KR19990015232A - A new esterification method of cephalosporin derivatives - Google Patents

Abstract

The present invention relates to a process for preparing a compound represented by the following formula 3 by reacting an alcohol or thiol compound represented by the following formula 4 with a carbodiimide compound represented by the following formula 5 in the presence of a catalyst to prepare a compound represented by the following formula 3, To a process for easily producing a compound represented by the following formula (1) without transposition of a double bond into? ³ ?? ² .

In this formula,

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

R ₂ represents hydrogen, halogen, hydroxy, triphenylphosphonium methyl halide or lower alkenyl, or lower alkyl which is unsubstituted or substituted by halogen, lower alkoxy, acyloxy or hydroxy,

n is an integer from 0 to 2,

R ₃ and R ₄ are each independently straight or branched chain lower alkyl; C ₃ -C ₇ cycloalkyl; Trityl; Trimethylsilyl; Phenyl unsubstituted or monosubstituted or disubstituted by halogen, lower alkyl, lower alkoxy, nitro or dialkylamino; 2-morpholinoethylmetho-p-toluenesulfonyloxy; Dimethylaminopropylmethyliodide; 3-dimethylaminopropylhydrochloride; Or 2,2-dimethyl-1,3-dioxolan-4-ylmethyl,

X represents oxygen or sulfur atom,

Ph represents phenyl.

Description

A new esterification method of cephalosporin derivatives

The present invention relates to a process for preparing a cephalosporin derivative represented by the following general formula (1), characterized in that a compound of the following general formula (2) is esterified with a novel compound of the general formula (3)

(2)

(3)

Formula 1

In this formula,

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

R ₂ represents hydrogen, halogen, hydroxy, triphenylphosphonium methyl halide or lower alkenyl, or lower alkyl which is unsubstituted or substituted by halogen, lower alkoxy, acyloxy or hydroxy,

n is an integer from 0 to 2,

R ₃ and R ₄ are each independently straight or branched chain lower alkyl; C ₃ -C ₇ cycloalkyl; Trityl; Trimethylsilyl; Phenyl unsubstituted or monosubstituted or disubstituted by halogen, lower alkyl, lower alkoxy, nitro or dialkylamino; 2-morpholinoethylmetho-p-toluenesulfonyloxy; Dimethylaminopropylmethyliodide; 3-dimethylaminopropylhydrochloride; Or 2,2-dimethyl-1,3-dioxolan-4-ylmethyl,

X represents oxygen or sulfur atom,

Ph represents phenyl.

In the definition of the substituent for the compound of formula (1), triphenylphosphonium methyl halide is 2-morpholinoethyl methane p-toluenesulfonyloxy represents a structure of , And dimethylaminopropylmethide is a compound represented by the formula .

The present invention also relates to a novel compound of the formula (3) used as a reactant in the process of the above formula (1) and a process for producing the same.

Generally, esterification of a carboxy group by protecting it is performed by a method of reacting an organic acid with an alcohol under an acid catalyst, a method using an acid chloride or mixed acid anhydride, and a dehydrating condensation agent such as dicyclohexylcarbodiimide (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 positional shift to cephem derivatives.

As for the known method applied to esterify the carboxylic acid of the cephalosporin derivative, the most commonly used method so far is to use a diazomethane derivative. However, in this method, it is troublesome to oxidize benzophenone hydrazone with an oxidizing agent such as mercury oxide to prepare the corresponding diphenyldiazomethane, and there is a problem that heavy metal contamination due to the oxidizing agent used is serious. . In addition, the diazomethane derivatives themselves are highly reactive and chemically unstable, which makes them difficult to handle and has a storage problem. Diazomethane compounds are generally toxic and explosive, so that the above method is used for industrial mass production (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 producing diphenylmethyl esters by using oxone (potassium monopersulfate triflate; 2KHSO ₅ .KHSO ₄ .K ₂ SO ₄ ) as an oxidizing agent has been reported (Tetrahedron Letter, 38 (7), 1239 1997). However, in this method, since the sulfolide of the three-photon nucleus is oxidized to sulfoxide by reacting the cephalosporin derivative, the starting material, benzophenone hydrazone, oxone, and a catalytic amount of iodine in the reaction vessel together, There is a disadvantage that the yield is decreased and the manufacturing cost is increased. In addition, since it is necessary to use a strong oxidizing agent, it is difficult to apply it to a substance containing a functional group sensitive to an oxidizing agent, and since it is an exothermic reaction, it is not suitable for mass production.

