JPS601177A - Alpha-amino acid, its derivative, and their preparation - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (R<1> is H, or lower alkyl; R<2> and R<3> are H, lower alkyl, lower alkoxy, or R<2> and R<3> are linked to form -CH=CH-CH=CH-; R<4> is H, or protecting group; n is 0-2). EXAMPLE:beta-( 2,3-Dihydro-6-hydroxy- 2,5,7,8-tetramethyl-2H-benzopyranyl )alanine hydrochloride. USE:An antioxidant. Showing improved activity than vitamin E, also useful as an intermediate for synthesizing an antioxidant. PREPARATION:An aldehyde shown by the formula II is reacted with ammonium carbonate and an alkali metal cyanide to give a hydantoin shown by the formula III, which is hydrolyzed to give a compound shown by the formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to α-amino acids represented by general formula (1) and derivatives thereof, and methods for producing them.

In the above formula, R1 represents a hydrogen atom or a lower alkyl group such as a methyl group, an ethyl group, a propyl group, or a butyl group. and W are the same or different hydrogen atoms; lower alkyl groups such as methyl, ethyl, propyl, butyl; or lower alkoxy groups such as methoxy, ethoxy, propoxy, butoxy, or Bi and t together form a -CH-CH-CH=CH- group. R
4 represents a hydrogen atom or a protective group. As the protecting group, any commonly used protecting group may be used as long as it achieves the purpose of preserving a hydroxyl group, such as an acyl group such as an acetyl group, a propionyl group, a butyryl group, a benzoyl group, a methyl group, an L -butyl group, triphenylmethyl group, benzyl group, trimethylsilyl group, etc. n is θ~2
means an integer of

Further, the α-amino acid derivative represented by the general formula (1) is
Specifically, alkyl esters of the α-amino acid such as methyl ester, ethyl ester, flobyl ester, methyl ester, octyl ester, tetradecyl ester, and stearyl ester; or alkali metal such as lithium salt, sodium salt, potassium salt, etc. salt; or the α
- Salts of mineral acids such as hydrochlorides, sulfates, and nitrates of amino acids or their esters; or organic sulfonates such as p-toluenesulfonates and methanesulfonates.

The α-amino acids and derivatives thereof represented by the general formula (I) provided by the present invention are novel compounds not described in known literature. Among these α-amino acids and derivatives thereof, those represented by the general formula (1) Those in which R4 is a hydrogen atom have an excellent antioxidant effect and are useful for oxygen-sensitive organic materials such as oils and fats, rubber products, and plastics.

It is useful as an antioxidant in processed foods, etc. General formula (
1) α-amino acids in which R4 is a hydrogen atom and the α-amino acids in which R4 is a hydrogen atom;
- Salts of amino acids and their esters are particularly suitable for use as antioxidants in processed foods, taking advantage of their water-soluble properties. Further, when R4 in the general formula (1) is a protecting group, a compound having the above-mentioned antioxidant action can be obtained by replacing this protecting group with a hydrogen atom by a conventional method. Among α-amino acids and their derivatives represented by general formula (1), salts are particularly highly water-soluble;
It is easy to separate these salts from fat-soluble impurities mixed in during production, and highly pure α-amino acids can be obtained by neutralizing the salts from which fat-soluble impurities have been removed using conventional methods. Furthermore, by subjecting this α-amino acid to a conventional esterification reaction, a highly purified α-amino acid ester can be obtained.

Recently, Vitamin 7 E has been attracting attention as a highly safe antioxidant, but it has not been used as a general-purpose antioxidant because it is relatively expensive and easily oxidized and colored.

As a result of intensive research to develop a new antioxidant that surpasses vitamin E, the present inventors found that the α-amino acid represented by the general formula (I) and its derivatives have an antioxidant effect superior to that of vitamin E. The inventors have discovered that these α-amino acids and their derivatives can be easily produced, and have led to the present invention.

According to the present invention, general formula (II) [wherein R1, R2, R3 and n have the same meanings as in general formula (1), and R has the same meaning as R4 in general formula (1)]
or represents a different hydrogen atom or protective group. ] by reacting the aldehyde represented by ammonium carbonate and an alkali metal cyanide [where R1, R2, W
, R and n have the same meanings as in general formula (I[). ] By obtaining a hydantoin represented by the formula (1) and then hydrolyzing the hydantoin, α represented by the general formula (1) is obtained.
-Amino acids can be produced.

