KR20040050438A - Novel process for preparing cefditoren - Google Patents

Abstract

PURPOSE: Provided is a process for preparing cefditoren, thereby cheaply preparing cefditoren which has wide range of antimicrobial spectrum in higher yield and purity without preparing E isomer by Wittig reaction. CONSTITUTION: The process for preparing cefditoren represented by formula (I) comprises the steps of: (i) reacting a compound of formula (II) with metal alkene compound such as 1,2-bis-tributylstananyl ethene of formula (III) in the presence of organic solvent and catalyst to prepare a Z type intermediate of formula (IV); and (ii) reacting the Z type intermediate of formula (IV) with cephem compound of formula (V), wherein R1 is C1-C5 alkyl; X is halogen atom such as chlorine, bromine and iodine; Y is halogen atom, triplate(-OTf), mesylate(-OMs) or tosylate(-OTs); PMB is p-methoxybenzyl as a carbonyl protecting group; the catalyst is Pd2dba3 or Pd(OAc)2 having a ratio of 2:1 with each of Pd(PPh3)4, PdCl2(PPh3)2, PdCl2(PhCN)2, PdCl2(MeCN)2 and P(o-tol)3; the organic solvent is dimethylformamide, dimethylsulfoxide or a mixed solvent thereof; the reaction temperature is 30 to 100 deg. C; and the reaction time is 10 to 15 hours.

Description

Novel process for preparing cefditoren}

The present invention is 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido which is a cephem compound known as the general name cefditoren represented by the following general formula (1): ] -3- [2- (4-methylthiazol-5-yl) vinyl] -3-cepem-4-carboxylic acid ( syn isomer , cis isomer ) compound (Japanese Patent No. 64503 No. 4,839,350 and European Patent No. 0175610), which are excellent cephalosphorin antibiotics, have low toxicity and a very broad spectrum of antimicrobial grams. It is known to have an excellent effect on the treatment and prevention of diseases caused by (gram-positive bacteria) or gram-negative bacteria (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.

The compound of formula 2 is 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetate derived by esterifying the 4-carboxyl group of the ceftitorene compound with a pivaloyloxymethyl group Amido] -3- [2- (4-methylthiazol-5-yl) vinyl] -3-cepem-4-carboxylic acid pivaloyloxymethyl ester (syn-isomer, cis isomer -isomer), a prodrug known by 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). .

Ceftitorene is less toxic to mammals but has a very broad spectrum of antimicrobial activity against Gram-positive and Gram-negative bacteria, while ceftitorene coating itself is not antibacterial but can be administered orally into a mammal's digestive system. It is useful as a prodrug that can be converted to ceftitorene, which is an antimicrobial activity, while the pivaloyloxymethyl group forming an ester in the digestive tract of a mammal is separated. 3- (2-substituted-vinyl) -sephalosporin antibiotics, such as ceftitorene and ceftitorene coating, generally indicate that their Z isomers are superior to the antibiotic properties of the E isomers (trans isomers). Known.

The 3- (2-substituted-vinyl) -sephalosporin antibiotics or their intermediates for synthesis, including ceftitorene, can be prepared in a number of ways, and one of the available preparations of these antibiotics is Wittig ( There is a method using the Wittig) reaction. In the process for the preparation of 3- (2-substituted-vinyl) separosporin antibiotics or their synthetic intermediates using the Wittig reaction, the reaction product always contains a mixture of the Z isomer (cis isomer) and the E isomer (trans isomer). It is obtained in the form of (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. 0734965A1) Due to the low yield of the desired target material, including the separation process, the overall efficient process was not achieved.

For example, as shown in the following scheme, 7-[(Z) -2-(aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- (Z)- 7-β-phenylacetamido-3- [2- (4-methylthiazol-5- used for the synthesis of (4-methylthiazol-5-yl) vinyl) -3-cepm-4-carboxylic acid (1) Treatment of p -methoxybenzyl ester of vinyl] -3-cef-4-carboxylic acid with sodium iodide in acetone to give the corresponding 3-iodine methyl derivative (2), which is converted to triphenylphosphine. The triphenylphosphonium iodide derivative (3) was treated to produce triphenylphosphonium iodide derivative (4), and in the presence of sodium bicarbonate in a heterogeneous reaction medium consisting of dichloromethane and water (4) 7-β-phenylacetamido-3- [2- (4-methylthiazol-5-yl) and 5-formyl-4-methylthiazole (5) were subjected to a Wittig reaction process at room temperature. Vinyl] -3-cefe-4-carboxylic acid-4- A methoxybenzyl ester (6) was produced.

