JP2000319244A - Optically active amino acid ester tartaric acid amide and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound which has a high optical purity and is useful as a raw material for medicines and agrochemicals. SOLUTION: A compound of formula I [R1 is an alkyl, (substituted) phenyl or a (substituted) aralkyl; R2 is an α-amino acid residue; R3 is hydrogen, methyl or methoxy; * means to be optically active], for example, 0, 0'-di p-toluoyl-D- tartaric acid.mono-L-(1,2-dibenzyloxycarbonyl) ethylamide. The compound of formula I can be produced, for example, by reacting an optically active amino acid ester of formula III (for example, L-asparaginic acid dibenzyl ester.para- toluene sulfonic acid salt) with an optically active diacyltartaric acid anhydride of formula IV (for example, 0, 0'-di para-toluoyl-D-tartaric acid anhydride) in a solvent at 0 to 100 deg.C, more preferably at room temperature to 40 deg.C, for 0.1 to 5.0 hr, if necessary, after a neutralization reaction giving a free state.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The optically active amino acid ester tartaramide is a compound useful as a raw material for medicines and agricultural chemicals. Further, since these optically active amino acid ester tartaramides are compounds having a plurality of asymmetric carbon atoms and having an aromatic ring, HPL using a normal analytical column is used.
With C, the optical purity can be determined accurately.

[0002]

2. Description of the Related Art Optically active amino acid ester tartaramide represented by the general formula (1) is a novel compound. Furthermore, there is no known method for producing these compounds.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide an amino acid ester tartaramide having a high optical purity and a method for producing the same.

[0004]

Means for Solving the Problems The present inventors have made intensive studies on amino acid tartrate amide having high optical purity and a method for producing the same, and as a result, have reached the present invention. That is, the present invention relates to general formula (1)

[0005]

Embedded image (Where R ¹ represents an alkyl group, an unsubstituted or substituted phenyl group, or an unsubstituted or substituted aralkyl group; R ² represents an α-amino acid residue; R ³ represents hydrogen; Represents a methyl or methoxy group.
Means an optically active substance. ) Is an optically active amino acid ester tartaramide. In addition, the general formula (2)

[0006]

Embedded image (Where R ¹ represents an alkyl group, an unsubstituted or substituted phenyl group, or an unsubstituted or substituted aralkyl group. R ² represents an α-amino acid residue. An optically active amino acid ester represented by the general formula (3):

[0007]

Embedded image (Where R ³ represents a hydrogen, methyl or methoxy group. * Means an optically active substance), by reacting an optically active diacyl tartaric anhydride represented by the general formula (1) )

[0008]

Embedded image (Where R ¹ represents an alkyl group, an unsubstituted or substituted phenyl group, or an unsubstituted or substituted aralkyl group; R ² represents an α-amino acid residue; R ³ represents hydrogen; Represents a methyl or methoxy group.
Means an optically active substance. The optically active amino acid ester tartaramide represented by the formula (1) can be produced. Further, the amino acid ester has the general formula (4)

[0009]

Embedded image (Where R ¹ represents an alkyl group, an unsubstituted or substituted phenyl group, or an unsubstituted or substituted aralkyl group. R ² represents an α-amino acid residue). In the case of racemic amino acid esters,
Achieved by reacting an optically active diacyl tartaric anhydride represented by the general formula (4) and the general formula (3) and then performing optical resolution to produce an optically active amino acid ester tartrate amide represented by the general formula (1). it can.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION As a raw material of the present invention, an amino acid ester represented by the general formula (2) or (4) is used. Here, the amino acid ester is often in the form of an acid addition salt for stable storage, but any of the forms of the acid addition salt can be used in a free state. As the acid addition salt, an inorganic acid salt such as hydrochloric acid and sulfuric acid, an organic sulfonic acid salt such as benzenesulfonic acid and toluenesulfonic acid, and an organic carboxylic acid salt such as acetic acid and propionic acid can be used. Both the L-form and the D-form can be used as the optically active amino acid ester of the general formula (2). Further, a racemic amino acid ester of the general formula (4) can also be used. Here, the racemic form means a mixture of the L-form and the D-form, and the mixing ratio may be any ratio. In general formulas (2) and (4), the ester residue may be an ester of a lower alcohol or an aromatic ester such as benzyl alcohol. As the aromatic ester, an aromatic nucleus may be substituted. For example, benzyl alcohol substituted with a lower alkyl group such as 4-methylbenzyl alcohol, 2,4-dimethylbenzyl alcohol, benzyl alcohol substituted with a lower alkoxy such as 4-methoxybenzyl alcohol, 3-chlorobenzyl alcohol, etc. And benzyl alcohol and phenylethyl alcohol esters substituted with halogen.

