KR20040077356A - Novel process for preparing cefditoren pivoxil - Google Patents

Abstract

The present invention relates to a novel process for the preparation of ceftitorene coating chambers and to novel compounds as intermediates useful in the preparation of ceftitorene coating chambers.

The production method of the present invention is characterized in that the cedidiene coating chamber compound is obtained by reacting an ide compound produced from a halide compound as an intermediate with an aldehyde compound and a Bitich compound, and has higher purity and higher yield than a conventional process. It can be obtained with a ditorene coating chamber, which can replace the conventionally known low yield non-economic preparation.

Description

Novel process for preparing cefditoren pivoxil}

The present invention provides ceftitorene coating chamber of the general formula (I), pivaloyloxymethyl 7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetami FIG. 3 relates to a process for the preparation of the 3 (Z)-(4-methylthiazol-5-yl) vinyl-3-cepem-4-carboxylic acid ester compound and to novel compounds as intermediates useful in the preparation.

The following general formula is a cephem compound known under the general name cefditoren, which is 7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido ] -3 (Z)-(4-methylthiazol-5-yl) vinyl-3-cepem-4-carboxylic acid ( syn isomer , cis isomer ) (Japanese Patent US Patent No. 4503, US Pat. No. 4,839,350 and European Patent No. 0175610).

Cefditorene is an excellent cephalosphorin antibiotic, a low toxicity and very broad antimicrobial spectrum for the treatment of diseases caused by gram-positive bacteria or gram-negative bacteria. And prophylactic effects are known (Kenji, Sakagami et al .; J. Antibiotics , 8 , pp91047-1050, 1990). The superior antimicrobial activity of ceftitorene against gram negative bacteria is that the cephem ring and the 4-methylthiazole-5-yl group are cis on the 3-vinyl group carbon-carbon double bond of the ceftitorene molecule. It is related to what the ceftitorene compound has in a Z configuration which is bonded by) -coordination.

7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetami derived by esterifying the 4-carboxyl group of the ceftitorene compound with a pivaloyloxymethyl group FIG.]-3 (Z)-(4-Methylthiazol-5-yl) vinyl-3-cepem-4-carboxylic acid ( syn isomer , cis isomer ) compound, ie ceftito A prodrug known under the generic name cefditoren pivoxil, which is a pale yellow powdery material with a melting point of 127 ° C to 129 ° C (Merck Index, 12th edition, p317).

The ceftitorene coating chamber is not an antimicrobial agent on its own but can be administered orally in the digestive organs of a mammal. It is useful as a prodrug that can be converted.

3- (2-substituted-vinyl) -cephalosporin antibiotics, such as ceftitorene and ceftitorene covering yarns, generally indicate that their Z isomers are superior to the antibiotic properties of the E isomers (trans isomers). Known.

The 3- (2-substituted-vinyl) -cephalosporin antibiotics or their synthetic intermediates, including ceftitorene, can be prepared in a number of ways, and one of the available preparations of these antibiotics is Wittig ( There is a way to use the Wittig) reaction. In the process for the preparation of 3- (2-substituted-vinyl) cephalosporin antibiotics or their synthetic intermediates using the Wittig reaction, the reaction product always comprises a mixture of the Z isomer (cis isomer) and the E isomer (trans isomer). It is obtained in the form (Japanese Patent Publication No. 91-264590, US Patent No. 5,233,035, European Patent Application Publication No. 0175610A2, International Patent Application PCT / JP94 / 01618, European Patent Application Publication No. 0834965A1) Due to the low yield of the desired material, the separation process was not included, resulting in a totally efficient process.

