KR100238645B1 - Novel esterification for cephalosporin derivative - Google Patents

Abstract

The present invention is prepared by reacting an alcohol or thiol compound of formula (4) with a carbodiimide compound of formula (5) in the presence of a catalyst to prepare a compound of formula (3), and then into a compound of formula (3) by a continuous or discontinuous process The present invention relates to a method for easily preparing a compound of formula (1) without esterification of a compound of the double bond to position shift △ ³ → △ ² .

In the above formula,

R ₁ is amino protected by a conventional aminoprotecting group, preferably 5-benzamido-5- (diphenylmethoxycarbonyl) valeramido, phenylacetylamino, phenoxyacetylamino, formylamino, N-phthalimido, benzylideneamino, p-methoxybenzylideneamino, salicylideneamino, t-butoxycarbonylamino or benzyloxycarbonylamino, and

R ₂ represents hydrogen, halogen, hydroxy, triphenylphosphoniummethyl halide or lower alkenyl, or lower alkyl substituted or unsubstituted by halogen, lower alkoxy, acyloxy or hydroxy,

n is an integer of 0 to 2,

R ₃ and R ₄ are each independently straight or branched lower alkyl; C ₃ -C ₇ cycloalkyl; Trityl; Trimethylsilyl; Phenyl unsubstituted or substituted 1 or 2 by halogen, lower alkyl, lower alkoxy, nitro or dialkylamino; 2-morpholinoethyl meto p-toluenesulfonyloxy; Dimethylaminopropyl methoxide; 3-dimethylaminopropyl hydrochloride; Or 2,2-dimethyl-1,3-dioxolan-4-ylmethyl,

X represents oxygen or sulfur atom,

Ph represents phenyl.

Description

New Esterification Method of Cephalosporin Derivatives

The present invention relates to a method for preparing a cephalosporin derivative of the general formula (1) characterized by esterifying a compound of the general formula (2) with a novel compound of the general formula (3).

Formula 2

Formula 3

Formula 1

In the above formula,

R ₁ is amino protected by a conventional aminoprotecting group, preferably 5-benzamido-5- (diphenylmethoxycarbonyl) valeramido, phenylacetylamino, phenoxyacetylamino, formylamino, N-phthalimido, benzylideneamino, p-methoxybenzylideneamino, salicylideneamino, t-butoxycarbonylamino or benzyloxycarbonylamino, and

R ₂ represents hydrogen, halogen, hydroxy, triphenylphosphoniummethyl halide or lower alkenyl, or lower alkyl substituted or unsubstituted by halogen, lower alkoxy, acyloxy or hydroxy,

n is an integer of 0 to 2,

R ₃ and R ₄ are each independently straight or branched lower alkyl; C ₃ -C ₇ cycloalkyl; Trityl; Trimethylsilyl; Phenyl unsubstituted or substituted 1 or 2 by halogen, lower alkyl, lower alkoxy, nitro or dialkylamino; 2-morpholinoethyl meto p-toluenesulfonyloxy; Dimethylaminopropyl methoxide; 3-dimethylaminopropyl hydrochloride; Or 2,2-dimethyl-1,3-dioxolan-4-ylmethyl,

X represents oxygen or sulfur atom,

Ph represents phenyl.

의 구조를 나타내고, "2-모폴리노에틸 메토 p-톨루엔설포닐옥시"는

의 구조를 나타내며, "디메틸아미노프로필 메티오다이드"는

의 구조를 나타낸다.In the substituent definition for the compound of Formula 1, "triphenylphosphoniummethyl halide"

And "2-morpholinoethyl meto p-toluenesulfonyloxy"

Represents the structure of "dimethylaminopropyl methoxide"

It shows the structure of.

The present invention also relates to a novel compound of formula (3) used as a reactant in the preparation method of formula (1) and a preparation method thereof.

In general, a method of esterifying a carboxyl group to protect it is firstly a method of reacting an organic acid with an alcohol under an acid catalyst, a second method using an acid chloride or mixed acid anhydride, and a third dehydrating condensing agent such as dicyclohexylcarbodiimide Methods such as Bull. Chem. Soc. Jpn., 54, 1267 (1981); Tetrahedron Lett., 24, 3365 (1983); and Tetrahedron Lett., 4475 (1978).

