KR20030061524A - Method for preparing arginine derivatives - Google Patents

Abstract

PURPOSE: A process for preparing arginine derivatives is provided, thereby providing solution to problems caused by the intermediate compound and decreasing the amount of tertiary amine used in a reaction. Therefore, arginine derivatives can be prepared in higher yield under mild conditions. CONSTITUTION: A process for preparing arginine derivatives comprises the steps of: (a) reacting arginine derivatives of the formula 3 with halocatecholborane of the formula 4 to prepare free amine arginine derivatives of the formula 2, wherein tert-butoxycarbonyl(carbamate) is removed; and (b) reacting the free amine arginine derivatives of the formula 2 with base in the presence of tertiary amine to prepare aryl group coupled arginine derivatives of the formula 1, wherein R1 is hydrogen or C1-C5 lower alkyl; Ar is phenyl, naphthalenyl, or quinolinyl; R2 is hydrogen, or C1-C5 lower alkyl; R3 is hydrogen or C1-C5 lower alkyl; and BOC is tert-butyloxycarbonyl.

Description

Preparation method of arginine derivative {METHOD FOR PREPARING ARGININE DERIVATIVES}

The present invention relates to a method for preparing an arginine derivative, and more particularly, in the production reaction of an arginine derivative, by absorption of a hydrochloride-type reaction intermediate formed in the step of removing tert-butyloxycarbonyl group (carbamate), which is a protecting group. The present invention relates to a method for preparing an arginine derivative capable of resolving deliquescent properties and simultaneously reducing the amount of tertiary amine base used.

Arginine derivatives are known materials that can be used as raw materials for inhibitors for thromboxane synthetase, as disclosed in Japanese Patent Laid-Open No. 62-34035.

As the arginine derivative, the protecting group is removed to introduce another functional group at the amine position of the compounds protected by the tert-butyloxycarbonyl group (carbamate). In most cases, anhydrous hydrochloric acid may be used to Prepare the intermediate.

[Formula 5]

(In Formula 5,

R is hydrogen or a lower alkyl group having 1 to 5 carbon atoms)

The intermediate represented by Chemical Formula 2 is prepared by the method of Scheme 1 below, as disclosed in Japanese Patent Laid-Open No. 62-34035.

Scheme 1

In the above method, anhydrous hydrochloric acid is used as a raw material for protecting group removal, and the compound produced by this method has a hydrochloride form for the amine.

The compound has deliquescent property by hygroscopicity. The deliquescent properties interfere with the coupling reaction with the aromatic sulfonyl compound after the step of removing the protecting group, and since the hydrochloric acid contained in the product must be removed in the next reaction, the amount of the tertiary amine required for the reaction is at least doubled. There is a problem in that it is necessary.

As a method for preventing such degradability, there is a method of distilling as it is in a state filled with an ether organic solvent and a method of working in a special environment from which moisture is removed. However, in the former case, the explosiveness of the ether is concerned, and in the latter case, the installation cost is high. In addition, since the reaction using hydrochloric acid reacts at a low temperature of about 0 ° C., there is a problem that the reaction conditions are not easy.

Therefore, in the method for preparing an arginine derivative capable of solving the deliquescent property of the hydrochloride-type reaction intermediate formed in the step of removing the tert-butyloxycarbonyl group (carbamate), which is a protecting group, and at the same time reducing the amount of the tertiary amine base. More research is needed.

In order to solve the above problems, the present invention solves the deliquescent property by the absorption of the reaction intermediate in the form of hydrochloride in the tert- butyloxycarbonyl group (carbamate) removal step as a protecting group, and at the same time reduce the amount of tertiary amine base It is an object of the present invention to provide a method for preparing arginine derivatives.

It is another object of the present invention to provide a method for preparing an arginine derivative having easy reaction conditions.

In order to achieve the above object, the present invention provides a method for producing an arginine derivative represented by the following formula (1),

In the manufacturing method of the arginine derivative represented by the following formula (1),

a) an arginine derivative compound represented by the following Chemical Formula 3 and the following Chemical Formula 4

By reacting the displayed halocatecholborane, tert-butoxycarbonyl group (carbamate)

To remove the arginine derivative of the free amine state represented by the formula (2)

Coordinating; And

b) a subunit of the free amine state prepared in step a) in the presence of a tertiary amine as base.