Here, examples of the alkali metal cyanide include sodium cyanide, potassium cyanide, and lithium cyanide. The reaction of the aldehyde represented by the general formula (n) with ammonium carbonate and an alkali metal cyanide can be carried out under conventionally known general hydantoin synthesis reaction conditions. For example, an aldehyde represented by the general formula (II) and an alkali metal cyanide in an amount of about 1 to 10 times the mole of the aldehyde, preferably about 1 to 10 times the mole, preferably about 1 to 3 times the mole of the aldehyde. water,
The reaction is carried out in a solvent such as methanol, ethanol, or tetrahydrofuran at a temperature of room temperature to 100°C, preferably 40 to 60°C, and then the resulting reaction mixture is knitted, and a small amount of concentrated hydrochloric acid is added to this concentrate. A hydantoin represented by the general formula (Ili) can be obtained by reacting about 1 to 10 times the molar amount at about 80 to 100°C. The α-amino acid represented by the general formula (1) can be produced by hydrolyzing the hydantoin thus obtained according to a conventional method. This hydrolysis reaction is carried out, for example, by mixing hydantoin with about 1 to 5 times the molar amount of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide in an aqueous solvent at 80 to 150°C, preferably at 100 to 130°C. ℃
The alkali present in the system is then neutralized with a mineral acid such as hydrochloric acid or sulfuric acid.

By subjecting the α-amino acid represented by the general formula (I) to the conventionally known general esterification reaction and/or salt-forming reaction, the α-amino acid represented by the general formula (1,) can be obtained. Esters or salts or salts of the α-amino acid esters can be obtained. For example, α-amino acid represented by general formula (1) and methyl alcohol, ethyl alcohol,
An alkyl alcohol such as flobyl alcohol, butyl alcohol, octyl alcohol, or stearyl alcohol is heated at about -20°C to +40°C in the presence of hydrogen chloride, sulfuric acid, thionyl chloride, etc. in an amount equivalent to or more than the α-amino acid.
After reaction, the corresponding α-amino acid ester is obtained by neutralizing the reaction mixture with aqueous sodium bicarbonate or the like. Alternatively, the α-amino acid represented by the general formula (1) or its ester is dissolved in water, methyl alcohol, ethyl alcohol, flobyl alcohol, f) lahydrofuran, diethyl ether, etc., and then the α-
Mineral acids such as hydrogen chloride, sulfuric acid, nitric acid, etc. in an approximately equivalent amount to the amino acid or its ester; organic sulfonic acids such as p-toluenesulfonic acid, methanesulfonic acid, etc.; or lithium hydroxide, sodium hydroxide 1. By reacting with an alkali metal hydroxide such as potassium hydroxide, a salt of the corresponding α-amino acid or its ester can be obtained.

α- represented by the general formula ([) obtained by the above method
Amino acids, esters thereof, and salts thereof can be separated and recovered by a general method for separating and recovering amino acids, esters thereof, and salts thereof.

The aldehyde represented by the general formula (1) used as a raw material can be easily obtained by oxidizing the alcohol represented by the following general formula (IV), which is a known compound, with chromic anhydride in the presence of pyridine. Helvetic
a Chimica Acta Volume 61, 837-84
3 (1978)].

1 The present invention will be specifically described below with reference to Examples and Test Examples.

(1) 2-(6-benzyloxy-2,3-dihydro-
3.38 r of 2,5,7,8-tetramethyl-2H-benzopyranyl)acetaldehyde and 25 Inl of ethanol
14 mts of water, 4.52 f of ammonium carbonate and 0.98 f of sodium cyanide were added to the solution.

The mixture was heated and stirred at 50 to 55°C for 4 hours. The obtained reaction solution was concentrated under reduced pressure, and 2rILl of concentrated hydrochloric acid was added thereto.
Heated at 0°C for 5 minutes. Cool the reaction solution.

Water was added to this, and the resulting precipitate pif was filtered, washed with water and diethyl ether, and dried under reduced pressure to obtain 5-((6-benzyloxy-2,3- 3.421 dihydro-2,5゜7.8-tetramethyl-2H-benzopyranyl)methyl]imidazolidine-2,4-dione was obtained (yield 83.8%)
.

FD mass spectrum: (MJ” 408MS NMR spectrum (90MHz) δDMSO-d6
"1.21 (8, 3H): 1.5~2.7 (m,
15H) ;.