In the above method, the intermediate 7-β-phenylacetamido-3-[(triphenylphosphoranilidene) methyl] -3-cepm-4-carboxylic acid-4-methoxybenzyl ester (4) Reaction with 5-formyl-4-methylthiazole (5) by TIG reaction to 7-β-phenylacetamido-3- [2- (4-methylthiazol-5-yl) vinyl] -3- Cefem-4-carboxylic acid-4-methoxybenzyl ester (6) is produced, and the reaction product is described in the literature that Z isomer (cis isomer) and E isomer (trans isomer) were obtained in a mixture of 4.7: 1. It is also described that these mixtures are difficult to separate from each other by column chromatography (Kenji, Sakagami et al .; J. Antibiotics , 8 , pp91047-1050, 1990). Therefore, the yield of the desired Z isomer which can be finally obtained was inevitably lowered.

In addition, in the production method described in Japanese Patent Application Laid-Open No. 95-188250 or the corresponding US Patent No. 5,616,703 or European Patent Application Publication No. 658558A1 shown in the following reaction scheme, 7-amino-3- [2- (4 The reaction product (5) obtained as -methylthiazol-5-yl) vinyl] -3-cefe-4-carboxylic acid or derivatives thereof is described as being a mixture of the Z isomer and the E isomer. 95-188250 converts a Z / E mixture of 7-amino-3- [2- (4-methylthiazol-5-yl) vinyl] -3-cefe-4-carboxylic acid into an amine salt and further obtains By carrying out the recrystallization method for the amine salt, a method for isolating the Z isomer is described, and it is described that the Z isomer obtained by removing the low activity E isomer as much as possible on the Z / E mixture can be obtained. . In fact, the yield of the target compound by this reaction process is very low at 31%.

Similarly, International Patent Application No. PCT / EP 92/02965 describes the content of E isomers by converting all protecting group-free cefe compounds into the form of hydrochloride, alkali salts, and amine salts, taking advantage of the solubility difference between the Z and E isomers. The method for reducing the amount of the present invention is disclosed. This method has the advantage that crystals are easily precipitated and thus can be easily separated and obtained through filtration. However, since the amount of the E isomers removed is inefficient, the overall yield is low. The loss of yield has a problem in that it is a burden on the cost in that the loss of the ceftitorene compound produced through several steps.

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

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 Wittig reaction, in which the Z isomer and the E isomer are formed at the same time due to the double bond of the vinyl group. Therefore, the conventional method for preparing 3- (2-substituted-vinyl) -sephalosporin using the Wittig reaction does not have good selectivity for Z isomer production compared to the production of E isomers, and isolating Z isomers from E isomers. For this reason, there are several drawbacks such as additional complicated operation, unsatisfactory yield of Z isomers, and in the case of carrying out the above-mentioned conventional methods, methylene chloride or methylene chloride- It was the conventional manufacturing method, such as using water.

In view of the above, there is still a need for a new production method for producing ceftitorene which is efficient, simple and economical in which the disadvantages of the known method are eliminated, and thus is prepared in high purity and high yield without separation of the target compound. The present invention has been completed by developing a novel method.

It is an object of the present invention to provide a ceftodirene coating chamber useful as a cephalosporin antibiotic, namely 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2 It is to provide a novel process for preparing-(4-methylthiazol-5-yl) vinyl] -3-cepm-4-carboxylic acid pivaloyloxy methyl ester.

In order to achieve the above object, the present invention is to react the compound of formula (II) as a starting material with a metal alkene compound such as 1,2-bis-tributylstannanyl ethene of formula (III) under an organic solvent and a catalyst Z The step of formula (I), characterized in that the first step of obtaining an intermediate compound of formula (IV) of the following type and a second step of reacting the intermediate compound with the cefem compound of formula (V) are carried out continuously. Provided is a novel process for the production of ditorene cladding compounds in high purity and high yield.

