KR0140323B1 - PROCESS FOR PREPARING OPTICAL ACTIVE Ñß-AMINOACID - Google Patents

Abstract

General formula

There is provided a method for producing a wide active α-amino acid represented by (I).

In the method of the present invention, α-amino acid having photoactivity is produced in high yield using proline or an analog thereof as a chiral assistant.

This method is a general formula

The compound of is reacted with an electrophilic reagent to undergo amido ring, and the resulting material is reduced to remove electrophilic functional groups and hydrolyzed under acidic conditions to obtain α-amino acid.

Provided that A = B = H, wherein the AXB moiety is a saturated or unsaturated conjugated carbon ring compound or heterocyclic compound, R is an alkyl or aryl group, Y is -CONH ₂ , C≡N, CONHNH ₂ , CON ₃ , CONHSO ₂ R ′ (where R ′ is alkyl or aryl), or CONHOR (where R is alkyl or Cbz), and the stereochemistry at the α position corresponds to R or S.

Description

Method for preparing photoactive α-amino acid

The present invention relates to a method for producing photoactive α-amino acids, and more particularly, to a method for photoactively preparing α-amino acids or derivatives thereof represented by the following general formula (I).

In which R is a chain or cyclic alkyl group or aryl group, and the stereochemistry at the α position corresponds to R (D) or S (L).

Amino acids are known as about 20 α amino acids (common α-aminoacid) which are components of natural protein and about 700 nonproteinaceous amino acids which are not components of protein.

Common amino acids are essential for the composition of all proteins, including enzymes, and are involved in life phenomena as components of metabolism in cells. Derivatives of amino acids are well known for their usefulness as neurotransmitters, enzyme inhibitors, and constituents of bioactive substances such as pharmaceuticals and pesticides, and can be used as intermediates, precursors or photoactive materials in the synthesis of complex compounds. It has high applicability. (Topics in Current Chemistry, Springer-Verlag, Berlin, 1983, p66 and 1984, p167).

For the production of amino acids, (1) fermentation, (2) protein hydrolysis, (3) enzyme synthesis, and (4) organic synthesis are widely used. The production by methods (1) and (3) is limited to amino acids that exist in nature, and the production by methods (4) has a limitation that it is not easy to make amino acids with high photoactivity. However, since enzyme inhibitors, antibiotics, and leaders of physiologically active substances require amino acids having various structures and conformations, methods of preparing photoactive amino acids by organic synthesis are becoming more important.

To synthesize photoactive amino acids, 1) a method of synthesizing non-photoactive amino acids and then photoactively decomposing them, and 2) a method of performing photoactive synthesis from the beginning. The first photoactive degradation method involves the problem of economics that the desired photoactive amino acid is only half of the compound, and the second photoactive synthesis method has a technical problem that it is difficult to obtain high optical yield.

In order to synthesize the structure of the α amino acid, the following methods are theoretically possible: 1) hydrogenation of dihydroamino acids, 2) alkylation of glycine, 3) α-amimination reaction, or 4) α carboxylation reaction. Do. Synthesis of Optically Active α-Amino Acids, Pergamon Press, Oxford, 1989.

It is an object of the present invention to provide a method for producing α-amino acids or derivatives thereof in high optical yield using intramolecular α-amimination reactions.

According to the present invention, general formula (II)

Of the compound of formula (II) by cyclization of the compound of Formula (II) by electrophilic reagent in the presence of a solvent, followed by reduction of the resulting material to remove the electrophilic functional groups, and acidic conditions. Hydrolysis under to obtain α-amino acid, a method for producing α-amino acid is provided.

Provided that A = B = H, wherein the A-X-B moiety is a saturated or unsaturated conjugated carbocyclic compound or heterocyclic compound; R is an alkyl or aryl group; Y is CONH2, C≡N, CONHNH2, CON3, CONHSO2R '(where R' is alkyl or aryl), or CONHOR (where R is alkyl or cbz): the stereochemistry at α Yes.

EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail.

In the present invention, a method capable of producing photoactive alpha -amino acid with high optical yield using proline or an analog thereof as a chiral assistant is provided.

The intermediate used in this process can be represented by the general formula (III) above, which will depend on the reactor attached.

The method of the present invention is described below. However, for the sake of convenience, when Y is CoNH 2 in the formula, that is, the compound of Formula II is

The following description will focus on the case of the proline derivative represented by the following (hereinafter simply referred to as general formula II ').