An optically active tartaric acid derivative anhydride, which is another raw material, is an ester of tartaric acid represented by the general formula (3) in which two hydroxyl groups are carboxylic acids. Here, the carboxylic acid for forming an ester is an aromatic carboxylic acid such as benzoic acid, paratoluic acid, 2,4-dimethylbenzoic acid, 4-methoxybenzoic acid, 4-chlorobenzoic acid, or phenylacetic acid. Aralkylcarboxylic acid and the like can be used. Preferably, it is represented by the general formula (3), and any of the L-form and D-form optically active tartaric acid derivatives can be used, but the optical purity is 99.5% e.
It is preferably at least e.

In the reaction method, the amino acid ester and the tartaric acid derivative anhydride are reacted in a solvent. When the amino acid ester is an acid addition salt, it is neutralized with an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide or an alkali metal carbonate such as sodium bicarbonate or sodium carbonate in advance and used after being released. . Any reaction solvent can be used as long as it does not inhibit the reaction. For example, hydrocarbons such as toluene, nitriles such as acetonitrile, ethers such as diethyl ether and tetrahydrofuran, and halogenated hydrocarbons such as dichloromethane and chloroform can be used. It does not matter if they coexist. However, if the base used for neutralizing the acid addition salt is excessive, the amino acid ester or the tartaric acid derivative anhydride is hydrolyzed. Therefore, it is preferable to use an equivalent amount of the base used for neutralization. The reaction temperature is preferably from 0 ° C to 100 ° C, more preferably from room temperature to 40 ° C. Although the reaction time depends on the reaction temperature and the amount of the optically active tartaric acid derivative anhydride used, it is usually completed within 0.1 to 5.0 hours. Under these conditions, the optical purity of the optically active tartaric acid derivative does not decrease. At the same time, the optical purity of the amino acid ester used as a raw material does not decrease. After completion of the reaction, isolation is performed by a usual method, but the isolation method varies depending on the type of amino acid ester and the type of tartaric acid derivative anhydride. For example, when aspartic acid dibenzyl ester and dibenzoyl-L-tartaric anhydride are reacted in chloroform, the reaction solution is washed with an acidic aqueous solution such as hydrochloric acid to remove unreacted aspartic acid diester and then concentrate the chloroform layer. -Aspartic acid dibenzyl ester tartaramide can be isolated by crystallization. When a racemic amino acid ester is used as a raw material, the obtained amino acid ester tartaramide is subjected to optical resolution. An ordinary method can be adopted for the optical division method. For example, a method of fractionation using a column, a method of recrystallization, or the like can be employed.

[0013]

The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the invention is limited thereto. The optical purity is HP
It was determined from the following equation by LC peak count.

[0014]

(Equation 1) X: Count of optically active amino acid ester tartaramide detected forward Y: Count of optically active amino acid ester tartaramide detected backward HPLC analysis conditions vary depending on the type of amino acid ester tartaramide, but the basic conditions are as follows.

