissolving the solvate in acidified water; (3) triethylamine is added to increase the pH of the solution to precipitate the desired crystalline monohydrate. The method of claim 13, wherein the final pH adjustment step of producing the desired crystalline monohydrate is carried out at a temperature of about 35 ° C. to 60 ° C. 15. The method of claim 13 wherein acetonitrile is added as an antisolvent during the final pH adjustment step. The seed of claim 13, wherein the desired 7- [D-α-amino-α- (3-chloro-4-hydroxyphenyl) acetamido] -3-methyl-3-cepem-4-carboxylic acid monohydrate (seed) A method of adding a crystal before or during the final pH adjustment step. The step (d) of claim 1, wherein the pH of the solution obtained from step (c) is adjusted in the presence of excess dimethylformamide or acetonitrile, thereby adjusting 7- [D-α-amino-α- (3-chloro- 4-hydroxyphenyl) acetamido] -3-methyl-3-cepem-4-carboxylic acid to form a dimethylformamide or acetonitrile solvate and contacting the solvate with water or a partially aqueous medium to give the desired crystallinity. Method of Precipitating Monohydrate. The step (d) of claim 1, wherein the pH of the solution obtained in step (c) is adjusted up to 7- [D-α-amino-α- (3-chloro-4-hydroxyphenyl) acetamido]- To form 3-methyl-3-cepem-4-carboxylic acid and contact the acid with water or partially aqueous medium to crystallize the desired monohydrate.

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