The compound of Formula II ′ is prepared by condensation with various α, β-unsaturated carboxylic acids through well-known techniques in amino acid and peptide chemistry using L- or D-proline as a starting material when A = B = H. can do.

Such a compound of general cine II 'is reacted with an electrophile reagent by changing a carboxamid group as it is or with N, O-bissilyl ether, and then reacted with an amido cyclization reaction to form III.

To yield the compound.

Examples of electrophilic reagent E + include Br2, I2, Hg2 +, RSe +, where R is alkyl or aryl, or RS + (R is alkyl or aryl).

The amidocyclic reaction can be carried out at a temperature range of -20 ° C to 150 ° C in the presence of a solvent, but is preferably performed at a temperature of -20 ° C to 50 ° C. Solvents that can be used include CH2Cl2, CH3CN, DMF, benzene and the like, but any other solvent used in this field may be used.

The cyclization can also be carried out in the presence or absence of a catalyst comprising light.

When A = B = H in the compound of Formula III, the stereochemistry of the α ′ position depends on the stereochemistry of the α position of proline, which is one of the starting materials.

For example, the stereochemistry at the α position in compound (III) derived from L-proline is S (L) and the stereochemistry at the α ′ position is mainly R (D) and α in compound (III) derived from D-proline. It has been found in the present invention that the stereosynthesis of the position is R (D) and the stereochemistry of the α 'position is mainly S (L). Therefore, the induction of [1,4] -chirality in the amidocyclic reaction of compound (II) used in the present invention was found to be L → D or D → L.

The compound of formula III produced by the amidocyclization reaction is then reduced to remove the electrophilic group E + and the product is hydrolyzed under acidic conditions to obtain the photoactive α-amino acids of general formula (I).

The purity of the photoactivity can be determined by the NMR technique in the compound represented by the general formula (III), or the optical rotation of the α-amino acid (1) can be determined by the Porraram method. When A = B = H, the proline obtained as a dispersion in hydrolysis can be reused for the preparation of compound (II) (A = B = H).

The method for preparing the photoactive α-amino acid from the general formula II 'has been described, but the preparation process is as follows.

The above description has been made for the general formula II 'in which Y is -CONH2 in general formula II, but this is merely illustrative, and the same is true even when Y is C≡N, CONHNH2, CON3, CONHSO2R', or CONHOR. It can be applied.

EMBODIMENT OF THE INVENTION Hereinafter, the Example of this invention is described.

However, this embodiment is only illustrative of the method of the present invention and should not be construed as limiting the scope of the present invention.

Example 1

1) Preparation of Phenylalanine

Step 1. Synthesis of (S) -N-cinnamoylproline

L-proline (1.15 g) was dissolved in 2N-NaOH (6 ml) and diluted with acetone (6 ml) at 0 ° C. Cinnamoyl chloride (1.67 g) was dissolved in acetone (7 ml) and 2N-NaOH (7 ml) and slowly added dropwise to the proline solution at 0 ° C. with stirring. After stirring the reaction mixture at room temperature for 6 hours, acetone was removed by distillation under reduced pressure. The remaining solution was washed with ether and the pH was adjusted to 2 with concentrated HCl. The acidified reaction mixture was extracted with ethyl acetate, and then the organic layer was washed several times with brine and distilled water and distilled under reduced pressure to obtain 2.3 g of the product, which was recrystallized from CH3OH to obtain 1.732 g of pure (S) -N-cinnaylylproline.

mp 175.6 ℃

α] _D = +11.52。 (c = 0.13, CH ₂ CL ₂ )

¹ H-NMR (CDCl 3 .D 2 O) δ 1.99-2.54 (4H, m), 3.64-3.82 (2H, m), 4.74 (1H, br.d), 6.71 (1H, D, J = 15.4 Hz), 7.26-7.56 (5H, m), 7.82 (1H, d, j = 15.4 Hz)

Step 2. Synthesis of (S) -N-cinnaylylprolineamide

(S) -N-cinnamoylproline (718 mg) and triethylamine (0.45 ml) prepared in step 1 were dissolved in CH 2 Cl 2 (100 ml), and then placed in an ice bucket and maintained at -20 ° C. Isobutylchloroformate (411 mg) was added dropwise and after 1 hour, NH 4 OH (29.7%, 5 ml) was added dropwise. After the generation of carbon dioxide, the mixture was stirred at this temperature for 30 minutes and at room temperature for 2 hours. The organic solvent was removed by distillation under reduced pressure, and the remaining reaction product was neutralized with 1N-HCl, and further distilled under reduced pressure, and recrystallized from water to obtain a white solid (601 mg).

