JPH051002A - Production of alpha-amino acid - Google Patents

Abstract

PURPOSE:To produce an alpha-amino acid or its optically active isomer useful as an intermediate for medicines, agricultural chemicals, functional materials, etc., from a 2-oxazoline compound by a simple and general method such as a hydrolysis or a substitution reaction. CONSTITUTION:An oxazoline compound of formula I (R<1>, R<2> are H, 1-16C alkyl, substituted alkyl, phenyl, substituted phenyl, benzyl, but R<1>not equal to R<2>; R<3> is 1-10C alkyl, substituted alkyl, phenyl, benzyl, substituted benzyl), especially its optically active isomer, preferably a 1,2-epoxyalkane compound of formula II or its optically active isomer is made to react with a nitrile compound in the presence of an acid catalyst, and the reactional product is hydrolyzed into an amyl alcohol compound, which is oxidized into an alpha-amino acid of formula III, especially its optical acid. A method for producing an alpha-amino acid having an alkyl, phenyl or benzyl except for OH has not been known.

Description

Detailed Description of the Invention

[0001]

The present invention relates to α, which is useful as an intermediate for producing pharmaceuticals, agricultural chemicals, functional organic materials and the like.
-It relates to a method for producing an amino acid.

[0002]

2. Description of the Related Art Amino acids are important compounds as intermediates for pharmaceutical synthesis and the like, but it has been difficult to obtain non-natural amino acids, particularly optically active forms thereof. In order to obtain such a compound, generally, an expensive asymmetric source is required (eg, Iwao Ojima, 56th Annual Meeting of the Chemical Society of Japan.
2404), which must be manufactured using a costly optical resolution method, and an inexpensive and general synthesis method has been desired.

On the other hand, as a method for synthesizing an amino acid from 2-oxazoline, a method for obtaining β-hydroxy-α-amino acid from 4-carbalkoxy-2-oxazoline as a starting material [eg, K. Pfister et al., Journal of A
American Chemical Society, 70 , 2297 (1948)] has been proposed.

[0004]

However, in the above method, only β-hydroxy-α-amino acid can be obtained, and an alkyl group other than hydroxy group, which is useful as a synthetic intermediate for pharmaceuticals,
An α-amino acid having a phenyl group, a benzyl group, etc. cannot be produced, and a method for producing these has not yet been known.

The present invention has been made in view of the above situation,
An object of the present invention is to provide a method for producing an α-amino acid useful as an intermediate for medicines, agricultural chemicals, functional materials, etc. and an optically active substance thereof.

[0006]

[Means for Solving the Problems] The following general formula 4

[Chemical 4] (In the above formula, R ¹ and R ² represent hydrogen, an alkyl group having 1 to 16 carbon atoms, a substituted alkyl group, a phenyl group, a substituted phenyl group, a benzyl group and a substituted benzyl group, and R ³ has 1 to 16 carbon atoms. Represents 10 alkyl groups, substituted alkyl groups, phenyl groups, substituted phenyl groups, benzyl groups, and substituted benzyl groups, R ¹ and R ² are not the same at the same time)
And particularly preferably, the 2-oxazoline compound represented by the above general formula 4 or an optical compound thereof obtained by reacting 1,2-epoxyalkanes or an optically active substance thereof with nitriles in the presence of an acid catalyst. After hydrolyzing the active substance to give 2-amino alcohol, it is oxidized to obtain the compound represented by the following general formula 5

[Chemical 5] (In the above formula, R ¹ and R ² are the same as above). Examples of the substituents contained in the substituted alkyl group, the substituted phenyl group and the substituted benzyl group in the above formulas 4 and 5 of the present invention include halogen, carboxy and phenyl.