On the other hand, a method of esterifying a cephalosporin derivative with 4-methoxybenzyl or the like is reported in J. Med. Chem. 33, 2522 (1990), similarly to the method according to the present invention. However, in this method, the double bonds of the three phe- nomena nuclei are partially transferred to? ³ ?? ² , and there is a problem that after the reaction, the mixing ratio of the? ² isomer:? ³ isomer is present as 1: Are very difficult to separate because of their similar physical and chemical properties. As a result, the yield is lowered and the manufacturing cost is increased. In short, until now, no simple and safe method for esterifying the carboxylic acid of the cephalosporin compound has been developed yet, and there is no method that can be applied to mass production.

Accordingly, the present inventors have developed a method for easily esterifying a carboxylic acid of a cephalosporin derivative without shifting the double bond from? ³ to? ² under mild conditions by improving the problems of the above-mentioned prior arts, As a result, it has been found that this object can be achieved efficiently and economically by using the novel compound of the formula (3) having a diphenylmethyl group as an esterifying agent. .

Accordingly, the present invention relates to a method for preparing a cephalosporin derivative of Formula 1, wherein the compound of Formula 3 is used as an esterifying agent.

The present invention also relates to novel compounds of formula (III) and their preparation. Hereinafter, the configuration of the present invention will be described in more detail.

The present invention relates to a process for preparing a cephalosporin derivative represented by the following general formula (1), characterized in that the compound of the general formula (2) is esterified with a novel compound of the general formula (3)

In this formula,

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

The process according to the present invention for preparing the compound of formula (1) achieves the effect that the double bond does not transfer under mild conditions by using the new cheap and easy-to-handle compound of formula (3) as an esterifying agent.

The reaction is preferably carried out in a reaction-inert organic solvent, and examples of the usable solvent include tetrahydrofuran, methylene chloride, N, N-dimethylformamide, N, N-dimethylacetamide, chloroform, ethyl acetate, acetone , Methanol, ethanol, isopropanol and t-butanol. More preferably, tetrahydrofuran, N, N-dimethylformamide or methanol can be used, and most preferably tetrahydrofuran is used.

The esterifying agent of the formula (3) may be used in an amount of 1 to 5 times the amount of the cephalosporin compound of the formula (2), preferably 1 to 2 times.

The reaction can be carried out in the range of -10 to 60 ° C for 1 to 24 hours to obtain good results, preferably in the range of -10 to 40 ° C, more preferably in the range of 0 to 30 ° C.

On the other hand, the compound of the formula (3) used as an esterification agent in the above Reaction Scheme 1 itself is a novel compound, and the compound and its preparation method are also objects of the present invention.

The compound of formula (3) can be used separately because it is easy to prepare and is very stable, and it can be used in the reaction of the reaction formula (1) immediately after separation.

In order to prepare the esterifying compound of formula (3) according to the present invention, an alcohol or thiol compound of the following formula (4) is reacted with a carbodiimide compound of the formula (5) in the presence of a catalyst according to Synthesis, 561 (1979) Quot; in the following description.

Formula 4

Formula 5

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

The method of preparing the compound of Formula 3 according to the present invention can be summarized as a reaction scheme as shown in Reaction Scheme 2 below.

In the above reaction, CuCl, CuCl ₂ , HBF ₄ , NaOCH ₃ , NaOEt and the like can be used as the catalyst. The amount of the catalyst to be used is usually 1/20 to 1/300 times the amount of the carbodiimide compound of formula Range, and more preferably in a range of 1/100 to 1/200 equivalents. However, when HBF ₄ is used as a catalyst, it forms a salt with the compound of formula (III) in which the catalyst is formed, so it is preferable to use 1 to 2 equivalents based on the carbodiimide compound.

The reaction may be carried out in the presence or absence of a solvent. Examples of the solvent that can be used in the reaction include N, N-dimethylformamide, tetrahydrofuran, chloroform, methylene chloride, dioxane and the like. However, a more preferable state is to proceed the reaction without a solvent. Since the solvent is not used in this way, the production method can remarkably reduce the generation of wastewater, and has a merit that manufacturing cost can be reduced due to a simple manufacturing process.