(Ⅰ)

(Ⅱ)

(Ⅲ)

(Ⅳ)

(Ⅴ)

In the above formula,

R ₁ is an alkyl group having 1 to 5 carbon atoms,

X is a halogen atom, chlorine, bromine, iodine atom,

Y is a halogen atom, a triflate (-OTf), a mesylate (-OMs) or a tosylate (-OTs) group, and PMB is a p- methoxybenzyl group which is a carbonyl protecting group.

The catalyst used in the above process is Pd (PPh ₃ ) ₄ , PdCl ₂ (PPh ₃ ) ₂ , PdCl ₂ (PhCN) ₂ , PdCl ₂ (MeCN) ₂ , P ( o- tol) ₃ and a ratio of 2: 1, respectively. Palladium catalysts, such as Pd ₂ dba ₃ or Pd (OAc) _{2 having} , can be used, and the amount of use is 0.1 to 20 mol, preferably 1 to 6 mol. For example, 5-bromo-4-methyl-thiazole compound (II) and 1,2-bis-tributylstannanyl ethene (1,2-bis) that are reactive agents The amount of -tributylstannanyl ethene) (III) used is in the range of 2 to 10: 1, preferably 2 to 3: 1.

In addition, organic solvents that can be used in the above production process include amides such as dimethylacetamide (DMA), dimethylformamide, hexamethylphosphoric triamide, acetonitrile, propionitrile, butyronitrile, Nitriles such as isobutyronitrile and vareronitrile, dimethylimidazole (DMI), dimethyl sulfoxide (DMF), and the like, tetrahydrofuran (THF), dioxane, and the like can be exemplified. It can be mixed and used.

In particular, preferred solvents include dimethylformamide and dimethyl sulfoxide as main solvents, and mixed solvents thereof are also possible.

Similarly, the reaction temperature in the process is 10 to 120 ° C, preferably 30 to 100 ° C, and the reaction time is 5 to 50 hours, preferably 10 to 15 hours.

Examples of the amino group protecting group of the general formula (V) include phenoxyacetamide and p -methylphenoxyacet as well as various groups described in Theodora W. Greenwj, Protective Groups in Organic Synthesis , p218-287, 1981. Amide, p -methoxyphenoxyacetamide, p -chlorophenoxyacetamide, p -bromophenoxyacetamide, phenylacetamide, p -methylphenylacetamide, p -methoxyphenylacetamide, phenylmonochloroacet Amide, phenyldichloroacetamide, phenylhydroxyacetamide, thienylacetamide, phenylacetoxyacetamide, α-oxophenylacetamide, benzamide, p -methylbenzamide, p -methoxybenzamide, p -chloro benzamide, p - bromo-benzamide, phenyl-glycyl amide or amino group of the amides, such as florisil protected article phenyl amide, phthalimide, nitrophthalimide ride can for example imides such as the mid- The. As a protecting group of the amino group of phenyl glycylamide and p -hydrophenylphenyl glycylamide, various groups described in Chapter 7 of the said document can be illustrated, As a protecting group of the hydroxyl group of p -hydroxyphenyl glycylamide, The various groups described in Chapter 2 of the said document can be illustrated.

As a protecting group of the carboxylic acid represented by PMB of the said General formula (V), in addition to the various groups described in Chapter 5 of the said document, an aryl group, benzyl group, p -methoxybenzyl group, p -nitrobenzyl group , Diphenylmethyl group, trichloromethyl group, trichloroethyl group, t -butyl group and the like can be exemplified.

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

The preparation process of the present invention may be chemically synthesized by the method shown in Scheme 1 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. .

In the above formula,

R ₁ is an alkyl group having 1 to 5 carbon atoms,

X is a halogen atom, chlorine, bromine, iodine atom,

Y is a halogen atom, triflate (-OTf), mesylate (-OMs) or tosylate (-OTs) group, and PMB is a paramethoxybenzyl group which is a carbonyl protecting group.

As in Scheme 1, 5-bromo-4-methyl thiazole of Structural Formula (II) as a starting material was reacted with tetrakis triphenylphosphine palladium (Pd (PPh ₃ ) ₄ ) and 1,2-bis under an organic solvent. React with tributylstannanyl ethene (III) to form compound Z of intermediate compound (IV), which is concentrated under an organic solvent with cefem compound (V) and tetrakis triphenylphosphine palladium. And cefditorene coating chamber (I) can be obtained.