By reacting an arylsulfonyl halide compound with a leginine derivative,

To prepare an arginine derivative represented by the formula

It provides a method for preparing an arginine derivative comprising:

[Formula 1]

In the formula of Formula 1,

R ₁ is hydrogen or a lower alkyl group having 1 to 5 carbon atoms,

Ar is an aromatic functional group which is phenyl, naphthalenyl, or quinolinyl.

[Formula 2]

In the formula (2),

R ₂ is hydrogen or a lower alkyl group having 1 to 5 carbon atoms.

[Formula 3]

In the formula (3),

R ₃ is hydrogen or a lower alkyl group having 1 to 5 carbon atoms,

BOC is a tert-butyloxycarbonyl group.

[Formula 4]

Hereinafter, the present invention will be described in detail.

The inventors of the present invention have studied argonine derivative compounds and halocatecholborane while studying a method for solving the deliquescent property of the hydrochloride-type reaction intermediate formed during the preparation of the arginine derivative and reducing the amount of the tertiary amine base. As a result of the preparation of the arginine derivative in the free amine state, it is possible to solve the deliquescent property due to the absorption of the reaction intermediate in the form of hydrochloride in the step of removing the tert-butyloxycarbonyl group (carbamate), which is a protecting group. It was confirmed that the amount can be reduced, and based on this, the present invention was completed.

The present invention is prepared by reacting the arginine derivative compound represented by the formula (3) with a halocatecholborane represented by the formula (3) to prepare an arginine derivative of the free amine state represented by the formula (2), in the presence of a tertiary amine as a base It is characterized by preparing an arginine derivative represented by the formula (1).

The preparation method of the present invention is according to the following Scheme 2, and Scheme 3.

Scheme 2

In the formula of Scheme 2,

X is a halogen group element which is chlorine, bromine or iodine.

The halocatecholborane represented by Formula 4 used in the present invention is preferably included in 2 to 3 molar equivalents, more preferably 2.1 to 2.6 molar equivalents, relative to the arginine derivative compound represented by Formula 3 above. Will be. The halocatecholborane can be selected from the group consisting of B-chlorocatecholborane, B-bromocatecholborane, and B-iodocatecholborane.

In the reaction of Step a) (Scheme 2), a methyl halide solvent such as methylene chloride or chloroform carbon tetrachloride may be used as a reaction solvent.

Scheme 3

In the formula of Scheme 3,

X is a halogen group element that is chlorine, bromine or iodine,

R 'is hydrogen or a lower alkyl group having 1 to 5 carbon atoms.

The tertiary amine used in the present invention is preferably included in 1 to 2 molar equivalents, more preferably 1.1 to 1.5 molar equivalents relative to the arginine derivative represented by the formula (1). The tertiary amine can be selected from the group consisting of trialkylamines, pyridine derivatives, and imidazole derivatives.

In the reaction of step b) (Scheme 3), a methyl halide solvent such as methylene chloride or chloroform carbon tetrachloride may be used as the reaction solvent. Moreover, it is preferable that reaction temperature is the range of 0-50 degreeC, More preferably, it is the range of 10-30 degreeC.

Hereinafter, preferred examples are provided to help understanding of the present invention, but the following examples are merely to illustrate the present invention, and the scope of the present invention is not limited to the following examples.

EXAMPLE

Example 1

(Preparation of arginine derivative from which tert-butoxycarbonyl group is removed)

27.3 g of an arginine derivative ethyl (2R, 4R) -1- [N ^G -nitro-N ^2- (tert-butoxycarbonyl) -L-arginyl) -4-methyl-2-piperidinecarboxylic acid is solvent It was dissolved in 130 mL of phosphorus methylene chloride. This was added dropwise at room temperature to a solution of 27.8 g of B-bromocatecholborane, halocatecholborane, dissolved in 500 mL of methylene chloride as a solvent. After stirring for 1 hour at room temperature, 130 mL of water was added and stirred for 20 minutes, and diluted with 1,000 mL of methylene chloride. This solution was washed twice with 200 mL of 10% aqueous sodium hydroxide solution and once with 200 mL of saturated sodium chloride solution. The organic layer separated as above was dried over anhydrous magnesium sulfate, and the solvent was distilled under reduced pressure to give 24.7 g of ethyl (2R, 4R) -1- (N ^G -nitro-L-arginyl) -4-methyl-2-pi. Ferridinecarboxylic acid white solid was obtained.

