KR19980029955A - Method for preparing N-alkyloxycarbonyl-B-alkylsulfonylvaline compound - Google Patents

Abstract

The present invention relates to a method of preparing the sulfonyl valine compound of formula 1 by alkylating and acylating the β-mercaptovaline compound of formula 2 to obtain a compound of formula 3, and oxidizing it. The process is shown in Scheme 1.

Wherein R ¹ and R ² are as indicated in the specification.

Description

Method for preparing N-alkyloxycarbonyl-β-alkylsulfonylvaline compound

The present invention relates to a method for preparing an N-alkyloxycarbonyl-β-alkylsulfonyl valine compound represented by the following formula (1), wherein the β-mercaptovaline compound represented by the formula (2) is alkylated and then acylated at the amino group position. The reaction is carried out to produce a compound represented by Chemical Formula 3, which is prepared by oxidation.

In the above formula,

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

R ² represents a C _1-5 lower alkyl group, an arylalkyl group, a C _3-6 alkenyl group, a C _3-7 incycloalkyl group or an acyloxyalkyl group.

The present invention also includes salts, hydrates and solvates thereof, and epimers, diastereo isomers and tautomeric isomers thereof, which may appear in formulas (1), (2) and (3).

N-alkyloxycarbonyl-β-alkylsulfonylvaline compounds of formula (1) are an important part of the N-terminal group of protease inhibitors of human immunodeficiency virus (HIV) and are useful for the development of therapeutic agents for AIDS. (European patent publications EP 601,486A1 and EP 490,667A2), and are also useful in tachykinin NK-1 receptor studies (Joisen et al., J. Med. Chem., 1994, 37, 1586).

Although many efforts have been made to prepare the N-alkyloxycarbonyl-β-alkylsulfonyl valine compounds of the formula (1), the general production method is hardly reported. The only known method for preparing the compound of Formula 1 is the method published by Joyen et al. (J. Med. Chem., 1994, 37, 1586), which is shown in Scheme 2 below.

As shown in Scheme 2, the preparation example describes only a method for preparing a single compound wherein R ¹ is methyl and R ² is a t-butyl group in the structure of Chemical Formula 1, and there are many steps of reaction, temperature, solvent, etc. Reaction conditions are not easy. And the yield in each reaction step is low, 58% and 70%, respectively.

Accordingly, the present inventors have conducted studies on the preparation of the N-alkyloxycarbonyl-β-alkylsulfonyl valine compound represented by Chemical Formula 1, and thus, various groups can be introduced into R ¹ and R ² , By discovering the low-level process that proceeds in yield, the present invention, which is a general method for preparing the compound represented by Formula 1, has been completed.

The present invention relates to a method for preparing an N-alkyloxycarbonyl-β-alkylsulfonyl valine compound of formula (1) from the β-mercaptovaline compound,

The present invention

A) a step of obtaining a compound of Chemical Formula 3 by reacting a halogenated alkyl and an alkyl chloroformate with a β-mercaptovaline compound of Chemical Formula 2 (first step);

B) oxidation of a compound of formula 3 to obtain an N-alkyloxycarbonyl-β-alkylsulfonylvaline compound of formula 1 (second step)

An object of the present invention is to provide a method for producing an N-alkyloxycarbonyl-β-alkylsulfonyl valine compound of the formula (1).

The present invention relates to a method of preparing a sulfonyl valine compound by alkylating a β-mercaptovaline compound to introduce an alkyl group, introducing a substituent to an amine position by an acylation reaction, and then oxidizing the same. The process is shown.

Scheme 1

In the above formula,

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

R ² represents a C _1-5 lower alkyl group, arylalkyl group, C _3-6 alkenyl group, C _3-7 cycloalkyl group, acyloxyalkyl group or the like.

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

First stage reaction; Alkylation reaction

The β-mercaptovaline compound of formula (2) is dissolved in a mixed solvent of a basic aqueous solution and a polar organic solvent at an appropriate temperature. A compound of formula 3 is obtained by sequentially reacting an alkylation agent, halogenated alkyl (R ¹ X), and an acylating agent, alkyl chloroformate (R ² OCOCl).

