JPS61260052A - Novel amino acid derivative and sweetener - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R1 and R3 are H, halogen, CN, NO2, 1-6C alkyl, CO2R'', etc.; R'' are 1-4C alkyl; R2 is O or S; n is 0-2; the structure of formula II containing the C labeled with * is L or DL isomer) and its salt. EXAMPLE:N-(4-nitrophenylcarbamoyl)-alpha-L-aspartyl-4-chloroanilide. USE:A sweetener. It has low calorific value, refreshing sweetness and high stability. PREPARATION:The objective compound of formula I can be produced by reacting (A) an alpha-aspartyl-substituted anilide of alpha-glutamine-substituted anilide derived from aspartic acid or glutamic acid and a substituted aniline with (B) a substituted phenyl isocyanate or a substituted phenyl isothiocyanate.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel amino acid derivative, a salt thereof, and a sweetener containing the same as an active ingredient.

In recent years, as dietary habits have become more sophisticated, obesity and the various diseases associated with it have become a problem, especially due to excessive intake of sugar, and there is a desire for the development of low-calorie or no-calorie sweeteners to replace sugar. There is. The main sweeteners that are widely consumed are saccharin and luteame, but saccharin leaves behind an aftertaste and is carcinogenic.

On the other hand, although luteme is superior in terms of safety and sweetness, it has some problems with stability.

The object of the present invention is to provide novel amino m derivatives and salts thereof, which have a mild sweet taste and are highly stable. An object of the present invention is to provide a low-calorie sweetener containing the same as an active ingredient.

The compound of the present invention is represented by the following general formula (1).

In the formula, R,, R3 is hydrogen, CN+NO2+
R' (alkyl having 1 to 6 carbon atoms), Co2R//
(H# is alkyl having 1 to 4 carbon atoms), R"Co, methyl halide.

R”O, C0NHR”, 5o2R”, 80R”,
R2Fi oxygen or sulfur atom, n is 0, 1. or 2,
and represents the basic amino acid residue.

Examples of the salts of the compounds of the present invention include salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, and salts with amines such as monoethanolamine. .

The method for synthesizing the compound of the present invention is the method described in the literature (J, Me
d Chem, 16.163 (1973)) and a substituted aniline with asno-carboxylic acid or glutamic acid and a substituted phenyl isocyanate or substituted phenyl inthiocyanate with an α-as/rutile substituted anilide or an α-glutamyl substituted anilide obtained according to Obtained by reacting. In addition, the intermediate Iα-as/mother rutylanilide and α-glutamylanilide can be prepared by other methods (J
, Mad Chem, 25, 397 (1982)
, i b i d, □, 1668 (1984)
) can also be used, but the method of synthesizing the compound of the present invention is not limited to these.

As a result of a sensory test, the compound of the present invention and its salt were found to have a strong sweet taste9. For example, the sweetness of N-(4-nitrophenylcarbamoyl)-α-L-as/ and rutile-4-chloroanilide is 5,400 times that of sugar and 4. i5. N
-(4-nitrophenylcar/gumoyl)-α-L-asno 4rutile-4-cyanoanilide was 4800 times as large.

Note that when the compound of the present invention or a salt thereof is used as a sweetener, it is of course possible to use it in combination with other sweeteners as long as there is no particular problem.

Example 114・After adding 20 d of trifluoroacetic anhydride to 7.191 (54.0 mmol) of mother acid, it was stirred at 40°C for 1 hour. is generated. Hexane ether was added to this, and the precipitated crystals were separated by suction filtration.

This crystal and 6.75 g of 4-chloroaniline (52,9
After stirring the mixture (mmol) in dioxane for 7 days, the dioxane was distilled off under reduced pressure. Ether was added to the concentrated residue, and the precipitated crystals of N-)lifluoroacetyl-α-L-7sno-9-rutyl-4-chloroanilide were separated by suction filtration. Yield jt4.991, yield 27.8%.