3.26 (8, 2H) i 4.0~4.3 (m
, IH) i4.6 (8, 2H): 7.25~
7.6 (m, 5H) (2) 5 obtained in (1) above
-((6-benzyloxy-2,3-dihydro-2,5
,7,8-tetramethyl-2H-benzopyranyl)methyl]imidazolidine-2,4-dione 3.15F, sodium hydroxide 1.6f and water 30d were heated in a sealed tube at 120°C for 15 hours. Stirred. Water was added to the resulting reaction solution, filtered to remove insoluble matter, the P solution was washed with diethyl ether, and the aqueous layer was neutralized with dilute hydrochloric acid. The formed precipitate was filtered, washed with water and diethyl ether, and dried under reduced pressure to obtain β-(6-benzyloxy-2,3-dihydro-2,5, 2.41 f of 7,8-tetramethyl-2H-benzopyranyl)alanine was obtained (yield: 78.7 g).

FD mass spectrum: (ME” 383MS NMR spectrum (90MHz) δDMSO-d6
"1.2 (8, aH); 1.5~z, 7 (m, tsH)
; 3.8-4.1 (m, IH) i 4.59
(8, 2H) i7.25~7.57 (m, 5H
) ; 7.6 to 9.5 (br, s, 3H) (8) β-(6-benzyloxy-2,3 obtained in (2) above
-dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl)alanine 2.30f in ethanol 200g
rnl, and to this solution were added 12 d of 1N hydrochloric acid and 2.0 d of 5% palladium/activated carbon, and the mixture was stirred at room temperature for 2 days under a hydrogen atmosphere. The resulting reaction solution was filtered,
Water was added to the F solution, and then low boiling point substances were distilled off under reduced pressure. By dissolving the residue in ethanol and recrystallizing it by adding diethyl ether to this solution, the following
β-(2,3-dihydro-6-hydro p) having the physical properties shown below.
1.21F crystals of xy-2,5,7,8-tetramethyl-2H-benzopyranyl)alanine hydrochloride were obtained (yield: 61.2%).

FD mass spectrum: [M-Hα] 293MS NMR spectrum (901VIHz) δDMSO-d
6'1.5 (a, 3H); 1.6-2.65 (m, 15
H): 3.8-4.1 (nl, 1ti); 7.4 (
br, s, 1ii): 8.5 (br, s, 3H)
In Example 1-(1), 2-(6-pendyl-2,3-dihydro-2,5,7,8-tetramethyl-2
3-(6-penzyloxy-2,3-dihydro-2 instead of H-benzopyranyl)acetaldehyde 3.382
, 5,7,8-tetramethyl-2H-benzopyranyl)
By carrying out the reaction and separation and recovery in the same manner as in Example 1-(1) except for using 3.52r of propionaldehyde, 5-[2-(6-benzyloxy-2,3-dihydrohydride) having the following physical properties was obtained. 3.17 f of -2,5°7.8-tetramethyl-2H-hen7''e ranyl)ethyl]imidazolidine-2,4-dione was obtained (yield: 75.1 h).

FD mass spectrum: (M)” 422MS NMR spectrum (90MHz) δDMSO-d6
'1.13(8,3I(): 1.3~2.7(m,
17H); 3.3 (br, s, 2H); 3.85~
4.1 (m, IH); 4.57 (a, 2H); 7.25
~7.6 (m, 5H) 5-( in Example 1-(2)
(6-benzyloxy-2,3-dihydro-2,5,7
,8-tetramethyl-2H-benzopyranyl)methyl]
5 for imidazolidine-2,4-dione 3.15F
-(2-(6-benzyloxy-2,3-dihydro-2
, 5,7,8-tetramethyl-2H-benzopyranyl)
Ethyl]imidazolidine-2,4-dione 3.26 ?
By performing the reaction and separation and recovery in the same manner as in Example 1-(2) except that 2-amino-4-(2-(6-benzyloxy-2,3-dihydro- 2.41 r of 2,5,7,8-tetramethyl-2H-benzopyranyl)]butyric acid was obtained (yield 78.6%).

FD mass spectrum: (M)” 397HMS.