Column: CAPCELL PAC SG1
20 (ODS) developing solution: 0.05% phosphoric acid aqueous solution / methanol = 50 /
50-30 / 70 Detection: UV 215 nm-254 nm The amino acids, alcohols, tartaric acid, organic acids, and solvents used in the examples were commercially available first grade reagents. Further, tartaric acid derivative anhydride is disclosed in Patent Publication 27735.
The compound produced by the method described in JP-A-87-27773 was used.

Example 1 13.3 g (0.1 mol) of L-aspartic acid (99.5% ee), 32.4 g (0.30 mol) of purified benzyl alcohol were placed in a 500 ml Dean-Stark azeotropic dehydrator. 22.8 g of paratoluenesulfonic acid monohydrate
(0.12 mol) and 250 ml of toluene, and the mixture was heated and refluxed at normal pressure for 10 hours while stirring to remove azeotropically dehydrated water. About 5.1 g of water was distilled off. Then, after cooling to 70 ° C. while stirring,
Washed twice with 80 g of water. After the water dissolved in the toluene layer was distilled off by azeotropic dehydration, the mixture was cooled to room temperature with stirring. The precipitated crystals were filtered and dried, and D-aspartic acid dibenzyl ester / p-toluenesulfonate was used.
3 g were obtained. The yield was 83.0% and the chemical purity was 99.6%. 19.4 g of the obtained L-aspartic acid dibenzyl ester / paratoluenesulfonate was suspended in 150 ml of chloroform, 16 g (0.04 mol) of a 10% aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 1 hour. . Then, the chloroform layer was separated, and 14.7 g of O, O'-diparatoluoyl-L-tartaric anhydride (0.04 g) was added.
Mol) was added and the mixture was again stirred at room temperature for 2 hours. When the chloroform layer was analyzed by HPLC, two peaks were detected and the optical purity of L-aspartic acid dibenzyl ester / paratoluenesulfonate used in the reaction was 59.0.
% Ee (FIG. 1 column CAPCE)
LL PAC SG120 developing solution Phosphoric acid aqueous solution (pH 2.
2) / Methanol = 38/62 v / v).

After the completion of the reaction, the reaction mixture is diluted with a 5% aqueous hydrochloric acid solution (50%).
After washing with chloroform, the chloroform layer was concentrated to O,
O'-Diparatoluoyl-L-tartaric acid mono (1,2-
Dibenzyloxycarbonyl) ethylamide 27.8
g was obtained. Use a column filled with 10 g of the concentrate and 500 ml of silica gel, and develop with toluene / cyclohexane.
After fractionation, the mixture was concentrated and 7.2 g of O, O'-diparatoluoyl-L-tartaric acid / mono-L- (1,2-dibenzyloxycarbonyl) ethylamide and O, O'-diparatoluoyl-L- 1.9 g of tartaric acid / mono-D- (1,2-dibenzyloxycarbonyl) ethylamide were obtained.

Example 2 4.9 g (10%) of dibenzyl D-aspartate / paratoluenesulfonate having an optical purity of 99.5% ee
(Mmol) was suspended in 50 ml of toluene, and 10 ml of a 1 N aqueous sodium hydroxide solution was added dropwise with stirring at room temperature. After stirring for 30 minutes, the aqueous layer was separated and removed. To the toluene layer was added 3.5 g (9.5 mmol) of O, O'-diparatoluoyl-D-tartaric anhydride, and the mixture was stirred at room temperature for 1 hour. As a result of analyzing the reaction solution by HPLC, O, O'-diparatoluoyl-D-tartaric acid
Mono-D- (1,2-dibenzyloxycarbonyl) ethylamide was detected, and it was confirmed that D-aspartic acid dibenzyl ester was not racemized at all in the reaction (FIG. 2 Measurement conditions were the same as in FIG. 1). ). Next, 5 ml of 1N hydrochloric acid was added to the reaction solution, and the mixture was stirred at room temperature for 10 minutes to remove unreacted D-aspartic acid dibenzyl ester. Then, the toluene layer was concentrated to 20 ml, and heated at 5 to 10 ° C. for 2 hours. Stirred. The precipitated crystals are filtered and dried to obtain O, O'-
Diparatol oil-D-tartaric acid / mono-D- (1,2-
5.1 g of dibenzyloxycarbonyl) ethylamide
Obtained. The isolation yield was 75%.