The 2-oxazoline compound 4 used as a starting material includes 2-methyl-4-methyl-2-oxazoline,
2-methyl-4-ethyl-2-oxazoline, 2-methyl-4-
Propyl-2-oxazoline, 2-methyl-4-butyl-2-
Oxazoline, 2-methyl-4-pentyl-2-oxazoline, 2-methyl-4-hexyl-2-oxazoline, 2-methyl-4-heptyl-2-oxazoline, 2-methyl-4-octyl-2-oxazoline, 2-Methyl-4-nonyl-2-oxazoline, 2-methyl-4-decyl-2-oxazoline, 2-
Methyl-4-undecyl-2-oxazoline, 2-methyl-4
-Dodecyl-2-oxazoline, 2-methyl-4-tridecyl
-2-oxazoline, 2-methyl-4-tetradecyl-2-oxazoline, 2-methyl-4-pentadecyl-2-oxazoline, 2-methyl-4-hexadecyl-2-oxazoline,
2-ethyl-4-methyl-2-oxazoline, 2-ethyl-4-
Ethyl-2-oxazoline, 2-ethyl-4-propyl-2-
Oxazoline, 2-ethyl-4-butyl-2-oxazoline, 2-ethyl-4-pentyl-2-oxazoline, 2-ethyl-4-hexyl-2-oxazoline, 2-ethyl-4-heptyl-2-oxazoline, 2-ethyl-4-octyl-2-oxazoline, 2-ethyl-4-nonyl-2-oxazoline,
2-ethyl-4-decyl-2-oxazoline, 2-ethyl-4-
Undecyl-2-oxazoline, 2-ethyl-4-dodecyl-
2-oxazoline, 2-ethyl-4-tridecyl-2-oxazoline, 2-ethyl-4-tetradecyl-2-oxazoline, 2-ethyl-4-pentadecyl-2-oxazoline, 2-
Ethyl-4-hexadecyl-2-oxazoline, 2-propyl-4-propyl-2-oxazoline, 2-propyl-4-butyl-2-oxazoline, 2-propyl-4-pentyl-2-
Oxazoline, 2-propyl-4-hexyl-2-oxazoline, 2-propyl-4-heptyl-2-oxazoline, 2-
Propyl-4-octyl-2-oxazoline, 2-propyl-
4-nonyl-2-oxazoline, 2-propyl-4-decyl-
2-Oxazoline, 2-propyl-4-undecyl-2-oxazoline, 2-propyl-4-dodecyl-2-oxazoline, 2-propyl-4-tridecyl-2-oxazoline, 2-
Propyl-4-tetradecyl-2-oxazoline, 2-propyl-4-pentadecyl-2-oxazoline, 2-propyl-
4-hexadecyl-2-oxazoline, 2-isopropyl-
4-hexyl-2-oxazoline, 2-isopropyl-4-octyl-2-oxazoline, 2-methyl-4-methyl-4-propyl-2-oxazoline, 2-methyl-4-methyl-4-butyl-2- Oxazoline, 2-methyl-4-methyl-4-pentyl-2-oxazoline, 2-phenyl-4-hexyl-2-
Oxazoline, 2-methyl-4-phenyl-2-oxazoline, 2-methyl-4- (p-fluorophenyl) -2-oxazoline, 2-methyl-4- (p-chlorobenzyl) -2-oxazoline, 2- Methyl-4- (4-biphenylyl) -2-oxazoline, 2-isopropyl-4-phenyl-2-oxazoline,
2-benzyl-4-hexyl-2-oxazoline, 2-methyl
Examples include 4-benzyl-2-oxazoline and the like.

As the optically active substance, the above-mentioned (+) or (-) compound can be exemplified.

As these compounds, those obtained by reacting 1,2-epoxyalkanes with nitriles in the presence of an acid catalyst may be conveniently used, and a specific method thereof is as follows. Prior application (see Japanese Patent Application No. 01-112114)
Are described in detail in.

In synthesizing the amino acid compound represented by the general formula 5, the 2-oxazolines represented by the general formula 4 are hydrolyzed to amino alcohols, which are then oxidized. For the hydrolysis of the 2-oxazolines to amino alcohols, it is preferable to add an acid such as hydrochloric acid, acetic acid or sulfuric acid as a catalyst, and the amount used is in the range of 0.5 to 10 equivalents relative to the oxazoline. Is good. This reaction may be carried out in the above-mentioned aqueous acid solution or by adding thereto an organic solvent which does not undergo hydrolysis such as alcohol, benzene or hexane. Reaction temperature is 0-2
It may be appropriately selected from the range of 00 ° C, particularly the range of 20 to 150 ° C. The reaction time is 0.5 depending on the reaction temperature.
It can be appropriately determined within a range of up to 30 hours. After completion of the reaction, the amino alcohol can be separated and recovered by neutralization with an alkali and extraction or distillation.