mp 171-2 ℃

α] _D = -17.98 ° (c = 1.11, CH ₃ OH)

¹ H-NMR (CDCL ₃ ) δ 2.03-2.52 (4H, m), 3.63-3.81 (2H, m), 4.75 (1H, br.d), 5.47 (1H, br), B.73 (1H, d , J = 15.4 Hz), 7.26 (1H, br), 7.35-7.55 (5H, m), 7.77 (1H, d, J = 15.4 Hz)

Step 3. Cyclization Reaction of (S) -N-cinnaylylprolineamide

Method 1 After dissolving (S) -N-cinnamoylprolineamide (108 mg) and triethylamine (0.14 ml) in CH 2 Cl 2 (10 ml), catalytic amounts of 4-dimethylaminoparadine and trimethylsilyl triflate (0.18 ml ) Was added and stirred for 2 h under Ar. The organics were removed by distillation under reduced pressure and the product was extracted using ether. This was dissolved in acetonitrile (7 ml), phenylseltenium bromide (110 mg) was added, and stirred at room temperature for 7 hours. To this solution was added 10% Na 2 SO 3 (10 ml) and 10% NaHCO 3 (20 ml) and extracted with CH 2 Cl 2. The extract was concentrated under reduced pressure distillation and the product was obtained by 110 mg of cyclized compounds having phenyl selenium through panchromatography (SiO 2).

mp 218-220 ℃

α] _D +177。 (c = 1.06, CHCl ₃ )

¹ H-NMR (CDCL ₃ ) δ 1.65-1.84 (CH, m), 2.58-2.61 (1H, m), 3.61 (2H, t), 4.21 (1H, d, J = 8.9Hz), 4.72 (1H, d, J = 8.9Hz *, 4.83 (1H, br, d), 6.19 (1H, br), 7.06-7.37 (10H, m) The peak ratios of 4.21 (d) and 4.32 (d) are 17.6 to 1.0 De corresponds to about 90%.

MS (FAB) m / z 400 (M + 1)

(Method 2) (S) -N-cinnaylylprolineamide (120 mg) and DMF (370 mg) were dissolved in CH3CN (10 ml), AgOTf (384 mg) and phenyl selenium bromide (354 mg) were added, and the mixture was kept at room temperature Ar for 16 hours. Stirred. In the same manner as in Method 1, 162 mg of a cyclic compound having phenyl selenium was obtained. The physical and chemical properties of the product were the same as those obtained in Method 1.

Step 4. Synthesis of D-phenylalanine Methyl Ester

The cyclized product (54 mg) obtained in step 3 was dissolved in THF (6 ml) and dissolved in NiCl 2. 6H 2 O (66 mg) was added to the dissolved CH 3 OH (2 ml). NaBH 4 (8.5 mg) was added dropwise to the solution cooled to 0 ° C., and stirred for 2 hours at room temperature and under Ar. The reaction mixture was filtered through celite and the filtrate was distilled under reduced pressure to obtain about 32 mg of product.

¹ H-NMR (CDCl 3) δ 1.65-1.86 (3H, m), 2.58-2.64 (1H, m), 3.10 (1H, dd, J = 14.5 7.6 Hz), 3.30 (1H, dd, J = 14.5 5.3 Hz ), 4.25 (1H, dd, J = 7.6 5.3.Hz), 4.83 (1H, br.d), 6.20 (1H, br), 7.30-7.50 (5H, m)

The product obtained above (31.2 mg) was dissolved in 6N-HCl (5 ml), stirred at room temperature for 1 hour, the pH was adjusted to 7, and then lyophilized. The resulting D-phenylalanine was dissolved in CH 3 OH, treated with HCl (gas), and then converted into D-phenylalanine methyl ester (21 mg) through plate chromatography (SiO 2).

α] _D -27.6。 (c = 0.445, EtOH); ee = 86.0%

¹ H-NMR (D ₂ O) δ 2.8 (1H, dd, J = 13.5 7.8 Hz), 3.1 (1H, dd, J = 13.6 5.2 Hz), 3.7 (3H, S), 7.2-7.3 (5H, m )

Example 2

Preparation of L Phenylalanine

Steps 1 and 2. Synthesis of (R) -N Cinnamoriproline and (R) -N-Cinnamoylprolineamide

According to the method described in steps 1 and 2 of Example 1, (R) -N-cinnamoylprolineamide was synthesized through (R) -N-cinnamoylproline as a starting material.

mp 171 ℃

α] _D +17.6。 (C = 1.04, CH ₃ OH)

¹ H-NMR (CDCl ₃ ) The same as (S) -N-cinnaylylprolineamide synthesized in step 2 of Example 1.