Example 3 19.4 g of L-aspartic acid dibenzyl ester / p-toluenesulfonate prepared in Example 1 was suspended in 150 ml of toluene.
6 g (0.04 mol) was added, and the mixture was stirred at room temperature for 1 hour. Next, the toluene layer was separated, and 14.7 g (0.04 mol) of O, O'-diparatoluoyl-L-tartaric anhydride was used.
Was added and the mixture was again stirred at room temperature for 2 hours. When the toluene layer was analyzed by HPLC, two peaks were detected, and it was found that the optical purity of L-aspartic acid dibenzyl ester / paratoluenesulfonate used in the reaction was 59.0% ee.

After the completion of the reaction, the reaction mixture is diluted with a 5% aqueous hydrochloric acid solution (50%).
After washing with 50 ml, the toluene layer was concentrated to 50 ml and then stirred at 5 to 10 ° C. for 2 hours. The precipitated crystals were filtered and dried to obtain 5.1 g of O, O'-diparatoluoyl-L-tartaric acid / mono-L- (1,2-dibenzyloxycarbonyl) ethylamide. The optical purity was 99.1% ee.

Example 4 The procedure of Example 2 was repeated except that D-aspartic acid dibenzyl ester / paratoluenesulfonate was changed to L-aspartic acid dibenzyl ester / paratoluenesulfonate. O, O'-diparatoluoyl-D-tartaric acid mono-L- (1,2-dibenzyloxycarbonyl) ethylamide represented by (5) was obtained.

[0022]

Embedded image Melting point 52-54 ° C. ¹ H NMR 2.2-2.4 ppm (6H), 2.7-3.1 ppm (4H) 4.8-5.0 ppm (4H), 5.0-5.1 ppm (1H) 5 0.8-6.1 ppm (2H), 7.0-8.0 ppm (20H) ¹³ C NMR 21 ppm, 22 ppm, 36 ppm, 49 ppm, 67 ppm, 68 ppm, 71 ppm, 72 ppm, 125 ppm, 126 ppm, 127-135 ppm (12C), 134 ppm 135ppm, 144ppm, 145ppm, 164.5pp m 165ppm, 166ppm, 170.2ppm, 170.4ppm, 170.5ppm IR 3600~2700cm -1, 1800~1650cm -1, 1600cm -1, 1550~1500cm -1, 1450cm - ¹ , 1430cm ^-1 , 140 ^{0cm -1, 1350~1150cm - 1, 1150~1040cm} -1, 1010cm -1, 920cm -1, 850cm -1, 760cm -1, the 700 cm ^-1 Example 5 Example 1 O, O'dipalmitoyl Rattle Oil O, represented by the formula (6) in the same manner as in Example 1 except that -L-tartaric anhydride was changed to O, O'-dibenzoyl-D-tartaric anhydride.
O'-dibenzoyl-D-tartaric acid / mono-L- (1,2
-Dibenzyloxycarbonyl) ethylamide was obtained.

[0023]

Embedded image Melting point 49-51 ° C. ¹ H NMR 2.7-3.1 ppm (2H), 4.6-5.0 ppm (5H) 5.9-6.1 ppm (2H), 7.1-7.6 ppm (18 H) 8.0-8.1 ppm (4H) ^13C NMR 36 ppm, 49 ppm, 67 ppm, 68 ppm, 71 ppm 68 ppm, 71 ppm, 72 ppm, 128-129 ppm (8C), 130.0 ppm, 130.1 ppm, 133 ppm, 135 ppm, 134 0.5 ppm, 135 ppm, 164.7 ppm, 165 ppm, 166 ppm, 169.5 ppm, 170.1 ppm, 170.4 ppm IR 3600-2700 cm ^-1 , 1800-1650 cm ^-1 , 1602 cm ^-1 , 1585 cm ^-1 , 1529 cm ^-1 , 1498 cm ^{-1, 1453cm -1, 1390cm -1 1300~1150cm -1, 1140~1030cm -1, 1025cm -1} , 907cm -1, 847cm -1, 752cm -1 714cm -1, Example 6 Example 1 O, O'dipalmitoyl Rattle oil -L- tartaric acid O, O'-diparaanisoyl-D-tartaric acid / mono-D- represented by the formula (7) in the same manner as in Example 1 except that the anhydride was changed to O, O'-diparaanisoyl-D-tartaric anhydride.
(1,2-Dibenzyloxycarbonyl) ethylamide was obtained.

