KR20040050437A - Novel process for preparing cefditoren - Google Patents

Abstract

PURPOSE: A process for preparing cefditoren is provided, 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 5-ethynyl-4-methyl thiazole compound of formula (II) with a compound of formula (IIIa) or (IIIb) in the presence of base and catalyst to prepare an intermediate of formula (IVa) or (IVb); and (ii) reacting the intermediate of formula (IVa) or (IVb) with cephem compound of formula (V) in the presence of catalyst and organic solvent, wherein X is halogen atom, triplate(-OTf), mesylate(-OMs) or tosylate(-OTs); PMB is p-methoxybenzyl as a carbonyl protecting group; the catalyst in the step (i) is £Rh(cod)Cl|2-P(iPr)3, £Rh(cod)Cl|2-PCy3 or £Ir(cod)Cl|2-P(iPr)3; the base is triethylamine or trimethylamine; and the catalyst in the step (ii) 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; and the organic solvent is dimethylformamide, dimethylsulfoxide or a mixed solvent thereof.

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). Gusev superior antimicrobial activity of the alkylene Ditto for gram-negative bacteria is Joseph Ditto alkylene carbon of the 3-vinyl group of the molecule carbon pemhwan II for binding of (cephem ring) and 4-methylthiazol-5-group is cis (cis 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-cephem-4-carboxylic acid pivaloyloxymethyl ester (De isomer (syn-isomer), cis-isomer (cis -isomer )), a prodrug known by the generic name cefditoren pivoxil, 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 way to use 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 (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 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 difference in solubility between 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 is a problem in that the cost of 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 provides a 5-ethynyl-4-methyl thiazole compound of formula (II) in the presence of a base and a catalyst of formula (IIIa) or (IIIb) A first step of reacting a boronating agent compound such as Z to obtain an intermediate compound of the following structural formula (IVa) or (IVb), and a second step of reacting the intermediate compound with the cefem compound of general formula (V) Provided is a novel process for obtaining a ceftitorene cladding compound of formula (I), characterized in that it is carried out in high purity and high yield.

(Ⅰ)

(Ⅱ)

(IIIa)

(IIIb)

(IVa)

(IVb)

(Ⅴ)

In the above formula,

X is a halogen atom, a triflate (-OTf), mesylate (-OMs) or tosylate (-OTs) group, PMB is a carbonyl protecting group (carbonyl protecting group) in para-methoxybenzyl (p -methoxybenzyl) group is .

The catalyst that can be used in the one-step reaction is [Rh (cod) Cl] ₂ -P (iPr) ₃ , [Rh (cod) Cl] ₂ -PCy ₃ (Cy is cyclohexyl) or [Ir (cod) Cl] ₂ -P (iPr) ₃ , and the available base is triethylamine (TEA) or trimethylamine (TMA), with a preferred amount of 1 to 2 equivalents.

The catalysts that can be used in the two-stage reaction are 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 palladium catalyst such as Pd ₂ dba ₃ or Pd (OAc) ₂ having a ratio of. The bases that can be used are inorganic carbonates, sodium carbonate, sodium hydroxide, lithium hydroxide and potassium hydroxide.

In addition, organic solvents that can be used in the above production process are 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 Amides such as benzamide, p -bromobenzamide, phenylglycidamide and phenylglycidamide protected with an amino group, and imides such as phthalimide and nitrophthalimide have. 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 said carboxylic acid of 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, and the manufacturing process of the present invention may be chemically synthesized by the method shown in Scheme 1 below, but is not limited thereto. Or, by appropriate changes in reagents and starting materials known to those skilled in the art.

In the above formula,

X 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, starting 5-bromo-4-methyl thiazole is reacted with an alkynyl silane in the presence of a base and a catalyst to give the 5-ethynyl-4-methyl-thiazole compound of formula (II). And 4,4,5,5-tetramethyl- [1,3,2] dioxaborolane (4,4,5,5-tetramethyl- [1,3) of formula (IIIa). (2) dioxaborolane) or a benzo [1,3,2] dioxaborole such as benzo [1,3,2] dioxaborole of the formula (IIIb) 4-methyl-5- [2- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) vinyl] thiazole (IVa) -[2- (4,4,5,5-tetra methyl- [1,3,2] dioxaborolan-2-yl) vinyl] thiazole) or 5- (2-benzo [1,3, 2] dioxabolol-2-yl-vinyl) -4-methyl thiazole (5- (2-benzo [1,3,2] dioxa borol-2-yl-vinyl) -4-methyl-thiazole) And the compound is cefem compound (V) and tetrakis triphenylphosphine palladium Concentrated under solvent-based, it is possible to obtain a chef Ditto alkylene coating chamber (Ⅰ).