The amino alcohol thus obtained is oxidized, and in this case, it is preferable to protect the amino group. This protection can be easily carried out by acting an acid halide such as acetyl chloride or benzoyl chloride. The amount of acid halide used is preferably in the range of 1 to 10 equivalents relative to the amino alcohol. The protection reaction is diethyl ether, tetrahydrofuran,
It is preferably carried out in an organic solvent such as benzene, toluene, hexane and dichloromethane. Further, it is preferable to add a tertiary amine such as triethylamine or pyridine or sodium carbonate to the above acid halide, and the amount thereof is preferably in the range of 1 to 10 equivalents relative to the amino alcohol. The reaction temperature in this case is in the range of -50 to 50 ° C,
Particularly, the range of -20 to 30 ° C is preferable. The reaction time can be appropriately determined within the range of 0.5 to 10 hours depending on the reaction temperature. After the completion of the reaction, the amide alcohol or the amide ester can be separated and recovered by using a known method such as phase separation, extraction and filtration.

The amide alcohol can be used as it is in the next oxidation reaction, but when the amide ester is obtained, it is preferably converted into the amide alcohol by hydrolysis with a base catalyst such as sodium hydroxide or potassium carbonate. . In this case, it may be carried out in the same manner as the above-mentioned hydrolysis of oxazoline except that a base catalyst is used instead of the acid catalyst.

For the oxidation of alcohol, it is preferable to use potassium permanganate, potassium dichromate or the like as an oxidizing agent, and it is preferable to use it in the range of 1 to 2 equivalents relative to the alcohol. This reaction may be carried out in an aqueous solution or by adding acetone thereto. Further, the reaction can be carried out by adding sodium hydroxide or magnesium sulfate to make the reaction solution alkaline or neutral.

The oxidation reaction temperature is preferably in the range of 0 to 100 ° C. The reaction time is appropriately determined within the range of 1 to 100 hours depending on the reaction temperature. After completion of the reaction, the oxidation product can be separated and recovered by using a known method such as phase separation, extraction, column chromatography and the like.

When oxidizing an amide alcohol protected with an amino group, acetyl amide alcohol is preferably used as the amide alcohol other than the lower aliphatic type because of the solubility of the amide alcohol in water. In the case of this acetylamide alcohol, the reaction is preferably carried out neutrally.

The amidocarboxylic acid obtained by protecting and oxidizing the amino group can be hydrolyzed into an amino acid by hydrolysis with an acid catalyst such as sulfuric acid or hydrochloric acid or a base catalyst such as potassium hydroxide. The reaction in this case may be carried out in the above aqueous acid or base solution or by adding an alcohol. The amount of the catalyst used, the reaction temperature, and the reaction time may be the same as in the other hydrolysis described above. After the reaction,
Amino acids can be separated and recovered by known methods such as release, filtration, and recrystallization.

The present invention will be specifically described below with reference to examples.

【Example】Example 1 Fluorination to (R)-(+)-1,2-epoxy octane (91% ee)
(S)-(−)-obtained by reacting hydrogen and acetonitrile
2-Methyl-4-hexyl-2-oxazoline 9.06 g (54
45 ml (135 mmol) of 3N hydrochloric acid was added to
The mixture was stirred at 00 ° C for 3 hours. After cooling down, this is alkali
Neutralize with, extract the reaction product with ether, and dry the extract.
It was dried over sodium sulfate. After distilling off the solvent, vacuum evaporation
After boiling, the boiling point is 95-100 ° C / 7mmHg, and the specific rotation (D, 25
(° C) = + 8.5 ° (c = 1.0, benzene) (S)
5.87 g (yield 75%) of-(+)-2-aminooctanol
Obtained.

This (S)-(+)-2-aminooctanol 1.
To 02 g (7 mmol) 70 ml ether, triethylamine 6.
8 ml (49 mmol) was added, and 2.5 ml (35 mmol) of acetyl chloride was added dropwise on a water bath under a nitrogen atmosphere. 3 at room temperature
After stirring for an hour, the reaction solution was poured into 150 ml of water and extracted with dichloromethane. The dichloromethane layer was washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 1.64 g of 2- (N-acetyl).
Aminooctyl acetate was obtained (yield 100%).

2- (N-acetyl) aminooctyl acetate 1.58 g (6.9 mmol), anhydrous potassium carbonate 4.28 g
(31 mmol) and 65 ml of methanol were mixed and stirred at room temperature for 17 hours, and then a 5% aqueous sodium hydrogen carbonate solution 100 was added.
ml was added and extracted with dichloromethane. The dichloromethane layer was washed with an aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was distilled off to obtain 0.85 g of 2- (N-acetyl) aminooctanol (yield 66%).