[0024]

Embedded image Melting point 52-54 ° C. ¹ H NMR 2.8-3.1 ppm (2H), 3.7-3.9 ppm (6H) 4.6-5.0 ppm (5H), 5.9-6.0 ppm (2H) 6 0.8-8.1 ppm (20H) ^13C NMR 36 ppm, 49 ppm, 55 ppm (2C), 67 ppm, 68 ppm, 71 ppm, 72 ppm, 113.6 ppm, 114 ppm, 120 ppm, 121 ppm, 128-129 ppm (16C), 132 ppm (2C), 135ppm (2C), 164ppm, 164.5ppm 165ppm, 166ppm, 170ppm, 170.5p pm IR 3600~2850cm -1, 2842cm -1, 2584cm -1, 1800~1650cm -1, 1607cm -1, 1581cm - 1, 1513cm ^-1 , 1457 cm ^-1 , ^{1443cm -1, 1400cm -1, 1390~1150cm -1} , 1094cm -1, 1026cm -1, 970cm -1, 847cm -1, 758cm - 1, 697cm -1 Example 7 DL-alanine benzyl ester p-toluenesulfonic acid 3.5 g (10 mmol) of salt was added to 50 m of chloroform.
and 10 ml of a 1 N aqueous solution of sodium hydroxide was added dropwise while stirring at room temperature. After stirring for 30 minutes, the aqueous layer was separated and removed. To the chloroform layer was added 3.5 g (9.5 mmol) of O, O'-diparatoluoyl-D-tartaric anhydride, and the mixture was stirred at room temperature for 1 hour. H
As a result of analysis by PLC, O, O ′ represented by the formula (8)
-Diparatol oil-D-tartaric acid / mono-L- (1,2
-Dibenzyloxycarbonyl) ethylamide (DL)
) And two peaks based on O, O'-diparatoluoyl-D-tartaric acid mono-D- (1,2-dibenzyloxycarbonyl) ethylamide (DD type) represented by formula (9) (Fig. 3 Column MIGHTYS
IL RP-18GP, developing solution 0.03% aqueous ammonia adjusted to pH 4.7 with acetic acid / acetonitrile = 67/33 v / v).

The reaction solution was concentrated, and the obtained crystals were recrystallized from toluene and subjected to optical resolution. As a result of analyzing the crystals by HPLC, O, O'-diparatoluoyl-
D-tartaric acid mono-D- (1-dibenzyloxycarbonyl) ethylamide (DD type) was detected. The optical purity was 99.5% ee or more (FIG. 4 under the same measurement conditions as in FIG. 3).

[0026]

Embedded image

[0027]

Embedded image Example 18 3.2 g (10 mmol) of D-alanine benzyl ester / paratoluenesulfonate having an optical purity of 99.6% ee was suspended in 50 ml of chloroform, and a 1N aqueous sodium hydroxide solution was stirred at room temperature while stirring. 10 ml was added dropwise. After stirring for 30 minutes, the aqueous layer was separated and removed. O, O'-Dianisoyl-D with 99.9% ee was added to the chloroform layer.
3.8 g (9.5 mmol) of tartaric anhydride are added,
The mixture was stirred at room temperature for 1 hour. Next, 15 ml of a 1N aqueous hydrochloric acid solution was added, and the mixture was stirred for 2 hours, and then the aqueous layer was separated and removed.
The chloroform layer was washed with 20 ml of water, dehydrated by adding anhydrous magnesium sulfate, and then filtered. The filtrate is concentrated, and the precipitated crystals are filtered and dried to obtain O, O'-dianisoyl-D-tartaric acid / mono-D-1 represented by the formula (10).
-Benzyloxycarbonylethylamide was obtained.