Step 3. Cyclization Reaction of (R) -N-cinnaylylprolineamide

Starting from (R) -N-cinnamoylprolineamide, a cyclic compound having a spent nile selenium was obtained through the reaction procedure described in step 3 (method 2) of Example 1.

Mp 218-220 ℃

α] _D -171.6。 (C = 1.19, CHCl ₃ )

¹ H-NMR (CDCl ₃ ) δ 1.8-2.01 (3H, m), 2.6-2.69 (1H, m), 3.54-3.62 (1H, m), 4.18-4.22 (1H, m), 4.70-4.73 (1H , m), 4,81-4.83 (1H, m), 7.06-7.38 (10H, m)

MS (FAB) m / z 400 (M + 1)

Step 4. Synthesis of Lphenylalanine Methyl Ester

The cyclized product obtained in step 3 was reduced and hydrolyzed in the same manner as in step 4 of Example 1 to obtain L-phenylalanine, which was converted to L-phenylalanine methyl ester by treatment with HCl (gas) and CH3OH. It was.

α] _D -29.5。 (C = 0.571, EtOH): ee = 91.9%

¹ H-NMR (D ₂ O) The same as the D-phenylalanine methyl ester obtained in Example 1.

Example 3

Preparation of (R) -2 Aminobutyl Acid

Step 1. Synthesis of (S) N-crotonylproline

L-proline (1.15 g) was dissolved in 2N-NaOH (6 ml) and diluted with acetone (6 ml) at 0 ° C. Crotonyl chloride (1.20 g) was dissolved in acetone (7 ml) and 2N-NaOH (7 ml) and slowly added dropwise to the solution. The reaction mixture was stirred at room temperature for 16 hours and then distilled under reduced pressure to remove acetone. The remaining solution was washed with ether and then the pH was adjusted to 2 with concentrated HCl. The acidified reactant was extracted with ethyl acetate, and the organic extract was washed with brine and distilled water and distilled under reduced pressure to obtain a product (1.39 g).

mp 156-158 ℃

α] _D 60.37 ° (c = 1.03, CH ₂ Cl ₂ )

¹ H-NMR (CDCl ₃ -D ₂ O) δ 1.83 (3H, dd), 2.0-2.06 (3H, m), 2.33 (1H, m), 3.51-3.66 (2H, m), 4,60 ( 1H, t), 6.11 (1H, d, J 15.5 Hz), 7.0 (1H, m)

Step 2 Synthesis of (S) -N-crotonylprolineamide

(S) -N-crotonylproline (915 mg) and triethylamine (510 mg) made above were dissolved in CH ₂ Cl ₂ (50 ml). After cooling the temperature of the reaction solution to 0 ℃ isobutyl chloroformate (748mg) was added dropwise and stirred for 1 hour. NH 4 OH (29.7%, 5ml) was added to the reaction solution, and the mixture was stirred at room temperature for 6 hours. The product was extracted using CH ₂ Cl ₂ , and the organic solvent was removed by distillation under reduced pressure. Pure product (595 mg) was obtained in the oil phase via tube chromatography (SiO ₂ ).

¹ H-NMR (CDCl ₃ ) δ 1.95 (3H, dd), 2.0-2.4 (4H, m), 3.51 (1H, m), 3.65 (1H, m), 4.65 (1H, d), 6.0 (1H , br), 6.15 (1H, d, J = 14hz), 6.84 (1H, m), 7.17 (1H, br)

Step 3. Cyclization Reaction of (S) -N-crotonylprolineamide

(S) -N-crotonylprolineamide (107 mg) and DMF (1.3 g) were dissolved in CH 3 weight (10 ml), and then phenyl selenium bromide (425 mg) and AgOTf (463 mg) were added. The reaction solution was stirred at room temperature and under Ar for 16 hours, and then treated as in Step 3 of Example 1 to obtain 152 mg of a cyclized compound having phenyl selenium.

¹ H-NMR (CDCl ₃ ) δ1.05 (3H, d, J = 7Hz), 1.60-1.81 (3H, m), 2.56-2.58 (1H, m), 2.6 (1H, m), 3.60 (2H, t), 4.2 (1H, d, J 8.5Hz), 4.82 (1H, br.d), 2.6 (1H), 6.25 (1H, br), 7.10, 7.30 (5H, m), δ4.2 (d) And peak ratio of 4.3 (d) was found to be 22 to 1, which is calculated as de = 91.4%.

