KR100225459B1 - Process for preparing sulfonyl valine peptide - Google Patents

Abstract

The present invention relates to a method for preparing a sulfonylvaline peptide compound from a salt of a sulfonylvaline organic acid, and the process is shown in Scheme 1 below.

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and X are as indicated in the specification.

Description

Method for preparing sulfonylvaline peptide compound

The present invention relates to a process for preparing a sulfonylvaline peptide compound represented by the following general formula (1), wherein a salt of the general formula (3) obtained from an N-alkyloxycarbonyl -? - alkylsulfonylvaline organic acid compound represented by general formula Coupling reaction.

In this formula,

R ¹ represents a C _1-5 lower alkyl group, an arylalkyl group or a C _3-7 cycloalkyl group,

R ² represents a C _1-5 lower alkyl group, an arylalkyl group, a C _3-7 alkenyl group, a C _3-7 cycloalkyl group or an acyloxyalkyl group,

R ³ is a C _1-12 alkyl group, a C _2-12 alkenyl group, a C _3-12 cyclo alkyl group, an acyloxy group, an alkylamino group, a saturated or unsaturated ring derivatives linked to C _3-6 carbon ring or a heterocycle And the N-terminal group of a conventional peptide compound,

X ⁺ represents Na ⁺ , K ⁺ , Li ⁺ or H ₂ N ⁺ R ⁴ R ⁵ ,

R ⁴ and R ⁵ each represents an alkyl group or a cycloalkyl group having ₃ to ₁₂ carbon atoms.

The present invention also includes salts, hydrates and solvates thereof and their epimers, diastereoisomers and tautomeric isomers which may be represented by the general formulas (1), (2) and (3)

The N-alkyloxycarbonyl-beta-alkylsulfonylvaline peptide compound of Formula 1 is an important part of the N-terminal group of the protease inhibitor of human immunodeficiency virus (HIV), and is a therapeutic agent for acquired immunodeficiency syndrome (AIDS) (European Patent Publication EP 601,486A1 and EP 490,667A2), tachykinin is also useful in NK-1 receptor studies (Joisen et al., J. Med. Chem., 1994, 37, 1586) .

The peptide compound of formula (1) can be obtained by a coupling reaction of a compound of formula (2) with an amine. Methods for preparing N-alkyloxycarbonyl- beta -alkylsulfonylvaline compounds of formula (2) include the method disclosed by Joisen et al. (J. Med. Chem., 1994, 37, 1586) The present inventors filed a patent application on the same date as that of the present invention.

In order to obtain the compound of formula (1), conventionally, the compound of formula (2) was obtained by a coupling reaction with an amine. A conventional method for preparing a sulfonylvaline peptide compound of formula (1) is shown in Scheme 2 below.

The N-alkyloxycarbonyl -? - alkylsulfonylvaline compounds of the formula (2) are easily produced in high yields. However, the characteristics of the compound are sticky oil phase, which makes purification difficult and quantitative coupling reaction difficult. Therefore, there is a difficulty in separating the excess reactant from the reaction mixture.

The inventors of the present invention have found that sulfonylvaline peptide compounds of formula (1) can be prepared directly from the salt of formula (3) and have completed the present invention. According to the method of the present invention, the sulfonylvaline peptide compound represented by the formula (1) can be directly obtained by using the salt of the formula (3) obtained from the compound of the formula (2) as a starting material.

On the other hand, the preparation of a salt of a sulfonylvaline compound is a reaction that has been widely used in purification of an organic acid, but the present inventors have reported for the first time that a coupling reaction is performed using a salt obtained by the above method as a starting material.

The present invention relates to a method for preparing a sulfonylvaline peptide compound of formula (1) from a sulfonylvaline compound,

The present invention is characterized in that a salt of a sulfonylvaline compound of the formula (3) is subjected to a coupling reaction with an amine to obtain a sulfonylvaline peptide compound of the formula (1).

The present invention relates to a method for preparing a sulfonylvaline peptide compound using a salt of the formula (3) as a starting material, wherein the salt of the formula (3), which is a starting material, Compound, and the overall reaction process is shown in Scheme 3 below.

In this formula,

R ¹ represents a C _1-5 lower alkyl group, an arylalkyl group or a C _3-7 cycloalkyl group,

R ² represents a C _1-5 lower alkyl group, an arylalkyl group, a C _3-7 alkenyl group, a C _3-7 cycloalkyl group or an acyloxyalkyl group,

R ³ is a C _1-12 alkyl group, a C _2-12 alkenyl group, a C _3-12 cyclo alkyl group, an acyloxy group, an alkylamino group, a saturated or unsaturated ring derivatives linked to C _3-6 carbon ring or a heterocycle And the N-terminal group of a conventional peptide compound,

X ⁺ represents Na ⁺ , K ⁺ , Li ⁺ or H ₂ N ⁺ R ⁴ R ⁵ ,

R ⁴ and R ⁵ each represents an alkyl group or a cycloalkyl group having ₃ to ₁₂ carbon atoms.