2- (N-acetyl) aminooctanol 0.
29 g (1.6 mmol), 10 ml of water and a small amount of magnesium sulfate are mixed, and potassium permanganate 0.33 g (2.1 mmo)
l) was added and the mixture was stirred at 60 ° C. for 2 hours. After allowing to cool, a saturated aqueous sodium hydrogen sulfite solution was added to dissolve the brown solid, and the pH was adjusted to 1 or less with concentrated hydrochloric acid, followed by extraction with ether. The ether layer was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 0.22 g of a crude product.

This was subjected to silica gel column chromatography (Wako gel C-200, φ1.8 cm × 30 cm, CH ₂ Cl ₂ : EtOH =
(9: 1, TLC plate detected with bromocresol green)
Then, 0.15 g of 2- (N-acetyl) aminooctanoic acid was obtained (yield 46%).

2- (N-acetyl) aminooctanoic acid 0.1
1.2 ml of 5N hydrochloric acid was added to 5 g (0.74 mmol) of 10
The reaction was carried out at 0 ° C for 5.5 hours. After allowing to cool, the white solid was repeatedly dissolved and concentrated in water and ethanol, then dissolved in 1.2 ml of ethanol, 1 ml of aniline was added, and the mixture was left for 1 hour in a refrigerator. The white solid is filtered off and ethanol 2
After washing with ml, vacuum dry at 50 ℃ for 1 hour, 0.06g
Crude 2-aminooctanoic acid was obtained (yield 51%). This was recrystallized with 4 ml of a mixed solution of water: ethanol = 1: 1,
After filtering off, washing with acetone and vacuum drying at 50 ° C. for 1 hour gave 0.04 g of L-2-aminooctanoic acid (100% ee confirmed by HPLC) ( Recrystallization yield 66%, total yield from 2-amino-4-hexyl-2-oxazoline 8%).

[0023]Example 2 To (R)-(-)-2-methyl-1,2-epoxyhexane (90% ee)
Obtained by the action of aluminum chloride and acetonitrile
(S) -4-butyl-2,4-dimethyl-2-oxazoline 3.
To 44 g (22 mmol), 18 ml of 3N hydrochloric acid was added, and 100
The mixture was stirred at 0 ° C for 3 hours. After allowing to cool, concentrate and add water and ethanol.
Repeatedly dissolve and concentrate with nol, vacuum dry and
3.52 g of no-2-methylhexanol hydrochloride were obtained. this
220 ml of ether and 21.4 ml of triethylamine (15
4 mmol) was added, and acetyl chloride was added on a water bath under a nitrogen atmosphere.
Chill 7.9 ml (110 mmol) was added dropwise. Stir at room temperature for 2 hours
After stirring, the reaction was poured into 300 ml of water and diluted with dichloro
Extracted with methane. Dichloromethane layer is sodium chloride
After washing with an aqueous solution, drying over anhydrous magnesium sulfate,
The solvent was distilled off and 4.33 g of 2- (N-acetyl) amino-2
-Methylhexyl acetate was obtained (yield 91%).

2- (N-acetyl) amino-2-methylhexyl acetate 4.33 g (20 mmol), methanol 220 m
1, 87 g (115 mmol) of anhydrous potassium carbonate were mixed, the mixture was stirred at room temperature for 5 hours, 250 ml of a 5% aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with dichloromethane. After washing the dichloromethane layer with an aqueous sodium chloride solution,
Dry over anhydrous magnesium sulfate and evaporate the solvent to 2.3.
1 g of 2- (N-acetyl) amino-2-methylhexanol was obtained (yield 58%).

2- (N-Acetyl) amino-2-methylhexanol 0.40 g (2.3 mmol), water 15 ml, and a small amount of magnesium sulfate were mixed, and potassium permanganate 0.51 g (3.5.
2 mmol) was added and the mixture was stirred at 70 ° C. for 4 hours. After allowing to cool, a saturated aqueous sodium hydrogen sulfite solution was added to dissolve the brown solid, concentrated hydrochloric acid was added to adjust the pH to 1 or less, and the mixture was extracted with ether. The ether layer was dried over anhydrous sodium sulfate and the solvent was distilled off to obtain 0.20 g of a crude product. This is subjected to silica gel column chromatography (Wako Gel C-20
0, φ1.8 cm × 35 cm, CH ₂ Cl ₂ : EtOH = 9: 1, TLC plate was detected with bromocresol green), the solvent was distilled off, and 0.04 g of 2- (N-acetyl) amino- 2-Methylhexanoic acid was obtained (yield 9%).