However, the above-mentioned general esterification methods are too violent reaction for use in protecting the carboxylic acid groups present in three pemhaek 4-position of the cephalosporin derivative of the aimed compounds of the present invention condition, In addition, under the condition △ ² It has been reported that there are various problems such as a positional shift to the cefe derivative.

Looking at the known methods applied to esterifying the carboxylic acid of the cephalosporin derivative, the most commonly used method so far is the use of diazomethane derivatives. In this method, however, benzophenonehydrazone is oxidized with an oxidizing agent such as mercury oxide to prepare the corresponding diphenyldiazomethane, and then it is troublesome to use it. In particular, heavy metal contamination by the oxidizing agent used causes serious problems. It is pointed out. In addition, the diazomethane derivatives themselves are very reactive and chemically unstable and difficult to handle, and there are storage problems, and the diazomethane compounds are generally toxic and explosive, so the method is used for industrial mass production. The following is almost impossible (see J. Antibiotics, 38 (12), 1738 (1985); Tetrahedron Letters, 37 (12), 1971 (1996); Org. Syn. Coll., 3, 351 (1955); J. Org., 24, 560 (1959)).

Recently, a method for preparing diphenylmethyl ester using oxone (potassium monopersulfate triple salt; 2KHSO ₅ · KHSO ₄ · K ₂ SO ₄ ) as an oxidizing agent is described in Tetrahedron Letter, 38 (7), 1239 ( 1997). However, in this method, the cephal nucleus sulfide is oxidized to sulfoxide by reducing the starting part of the cephalosporin derivative and the reaction reagent benzophenonehydrazone, oxone, and catalytic amount of iodine together in the reaction vessel. The process has to be done, and there is a disadvantage in that the yield is reduced and the manufacturing cost is increased. In addition, since a strong oxidant must be used, it is difficult to apply to a material containing a functional group sensitive to the oxidant, and because it is exothermic, it has disadvantages that are not suitable for mass production.

On the other hand, a method for esterifying a cephalosporin derivative with 4-methoxybenzyl or the like is analogous to the method according to the present invention (J. Med. Chem. 33, 2522 (1990)). However, this method has a problem in that the double bond of the cefe nucleus is transferred to some Δ ³ → Δ ² , so that after the reaction, a mixture having a mixing ratio of △ ² isomers: △ ³ isomers is 1: 1, in particular, the produced isomers. Are very difficult to separate because their physical and chemical properties are similar. Therefore, due to this decrease in yield and increase in manufacturing costs, the situation has not been industrially used. In short, until now, a simple and safe esterification method of the carboxylic acid of the cephalosporin compound has not been developed, and there is no method applicable to mass production.

Accordingly, the present inventors have developed a method of easily esterifying the carboxylic acid of the cephalosporin derivative without industrial transfer of the double bond to Δ ³ → Δ ² in milder conditions, thereby improving the problems of the above-mentioned prior arts. A systematic study was carried out over the years, and as a result, it was found that the use of the novel compound of formula 3 having a diphenylmethyl group as an esterifying agent can achieve this purpose efficiently and economically, and to complete the present invention. It became.

Accordingly, the present invention relates to a method for preparing the cephalosporin derivative of Chemical Formula 1 by using the compound of Chemical Formula 3 as an esterifying agent.

The present invention also relates to a novel compound of formula (3) and a preparation method thereof. Hereinafter, the configuration of the present invention in more detail.

The present invention relates to a process for preparing a cephalosporin derivative of the general formula (1) characterized by esterifying a compound of the general formula (2) with a novel compound of the general formula (3) as shown in Scheme 1 below.

In the above formula,

R ₁ to R ₄ , n, X and Ph are as defined above.

The process according to the invention for the preparation of compounds of formula (1) achieves the effect of not transferring double bonds under mild conditions by using a new, inexpensive and easy to handle compound of formula (3) as an esterifying agent.