NMR spectrum (90MHz) δCD5OD
'1.24, 1.28 (8, 3H); 1.6-2. s(
m, 17H): 4.1-4.45 (m, IH); 4.6
8 (S, 2H); 4.73 (8, 3H); 7.2-7.
5(m,5H) In Example 1-(8), β-(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-benzohyranyl)alanine 2.3O
2-amino-4-(2-(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl))]butyric acid 2.38f was used as substitute for f. By performing the reaction and separation and recovery in the same manner as in Example 1-(8) except for this, 2-2-2 having the following FD mass spectrum was obtained.
1.26 r of crystals of amino-4-[2-(2,3-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-pe/zopyranyl)]butyric acid hydrochloride were obtained (yield 61
．． 1q6).

FD mass spectrum: (ILI” 307 Example 3~
10 In Example 1-(1), 2-(6-benzyloxy-2,3-dihydro-2,5,7,8-tetramethyl-2H-benzopyranyl)acetaldehyde 3.
38? Example 1-(
The corresponding hydantoins were obtained by carrying out the reaction and separation and recovery in the same manner as in 1). The results are shown in the first thorn.

Fruit 7i11J 1- (5-[(6-benzylo-2,4-dione in a) 3.159 (7,7 mmol
) The reaction and separation and recovery were carried out in the same manner as in Example 1-(2), except that 7.7 rn mol of hydantoin shown in Table 2 obtained by the same method as above was used instead. The corresponding α-amino acids were obtained. The results are shown in Table 2.

In Example 1-(8), β-(6-benzyloxy-
2,3-dihydro-2,5,7,8-tetramethyl-2
H-he7zopyra”k) 1 Rani 72.30f (6 mmol
Example 1 except that 6 mmol of the α-amino acid shown in Table 3 obtained by the same method as above was used instead of
-(By carrying out the reaction and separation and recovery in the same manner as in 81, the corresponding α-amino acid hydrochlorides were obtained. The results are shown in Table 3.〇Test Examples 1 to 16 Linoleic Acid Antioxidant Test 10" A sample solution of 10 Kl'5r was prepared by adding 0.2 weight of the test compound relative to linoleic acid to the boric acid buffer of M!J Sodium Nolate Table 9. .2 Al was heated at 70°C for a certain period of time.

To the heated solution, 4.7 ml of 75% ethanol and 0.1ml of 30% rhodan ammonium were added, stirred well, and then ferrous chloride solution [barium chloride aqueous solution (0.5?/ Add ferrous sulfate aqueous solution (0.6f / 50ml) and 10d of concentrated hydrochloric acid to 50ml), stir well, let stand for a while, and use the obtained supernatant] and leave for exactly 3 minutes. later,
The absorbance of this solution at 500 mμ was measured. In this way, the trivalent iron produced by the oxidation effect of the peroxide of sodium linoleate was quantified, and the antioxidant effect of the test compound was determined [Food Engineering Experiment Book (J:), Kyoto University Intermediate Association]. See Undergraduate Food Engineering Department Silk, pp. 634-635]. The greater the light absorption of the solution after heating, the greater the amount of sodium linoleate peroxide produced. The results are shown in Table 4.

1 Blank 0.03 0.09 0.230.29
2 α-Tocopherol *-0,070,190,30
3 Ascorbic acid -0,100,210,3041 sli'e:y acid sodium - 0.11 0.17 0.
18um was used to dissolve it.

Claims (1)

[Claims] 1. General formula (in the formula, 11 represents a hydrogen atom or a lower alkyl group. R2 and R3 are the same or different) represents a hydrogen atom, a lower alkyl group, or a lower alkoxy group, or t and R3 together form a -CH-CH~CH=CH- group. R4 represents a hydrogen atom or a protective group. α-amino acids, esters thereof, and salts thereof, represented by 0), where n represents an integer of 0 to 2. 2. General formula (in the formula, R1 represents a hydrogen atom or a lower alkyl group; R2 and V represent the same or different hydrogen atoms, a lower alkyl group, or a lower alkoxy group, or R2 and R3 are taken together) -CH=CH-CH=CH-. Group is formed. R represents a hydrogen atom or a protecting group. n represents an integer from θ to 2), ammonium carbonate, and an alkali metal cyanide. By reacting the general formula. (In the formula, R1, 11?, R3, R and n are as defined above.) By obtaining a hydantoin represented by the formula and then hydrolyzing the hydantoin, the general formula (in the formula, R, R'' , R
' and n are as defined above, and W represents a hydrogen atom or a protective group, which is the same as or different from R. ) A method for producing the above α-amino acid, an ester thereof, or a salt thereof, characterized in that the α-amino acid is subjected to an esterification reaction and/or a salt-forming reaction as required.