The first step in the reaction process is to replace the halo group of the 5-halo-4-methyl thiazole compound with an alkyne group. , , or Preferred examples of the catalyst include bisphenylphosphine chloro palladium (PdCl ₂ (PPh ₃ ) ₂ ) and copper iodide, and the base used may be triethylamine, N-methylmorpholine, pyrrolidine, or the like. , Piperidine, benzylamine, diethylamine, diisopropylethylamine, dimethylethylamine, dimethylbenzylamine, triethanolamine, tetramethylethylenediamine, dimethylethylidenediamine and the like, and sodium carbonate and hydroxide as inorganic bases. Sodium, lithium hydroxide, potassium hydroxide and the like, triethylamine and potassium hydroxide are most preferred, and the lower alcohols and water which are polar solvents can be used as a solvent.

The second step is to hydroborate the triple bond of the 5-ethynyl-4-methyl thiazole compound of formula (II) to produce an intermediate compound of type Z. Pinacolborane (4,4,5,5-tetramethyl- [1,3,2] dioxaborolane) of IIIa) or catecholborane (benzo [1,3,2] dioxane of formula (IIIb) Borol), and the catalyst is [Rh (cod) Cl] ₂ -P (iPr) ₃ , [Rh (cod) Cl] ₂ -PCy ₃ (Cy is cyclohexyl) or [Ir (cod) Cl] ₂ P (iPr) ₃ and the like are preferred.

In order to increase the reaction yield of the present invention, addition of a base is essential. The reaction proceeds even when the reaction is performed without using a base, but the yield is only 40 to 60%. On the other hand, when a certain amount of base is added, the Z isomer can be obtained in a yield of 80% or more, in particular, Z The content of the isomer does not change, but is maintained at 90% or more. Examples of the base usable in the reaction include triethylamine, N-methylmorpholine, pyrrolidine, piperindine, benzylamine, diethylamine, diisopropylethylamine, dimethylethylamine, dimethylbenzylamine, Triethanolamine, tetramethylethyleneamine, dimethylethylideneamine, and the like, and inorganic bases include sodium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, and the like, preferably triethylamine (TEA) or trimethylamine (TMA). As a preferred usage amount, it is 1 to 2 equivalents.

The above three step is to react the resulting Z-type intermediate compound (IVa) or (IVb) with the cefe compound (V), the catalyst that can be used in the two-step reaction is Pd (PPh ₃ ) ₄ , PdCl Palladium such as Pd ₂ dba ₃ or Pd (OAc) ₂ having a ratio of ₂ (PPh ₃ ) ₂ , PdCl ₂ (PhCN) ₂ , PdCl ₂ (MeCN) ₂ , P ( o- tol) ₃ and 2: 1, respectively Catalysts are preferred, and organic solvents that can be used include amides such as dimethylacetamide (DMA), dimethylformamide, hexamethylphosphoric triamide, acetonitrile, propionitrile, butyronitrile and isobuty. Nitriles such as ronitrile and vareronitrile, tetrahydrofuran (THF), dioxane and the like, such as dimethylimidazole (DMI) and dimethyl sulfoxide (DMF), may be exemplified, Can be used.

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.

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 5-ethynyl-4-methyl thiazole compound

54.0 g (0.26 mol) of 5-bromo-4-methyl thiazole, 20.9 g (0.22 mol) of ethynyl trimethylsilane and 5 g of potassium hydroxide were dissolved in methanol, and ditriphenylphosphine chlorine palladium (PdCl ₂ (PPh _{3 2} ) 10.5 g and 6.7 g of triethylamine were added and stirred under reflux. The reactant was cooled and distilled water was added, and the resulting precipitate was filtered, washed with distilled water and dried to give 23.29 g of 5-ethynyl-4-methyl thiazole (yield: 79%).

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.43 (1H, s), 8.47 (1H, s), 2.53 (3H, s).