The base of the basic aqueous solution that can be used at this time includes sodium hydroxide or potassium hydroxide.

Polar organic solvents that may also be used include dioxane, dimethylformamide, acetonitrile or tetrahydrofuran.

Moreover, the appropriate reaction temperature is from 0 ° C to room temperature, preferably 5 ° C or less.

In this case, in the halogenated alkyl (R ¹ X), R ¹ is a lower alkyl group, an arylalkyl group, or a C _3-7 cycloalkyl group, which is C _1-5 , and the like, and X is a halide such as iodine, bromide or chloride. It is suitable.

In addition, R ² an alkyl chloroformate (R ² OCOCl) used at this time is such as a C _1-5 lower alkyl group, an aryl group, a C _3-6 alkenyl group, C _3-7 alkyl group or a cyclo acyloxy group It is suitable.

Also suitable reaction time is 3 hours to 8 hours after addition of alkyl halide (R ¹ X), 2 hours to 6 hours after addition of alkyl chloroformate (R ² OCOCl), preferably halogenated alkyl (R 5 hours after the addition of ¹ X) and 3 hours after the addition of alkyl chloroformate (R ² OCOCl).

After completion of the reaction, the compound of formula 3 obtained through a general purification process can be used directly in the next reaction without further purification. In addition, the reaction proceeds under mild conditions, and the yield of the target compound is very high.

Second stage reaction; Oxidation reaction

The compound of formula 3 is dissolved in a suitable polar solvent, cooled after adding water. The oxidizing agent is slowly added thereto and stirred for a predetermined time at a proper temperature. After the reaction is completed, the solvent is distilled off under reduced pressure, and the concentrate is subjected to a conventional purification process to obtain a sulfonylvaline compound of Chemical Formula 1.

At this time, as the solvent that can be used, an alcohol such as methanol, ethanol or a polar solvent such as acetonitrile is possible, and methanol is particularly preferable.

In addition, oxidants which can be used at this time include oxone (potassium peroxymonosulfate), hydrogen peroxide and m-chloroperbenzoic acid, and the like, and particularly easy and economical oxone is preferable.

Moreover, the suitable reaction temperature is 0 to 30 degreeC, Preferably it is 25 degrees C or less.

Suitable reaction time is also 12 hours to 48 hours and preferably 24 hours or more.

The N-alkyloxycarbonyl-β-alkylsulfonyl valine compound of the formula (1) obtained by the above method maintains the optical activity of the starting material as it is. In addition, the reaction proceeds under mild conditions and the yield of the target compound is very high.

Hereinafter, the present invention will be described in detail by examples. The examples are illustrative only of the present invention and the present invention is not limited by the examples.

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

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

4.50 g (30 mmole) of β-mercapto-L-valine was added to a mixture of 60 ml of dioxane and 20 ml of water, cooled to 0 ° C., and then dissolved by adding 10 ml of 6N aqueous sodium hydroxide solution. 4.62 g (33 mmole) of methane iodide was added to the solution, followed by stirring at 0 ° C. for 3 hours, followed by stirring at room temperature for 2 hours. The methylation reaction was cooled to 0 ° C. and 5 ml of 6N aqueous sodium hydroxide solution and 40 ml of 1 M toluene solution of isopropyl chloroformate were slowly added. The reaction was stirred at 0 ° C. for 1 hour and then at room temperature for 2 hours before the reaction was terminated. After completion of the reaction, the solvent was distilled off under reduced pressure, and then 50 ml of water and ether were added to remove unreacted isopropyl chloroformate and the organic layer was removed. 10 ml of ethyl acetate was added to the aqueous layer and the pH was lowered to 3 or less with 6N aqueous hydrochloric acid. The organic layer was separated, dried over anhydrous MgSO _4, and the solvent was distilled off under reduced pressure to yield 5.50 g (yield 77%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 1.30 (s, 6H), 1.48 (s, 6H), 2.13 (s, 3H), 4.41 (m, 1H), 4.99 (m, 1H), 5.61 (m, 1H) , 8.50 (br, 1 H)