(B) α-L-asuno9 rutile-4-chloroanilide 7,4 in which 4.0 g of N-trifluoroacetyl-α-L-7 spalty-4-chloroanilide was heated to 85°C.
The mixture was added to 44 d of M ammonia water, stirred for 5 minutes, and then immediately cooled to room temperature. Dry and harden concentrated rice under reduced pressure.
The crystals of L-asnoyartyl-4-chloroanilide were re-crystallized from acetonitrile. Yield 2.351 Yield 82.0
%.

(C)N-(4-nitrophenylcarbamoyl)-α-
Riichi Asunoya Rutyl-4-chloroanilide α-L-as/4 Rutyl-4-chloroanilide 0.75
．． 9 (3,09 mmol) and anhydrous sodium carbonate 0.1
7N (1.6 mmol) was dissolved in 50 dlC of water, and 4-nitrophenyl isocyanate 0.51 (3
, 05 mmol) t-THF dissolved in 25 at was added, stirred for 2 hours, and the reaction solution was concentrated under reduced pressure to remove THF, and the concentrated solution was extracted and washed with ether. In the resulting aqueous layer -
Hydrochloric acid was added until the value was around 2.5, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 0.95 g of pale yellow crystals of the target product. Yield 77-1,
169-170C.

Example 2 N-(4-chlorophenylcarbamoyl)
-α-L-asno-9rutile-4-chloroanilide Example 1 (4-chlorophenyliso7ane by the same operation as Q) 0.23 g,! : From 0.41 g of α-L-asuno-9rutile-4-chloroanilide, 0.46# of colorless crystals of the target product were obtained. Yield 77.4%, ap.

178-180℃.

1[11J3 N-phenylcarbamoyl-α-L-
Example 1 from 7S/glutyl-4-chloroanilide phenyl isocyanate 0.38, P and α-L-7Sno9rutile-4-chloroanilide IIi
A colorless target crystal of 0.91 was obtained by the same method as in (C).
I got g. Yield 79.4'j,ry! p, 169-1
7I C,.

Example 4 N-(4-nitrophenylcarbamoyl)-
α-L-asuno and rutile-4-cyanoanilide (4)
α-L-7S/IP Rutile-4-Cyanoanilide Example 1o (AJ, Synthesized from L-As Guragi/Dan and 4-cyanoaniline by the same method as (B). The obtained α The crude crystals of -L-asz4rutile-4-cyanoanilide were recrystallized from 1-butanol.

(B) N-(4-nitroenylcarnogumoyl)-α
-L-Aspartyl-4-cyanoanilide α-L-Aspartyl-4-cyanoanilide The desired product was obtained by the same method as in Example 1 (Q) from 0.26 g of L-aspartyl-4-cyanoanilide and 0.169 g of 4-nitrophenyl incyanate. pale yellow crystal 0.35p
I got it. Yield 88 cm, bow p, 102-106°C.

Example s N-(4-chlorophenylcarbamoyl)
-α-L-as/glutyl-4-cyanoanilide ゛α
From 0.28 g of -L-aspartyl-4-cyanoanilide and 0.15 g of 4-/lorophenyl isocyanate, 0.309 g of colorless crystals of the target product were obtained in the same manner as in Example 1 (0). Yield: 78 %, River 9176-17
7℃.

! [Example 6 N-(4-nitrophenylcarbamoyl)
-α-L-as/4-rutile anilide (4) α-L-aspartyl anilide Synthesized from L-aspartic acid and aniline in the same manner as in Example 1 (4) and (B). Yield 18.2%.

(B) N-(4-nitrophenylcarpamoyl)-α-
L-Ass? Rutile anilide α-L-ame-9 Rutile anilide 0.49II and 4-
From 0.25.9 g of ditrophenyl isocyanate, 0.3 g of pale yellow crystals of the desired product were obtained in the same manner as in Example 1 (C). Yield 53.7%, rr! p165-1
67℃.