To 0.04 g (0.2 mmol) of 2- (N-acetyl) amino-2-methylhexanoic acid was added 1 ml of 5N hydrochloric acid,
The reaction was carried out at 100 ° C for 6 hours. After allowing to cool, concentration, dissolution with water and ethanol, and concentration were repeated, and then the residue was dissolved in ethanol (0.6 ml) and aniline (2 ml) was added to precipitate a jelly-like solid. After standing in the refrigerator for 1 hour, add acetone and filter the white powder, wash with acetone, and leave at 50 ° C.
After vacuum drying for 1 hour, 0.01 g of crude 2-amino-2-methylhexanoic acid was obtained. This product was identified as L-2-amino-2-methylhexanoic acid with 96% ee by HPLC (CHIRALPAK WH) with the racemic compound shown in Example 3.

[0027]Example 3 Racemic 2-methyl-1,2-epoxyhexane with al chloride
4-butyl-obtained by the action of minium and acetonitrile
To 3.72-g (24 mmol) of 2,4-dimethyl-2-oxazoline
Add 20 ml of 3N hydrochloric acid and stir at 100 ° C for 3 hours.
Then, concentrate and dry to dryness, 2-amino-2-methylhexano
And hydrochloride. 240 ml ether, triethylamine
23.3 ml (168 mmol) was added, and the mixture was chlorinated under a nitrogen atmosphere.
Acetyl 8.6 ml (120 mmol) was added dropwise at room temperature to 1.5.
After stirring for an hour, pour into water and extract with dichloromethane,
It was dried over anhydrous magnesium sulfate. Evaporate off the solvent 5.
48 g of 2- (N-acetyl) amino-2-methylhexyl lua
Cate was obtained (yield 100%).

To this, 220 ml of methanol and 17.25 g (125 mmol) of anhydrous potassium carbonate were added, and the mixture was stirred at room temperature for 18 hours, then a 5% aqueous sodium hydrogen carbonate solution was added, extracted with dichloroethane, and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 3.06 g of 2- (N-acetyl) amino-2-methylhexanol (yield 70%).

Further, 3.98 g (25 mmol) of potassium permanganate was added in water to which magnesium sulfate was added,
The mixture was stirred at 70 ° C. for 4 hours and treated in the same manner as in Example 2 to obtain 2.00 g of a crude product containing 2- (N-acetyl) amino-2-methylhexanoic acid. Without isolation by column chromatography, add 50 ml of 5N hydrochloric acid, and add 100 ° C.
The mixture was stirred for 5 hours and treated in the same manner as in Example 2 to give 0.32 g.
2-amino-2-methylhexanoic acid was obtained (yield 12
%, 4-butyl-2,4-dimethyl-2-oxazoline (9% overall yield).

[0030]

INDUSTRIAL APPLICABILITY The present invention is derived from epoxides.
-Α-amino acids can be produced by a simple and general method such as hydrolysis or substitution reaction using oxazolines as starting materials, and optically active α-amino acids can be produced by using optically active 2-oxazolines as starting materials. It has a special effect that amino acids can be produced.

Claims (4)

[Claims] 1. The following general formula 1 (In the above formula, R ¹ and R ² represent hydrogen, an alkyl group having 1 to 16 carbon atoms, a substituted alkyl group, a phenyl group, a substituted phenyl group, a benzyl group and a substituted benzyl group, and R ³ has 1 to 16 carbon atoms. Represents 10 alkyl groups, substituted alkyl groups, phenyl groups, substituted phenyl groups, benzyl groups, and substituted benzyl groups, R ¹ and R ² are not the same at the same time)
The 2-oxazolines represented by are hydrolyzed to amino alcohols and then oxidized to give the following general formula: (Wherein R ¹ and R ² are the same as above). 2. An optically active α-amino acid characterized in that the compound represented by the general formula 1 of claim 1 hydrolyzes optically active 2-oxazolines to amino alcohols and then oxidizes them. Manufacturing method. 3. In claim 1, 2-oxazolines are represented by the following general formula: (Wherein R ¹ and R ² are the same as above) 1,
A method for producing an α-amino acid, which is obtained by reacting a 2-epoxyalkane with a nitrile in the presence of an acid catalyst. 4. The optically active 2-oxazoline according to claim 2, which is obtained by reacting an optically active form of a compound represented by the general formula 3 of claim 3 with a nitrile in the presence of an acid catalyst. Optically active α- characterized by being
Amino acid production method.