For example, as shown in Scheme (1) below, 7-[(Z) -2-(aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- (Z) 7-β-phenylacetamido-3- [2- (4-methylthiazole- used for the synthesis of-(4-methylthiazol-5-yl) vinyl) -3-cepm-4-carboxylic acid P -methoxybenzyl ester of 5-yl) vinyl] -3-cef-4-carboxylic acid (1) was treated with sodium iodide in acetone to produce the corresponding 3-iodine methyl derivative (2) Is treated with triphenylphosphine to give triphenylphosphonium-iodine derivative (3), and the triphenylphosphonium-ioda in the presence of sodium bicarbonate in a heterogeneous reaction medium consisting of dichloromethane and water Yide compound (4) and 5-formyl-4-methylthiazole (5) were reacted at room temperature by Vitich 7-β-phenylacetamido-3- [2- (4-methylthiazole-5-yl ) Vinyl] -3-cepem-4-carboxylic acid-4-methoxybene The ester (6) it was produced.

In the above method, 7-β-phenylacetamido-3-[(triphenylphosphoranilidene) methyl] -3-cepem-4-carboxylic acid-4-methoxybenzyl ester (4) as an intermediate is Reaction with 5-formyl-4-methylthiazole (5) by Wittich reaction to 7-β-phenylacetamido-3- [2- (4-methylthiazol-5-yl) vinyl] -3 Cefem-4-carboxylic acid-4-methoxybenzyl ester (6) is produced, the reaction product of which Z isomer (cis isomer) and E isomer (trans isomer) is obtained in a mixture of 4.7: 1. It is also described that the mixtures are difficult to separate from each other by column chromatography (Kenji, Sakagami et al .; J. Antibiotics , 8 , pp 1047-1050, 1990). Therefore, the yield of the desired Z isomer which can be finally obtained was inevitably lowered.

In addition, the manufacturing method of the following reaction formula (2) is a manufacturing method disclosed in Japanese Patent Application Laid-Open No. 95-188250 or its corresponding US Patent No. 5,616,703 and European Patent Application Publication No. 658558A1, and 7-amino-3- [ Reaction product (5) obtained as 2- (4-methylthiazol-5-yl) vinyl] -3-cefe-4-carboxylic acid or derivatives thereof is described as being a mixture of the Z and E isomers, Japanese Patent Application Laid-Open No. 95-188250 discloses a Z / E mixture of 7-amino-3- [2- (4-methylthiazol-5-yl) vinyl] -3-cefe-4-carboxylic acid with an amine salt. The method for isolating the Z isomer is described by converting to and performing a recrystallization method on the obtained amine salt, and the Z / E mixture can be obtained by removing the Z isomer as low as possible on the chromatography. Yes is described. In fact, the yield of the target compound by this reaction process is very low at 31%.

In addition, International Patent Application No. PCT / EP 92/02965 describes the content of the E isomer by using the solubility difference between the Z and E isomers by converting all protecting group-free cefe compounds into the form of hydrochloride, alkali salt, or amine salt. A method of reducing is disclosed, which has the advantage that crystals are easily precipitated and can be easily separated and obtained through filtration, but the amount of E isomers removed is inefficient and overall yield is low. Loss of cost is a problem in that the cost of the loss of the ceftitorene compound produced through several steps.

In synthesizing ceftitorene, the reaction of introducing a vinyl group into the C-3 position of the cefem compound is usually carried out through a Wittich reaction, wherein the Z and E isomers are stericized simultaneously due to the double bond of the vinyl group. Since the conventional method for preparing 3- (2-substituted-vinyl) -cephalosporin using the Wittich reaction, the selectivity of Z isomer generation is not as good as that of the E isomer, and to isolate the Z isomer from the E isomer. There are several drawbacks such as additional complicated operation, and unsatisfactory practical yield of Z isomers. In addition, the conventional methods mostly use similar methylene chloride or methylene chloride-water as reaction medium. It was a conventional manufacturing method of.

Thus, 3- (2-substituted-vinyl) -cephalosporin, which makes it possible to obtain the desired Z isomer in high yield among 3- (2-substituted-vinyl) -cephalosporin compounds made by the Wittich reaction. There is a need for new preparations of compounds.

The inventor of the present invention has studied an efficient, simple and economical process for producing ceftitorene, which eliminates the disadvantages of the above known methods. The reaction was found to complete the present invention by discovering that the Z isomer of the ceftitorene coating chamber as the target compound can be produced in high purity and high yield.