Steps 1 and 2 of the reaction process are using a Stille reaction, and as catalysts, PdCl ₂ (PPh ₃ ) ₂ , PdCl ₂ (PhCN) ₂ , PdCl ₂ (MeCN) ₂ , P ( o − tol) ₃ and a palladium catalyst such as Pd ₂ dba ₃ or Pd (OAc) ₂ , each having a ratio of 2: 1, preferably tetrakis triphenylphosphine palladium (Pd (PPh ₃ ) ₄ ), The use amount is 0.1-20 mol, Preferably it is 1-6 mol. Organic solvents that can be used include amides such as dimethylacetamide (DMA), dimethylformamide, hexamethylphosphoric triamide, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, and varero Nitriles, such as a nitrile, dimethyl imidazole (DMI), dimethyl sulfoxide (DMF), tetrahydrofuran (THF), dioxane, etc. can be illustrated, and can be used individually or in mixture of 2 or more types.

In addition, the above solvent is mainly used, and other ordinary solvents, for example, lower alkyl carboxylic acids such as methyl formate, ethyl formate, propyl formate, butyl formate, methyl acetate, ethyl acetate, propyl acetate, and ethyl propionate Ethers such as alkyl esters, diethyl ether, ethyl propyl ether, ethyl butyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, methyl cellosolve, dimethoxyethane, tetrahydrofuran, di Cyclic ethers such as oxane, substituted or unsubstituted aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene and anisole, hydrocarbons such as pentane, hexane, heptane and octane, cyclopentane and cyclohexane Cycloalkanes such as, cycloheptane and cyclooctane, dichloromethane, chloroform, dichloroethane, trichloroethane, dibromoethane, propylene dichloride, tetrachloride Carbon, it is also possible to use a mixed solvent in combination with halogenated hydrocarbons such as Freons.

In particular, preferred solvents include dimethylformamide and dimethyl sulfoxide as main solvents, and mixed solvents thereof are also possible.

Similarly, the reaction temperature in the process is 10 to 120 ° C, preferably 30 to 100 ° C, and the reaction time is 5 to 50 hours, preferably 10 to 15 hours.

In addition, the amount of 5-bromo-4-methyl thiazole compound (II) and 1,2-bis-tributylstannanyl ethene (III) which are reactive agents is 2 to 10: 1, preferably 2 to 3: It is in the range of 1.

As described above, the present invention can produce the ceftitorene coating chamber compound of the general formula (I) in a significantly higher yield than the known method requiring the separation process of the Z isomer and the E isomer. It is a simple and economic 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- (Z)-(2-tributylstannanyl vinyl) -thiazole

54.0 g (0.26 mol) of 5-bromo-4-methyl thiazole and 72.6 g (0.12 mol) of 1,2-bis-tributylstannanyl ethene were dissolved in 300 ml of DMF, followed by tetrakis triphenylphosphine palladium ( 11.544 g of Pd (PPh ₃ ) ₄ ) was added thereto, and the mixture was stirred under reflux. The reaction was cooled and distilled water was added to precipitate the resulting precipitate, which was then washed with distilled water and dried to give 43.17 g of 4-methyl-5- (Z)-(2-tributylstannanyl vinyl) -thiazole (yield: 82%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.72 (s, 1H), 6.72 (d, J = 9.6 Hz, 1H), 5.24 (d, J = 9.61 Hz, 1H), 2.52 (s, 3H), 1.30-1.35 (m, 18H), 0.96 (t, J = 7.1 Hz, 9H)

Example 2. Preparation of 4-methyl-5- (Z)-(2-trimethylstannanyl vinyl) -thiazole

54.0 g (0.26 mol) of 5-bromo-4-methyl thiazole and 42.1 g (0.12 mol) of 1,2-bis-trimethylstannananyl ethene were dissolved in 300 ml of DMF, followed by tetrakis triphenylphosphine palladium (Pd). (PPh ₃ ) ₄ ) 11.544 g was added and the mixture was stirred under reflux. The reactant was cooled, distilled water was added, the resulting precipitate was filtered, washed with distilled water and dried to give 29.13 g of 4-methyl-5- (Z)-(2-trimethylstannanyl vinyl) -thiazole (yield: 75 %) Was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.74 (s, 1H), 6.58 (d, J = 9.6 Hz, 1H), 5.25 (d, J = 9.6 Hz, 1H), 2.43 (s, 3H), 0.9 (s, 9 H)