The reaction is preferably carried out in a reaction-inert organic solvent, in which solvents usable are tetrahydrofuran, methylene chloride, N, N-dimethylformamide, N, N-dimethylacetamide, chloroform, ethyl acetate, acetone And one or more selected from methanol, ethanol, isopropanol and t-butanol. More preferably, tetrahydrofuran, N, N-dimethylformamide or methanol may be used, and most preferably tetrahydrofuran is used.

The esterifying agent of Formula 3 may be used in the same amount or in an excess of 1 to 5 equivalents based on the cephalosporin compound of Formula 2, preferably 1 to 2 equivalents.

The reaction can be obtained by performing for 1 to 24 hours in the range of -10 to 60 ℃, preferably in the range of -10 to 40 ℃, more preferably 0 to 30 ℃.

On the other hand, the compound of the formula (3) used as an esterifying agent in Scheme 1 is a novel compound itself, and the preparation method thereof is also a subject of the present invention.

The compound of formula 3 is a very practical compound because it is easy to prepare and very stable and can be used separately or in the reaction of the reaction scheme 1 in the next step without separation.

In order to prepare an esterifying compound of Formula 3 according to the present invention, an alcohol or thiol compound of Formula 4 is reacted with a carbodiimide compound of Formula 5 in the presence of a catalyst, which is described in Synthesis, 561 (1979). It can proceed with reference to the description in.

Formula 4

Formula 5

Wherein R ₃ , R ₄ , X and Ph are as defined above.

The preparation method of the compound of formula 3 according to the present invention is shown in Scheme 2 below.

In the reaction, CuCl, CuCl ₂ , HBF ₄ , NaOCH ₃ , NaOEt, etc. may be used as the catalyst, the amount of which is typically 1/20 to 1/300 equivalent times based on the carbodiimide compound of Formula 5 The range is preferred, and more preferably used in the range of 1/100 to 1/200 equivalent times. However, when HBF ₄ is used as a catalyst, since the catalyst forms a salt with the compound of Formula 3, it is preferable to use 1 to 2 equivalents based on the carbodiimide compound.

The reaction may be carried out in the absence or presence of a solvent, and solvents usable when reacting in a solvent include N, N-dimethylformamide, tetrahydrofuran, chloroform, methylene chloride, dioxane and the like. However, a more preferred state is to proceed with the reaction without solvent. Since the solvent may not be used as described above, the manufacturing method can significantly reduce the generation of wastewater, and also has the advantage of reducing the manufacturing cost due to a simple manufacturing process.

The reaction is carried out at a temperature range of -10 to 100 ° C, preferably at 0 to 50 ° C, most preferably at 0 to 30 ° C. The reaction time is not critical and may vary depending on the compound participating in the reaction.

The compound of formula 3 prepared according to the scheme of Scheme 2 may be used for the reaction of Scheme 1 to prepare a compound of formula 1 after separation through distillation (discontinuous reaction), if necessary It is also possible to proceed with the reaction of Scheme 1 in one vessel (continuous reaction; One-pot Reaction).

As the reactions of the reaction schemes 1 and 2 described above, the degree of formation of the compounds of Formulas 1 and 3 may be confirmed using any one of TLC, GC, HPLC, NMR, and IR. In the preparation of the compound, IR was used to observe the progress of the reaction, and in the preparation of the compound of Formula 1 through esterification, NMR was used to observe the transition of the double bond during the reaction.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, these examples are only for the understanding of the present invention, and the scope of the present invention is not limited by them in any sense.

Example 1

Preparation of N, N'-diisopropyl-O-diphenylmethyl isourea

A) A mixed solution of 1.6 g of N, N'-diisopropylcarbodiimide and 7 mg of copper chloride (I) was cooled to 0 ° C. and 2.3 g of diphenylmethanol was slowly added thereto over 30 minutes while stirring. After stirring for 1 hour at the same temperature, the mixture was stirred at room temperature. By IR analysis, the reaction endpoint was determined by confirming the disappearance of the diimide absorption band characteristically at 2100 cm ⁻¹ and the characteristic absorption band of isourea at 1660 cm ⁻¹ . After the reaction was completed, hexane was added to the reaction solution, an insoluble matter was removed using a neutral alumina filter pad, washed with hexane, and the filtrate was concentrated to give 3.7 g (yield 94%) of the title compound. The residue obtained can be distilled under reduced pressure, if necessary, to obtain the title compound in a pure state.