[0028]

Embedded image

[0029]

According to the present invention, industrially useful high optical purity aspartic acid diester tartaramide can be produced by a simple operation. When the optically active aspartic acid diester is used as a raw material, the optical purity of aspartic acid diester as a raw material can be determined by analyzing the reaction solution using a usual column, since the optical purity of aspartic acid does not decrease.

[Brief description of the drawings]

FIG. 1 is a view showing an HPLC peak of L-aspartic acid dibenzyl ester / paratoluenesulfonate in Example 1.

FIG. 2 is a view showing an HPLC peak of D-aspartic acid dibenzyl ester in Example 2.

FIG. 3 shows O, O′-diparatoluoyl-D-tartaric acid / mono-L- (1-benzyloxycarbonyl) ethylamide and O, O′-diparatoluoyl-D in Example 7.
It is a figure which shows the HPLC peak of the mixture of -tartaric acid and mono-D- (1-dibenzyloxycarbonyl) ethylamide.

FIG. 4 is a view showing an HPLC peak of O, O′-diparatoluoyl-D-tartaric acid / mono-D- (1-benzyloxycarbonyl) ethylamide in Example 7.

Claims (5)

[Claims] 1. A compound of the general formula (1) (Where R ¹ represents an alkyl group, an unsubstituted or substituted phenyl group, or an unsubstituted or substituted aralkyl group; R ² represents an α-amino acid residue; R ³ represents hydrogen; Represents a methyl or methoxy group.
Means an optically active substance. ) An optically active amino acid ester tartaramide represented by the formula: 2. A compound of the general formula (2) (Where R ¹ represents an alkyl group, an unsubstituted or substituted phenyl group, or an unsubstituted or substituted aralkyl group. R ² represents an α-amino acid residue. And an optically active amino acid ester represented by the following general formula (3): (Where R ³ represents hydrogen, methyl, or methoxy group. * Means an optically active substance.) A general formula characterized by reacting an optically active diacyl tartaric anhydride represented by the formula: (1) (Where R ¹ represents an alkyl group, an unsubstituted or substituted phenyl group, or an unsubstituted or substituted aralkyl group; R ² represents an α-amino acid residue; R ³ represents hydrogen; Represents a methyl or methoxy group.
Means an optically active substance. A method for producing an optically active amino acid ester tartaramide represented by the formula: 3. A compound of the general formula (4) (Where R ¹ represents an alkyl group, an unsubstituted or substituted phenyl group, or an unsubstituted or substituted aralkyl group. R ² represents an α-amino acid residue). An amino acid ester and a compound represented by the general formula (3): (Where R ³ represents a hydrogen, methyl or methoxy group. * Means an optically active substance). After reacting an optically active diacyl tartaric anhydride represented by General formula (1) characterized by the following: (Where R ¹ represents an alkyl group, an unsubstituted or substituted phenyl group, or an unsubstituted or substituted aralkyl group; R ² represents an α-amino acid residue; R ³ represents hydrogen; Represents a methyl or methoxy group.
Means an optically active substance. A method for producing an optically active amino acid ester tartaramide represented by the formula: 4. α represented by the general formulas (2) and (4)
The method for producing an optically active amino acid ester tartaramide according to claim 2 or 3, wherein the amino acid is aspartic acid or alanine. 5. The optically active amino acid ester tartaramide according to claim 1, wherein R ^{2 of the} α-amino acid residue represented by the general formula (1) is a residue of aspartic acid or alanine.