Each step reaction of the present invention will be described in more detail as follows.

Manufacture of salt

The N-alkyloxycarbonyl -? - alkylsulfonylvaline compound of formula (2) is dissolved in a minimum amount of a nonpolar organic solvent such as ether, and then an appropriate base is slowly added dropwise at an appropriate temperature. This is stored in a refrigerator for a certain period of time to obtain a compound of formula (3), which is a salt of the N-alkyloxycarbonyl -? - alkylsulfonylvaline compound of formula (2).

As the base which can be used at this time, an inorganic base such as sodium hydroxide, potassium hydroxide, lithium hydroxide or the like or an organic base such as diisopropylamine, di-t-butylamine, dicyclohexylamine (DCHA) Dicyclohexylamine can be used.

Also suitable reaction temperatures are 0 ° C to 30 ° C, preferably less than 5 ° C.

The suitable reaction time is 12 hours to 48 hours, preferably 24 hours or more.

The compound of the formula (3), which is a salt of the N-alkyloxycarbonyl -? - alkylsulfonylvaline compound of the formula (2) obtained by the above-mentioned method, is obtained in a handleable solid state and is very Purity is high. Also, since dicyclohexylamine (DCHA) used to make the salt of formula ( ^III ) does not act competitively with the amine (H ₂ NR ³ ) to be added in the coupling reaction, when the salt of formula The coupling compound of the desired formula (1) can easily be obtained in a large amount.

Coupling reaction

The compound of formula (3) is dissolved in a solvent and then cooled. Appropriate coupling reagent and amine (H ₂ NR ³ ) are added thereto and stirred for a certain period of time. After the reaction is completed, water and a solvent are added to dilute the reaction product, followed by purification to obtain a sulfonylvaline peptide compound of formula (1).

The solvent which can be used here is usually a solvent, and methylene chloride is particularly preferable.

As coupling reagents that can be used at this time, conventional coupling reagents can be used. In particular, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC), dicyclohexylcarbodiimide , Benzotriazole-1-reyloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP), pivaloyl chloride, isobutyl chloroformate are preferable.

Amines which can be used also include amines which are customary and are specifically D- (+) - alpha -methylbenzene, (5S) -amino- (3S, 4R) -epoxy- 1R) - (phenylmethyl) propyl] -6-phenylhexanamide.

A suitable cooling temperature is suitably in the range of -80 캜 to 30 캜, preferably -40 캜.

Hereinafter, the sulfonylvaline compound used in the present invention and a method for producing the salt thereof will be described with reference to Preparation Examples.

Preparation Example 1: Preparation of N-isopropyloxycarbonyl-β-methanesulfonyl-L-valine

(Step 1) Preparation of N-isopropyloxycarbonyl-? - (S-methyl) -L-valine

4.50 g (30 mmole) of? -mercapto-L-valine was added to a mixture of 60 ml of dioxane and 20 ml of water, cooled to 0 占 폚 and dissolved by adding 10 ml of 6N aqueous sodium hydroxide solution. To this solution was added 4.62 g (33 mmole) of iodomethane, stirred at 0 < 0 > C for 3 hours and then at room temperature for 2 hours. The methylated reaction product was cooled to 0 占 폚 and 5 ml of a 6N sodium hydroxide aqueous solution and 40 ml of a 1M toluene solution of isopropyl chloroformate were slowly added thereto. The reaction was stirred at 0 < 0 > C for 1 hour, then at room temperature for 2 hours and then the reaction was terminated. After completion of the reaction, the solvent was distilled off under reduced pressure, and then diluted with 50 ml of water to remove unreacted isopropyl chloroformate and extracted with 60 ml of ether. The aqueous layer is lowered to pH 2 or less using concentrated hydrochloric acid, and then extracted with methylene chloride (60 ml × 2). The solvent was distillated under reduced pressure to obtain 5.50 g (yield 77%) of the title compound.

_{^{1 H NMR (CDCl 3):}} δ (ppm) 1.30 (S, 6H), 2.13 (S, 3H), 4.41 (m, 1H), 4.99 (m, 1H), 5.61 (m, 1H), 8.50 (br , 1H)

(Step 2) Preparation of N-isopropyloxycarbonyl-β-methanesulfonyl-L-valine

3 equivalents of oxone and 20 ml of water are placed in a reaction vessel and cooled to 0 占 폚. 5.50 g (22 mmole) of the product obtained in (step 1) above are dissolved in 20 ml of methanol. It is slowly added to the above oxone aqueous solution while paying attention to the intense heat, and then stirred at room temperature for two days. After completion of the reaction, the remaining solid is filtered and the filtrate is distilled off under reduced pressure. Methanol is sufficiently distilled off and the remaining aqueous layer is extracted with methylene chloride (20 ml x 2). This was dried over anhydrous magnesium sulfate and distilled under reduced pressure to obtain 5.70 g (yield 92%) of the title compound.