(Manufacture of arginine derivative in which aryl group is bonded)

24.7 g of the ethyl (2R, 4R) -1- (N ^G -nitro-L-arginyl) -4-methyl-2-piperidinecarboxylic acid obtained above was dissolved in 200 mL of chloroform as a solvent, and then maintained at 5 ° C. It was. 7.4 g of triethylamine which is a tertiary amine and 14.8 g of 3-methyl- quinolinesulfonyl chloride which are an arylsulfonyl halide compound were thrown in this order. After stirring for 3 hours at room temperature, the reaction solution was washed twice with 50 mL of water. The organic layer separated as described above was dried over anhydrous magnesium sulfate, the solvent was distilled under reduced pressure, and the residue was purified by column chromatography (chloroform: methyl alcohol = 20: 1) to obtain 33.1 g of an amorphous solid, ethyl (2R, 4R) -1. 30 g of-[N ^G -nitro-N ^2- (3-methyl-8-quinolinesulfonyl) -L-arginyl) -4-methyl-2-piperidinecarboxylic acid were obtained.

Example 2

(Preparation of arginine derivative from which tert-butoxycarbonyl group is removed)

27.3 g of an arginine derivative ethyl (2R, 4R) -1- [N ^G -nitro-N ^2- (tert-butoxycarbonyl) -L-arginyl) -4-methyl-2-piperidinecarboxylic acid is solvent It was dissolved in 130 mL of phosphorus methylene chloride. This was added dropwise at room temperature to a solution of 21.6 g of B-chlorocatecholborane, halocatecholborane, dissolved in 500 mL of methylene chloride as a solvent. After stirring for 1 hour at room temperature, 130 mL of water was added and stirred for 20 minutes, and diluted with 1,000 mL of methylene chloride. This solution was washed twice with 200 mL of 10% aqueous sodium hydroxide solution and once with 200 mL of saturated sodium chloride solution. The organic layer separated as above was dried over anhydrous magnesium sulfate, and the solvent was distilled under reduced pressure to give 25.1 g of ethyl (2R, 4R) -1- (N ^G -nitro-L-arginyl) -4-methyl-2-pi. Ferridinecarboxylic acid white solid was obtained.

(Manufacture of arginine derivative in which aryl group is bonded)

24.7 g of the ethyl (2R, 4R) -1- (N ^G -nitro-L-arginyl) -4-methyl-2-piperidinecarboxylic acid obtained above was dissolved in 200 mL of chloroform as a solvent, and then maintained at 5 ° C. It was. To this, 5.8 g of pyridine as a tertiary amine and 14.8 g of 3-methyl-quinolinesulfonyl chloride as an arylsulfonyl halide compound were added in this order. After stirring for 3 hours at room temperature, the reaction solution was washed twice with 50 mL of water. The organic layer separated as described above was dried over anhydrous magnesium sulfate, the solvent was distilled under reduced pressure, and the residue was purified by column chromatography (chloroform: methyl alcohol = 20: 1) to obtain 33.1 g of an amorphous solid, ethyl (2R, 4R) -1. 28.4 g of-[N ^G -nitro-N ^2- (3-methyl-8-quinolinesulfonyl) -L-arginyl) -4-methyl-2-piperidinecarboxylic acid were obtained.

Comparative example

(Preparation of tert-butoxycarbonyl group removed arginine derivative)

30 g of arginine derivative ethyl (2R, 4R) -1- [N ^G -nitro-N ^2- (tert-butoxycarbonyl) -L-arginyl) -4-methyl-2-piperidinecarboxylic acid After dissolving in 30 mL of ethyl acetate phosphorus, 80 mL of 10% anhydrous ethyl chloride acetate solution was added while maintaining 0 ° C. After stirring for 3 hours, 200 mL of ethyl ether was added. At this point, a white solid was obtained, but soon absorbed moisture to give a gel-like product, which was washed with ethyl ether to give ethyl (2R, 4R) -1- (N ^G -nitro-L-arginyl) -4 -Methyl-2-piperidinecarboxylic acid hydrochloride was obtained.