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

5.50 g (22 mmole) of the product obtained in (Step 1) was dissolved in 40 ml of methanol, and 20 ml of water was added to the resulting solution, followed by cooling to 0 ° C. Oxon 3 equivalent to the solution was slowly added to the reaction mixture so that the temperature did not exceed 25 ℃ and stirred at room temperature for 24 hours. After completion of the reaction, the remaining solids were removed by filtration, the solvent of the filtrate was distilled off under reduced pressure, and the pH was adjusted to 10 with 1N aqueous sodium hydroxide solution. 10 ml of ether was added, the organic layer was removed, and the aqueous layer was adjusted to pH 2 using 2N potassium hydrosulfate aqueous solution and 50 ml of dichloromethane was added thereto. The organic layer was separated, dried over MgSO _4, and the solvent was evaporated under reduced pressure to yield 5.70 g (yield 92%) of the title compound.

¹ H NMR (CDCl ₃ ) δ 1.27 (m, 6H), 1.53 (s, 3H), 1.61 (s, 3H), 2.99 (s, 3H), 3.76 (br, 1H), 4.72 (m, 1H) , 4.98 (m, 1 H), 5.97 (br, 1 H)

Example 2 Preparation of N-benzyloxycarbonyl-β-methanesulfonyl-L-valine

(Step 1) Preparation of N-benzyloxycarbonyl-β- (S-methyl) -L-valine

The title compound was obtained in a similar manner to (Step 1) of Example 1 using β-mercapto-L-valine, methane iodide and benzyl chloroformate (yield 85%).

¹ H NMR (CDCl ₃ ) δ 1.45 (s, 6H), 2.50 (s, 3H), 4.50 (d, 1H), 4.90 (m, 1H), 5.00 (s, 2H), 7.05-7.15 (m, 5H)

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

Starting from the product obtained in (Step 1) of Example 2, the title compound was obtained by a method similar to (Step 2) of Example 1 (yield 94%).

¹ H NMR (CDCl ₃ ) δ 1.45 (s, 6H), 1.53 (s, 3H), 2.96 (s, 3H), 4.60 (d, 1H), 4.85 (m, 1H), 5.05 (s, 2H) , 7.05-7.18 (m, 5H)

Example 3 Preparation of N-isobutyloxycarbonyl-β-methanesulfonyl-L-valine

(Step 1) Preparation of N-isobutyloxycarbonyl-β- (S-methyl) -L-valine

The title compound was obtained using a β-mercapto-L-valine, methane iodide and isobutyl chloroformate in a similar manner to (Step 1) of Example 1 (yield 90%).

¹ H NMR (CDCl ₃ ) δ 1.10 (m, 6H), 1.20 (m, 1H), 1.45 (m, 6H), 2.15 (s, 3H), 4.55 (s, 2H), 5.30 (m, 1H)

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

Starting from the product obtained in (Step 1) of Example 3, the title compound was obtained by a method similar to (Step 2) of Example 1 (yield 92%).

¹ H NMR (CDCl ₃ ) δ1.05 (m, 6H), 1.18 (m, 1H), 1.50 (s, 3H), 1.58 (s, 3H), 2.90 (s, 3H), 4.62 (m, 1H) , 4.90 (m, 2H), 5.30 (m, 1H)

In order to demonstrate the optical activity of N-isopropyloxycarbonyl-β-methanesulfonyl-L-valine obtained in (Step 2) of Example 1 above, 99% or more of D-(+) Reaction with -α-benzylmethylamine was attempted and this is shown in Example 4.

Example 4 Reaction of D-(+)-α-benzylmethylamine with N-isopropyloxycarbonyl-β-methanesulfonyl-L-valine

In 5 ml of dichloromethane, 460 mg of N-isopropyloxycarbonyl-β-methanesulfonyl-L-valine, which was obtained in Example 1 (Step 2), was dissolved, and then cooled to -40 ° C. One equivalent of 4-methylmorpholine (0.18 ml) and one equivalent of isobutyl chloroformate (0.22 ml) are sequentially added to the reaction, followed by stirring for 30 minutes. A solution of 1 equivalent of D-(+)-α-benzylmethylamine (0.21 ml) dissolved in 1 ml of dichloromethane was added, followed by stirring at the same temperature for 30 minutes and at room temperature for 1 hour. After the reaction was completed, the reaction mixture was diluted by adding water and dichloromethane, and the organic layer was washed sequentially with saturated aqueous NaHCO ₃ , 1N KHSO ₄ aqueous solution, and brine. The organic layer was dried over MgSO ₄ and the concentrated solution obtained by distillation of the solvent under reduced pressure was analyzed by HPLC and purified by column chromatography. Only one isomer was identified.