_{^{1 H NMR (CDCl 3):}} δ (ppm) 1.27 (m, 6H), 1.53 (s, 3H), 2.99 (s, 3H), 3.76 (br, 1H), 4.72 (m, 1H), 4.98 (m , ≪ / RTI > 1H), 5.97 (br, 1H)

Preparation Example 2: Preparation of N-isopropyloxycarbonyl-β-methanesulfonyl-L-valine dicyclohexylamine salt

5.70 g (20.3 mmole) of the product obtained in (Step 2) of Preparation Example 1 was dissolved in 60 ml of ether and cooled to 5 占 폚. 4.04 g (22.3 mmole) of dicyclohexylamine is slowly added, and the mixture is stirred for 1 hour or more. The mixture is allowed to stand at less than 5 ° C for one day to produce sufficient solids. The resulting solid was filtered, washed with 30 ml of ether and sufficiently dried to obtain 8.92 g (yield 95%) of the title compound.

¹ H NMR (CDCl ₃ ):? (Ppm) 1.22 (m, 12H), 1.46 (m, 4H), 1.53 (d, (M, 2H), 4.41 (d, IH), 4.8 (m, IH), 5.76

Hereinafter, the present invention will be described in detail with reference to examples. The examples are illustrative of the present invention and are not intended to limit the scope of the present invention.

Example 1 Preparation of N - [(N-isopropyloxycarbonyl- beta -methanesulfonyl) -L-valinyl] - (R) -methylbenzylamine using isobutyl chloroformate

462 mg of N-isopropyloxycarbonyl-beta-methanesulfonyl-L-valine dicyclohexylamine salt, which was the product obtained in Preparation Example 2, was dissolved in 5 ml of methylene chloride and then cooled to -40 ° C. 1 equivalent (0.13 ml) of isobutyl chloroformate was added to the reaction mixture, followed by stirring for 1 hour. A solution of 1 equivalent (0.13 ml) of D - (+) -? - methylbenzylamine in 0.5 ml of methylene chloride was added thereto, followed by stirring at the same temperature for 30 minutes and at room temperature for 1 hour. After the reaction was completed, water and methylene chloride were added to dilute the reaction product, and the organic layer was sequentially washed with a saturated aqueous NaHCO ₃ solution, a 1 N KHSO ₄ aqueous solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by column chromatography to obtain 269 mg (yield 70%) of the desired amide compound.

_{^{1 H NMR (CDCl 3):}} δ (ppm) 1.13 (m, 6H), 1.37 (s, 3H), 1.42 (d, 3H), 1.50 (s, 3H), 2.78 (s, 3H), 4.53 (d (D, IH), 4.78 (d, IH), 4.78 (m,

Example 2 Synthesis of N - [(N-isopropyloxycarbonyl- beta -methanesulfonyl) -L-valinyl] - ((N-isopropyloxycarbonyl-beta -methanesulfonyl) R) -methylbenzylamine < / RTI >

462 mg of N-isopropyloxycarbonyl-beta-methanesulfonyl-L-valine dicyclohexylamine salt, which was the product obtained in Preparation Example 2, was dissolved in 10 ml of methylene chloride, and then cooled to 0 占 폚. 213 mg of HOBt, 100 mg of N-methylmorpholine, 125 mg of D - (+) - alpha -methylbenzylamine and a catalytic amount of 4-dimethylamino Pyridine were added sequentially to the reaction mixture, followed by stirring for 24 hours. After the reaction was completed, the reaction mixture was diluted with water and methylene chloride, and the organic layer was successively washed with a saturated aqueous NaHCO ₃ solution, an aqueous IN KHSO ₄ solution, and brine. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by column chromatography to obtain 288 mg (yield 75%) of the desired amide compound.

_{^{1 H NMR (CDCl 3):}} δ (ppm) 1.13 (m, 6H), 1.37 (s, 3H), 1.42 (d, 3H), 1.50 (s, 3H), 2.78 (s, 3H), 4.53 (d (D, IH), 4.78 (d, IH), 4.78 (m,

Example 3 Preparation of N - [(N-isopropyloxycarbonyl- beta -methanesulfonyl) -L-valinyl] - (R) -methylbenzylamine using dicyclohexylcarbodiimide (DCC)

Prepared in a similar manner to Example 2 using dicyclohexylcarbodiimide (DCC) as the coupling reagent, to obtain 238 mg (62% yield) of the desired compound.