IR (neat) cm ^-1 : 1660

¹ H NMR (CDCl ₃ ) δ 1.01 (6H, d), 1.13 (6H, d), 3.12 (1H, brs), 3.40 (1H, brs), 3.97 (1H, brs), 7.07 (1H, s), 7.20-7.40 (10H, m)

Elemental Analysis: Theoretical Value (%) C, 77.38; H, 8. 44; N, 9.02

Found (%) C, 77.31; H, 8.33; N, 9.00

B) The title compound was obtained in the same manner as in Example 1 a) except that copper chloride (II) was used as the reaction catalyst (yield 93%).

C) The title compound was obtained in the same manner as in Example 1 a) except that sodium methoxide was used as the reaction catalyst (yield 90%).

D) The title compound was obtained in the same manner as in Example 1 a) except that sodium ethoxide was used as the reaction catalyst (yield 91%).

E) 1.6 g of N, N'-diisopropylcarbodiimide and 2.3 g of diphenylmethanol are dissolved in 7 ml of methylene chloride, and then 2.26 g of tetrafluoroborane (HBF ₄ ) diethyl ether is added thereto. The solution diluted in ml was added slowly. The reaction mixture was stirred for 1 hour, cooled to 0 ^° C., and then slowly added 50 ml of anhydrous ether to give 4.64 g (92% yield) of HBF ₄ salt of N, N'-diisopropyl-O-diphenylmethylisourea. Obtained. The HBF ₄ salt thus obtained was dissolved in water, neutralized with sodium hydroxide solution, extracted with petroleum ether, washed with water, dried and concentrated under reduced pressure to obtain 3.54 g (yield 90%) of the title compound.

F) In Example 1) a) except that 1.6 g of N, N'-diisopropylcarbodiimide was dissolved in 2 ml of N, N-dimethylformamide and copper chloride (I) was added thereto. The reaction was carried out in the same manner to yield 3.58 g (91%) of the title compound.

G) Reaction as in Example 1) a) except that 1.6 g of N, N'-diisopropylcarbodiimide was dissolved in 5 ml of tetrahydrofuran and copper chloride (I) was added thereto. To give 3.6 g (91% yield) of the title compound.

Example 2

Preparation of N, N'-dicyclohexyl-O-diphenylmethyl isourea

A) 20.6 g of N, N'-dicyclohexylcarbodiimide and 18.4 g of diphenylmethanol were reacted in the same manner as in Example A) at 35 to 45 ° C. to obtain 38 g (yield 97%) of the title compound. It was.

IR (neat) cm ^-1 : 1665

¹ H NMR (CDCl ₃ ) δ 3.00 (1H, brs), 3.29 (1H, brs), 3.85 (1H, brs), 7.10 (1H, s)

B) in Example 2 a) except that 20.6 g of N, N'-dicyclohexylcarbodiimide was dissolved in 10 ml of N, N-dimethylformamide and copper chloride (I) was added thereto. In the same manner as in, 35g (yield 90%) of the title compound was obtained.

C) The same reaction as in Example 2) a) except that 20.6 g of N, N'-dicyclohexylcarbodiimide was dissolved in 50 ml of tetrahydrofuran and copper chloride (I) was added thereto. This gave 36 g (92% yield) of the title compound.

Example 3

Preparation of Diphenylmethyl 3-acetoxymethyl-7β-phenylacetylamino-3-cepem-4-carboxylate

A) 3.9 g of 3-acetoxymethyl-7β-phenylacetylamino-3-cepem-4-carboxylic acid was dissolved in 20 ml of tetrahydrofuran, and the reaction solution was cooled to 0 deg. A solution of 6 g of N, N'-diisopropyl-O-diphenylmethylisourea diluted in 10 ml of tetrahydrofuran was added dropwise thereto, and the reaction temperature was raised to room temperature and stirred for 18 hours. . The resulting urea was removed by filtration, and the filtrate was concentrated. 100 ml of diethyl ether was added to the residue, followed by stirring at room temperature for 1 hour. The resulting precipitate was filtered to give 5.1 g (90% yield) of the title compound.