Example 3 Ceftitorene Covering Room Preparation

43.17 g (0.01 mol) of 4-methyl-5- (Z)-(2-tributylstannanyl vinyl) -thiazole prepared in Example 1 were dissolved in 300 ml of DMF and tetrakis triphenyl 15.2 g of phosphine palladium (Pd (PPh ₃ ) ₄ ) was added and the mixture was stirred under reflux. 2.6 g of POCl _{3 , 3} g _of pyridine, 30 mg (0.27 mmol) of trifluoroacetic acid (CF ₃ COOH) and 30 ml of anisole were added to the reaction mixture, and the resulting precipitate was filtered by distilled water. Washed with distilled water and dried to produce 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2- (4-methylthiazole-5- Il) vinyl] -3-cef-4-carboxylic acid was obtained, and 3.2 g of sodium carbonate and 10.7 g (0.05 mol) of pivaloyloxymethyl iodide were dissolved and added to 100 ml of DMF. -[2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2- (4-methylthiazol-5-yl) vinyl] -3-cepem-4 A carboxylic acid pivaloyloxy methyl ester compound was obtained (yield: 70.7%).

As a result, ceftitorene, ie, 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3-, having an excellent effect on the Gram-positive and Gram-negative bacteria herein. The novel process for the preparation of [2- (4-methylthiazol-5-yl) vinyl] -3-cepem-carboxylic acid pivaloyloxy methylester is simplified by simplifying the process steps by the existing Wittig reaction. It was confirmed that the invention is an economically and industrially useful invention by significantly increasing the yield using a known method.

Ceftitorene cladding, a useful antimicrobial agent having a broad antimicrobial spectrum of the present invention, namely 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2- A process for the preparation of (4-methylthiazol-5-yl) vinyl] -3-cefem-carboxylic acid pivaloyloxy methyl ester, comprising a safe and simplified process without generation of the E isomer by the Wittig reaction. It is possible to economically produce high purity and high yield of ceftitorene cladding compound.

Claims (7)

Reacting a compound of formula (II) with a metal alkene compound such as 1,2-bis-tributylstannanyl ethene of formula (III) under an organic solvent and a catalyst to obtain an intermediate compound of formula (IV) A process for producing ceftitorene coating chamber of general formula (I), characterized in that the step 1 and a second step of reacting this intermediate compound with the cefem compound of general formula (V) are carried out continuously. (Ⅰ) (Ⅱ) (Ⅲ) (Ⅳ) (Ⅴ) In the above formula, R ₁ is an alkyl group having 1 to 5 carbon atoms, X is a halogen atom, chlorine, bromine, iodine atom, Y is a halogen atom, triflate (-OTf), mesylate (-OMs) or tosylate (-OTs) group, and PMB is a paramethoxybenzyl group which is a carbonyl protecting group. The catalyst of claim 1, wherein the catalyst is Pd (PPh ₃ ) ₄ , PdCl ₂ (PPh ₃ ) ₂ , PdCl ₂ (PhCN) ₂ , PdCl ₂ (MeCN) ₂ , P ( o- tol) ₃ and 2: 1, respectively. A method for producing a palladium catalyst such as Pd ₂ dba ₃ or Pd (OAc) ₂ having a ratio of. The method according to claim 2, wherein the amount of the palladium catalyst is 1 to 6 moles. The method of claim 1, wherein the organic solvent is dimethylformamide, dimethyl sulfoxide, or a mixed solvent thereof. The method according to claim 1, wherein the amount of the 5-bromo-4-methyl thiazole compound (II) and 1,2-bis-tributylstannanyl ethene (III) is in the range of 2 to 3: 1. The method of claim 1, wherein the reaction temperature is 30 to 100 ℃. The method according to claim 1, wherein the reaction time is 10 to 15 hours.