The reaction is carried out at a temperature range of -10 to 100 캜, preferably 0 to 50 캜, most preferably 0 to 30 캜. 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 method of Scheme 2 may be used in the reaction of Scheme 1 for the preparation of the compound of formula (1) after separation by distillation (discontinuous reaction) and, if necessary, The reaction of Scheme 1 may be continued in one vessel (continuous reaction: One-pot Reaction).

The degree to which the compounds of formulas (1) and (3) are produced by proceeding the reaction of the above-mentioned reaction formulas 1 and 2 can be confirmed by using any one of TLC, GC, HPLC, NMR and IR. In particular, During the preparation of the compound, IR was used to observe the progress of the reaction. During the preparation of the compound of formula (1) via esterification, NMR was used to observe the transition of the double bond during the reaction.

Hereinafter, the present invention will be described more specifically with reference to the following examples. However, these embodiments are provided to aid understanding of the present invention, and the scope of the present invention is not limited thereto in any sense.

Example 1

Preparation of N, N'-diisopropyl-O-diphenylmethylisourea

A) A mixture of 1.6 g of N, N'-diisopropylcarbodiimide and 7 mg of copper (I) chloride was cooled to 0 ° C and 2.3 g of diphenylmethanol was gradually added thereto over 30 minutes while stirring. The mixture was further stirred at the same temperature for 1 hour and then at room temperature. By IR analysis, the diimide-absorption band appears characteristically in 2100cm ^-1 disappeared and the reaction end point was determined by checking the characteristic absorption bands appear at 1660cm ^-1 yisowoo LEA. After the reaction was completed, hexane was added to the reaction solution, insolubles were removed using a neutral alumina filter pad, and then washed with hexane. The filtrate was concentrated to obtain 3.7 g (yield 94%) of the title compound. If necessary, the obtained residue can be distilled under reduced pressure to give 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 (10 H, m)

Elemental analysis: Theoretical (%) 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 (yield 93%) by reacting in the same manner as in Example 1, a) except that copper (II) chloride was used as the reaction catalyst.

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

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

1.6 g of N, N'-diisopropylcarbodiimide and 2.3 g of diphenylmethanol were dissolved in 7 ml of methylene chloride, followed by the addition of 2.26 g of tetrafluoroborane acid (HBF ₄ ) diethyl ether to methylene chloride 7 Ml was slowly added to the solution. The reaction solution was stirred for 1 hour, cooled to 0 ^° C, and then 50 ml of anhydrous ether was gradually added to obtain 4.64 g (yield 92%) of HBF ₄ salt of N, N'-diisopropyl-O-diphenylmethylisourea ≪ / RTI > 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 give 3.54 g (yield 90%) of the title compound.

(F) A solution prepared by dissolving 1.6 g of N, N'-diisopropylcarbodiimide in 2 ml of N, N-dimethylformamide and adding copper chloride (I) thereto, To give 3.58 g (yield 91%) of the title compound.

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

Example 2

Preparation of N, N'-dicyclohexyl-O-diphenylmethylisourea

A) 20.6 g of N, N'-dicyclohexylcarbodiimide and 18.4 g of diphenylmethanol were reacted at 35 to 45 ° C in the same manner as in Example 1) a) to give 38 g (yield 97%) of the title compound Respectively.

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) A solution prepared by dissolving 20.6 g of N, N'-dicyclohexylcarbodiimide in 10 ml of N, N-dimethylformamide and adding copper chloride (I) thereto, To give 35 g (yield 90%) of the title compound.

C) Except that 20.6 g of N, N'-dicyclohexylcarbodiimide was dissolved in 50 ml of tetrahydrofuran, and copper (I) chloride was added thereto, the reaction was carried out in the same manner as in Example 2) To give 36 g (yield 92%) of the title compound.