(Manufacture of arginine derivative in which aryl group is bonded)

25 g of ethyl (2R, 4R) -1- (N ^G -nitro-L-arginyl) -4-methyl-2-piperidinecarboxylic acid hydrochloride was dissolved in 200 mL of chloroform as a solvent, and then maintained at 5 ° C. 13.6 g of triethylamine as a tertiary amine and 14.7 g of 3-methyl-quinolinesulfonyl chloride as an arylsulfonyl halide compound were added thereto in this order. After stirring for 3 hours at room temperature, the reaction solution was washed twice with 50 mL of water. The organic layer separated as described above was dried over anhydrous magnesium sulfate, the solvent was distilled under reduced pressure, and the residue was purified by column chromatography (chloroform: methyl alcohol = 20: 1) to give 32.5 g of an amorphous solid, ethyl (2R, 4R) -1. 22.1 g of-[N ^G -nitro-N ^2- (3-methyl-8-quinolinesulfonyl) -L-arginyl) -4-methyl-2-piperidinecarboxylic acid were obtained.

Experimental Example

Determination and dehydration of the arginine derivative obtained by removing the tert-butoxycarbonyl group prepared in Example 1 or 2, and Comparative Example, and the yield, and measuring the yield of the arginine derivative bonded to the aryl group as the final product The results are shown in Table 1 below.

division Example 1 Example 2 Comparative example Remove protector Way Halocatecholborane Halocatecholborane HCl Dissolution × × ○ Yield (%) 95.1 96.6 Not measurable Aryl bonds Tertiary amine Triethylamine Pyridine Triethylamine equivalent weight 1.1 1.1 2.2 Yield (%) 94.2 89.2 67.8

Through Table 1, the arginine derivatives of the protecting groups of Example 1 and Example 2 using halocatecholborane according to the preparation method of the present invention have been solved by hygroscopic, hydrochloric acid (HCl) in anhydrous conditions The comparative example using did not solve the deliquescent property. In addition, Example 1, Example 2 of the present invention was able to reduce the amount of the tertiary amine to 1/2 times the comparative example, it was confirmed that the yield is also superior to the comparative example.

As described above, according to the production method of the present invention to solve the deliquescent property by the absorption of the reaction intermediate in the form of hydrochloride in the tert-butyloxycarbonyl group (carbamate) removal step of protecting group, and at the same time the amount of tertiary amine base In addition to reducing the reaction conditions, the reaction conditions are easy and there is an effect that can be produced in the arginine derivative in a high yield.

Claims (5)

In the manufacturing method of the arginine derivative represented by the following formula (1), a) an arginine derivative compound represented by the following Chemical Formula 3 and the following Chemical Formula 4 By reacting the displayed halocatecholborane, tert-butoxycarbonyl group (carbamate) To remove the arginine derivative of the free amine state represented by the formula (2) Coordinating; And b) a subunit of the free amine state prepared in step a) in the presence of a tertiary amine as base. By reacting an arylsulfonyl halide compound with a leginine derivative, To prepare an arginine derivative represented by the formula Method for producing an arginine derivative comprising: [Formula 1] In the formula of Formula 1, R ₁ is hydrogen or a lower alkyl group having 1 to 5 carbon atoms, Ar is an aromatic functional group which is phenyl, naphthalenyl, or quinolinyl; [Formula 2] In the formula (2), R ₂ is hydrogen or a lower alkyl group having 1 to 5 carbon atoms; [Formula 3] In the formula (3), R ₃ is hydrogen or a lower alkyl group having 1 to 5 carbon atoms, BOC is a tert-butyloxycarbonyl group. [Formula 4] The method of claim 1, The halocatecholborane represented by the general formula (4) of the step a) of the arginine derivative is contained in 2 to 3 molar equivalents to the arginine derivative compound represented by the formula (3). The method of claim 1, The halocatecholborane of the halocatecholborane represented by the formula (4) of step a) is arginine derivative selected from the group consisting of B-chlorocatecholborane, B-bromocatecholborane, and B-iodocatecholborane Manufacturing method. The method of claim 1, The tertiary amine of step b) is prepared in an arginine derivative containing 1 to 2 molar equivalents to the arginine derivative represented by the formula (1). The method of claim 1, Tertiary amine of step b) is selected from the group consisting of trialkylamine, pyridine derivatives, and imidazole derivatives.