MS (FAB) m / z = 338 (M + l)

Step 4. Synthesis of (R) -2-Aminobutyl Acid

The cyclized product (100 mg) obtained in step 3 was dissolved in THF (5 ml) and NiCl 2 .6H 2 O (143 mg) was added to the dissolved CH 3 OH (5 ml) and cooled to 0 ° C. NaBH 4 (72 mg) was added dropwise to the reaction solution, followed by stirring for 4 hours at room temperature Ar. The reaction was filtered through celite, and the filtrate was concentrated under reduced pressure, and the product (45 mg) was obtained using tube chromatography (SiO 2).

¹ H-NMR (CDCl ₃ ) δ1.0 (3H, t), 1.60-1.82 (3H, m), 1.85 (2H, m), 2.8 (1H, m), 2.60 (1H, m), 3.61 (2H , t), 3.90 (1H, t), 4.84 (1H, t), 6.24 (1H, br), δ 3.90 (t) and 3.80 (t) peak ratios were 21 to 1. It corresponds to 91%.

The obtained product (27mg) was dissolved in 6N HCl (3mm) and stirred at room temperature for 1 hour. The pH of the solution was adjusted to 7 and then lyophilized. The product was taken up in CH ₃ OH (5 ml), cooled to 0 ° C. and concentrated H ₂ SO ₄ (1 ml) was added dropwise. After stirring at room temperature for 3.5 hours, the pH was adjusted to 7-8 and lyophilized. The resulting solid was dissolved in CH ₃ OH, filtered, and the filtrate was purified by distillation under reduced pressure. The resulting impure product was purified by chromatography (Si ₂ O) to obtain 2-aminobutyl acid methyl ester (16 ml). 2-aminobutyl acid methyl ester was dissolved in CH ₃ OH (3 ml) and H ₂ O (1 ml) with LiOH (6.4 mg), stirred at 0 ° C. for 2.5 hours, adjusted to pH 7, and lyophilized. The solid product was dissolved in CH ₃ OH again and filtered, and the filtrate was lyophilized to obtain a white solid 2-aminobutyl acid.

α] _D -7.14。 (C = 1.61, H2O)

¹ H-NMR (D ₂ O) δ 1.0 (3H, t), 1.9 (2H, dq), 3.7 (1H, t).

¹³ C-NMR (D ₂ O, pH 5.1)) δ 176.1, 57.2, 25.0, 9.7

The photoactive purity based on rotation was found to be ee-90%.

Claims (7)

Formula III The compound of Formula 1 is cyclized by an amidocyclic reaction with an electrophilic reagent in a solvent, and the resulting material is reduced to remove an electrophilic functional group and hydrolyzed under acidic conditions. A method for producing a photoactive α-amino acid, characterized by obtaining α-amino acid of I. Provided that A = B = H, or the A-X-B moiety is a saturated or unsaturated carbocyclic compound or a heterocyclic compound, R is an alkyl or aryl group, Y is -CONH ₂ , C≡N, CONHNH ₂ , CON ₃ , CONHSO ₂ R '(where R' is alkyl or aryl), or CONHOR (where R is alkyl or Cbz ) And the stereochemistry at the α position corresponds to R or S. With the proviso that R in formula I is a chain or cyclic alkyl group or an aryl group, and the stereochemistry at the α position corresponds to R (D) or S (L). According to claim 1, wherein the general formula II compound is Formula II ' And a method for producing α-amino acid, characterized in that it is prepared by condensing L- or D-proline with α, β-unsaturated carboxylic acid. (Wherein A = B = H and R is as defined above) The method of claim 2, wherein the compound of Formula II 'is N-cinnamoylproline amide, and the α-amino acid is phenylalanine methyl ester. The method of claim 2, wherein the compound of Formula II 'is N-crotonyl prolineamide, and the α-amino acid is 2-aminobutyl acid. The method of claim 1, wherein the electrophilic reagent is selected from the group consisting of Br ₂ , I ₂ , Hg ²⁺ , RSe ⁺ (where R is an alkyl or aryl group) or RS + (where R is an alkyl or aryl group) Α-amino acid production method characterized in that. The method of claim 1, wherein the solvent is selected from the group consisting of CH ₂ Cl ₂ , CH ₃ CN, DMF, and benzene. The method of claim 1, wherein the cyclization reaction is α-amino acid production method, characterized in that carried out at -20 ℃ to 50 ℃ temperature.