Example 3

Preparation of diphenylmethyl 3-acetoxymethyl-7? -Phenylacetylamino-3-cephem-4-carboxylate

A) 3.9 g of 3-acetoxymethyl-7? -Phenylacetylamino-3-cephem-4-carboxylic acid was dissolved in 20 ml of tetrahydrofuran, and the reaction solution was cooled to 0 占 폚. To this was added dropwise a solution of 6 g of N, N'-diisopropyl-O-diphenylmethylisourea prepared in Example 1 in 10 ml of tetrahydrofuran, the reaction temperature was raised to room temperature, and the mixture was 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 resulting residue, and the mixture was stirred at room temperature for 1 hour. The resulting precipitate was filtered to give 5.1 g (yield 90%) 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 (1H, d), 6.92 (1H, s), 7.32 (15H, m)

B) In the same manner as in Example 3 (1) except that 7.8 g of N, N'-dicyclohexyl-O-diphenylmethylisourea was used in place of N, N'-diisopropyl- ) To give the title compound (yield 89%).

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

In a separately prepared vessel, 3.9 g of 3-acetoxymethyl-7? -Phenylacetylamino-3-cephem-4-carboxylic acid was dissolved in 20 ml of tetrahydrofuran and the reaction solution was cooled to 0 占 폚. The isourea solution prepared in the previous step was added dropwise thereto, and then 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, and the mixture was stirred at room temperature for 1 hour. The resulting precipitate was filtered to give 5.2 g of the title compound (total yield 92%).

Example 4

Preparation of diphenylmethyl 3-hydroxymethyl-7? -Phenylacetylamino-3-cephem-4-carboxylate

A) Except that 3.5 g of 3-hydroxymethyl-7? -Phenylacetylamino-3-cephem-4-carboxylic acid and 4.04 g of N, N'-diisopropyl-O-diphenylmethylisourea were reacted The procedure of Example 3, step a) was followed to give 4.74 g (yield 92%) of the title compound.

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

B) The procedure of Example 4 was repeated except that 7.8 g of N, N'-dicyclohexyl-O-diphenylmethylisourea was used in place of N, N'-diisopropyl-O-diphenylmethylisourea. A), the title compound was obtained (yield: 90%).

Example 5

Preparation of diphenylmethyl 3-acetoxymethyl-7? -Phenylacetylamino-3-cephem-4-carboxylate-1-sulfoxide

A) 4.06 g of 3-acetoxymethyl-7? -Phenylacetylamino-3-cephem-4-carboxylic acid-1-sulfoxide and 4.04 g of N, N'-diisopropyl-O-diphenylmethylisourea were reacted , The title compound (4.98 g, yield: 87%) was obtained.

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 (1H, d), 6.92 (1H, s), 7.32 (15H, m)

B) The procedure of Example 5 was repeated except that 7.8 g of N, N'-dicyclohexyl-O-diphenylmethylisourea was used in place of N, N'-diisopropyl-O-diphenylmethylisourea. A), the title compound was obtained (yield: 90%).

Example 6

Preparation of diphenylmethyl 3-hydroxymethyl-7? -Phenylacetylamino-3-cephem-4-carboxylate-1-sulfoxide

A) 3.64 g of 3-hydroxymethyl-7? -Phenylacetylamino-3-cephem-4-carboxylic acid-1-sulfoxide and 4.04 g of N, N'-diisopropyl-O-diphenylmethylisourea were reacted , 4.51 g (yield 85%) of the title compound was obtained.

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

B) The procedure of Example 6 was repeated except that 7.8 g of N, N'-dicyclohexyl-O-diphenylmethylisourea was used in place of N, N'-diisopropyl-O-diphenylmethylisourea. A), the title compound was obtained (yield: 89%).

Example 7

Preparation of diphenylmethyl 7? - [5-benzamido-5- (diphenylmethoxycarbonyl) valeramido] -3-hydroxymethyl-3-cephem-4-

A) In a mixed solution of 100 ml of water and 60 ml of acetone, 12 g of sodium salt of deacetylcellosporin C was dissolved and cooled to 0 占 폚. To this was slowly added 4.2 g of benzoyl chloride with vigorous stirring and 20% aqueous sodium carbonate while adjusting the pH of the reaction mixture to 6.5 to 7.5. After stirring for about 1 hour, the 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, the reaction solution was cooled to 0 ° C, and 37 g of N, N'-diisopropyl-O-diphenylmethylisourea in 20 ml of tetrahydrofuran was slowly added dropwise Respectively. Thereafter, the reaction was completed by stirring at room temperature for 17 hours, and the resulting insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. To the residue obtained, 400 ml of diethyl ether was added and 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 (1H, d), 5.8 (1H, dd), 6.85 (1H, s), 6.95 (1H, s), 7.11-7.82

B) The procedure of Example 7 was repeated except that 36 g of N, N'-dicyclohexyl-O-diphenylmethylisourea was used instead of N, N'-diisopropyl-O-diphenylmethylisourea ), The title compound was obtained (yield: 83%).