It is an object of the present invention to provide a novel process for the preparation of ceftitorene coating threads useful as cephalosporin antibiotics and novel compounds as intermediates useful for the preparation of these compounds.

In order to achieve the above object, the present invention is a first step of reacting a halide compound of the general formula (II) with triphenylphosphine in the presence of a metal salt to obtain a phosphonium salt of the general formula (III); A second step of reacting the phosphonium salt with a base to obtain an lide compound of the following general formula (IV); It provides a method for producing a ceftitorene coating chamber of the general formula (I) characterized in that the third step of the step of reacting the yilide compound with an aldehyde compound of the general formula (V) in a continuous manner.

Where

X is a halogen atom;

R and R 'are an amino group protecting group and a carboxy group protecting group, respectively.

The metal salt usable in the first step of the process is preferably sodium chloride, sodium iodide, potassium chloride or potassium iodide, more preferably sodium iodide.

Preferred solvents are acetone, dioxane, acetonitrile, chloroform, dichloromethane, tetrahydrofuran, ethyl acetate or N, N-dimethylformamide, more preferably acetone.

Moreover, reaction temperature is -25-30 degreeC, More preferably, it is -10-20 degreeC.

Bases usable in the second stage include sodium hydrogen carbonate, sodium carbonate, alkali metal hydride, alkali metal amide, alkali metal hydroxide, alkali metal acetate, tri- (lower) alkylamine, N-lower alkylmorpholine, N , N- (lower) alkylbenzylamine, N, N-di- (lower) alkylaniline or pyridine are preferred, and more preferably sodium hydride.

The solvent usable in the third step is preferably water, acetone, dioxane, acetonitrile, chloroform, dichloromethane, tetrahydrofuran, ethyl acetate, N, N'-dimethylformamide, or mixtures thereof, more preferably. Preferably dichloromethane, N, N'-dimethylformamide or mixtures thereof.

The reaction is preferably performed at a temperature range of -40 to 30 ° C, more preferably -20 to 25 ° C.

As the amino group protecting group (R) of the general formula (V), in addition to various groups described in Theodora W. Greenwj, Protective Groups in Organic Synthesis , p218-287, 1981, phenoxyacetamide, p -methylphenoxy Cyacetamide, p -methoxyphenoxyacetamide, p -chlorophenoxyacetamide, p -bromophenoxyacetamide, phenylacetamide, p -methylphenylacetamide, p -methoxyphenylacetamide, phenylmono Chloroacetamide, phenyldichloroacetamide, phenylhydroxyacetamide, thienylacetamide, phenylacetoxyacetamide, α-oxophenylacetamide, benzamide, p -methylbenzamide, p -methoxybenzamide, p -chloro-benzamide, p-bromo-benzamide, phenyl-glycyl are amides, such as phthalic amide or amino group is protected phenyl glycyl amide imide, nitrophthalimide deionized be exemplified imides such as the mid- There. Examples of the protecting group for the amino group of phenylglycosylamide and p -hydrophenylphenylglycosylamide include various protecting groups described in Chapter 7 of the document, and examples of protecting groups for the hydroxyl group of p -hydroxyphenylglyciamide. And various protecting groups described in Chapter 2 of the document.

As protecting group (R ') of the carboxy group of the said General formula (V), in addition to the various protecting groups described in Chapter 5 of the said document, an aryl group, benzyl group, p -methoxybenzyl group, p -nitrobenzyl group, di A phenylmethyl group, trichloromethyl group, trichloroethyl group, t -butyl group etc. can be illustrated.

The present invention is also characterized in that the compound of formula (IV) is provided as an intermediate useful in the production of ceftitorene coating chambers.

The lide compound of the general formula (IV) includes a compound having the following ionized resonance structure.

As shown in the following Scheme (3), the lylide compound is obtained by reacting a phosphonium salt of the general formula (III) with a base in a reaction solvent.

Bases that can be used include sodium hydrogen carbonate, sodium carbonate, alkali metal hydrides, alkali metal amides, alkali metal hydroxides, alkali metal acetates, tri- (lower) alkylamines, N-lower alkylmorpholines, N, N- Preference is given to (lower) alkylbenzylamines, N, N-di- (lower) alkylanilines or pyridine, more preferably sodium hydrogen carbonate.