Example 4 Synthesis of N - [(N-isopropyloxycarbonyl-β-methanesulfonyl) -L- (2-isopropyloxycarbonylphenyl) -methanesulfonamide Using Benzotriazol- Valinyl] - (R) -methylbenzylamine

Was prepared in the same manner as in Example 2, using benzotriazole-1-reyloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP) as a coupling reagent to give 303 mg (yield 79% ≪ / RTI >

Example 5 Preparation of N - [(N-isopropyloxycarbonyl -? - methanesulfonyl) -L-valinyl] - (R) -methylbenzylamine using pivaloyl chloride

This compound was prepared in the same manner as in Example 1, using pivaloyl chloride as the coupling reagent, to obtain 77 mg (yield 20%) of the desired compound.

Example 6 Synthesis of (3S, 4R) -Ethoxy- (5S) - [[N - [(1- methylethoxy) carbonyl] -3- (methylsulfonyl) -L-valinyl] Preparation of 2-methyl- (1R) - [(phenyl) -carbonyl] propyl] -6-phenylhexanamide

Coupling reaction was carried out by the same method as in Example 1 to give 463 mg (yield 72%) of the title compound.

¹ H NMR (CDCl ₃ ):? (Ppm) 0.78 (d, 3H), 1.01 (d, 3H), 1.28 (d, (M, 1H), 2.13 (m, 1H), 2.19 (m, 1H) ), 3.32 (m, 1 H), 4.12 (m, 1 H), 4.60 (d, (m, 2H), 7.79 (m, IH), 7.97 (d, 2H)

The present invention relates to a novel method for preparing a sulfonylvaline peptide compound, and a sulfonylvaline peptide compound is prepared using a salt obtained from a sulfonylvaline compound as a starting material.

According to the preparation method of the present invention, instead of the sulfonylvaline peptide preparation method in the conventional sulfonylvaline compound, a salt of a sulfonylvaline compound is prepared from a sulfonylvaline compound, and a sulfonylvaline peptide The process becomes easier to handle and the salt is obtained in a solid state, so that the sulfonylvaline peptide compound can be quantitatively prepared.

In addition, according to the preparation method of the present invention, a sulfonylvaline peptide compound is prepared by converting a sulfonylvaline compound in an oil state into a salt in a solid state, so that it is difficult to separate the sulfonylvaline compound in an oil state from the reaction mixture It may not go through steps.

Further, according to the production process of the present invention, since the salt obtained from the sulfonylvaline compound has a high purity so that purification is not necessary, there is an advantage that the purification process for the next reaction need not be performed. Also, the yield of the coupling reaction is high since the base for making the salt does not act competitively on the base and the coupling reagent used in the coupling reaction.

Therefore, according to the production method of the present invention, it can be seen that the sulfonylvaline peptide compound has an excellent effect of producing a simple and high purity compound as compared with the conventional method.

Claims (4)

A method for producing a sulfonylvaline peptide compound, which comprises dissolving a salt of a sulfonylvaline organic acid in a solvent, followed by a coupling reaction using an amine and a coupling reagent. Scheme 1 In this formula, R ¹ represents a lower alkyl group, an arylalkyl group or a C _3-7 cycloalkyl group which is C _1-5 , R ² is a C _1-5 lower alkyl group, an aryl group, a C _3-7 alkenyl group, C _3-7 cyclo alkyl group or represents an acyloxy group, R ³ is selected from the group _consisting of a C _1-12 alkyl group, a C _2-12 alkenyl group, a C _3-12 cycloalkyl group, an acyloxyalkyl group, an alkylamino group, a C _3-6 carbon ring or a saturated or unsaturated ring- Terminal group of a peptide compound. X ⁺ represents Na ⁺ , K ⁺ , Li ⁺ or H ₂ N ⁺ R ⁴ R ⁵ , R ⁴ and R ⁵ each represents an alkyl group or a cycloalkyl group having ₃ to ₁₂ carbon atoms. The coupling reagent of claim 1 wherein the coupling reagent is selected from the group consisting of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC), dicyclohexylcarbodiimide (DCC), benzotriazol- (Dimethylamino) phosphonium hexafluorophosphate (BOP), pivaloyl chloride, isobutyl chloroformate. The method according to claim 1, wherein the solvent in the coupling reaction step is methylene chloride. The method of claim 1 wherein the amine is selected from the group consisting of (5S) -amino- (3S, 4R) -epoxy-N- [2-methyl- (1R) - (phenylmethyl) propyl] How to reconstitute peptides