IR (nujol) cm ^-1 : 1765, 1715, 1650

¹ H NMR (CDCl ₃ ) δ 2.0 (3H, s), 3.4 (2H, ABq), 3.62 (2H, ABq), 4.9 (2H, ABq), 4.93 (1H, d), 5.85 (1H, m), 6.25 (1 H, d), 6.92 (1 H, s), 7.32 (15 H, m)

B) Example 3, except that 7.8 g of N, N'-dicyclohexyl-O-diphenylmethylisourea is used instead of N, N'-diisopropyl-O-diphenylmethylisourea In the same manner as in (a), the title compound was obtained (yield 89%).

C) A mixture of 2.44 g of N, N'-diisopropylcarbodiimide and 10 mg of copper chloride (I) was cooled to 0 deg. C and 3.56 g of diphenylmethanol was slowly added over 30 minutes while stirring. After stirring for 1 hour at the same temperature, the mixture was stirred at room temperature. The reaction end point was determined in the same manner as in Example 1) a), and the reaction solution was filtered, and 10 ml of tetrahydrofuran was added thereto to prepare an isourea solution.

In a separately prepared container, 3.9 g of 3-acetoxymethyl-7β-phenylacetylamino-3-cepem-4-carboxylic acid was dissolved in 20 ml of tetrahydrofuran and the reaction solution was cooled to 0 ° C. The isourea solution prepared in the previous step was added dropwise thereto, and the reaction temperature was raised to room temperature and stirred for 18 hours. The resulting urea was removed by filtration, and the filtrate was concentrated. 100 ml of diethyl ether was added to the residue, which was then stirred at room temperature for 1 hour. The resulting precipitate was filtered to give 5.2 g (92% of total yield) of the title compound.

Example 4

Preparation of Diphenylmethyl 3-hydroxymethyl-7β-phenylacetylamino-3-cepem-4-carboxylate

A) 3.5 g of 3-hydroxymethyl-7β-phenylacetylamino-3-cepem-4-carboxylic acid and 4.04 g of N, N'-diisopropyl-O-diphenylmethylisourea are reacted. In the same manner as in Example a), 4.74 g (yield 92%) of the title compound were obtained.

IR (nujol) cm ^-1 : 3300, 1765, 1715, 1650

¹ H NMR (DMSO-d ₆ ) δ 3.61 (2H, s), 3.62 (2H, s), 4.27 (2H, d), 4.93 (1H, d), 5.13 (1H, d), 5.73 (1H, dd ), 6.91 (1H, s), 7.12-7.70 (15H, m), 9.13 (1H, d)

B) Example 4 except that 7.8 g of N, N'-dicyclohexyl-O-diphenylmethylisourea is used instead of N, N'-diisopropyl-O-diphenylmethylisourea. The title compound was obtained in the same manner as in a) (yield 90%).

Example 5

Preparation of Diphenylmethyl 3-acetoxymethyl-7β-phenylacetylamino-3-cepem-4-carboxylate-1-sulfoxide

A) 4.06 g of 3-acetoxymethyl-7β-phenylacetylamino-3-cepem-4-carboxylic acid-1-sulfoxide and 4.04 g of N, N'-diisopropyl-O-diphenylmethylisourea are reacted. Except for that, the same procedure as in Example 3) a) gave 4.98 g (87% yield) of the title compound.

IR (nujol) cm ^-1 : 1765, 1715, 1650

¹ H NMR (CDCl ₃ ) δ 2.0 (3H, s), 3.62 (2H, ABq), 3.85 (2H, ABq), 4.9 (2H, ABq), 4.93 (1H, d), 5.85 (1H, m), 6.25 (1 H, d), 6.92 (1 H, s), 7.32 (15 H, m)

B) Example 5 except that 7.8 g of N, N'-dicyclohexyl-O-diphenylmethylisourea is used instead of N, N'-diisopropyl-O-diphenylmethylisourea. The title compound was obtained in the same manner as in a) (yield 90%).