Example 2. Preparation of 4-methyl-5- (Z)-[2- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) vinyl] thiazole

To 11.0 g (0.07 mol) of 5-ethynyl-4-methyl thiazole prepared in Example 1, 4.3 g of [Rh (cod) Cl] ₂ , 6.7 g of phosphine ligand (P (iPr) ₃ ), and 0.101 g of TEA (1 mmol) and 14.3 g (0.05 mol) of 4,4,5,5-tetramethyl- [1,3,2] dioxaborolane were added and stirred under reflux at 80 ° C. for 4 hours. The reactant was cooled and distilled water was added, and the resulting precipitate was filtered, washed with distilled water and dried to obtain 4-methyl-5- (Z)-[2- (4,4,5,5-tetramethyl- [1 , 3,2] dioxaborolan-2-yl) vinyl] thiazole 10.725 g (yield: 75%) was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.71 (s, 1H), 6.66 (d, J = 10.2 Hz, 1H), 5.25 (d, J = 10.2 Hz, 1H), 2.47 (5, 3H0, 1.26 (2, 12H).

Example 3. Preparation of 5- (Z)-(2-benzo [1,3,2] dioxaborole-2-yl-vinyl) -4-methyl thiazole

To 11.0 g (0.07 mol) of 5-ethynyl-4-methyl thiazole prepared in Example 1, 4.3 g of [Rh (cod) Cl] ₂ , 6.7 g of phosphine ligand (P (iPr) ₃ ) and 0.101 g of TEA (1 mmol) and 14.0 g (0.05 mol) of benzo [1,3,2] dioxaborole were added and stirred under reflux at 80 ° C. for 4 hours. The reactant was cooled, distilled water was added, the resulting precipitate was filtered, washed with distilled water and dried to give 5- (Z)-(2-benzo [1,3,2] dioxaborole-2-yl-vinyl). 11.34 g (yield: 81%) of 4-methyl thiazole were obtained.

¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.71 (s, 1H), 6.65 (m, 4H0, 6.66 (d, J = 10 Hz, 1H), 5.23 (d, J = 10 Hz, 1H), 2.47 (s, 3 H).

Example 4 Preparation of Ceftitorene Covering Room Compounds

4-Methyl-5- (Z)-[2- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) vinyl] prepared in Example 2 above] 10.725 g (0.0375 mol) of thiazole and the cefe compound were dissolved in 300 mL of DMF, and 15.2 g of tetrakis triphenylphosphine palladium (Pd (PPh ₃ ) ₄ ) was added thereto, followed by reflux stirring. 2.6 g of POCl _{3 , 3} g _of pyridine, trifluoroacetic acid (CF ₃ COOH, trifluoroacetic acid) (30 mg, 0.27 mmol) and 30 ml of anisole were added to the reaction mixture, and the resulting precipitate was filtered by distilled water. , And then rinsed with distilled water and dried to produce 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2- (4-methylthiazole- 5-yl) vinyl] -3-cepem-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. 7- [2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido] -3- [2- (4-methylthiazol-5-yl) vinyl] -3-cepem- The 4-carboxylic acid pivaloyloxy methyl ester compound was obtained (yield: 72.3%).

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 coating compound.

Claims (6)

The 5-ethynyl-4-methyl thiazole compound of formula (II) is reacted with a boronating agent compound such as formula (IIIa) or (IIIb) in the presence of a base and a catalyst to form Z of the following formulas (IVa) or (IVb) A first step of obtaining an intermediate compound and a second step of reacting the intermediate compound with the cefem compound of formula (V) are carried out continuously. . (Ⅰ) (Ⅱ) (IIIa) (IIIb) (IVa) (IVb) (Ⅴ) In the above formula, X is a halogen atom, a triflate (-OTf), mesylate (-OMs) or tosylate (-OTs) group, PMB is a para-methoxybenzyl carbonyl protecting group (p -methoxybenzyl) group. The method of claim 1, wherein the catalyst of the first step is [Rh (cod) Cl] ₂ -P (iPr) ₃ , [Rh (cod) Cl] ₂ -PCy ₃ or [Ir (cod) Cl] ₂ -P ( iPr) ₃ phosphorus preparation method. The method according to claim 1, wherein the base is triethylamine or trimethylamine. The production method according to claim 1, wherein the amount of base used is 1 to 2 equivalents. The catalyst of claim 1, wherein the catalyst of step 2 is Pd (PPh ₃ ) ₄ , PdCl ₂ (PPh ₃ ) ₂ , PdCl ₂ (PhCN) ₂ , PdCl ₂ (MeCN) ₂ , and P ( o- tol) ₃ , respectively. A process for producing a palladium catalyst such as Pd ₂ dba ₃ or Pd (OAc) ₂ having a ratio of 2: 1. The method of claim 1, wherein the organic solvent of the second step is dimethylformamide, dimethyl sulfoxide or a mixed solvent thereof.