In addition, the reaction solvent is preferably used selected from water, acetone, dioxane, acetonitrile, chloroform, dichloromethane, tetrahydrofuran, ethyl acetate, N, N'-dimethylformamide and mixtures thereof. Is a mixed solvent of water and methanol.

The reaction is preferably carried out at a temperature range of -40 to 30 ℃, more preferably -20 to 25 ℃.

Hereinafter, the manufacturing process of the present invention will be described in detail by the following scheme.

The manufacturing process of the present invention may be chemically synthesized by the method shown in Scheme (4) below, but is not limited to this example, and may be prepared by appropriate changes of reagents and starting materials known to those skilled in the art. Can be.

As in Scheme (4) above, 5-bromomethyl-4-methylthiazole (2) is treated with sodium iodide and triphenylphosphine in acetone to give triphenyl phosphonium salt (3). Sodium hydride was added to the triphenyl phosphonium salt to form a triphenyl phosphonium lide compound (4), and then reacted in a heterogeneous mixed solvent of aldehyde compound (5) and dichloromethane-water at room temperature to react with vinyl derivatives ( Z-isomers and E-isomers) 6 are obtained. Each isomer is recrystallized and separated by column chromatography. The phenylacetyl group in a compound is removed using a well-known imino chloride method, and silica gel column chromatography is carried out to obtain an amino ester compound (7). The obtained compound was subjected to a coupling reaction with 2- (2-tritylaminothiazol-4-yl) -2 (Z) -methoxyimino acetic acid (8) using POCl ₃ as a coupling agent to protect the carboxyl group. After (9) is obtained, the protecting group of the compound is removed using CF ₃ COOH-anisole and column chromatography is performed to obtain ceftitorene (10). In addition, the obtained compound (10) can be added to sodium bicarbonate and iodine methyl pivalate in dimethylformamide (DMF) to obtain the pivaloyl methyl ester compound (1).

Triphenylphosphine is a bulky reagent that SN2 attacks a three-dimensionally small halogenated alkyl to form an illide compound. Therefore, it reacts well with primary or methyl halides without steric hindrance and sometimes with secondary halides without steric hindrance, but the reaction rate is slow and the yield is low.

The production method of the present invention is characterized in that the lylide compound of the general formula (IV) derived from the halide compound is used as an intermediate, and reacted with aldehyde to obtain ceftitorene coating chamber.

The present invention can produce the ceftitorene-coated compound of general formula (I) in a significantly higher yield than the known method by using an lide compound derived from a halide compound, and thus is simpler and more economical than the known method. Phosphorus manufacturing method.

The invention can be better understood by the following examples, which are intended to illustrate the invention and are not intended to limit the scope of protection.

Example 1 Preparation of 4-Methyl-5-triphenylphosphiniummethyl-thiazole iodine

5-Bromomethyl-4-methylthiazole (10 g) was dissolved in acetone (200 mL), triphenylphosphine (2.55 g) and sodium iodide (1.47 g) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was distilled under reduced pressure to obtain 4-methyl-5-triphenylphosphiniummethyl-thiazole iodine (13.6 g).

Example 2. Preparation of p-methoxybenzyl 7-phenylacetamido-3 (Z)-(4-methylthiazol-5-yl) vinyl-3-cepem-4-carboxylic acid ester

The phosphonium iodide compound (13.6 g) obtained in Example 1 was dissolved in dichloromethane (100 mL), and then 3-formyl-8-oxo-7-phenylacetylamino-5-thia-1-aza-ratio Add cyclo [4.2.0] oct-2-ene-2-carboxylic acid 4-methoxybenzyl ester (13.4 g) (manufactured by Otsuka Chemical Co., Japan) and 7% aqueous sodium carbonate solution (100 ml) at room temperature for 15 hours. Was stirred. The organic layer was washed with 10% sodium hydrogen sulfate solution and brine, dried over anhydrous magnesium sulfate (MgSO ₄ ) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: benzene: ethyl acetate = 3: 2) to give a yellow powder of ρ-methoxybenzyl 7-phenylacetamido-3- (4-methylthiazole- 5-yl) vinyl-3-cepem-4-carboxylic acid ester (4 g) was obtained.

mp: 78-82 ° C.