Example 6

Preparation of Diphenylmethyl 3-hydroxymethyl-7β-phenylacetylamino-3-cepem-4-carboxylate-1-sulfoxide

A) 3.64 g of 3-hydroxymethyl-7β-phenylacetylamino-3-cepem-4-carboxylic acid-1-sulfoxide and 4.04 g of N, N'-diisopropyl-O-diphenylmethylisourea are reacted. Except for that point, 4.51 g (yield 85%) of the title compound was obtained in the same manner as in Example 3A).

IR (nujol) cm ^-1 : 3400, 1765, 1715, 1660

¹ H NMR (DMSO-d ₆ ) δ 3.62 (2H, s), 3.95 (2H, s), 4.27 (2H, d), 4.91 (1H, d), 5.13 (1H, d), 5.8 (1H, dd ), 6.91 (1H, s), 7.12-7.70 (15H, m), 9.13 (1H, d)

B) Example 6 except that 7.8 g of N, N'-dicyclohexyl-O-diphenylmethylisourea is used instead of N, N'-diisopropyl-O-diphenylmethylisourea. The title compound was obtained in the same manner as in a) (yield 89%).

Example 7

Preparation of Diphenylmethyl 7β- [5-benzamido-5- (diphenylmethoxycarbonyl) valeramido] -3-hydroxymethyl-3-cepem-4-carboxylate

A) 12 g of deacetylcephalosporin C sodium salt was dissolved in a mixed solution of 100 ml of water and 60 ml of acetone and cooled to 0 ° C. 4.2 g of benzoyl chloride was slowly added dropwise thereto while vigorously stirring and adjusting the pH of the reaction solution to 6.5 to 7.5 with 20% aqueous sodium carbonate solution. After stirring for about 1 hour, acetone was removed under reduced pressure, and the aqueous layer was washed with ethyl acetate. The pH of the aqueous layer was adjusted to 2.5 using 6N HCl and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure. 100 ml of tetrahydrofuran was added to the obtained residue, and the reaction solution was cooled to 0 deg. C, and 37 g of N, N'-diisopropyl-O-diphenylmethylisourea in 20 ml of tetrahydrofuran was slowly added dropwise. It was. Thereafter, the mixture was stirred at room temperature for 17 hours to complete the reaction, and the resulting insolubles were filtered and removed, and the filtrate was concentrated under reduced pressure. 400 ml of diethyl ether was added to the obtained residue, the mixture was stirred for 1 hour, and then the precipitate was filtered to give 20 g (yield 81%) of the title compound.

IR (nujol) cm ^-1 : 3400, 1765, 1730, 1660

¹ H NMR (DMSO-d ₆ ) δ 1.51-2.52 (6H, m), 3.41 (2H, s), 3.71 (2H, s), 4.32 (2H, m), 4.73 (1H, m), 5.2 (1H , d), 5.8 (1H, dd), 6.85 (1H, s), 6.95 (1H, s), 7.11-7.82 (25H, m), 8.85 (2H, m)

B) Example 7 except that 36 g of N, N'-dicyclohexyl-O-diphenylmethylisourea is used instead of N, N'-diisopropyl-O-diphenylmethylisourea. In the same manner as in), the title compound was obtained (yield 83%).

Example 8

Preparation of Diphenylmethyl 7β- [5-benzamido-5- (diphenylmethoxycarbonyl) valeramido] -3-acetoxymethyl-3-cepem-4-carboxylate

A) 7.5 g (yield 88%) of the title compound were obtained in the same manner as in Example 7A) except that 4.15 g of cephalosporin C was used.