Example 8

Preparation of diphenylmethyl 7? - [5-benzamido-5- (diphenylmethoxycarbonyl) valeramido] -3-acetoxymethyl-3-cephem-

A) By carrying out in the same manner as in the step a) of Example 7 except that 4.15 g of cephalosporin C was used, 7.5 g (yield 88%) of the title compound was obtained.

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 (2H, m), 5.17 (1H, d), 5.75 (1H, dd), 6.80 (1H, s), 6.92 (1H, s), 7.21-7.82

B) The procedure of Example 8 was repeated except that 12 g of N, N'-dicyclohexyl-O-diphenylmethylisourea was used instead of N, N'-diisopropyl-O-diphenylmethylisourea ), The title compound was obtained (yield: 90%).

[0053] By using the present invention as described above,

First, it is possible to produce the desired compound of formula (I) under neutral and very mild conditions using raw materials that are inexpensive and readily available,

Second, the compound of formula (3) used as an esterifying agent is very stable and can be stored for 6 months or longer when stored in a dry cold cow,

Third, the compound of formula (1) may be prepared by performing a one-pot reaction in a container without separating the compound of formula (3) if necessary,

Fourth, the reaction for preparing the compound of formula (III) can be carried out by directly contacting the reactants in the absence of an organic solvent, thereby dramatically reducing the generation of wastewater. In addition, the entire reaction can be performed at room temperature, And,

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

Sixth, since the urea derivative formed after completion of the reaction for preparing the compound of formula (1) is not dissolved in the reaction solution after the reaction, it can be removed by a simple filtration process, and the desired reaction product can be easily isolated.

Accordingly, the compound of formula 3 according to the present invention and the method of 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 producing a cephalosporin derivative represented by the following formula (1), characterized by esterifying a compound represented by the following formula (2) (2) (3) Formula 1 In this formula, R ₁ is amino protected by a common amino protecting group, preferably 5-benzamido-5- (diphenylmethoxycarbonyl) valeramido, phenylacetylamino, phenoxyacetylamino, formylamino, N-phthalimido, benzylideneamino, p-methoxybenzylideneamino, salicylideneamino, t-butoxycarbonylamino or benzyloxycarbonylamino, R ₂ represents hydrogen, halogen, hydroxy, triphenylphosphonium methyl halide or lower alkenyl, or lower alkyl which is unsubstituted or substituted by halogen, lower alkoxy, acyloxy or hydroxy, n is an integer from 0 to 2, R ₃ and R ₄ are each independently straight or branched chain lower alkyl; C ₃ -C ₇ cycloalkyl; Trityl; Trimethylsilyl; Phenyl unsubstituted or monosubstituted or disubstituted by halogen, lower alkyl, lower alkoxy, nitro or dialkylamino; 2-morpholinoethylmetho-p-toluenesulfonyloxy; Dimethylaminopropylmethyliodide; 3-dimethylaminopropylhydrochloride; Or 2,2-dimethyl-1,3-dioxolan-4-ylmethyl, X represents oxygen or sulfur atom, Ph represents phenyl. The process according to claim 1, wherein the reaction is carried out in a solvent selected from tetrahydrofuran, methylene chloride, N, N-dimethylformamide, N, N-dimethylacetamide, chloroform, ethyl acetate, acetone, methanol, ethanol, isopropanol and t- In a reaction-inert organic solvent. The method according to 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 process according to claim 1, wherein the reaction is carried out at a temperature ranging from -10 to 60 占 폚 for 1 to 24 hours. The process 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 member selected from the group consisting of CuCl, CuCl _2, HBF _4, NaOCH _3, and NaOEt. 7. The method of claim 6, wherein 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 used in an amount of 1/20 to 1 / 300 equivalent of the method used. 6. The method of claim 5, wherein the reaction proceeds in the absence of a solvent. The method according to claim 1, wherein the compound of formula (3) prepared according to claim 5 is continuously reacted with the compound of formula (2) in a vessel without being separated from the reaction solution. A compound of formula (3) (3) Wherein R ₃ , R ₄ , X and Ph are as defined in claim 1.