IR: 3200-3350, 1790, 1730, 1670, 1620cm ^-1

NMR (CDCl ₃ ) δ: 2.39 (3H, s, CH ₃ ), 3.15, 3.45 (2H, ABq, J = 16 Hz, 2H), 3.62 (2H, s, CH ₂ ), 377 (3H, s, OCH ₃ ), 5.00 (1H, d, J = 5 Hz, 6H), 5.08 (2H, s, CH ₂ ), 5.82 (1H, dd, J = 5.8 Hz, 7H), 6.15 (1H, d, J = 8 Hz, CONH ), 6.40 (2H, d, J = 14 Hz, arom), 6.80 (1H, d, J = 11 Hz, CH =), 7.1-7.3 (8H, m, CH = arom), 8.52 (1H, s, thiazole 2 -H)

FD-MS m / z 562 (M + H) +

Example 3. Preparation of p-methoxybenzyl 7-amino-3 (Z)-(4-methylthiazol-5-yl) -3-cepem-4-carboxylic acid ester

In a solution of pyridine (1.44 mL) and phosphorus pentachloride (1.1 mg) in dichloromethane (30 mL), the compound (1 g) obtained in Example 2 was dissolved in dichloromethane (5 mL) at -30 ° C. The solution was added. The reaction mixture was stirred at 0-5 ° C. for 2 hours, then the reaction mixture was placed in methanol (30 mL) at −20 ° C. and stirred at 0-5 ° C. for 1 hour. The mixture was separated with dichloromethane (40 mL) and brine (20 mL) with cooling. The pH was adjusted to 2.0 with 7% aqueous sodium carbonate solution and stirred at 0-5 ° C. for 1 hour. The separated organic layer was washed with brine and sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: benzene: ethyl acetate = 3: 1) and recrystallized from ethyl acetate to give light yellow crystals of p-methoxybenzyl 7-amino-3 (Z)-(4-methylthiazole- 5-yl) -3-cepem-4-carboxylic acid ester (615 mg) was obtained.

mp: 141-142 ° C

Example 4. p-methoxybenzyl 7-[(Z) -2- (2-tritylaminothiazol-4-yl) -2-methoxyimino-pentamido] -3 (Z) -4- Preparation of Methylthiazol-5-yl) vinyl] -3-cepem-4-carboxylic acid ester.

Compound (615 mg) and (Z) -2- (tritylaminothiazol-4-yl) -2-methoxyiminoacetic acid (634 mg) obtained in Example 3 were converted to dichloromethane (pyridine (0.45 mL)). 40 ml) and then a solution of POCl ₃ (297 mg) dissolved in dichloromethane (3 ml) at −20 ° C. was added dropwise. After stirring at −20 to −10 ° C. for 2 hours, the reaction mixture was poured into water (20 mL). The separated organic layer was washed with water and brine, and then dried under reduced pressure and dried over anhydrous magnesium sulfate. The residue was purified by column chromatography (developing solvent: benzene: ethyl acetate = 5: 1) to give pale-methoxybenzyl 7-[(Z) -2- (2-tritylaminothiazol-4-yl) as a pale yellow powder. -2-methoxyimino-pentamiamido] -3 (Z) -4-methylthiazol-5-yl) vinyl] -3-cefe-4-carboxylic acid ester (877 mg) was obtained.

mp: 134-136 ° C

Example 5. 7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3 (Z)-(4-methylthiazole-5- (I) Preparation of Vinyl-3-Cefe-4-carboxylic Acid.