IR (nujol) cm ^-1 : 1765, 1725, 1650

¹ H NMR (DMSO-d ₆ ) δ 1.47-2.54 (6H, m), 2.13 (3H, s), 3.45 (2H, s), 3.74 (2H, s), 4.32 (2H, m), 4.73 (1H , m), 5.17 (1H, d), 5.75 (1H, dd), 6.80 (1H, s), 6.92 (1H, s), 7.21-7.82 (25H, m), 8.82 (2H, m)

B) Example 8, except that 12 g of N, N'-dicyclohexyl-O-diphenylmethylisourea is used instead of N, N'-diisopropyl-O-diphenylmethylisourea. In the same manner as in), the title compound was obtained (yield 90%).

By using the present invention as described above,

First, the desired compound of formula 1 can be prepared under neutral and very mild conditions using inexpensive and readily available raw materials,

Second, the compound of Formula 3 used as an esterification agent is very stable, and when stored in a dry cool dark place can be stored for a long time more than 6 months,

Third, after preparing the compound of Formula 3, the compound of Formula 1 can be prepared by carrying out a one-pot reaction in a container without separating it if necessary,

Fourth, the reaction for preparing the compound of formula (3) can be made by contacting the reactants directly in the absence of an organic solvent can dramatically reduce the generation of waste water, the overall reaction can be performed at almost room temperature, such as industrial application Very easy to

Fifth, the transition of the double bond position, which is a serious problem in the esterification reaction of the cephalosporin derivative, does not occur at all in the method according to the present invention.

Sixth, since the urea derivative produced after the completion of the reaction for preparing the compound of Formula 1 is not soluble in the reaction solution after the reaction can be removed by a simple filtration process has the advantage that the isolation of the desired reaction product is very easy.

Therefore, the compound of formula 3 according to the present invention and a method for preparing the compound of formula 1 using the compound are expected to be very useful in the field of cephalosporin antibiotics.

Claims (10)

A method for preparing a cephalosporin derivative of formula (I) characterized by esterifying a compound of formula (II) with a compound of formula (3): Formula 2

Formula 3

Formula 1

In the above formula, R ₁ is 5-benzamido-5- (diphenylmethoxycarbonyl) valeramido, phenylacetylamino, phenoxyacetylamino, formylamino, N-phthalimido, benzylideneamino, p-methoxybenzyl A protected amino selected from the group consisting of lideneamino, salicylideneamino, t-butoxycarbonylamino or benzyloxycarbonylamino, R ₂ represents hydrogen, halogen, hydroxy, triphenylphosphoniummethyl halide or Lower alkenyl or lower alkyl unsubstituted or substituted by halogen, lower alkoxy, acyloxy or hydroxy, n is an integer from 0 to 2, and R ₃ and R ₄ are each independently cyclohexyl or Isopropyl, X represents oxygen or sulfur atom, Ph represents phenyl. The reaction of claim 1 wherein the reaction is selected from tetrahydrofuran, methylene chloride, N, N-dimethylformamide, N, N-dimethylacetamide, chloroform, ethyl acetate, acetone, methanol, ethanol, isopropanol and t-butanol Method of carrying out in at least a reaction-inert organic solvent. The method of claim 1, wherein the compound of formula 3 is used in an amount of 1 to 5 equivalents based on the compound of formula 2. The method of claim 1, wherein the reaction is carried out at a temperature range of −10 to 60 ° C. for 1 to 24 hours. The method of claim 1, wherein the compound of formula 3 is prepared by reacting an alcohol or thiol compound of formula 4 with a carbodiimide compound of formula 5 in the presence of a catalyst. Formula 4

Formula 5

Wherein R ₃ , R ₄ , X and Ph are as defined in claim 1. The method of claim 5, wherein the catalyst is at least one selected from CuCl, CuCl ₂ , HBF ₄ , NaOCH _3, and NaOEt. The HBF ₄ catalyst is used in an amount of 1 to 2 equivalents based on the carbodiimide compound of Formula 5, and the other catalyst is 1/20 to 1 based on the carbodiimide compound of Formula 5. How to use / 300 equivalent times. The process of claim 5 wherein the reaction proceeds in the absence of solvent. A process according to claim 1, wherein the compound of formula 3 prepared according to claim 5 is reacted with the compound of formula 2 continuously in one vessel without being separated from the reaction solution. A compound of formula Formula 3

Wherein R ₃ , R ₄ , X and Ph are as defined in claim 1.