¹ H NMR (CDCl ₃ ) δ1.13 (m, 6H), 1.37 (s, 3H), 1.42 (d, 3H), 1.50 (s, 3H), 2.78 (s, 3H), 4.53 (d, 1H) , 4.78 (d, 1H), 4.96 (m, 3H), 5.82 (d, 1H), 7.00 (br, 1H), 7.15-7.27 (m, 5H)

The present invention relates to a novel method for preparing a sulfonyl valine-based compound. The present invention provides an alkyl group by alkylating a β-mercaptovaline compound and introducing a substituent at an amine position by an acylation reaction, followed by oxidation. To prepare a sulfonyl valine-based compound.

According to the production method of the present invention, the beta -mercaptovaline compound can be reacted more easily by reacting under mild conditions that are easy to deal with reaction conditions such as temperature and solvent. In addition, various kinds of alkylating agents and acylating agents can be used, so that various substituents can be introduced. In addition, the compound of Formula 3, in which various substituents are introduced, is very high in purity and can be used immediately in the next reaction without further purification, and also has a high yield and can be used as an excellent reaction intermediate.

In addition, according to the production method of the present invention, it is possible to effectively prepare the N-alkyloxycarbonyl-β-alkylsulfonyl valine compound of the formula (1) while maintaining the optical activity of the starting material.

Claims (7)

A) alkylating the β-mercaptovaline compound of Formula 2 using an alkyl halide as an alkylating agent and acylating using an alkyl chloroformate as the acylating agent to obtain a compound of formula 3 having an alkyl group and an acyl group introduced therein; (First step); B) reacting the compound of formula 3 with an oxidizing agent to obtain an N-alkyloxycarbonyl-β-alkylsulfonylvaline compound of formula 1 (second step) A method for producing an N-alkyloxycarbonyl-β-alkylsulfonylvaline compound of formula (1) consisting of: Scheme 1 In the above formula, R ¹ represents a lower alkyl group, an arylalkyl group, a C _3-7 cycloalkyl group, or the like, which is C _1-5 , R ² represents a C _1-5 lower alkyl group, arylalkyl group, C _3-6 alkenyl group, C _3-7 cycloalkyl group, acyloxyalkyl group or the like. The N-alkyloxycarbonyl-β-alkylsulfonylvaline of formula 1 wherein the alkylating agent of the first stage reaction is halogenated alkyl (R ¹ X) and the acylating agent is alkyl chloroformate (R ² OCOCl). Method for preparing the compound. The method for preparing an N-alkyloxycarbonyl-β-alkylsulfonylvaline compound of formula 1 according to claim 1, wherein the reaction solvent of the first stage reaction is a mixed solvent of a basic aqueous solution and a polar organic solvent. The N-alkyloxycarbonyl-β-alkylsulfonylvaline compound of formula 1 according to claim 1, wherein the oxidizing agent of the second stage reaction is oxone (potassium peroxymonosulfate), hydrogen peroxide and m-chloroperbenzoic acid. Way. The method for preparing an N-alkyloxycarbonyl-β-alkylsulfonylvaline compound according to claim 4, wherein the oxidant is oxone. The method of claim 1, wherein the reaction solvent of the second stage reaction is an alcohol such as methanol, ethanol, or a polar solvent such as acetonitrile. The N-alkyl of formula 1 according to claim 1, wherein the N-alkyloxycarbonyl-β-alkylsulfonylvaline compound comprises salts, hydrates and solvates thereof and epimers, diastereo isomers and tautomer isomers thereof. Process for the preparation of oxycarbonyl-β-alkylsulfonylvaline compound.