Anisole (0.75 mL) and trifluoroacetic acid (3 mL) were added to the compound (300 mg) obtained in Example 4, and the mixture was reacted at 0 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure, diluted with isopropyl ether (150 mL) and the precipitate was separated. The resulting powder was dissolved in a mixed solution of water (2 mL) and ethyl acetate (5 mL) and the pH was adjusted to 7.2 with sodium hydrogen carbonate. The aqueous layer was purified by column chromatography (developing solvent: water: acetone = 4: 1), and lyophilized to give 7-[(Z) -2- (2-aminothiazol-4-yl)-as pale yellow crystals. 2-methoxyiminoacetamido] -3 (Z)-(4-methylthiazol-5-yl) vinyl-3-cepem-4-carboxylic acid (143 mg) was obtained.

mp: 195-200 ° C.

Example 6. Pivaloyloxymethyl 7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3 (Z)-(4-methyl Preparation of thiazol-5-yl) vinyl-3-cepem-4-carboxylic acid esters.

The compound (50 mg) obtained in Example 5 was dissolved in DMF (5 mL), and a solution in which iodine methyl pivalate (160 mg) was dissolved in DMF (2 mL) was added and reacted at -20 ° C. Cold water (30 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (30 mL). The organic layer was washed with water (20 mL) and brine (20 mL), dried and distilled under reduced pressure. The residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate) to give a pale yellow powder of pivaloyloxymethyl 7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoa. Setamido] -3 (Z)-(4-methylthiazol-5-yl) vinyl-3-cepem-4-carboxylic acid ester (42 mg) was obtained.

mp: 127-129 ° C.

Ceftitorene cladding which is a useful antimicrobial agent with a broad antimicrobial spectrum of the present invention, namely pivaloyloxymethyl 7-[(Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoa Cetamido] -3 (Z)-(4-methylthiazol-5-yl) vinyl-3-cepem-4-carboxylic acid ester, comprising a lide compound and an aldehyde derived from a halide compound By reacting the compound with Wittich, it is possible to economically produce high purity and high yield of ceftitorene coating chamber compound, which is industrially useful.

Claims (9)

A first step of reacting a halide compound of formula (II) with triphenylphosphine in the presence of a metal salt to obtain a phosphonium salt of formula (III); A second step of reacting the phosphonium salt with a base to obtain an lide compound of the following general formula (IV); A process for preparing ceftitorene coating chamber of the general formula (I), characterized in that the third step of the step of reacting the yilide compound with the aldehyde compound of the general formula (V): Where X is a halogen atom; R and R 'are an amino group protecting group and a carboxy group protecting group, respectively. The method of claim 1, wherein the base in the second step is sodium hydrogen carbonate, sodium carbonate, alkali metal hydroxide, alkali metal amide, alkali metal hydroxide, alkali metal acetate, tri- (lower) alkylamine, N-lower alkyl Morpholine, N, N- (lower) alkylbenzylamine, N, N-di- (lower) alkylaniline or pyridine. The method of claim 1, wherein the solvent in the third step is water, acetone, dioxane, acetonitrile, chloroform, dichloromethane, tetrahydrofuran, ethyl acetate, N, N'-dimethylformamide or mixtures thereof. The manufacturing method to make. The method of claim 1, wherein the reaction temperature in the third step is -40 to 30 ℃. Ilide compound of the following general formula (IV) which has a novel chemical structure in the manufacturing method of a ceftitorene coating room. A process for preparing the lide compound of formula (IV), wherein the phosphonium salt of formula (III) is prepared by reacting with a base in a reaction solvent: 7. The base of claim 6 wherein the base is sodium hydrogen carbonate, sodium carbonate, alkali metal hydride, alkali metal amide, alkali metal hydroxide, alkali metal acetate, tri- (lower) alkylamine, N-lower alkylmorpholine, N , N- (lower) alkylbenzylamine, N, N-di- (lower) alkylaniline or pyridine. The process according to claim 6, wherein the reaction solvent is water, acetone, dioxane, acetonitrile, chloroform, dichloromethane, tetrahydrofuran, ethyl acetate, N, N'-dimethylformamide twisting mixtures thereof. . The method of claim 6, wherein the reaction temperature in the reaction is -40 to 30 ℃.