Example 7 Example from N-(4-chlorophenylcarbamoyln-α-L-7snoQ rutyl-anilide α-L-7su and rutileanilide 0.49.1:4-chlorophenyliso7ane) 0.23N 1
By the same method as Q, the target colorless crystal 0.44
Remember N. Yield 81.1%, rQP, 238°C (decomposed).

Example 8 N-(4-nitrophenylcarbamoyl)
-α-L-daltamy-4-chloroanilide (A)N-
(t-butoxycar♂yl)-α-L-daltamyl-4
-ri0roanilito γ-pennorester N-t-butoxycarbonyl-L-glutami 7! r-Pennor ester 7,92, @ 4-10 Roanyl y3.00#t
-rio o ho/I/A 100 (1: VC bath, water cooling, nocyclohexyl carnoimide 4.84
I was added. The mixture was stirred for 1 hour under water cooling, and then stirred overnight at room temperature.

The precipitated dicyclohexylurea eF was separated and concentrated with liquid F under reduced pressure. The concentrated residue was dissolved in ethyl acetate and washed successively with 4% citric acid and 4% sodium carbonate water. After drying the obtained ethyl acetate solution over anhydrous sodium sulfate, ethyl acetate was distilled off under reduced pressure, and hexane was added to the residue to solidify it.

fiN-(t-butoxycar&nyl)-α-L by filtration
9.84 J' of colorless crystals of -glu, tamyl-4-chloroanilide r-benzyl ester were obtained. Yield 93.7%
.

(B) Dissolve N-(L-toxycargenyl)-α-L-glutami, add 1NNaOH21CC, and add
The mixture was stirred for a minute.

Methanol and THF were distilled off under reduced pressure to obtain 1
Add water and ether to the 111 condensate, wash and extract. To the resulting aqueous layer was added 10% citric acid to a concentration of 3, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and then dried over anhydrous sodium sulfate. Ethyl acetate was distilled off under reduced pressure, and hexane was added to the resulting residue to solidify it. Colorless crystals of N-(t-butoxycarzanyl)-α-L-glutamyl-4-chloroanilide were obtained by filtration6. -09.
I got a 9. Yield 77.5%.

(Q α-L-glutamyl-4-chloroanilide N-(
T-butoxylic? α-L-glutamyl-4-
Chloranilide 6.09N, trifluoro vinegar & 30CC
was added and stirred at room temperature for 1 hour.

The reaction solution was concentrated under reduced pressure, methanol and water were added to the obtained oily residue, and triethylamine was added until pJ (6) was reached. When condensed under reduced pressure to about 60 CCKII, crystals were precipitated. After leaving it in the refrigerator overnight, it was aspirated. Colorless crystals of α-L-glutamyl-4-chloroanilide were obtained by filtration. Drying chamber II 3.19J, yield 73.1%.

CD) N-(4-nitrophenylcarbamoyl)-α-
N-(4 -Nitrophenylcarbamoyl)-α-L-glutamyl-4-chloroanilide (0.40.9%) was obtained as pale yellow crystals.

Yield 62.6%, n1p, 179'C (decomposed).

Example 9 N-(4-nitrophenylcarbamoyl)
-α-L-aspartyl-4-nitroanilide (4)
N-(4-nitrophenylcarbamoyl)-L-aspartic acid 4.75 L-aspartic acid in 100 cc of NaOH
I was dissolved, and to this was added a suspension of 4-nitrophenyl isocyanate 5I in 40 CCIC' of toluene, and the mixture was stirred vigorously at room temperature for 1 hour. After removing the toluene layer from the reaction solution by layer separation, hydrochloric acid was added to the aqueous layer until the pH reached 1. After concentrating it to about half, store it in the refrigerator.
I left it for the night. The precipitated crystals were separated using suction PJ7I, and reconstituted from water to produce pale yellow crystals of N-(4-nitrophenylcarbamoyl)-L-7suginic acid.

Dry 112.97.5 i', yield 32.8%.

CB) N-(4-nitrophenylcarbamoyl)-L-
Aspartic anhydride N-(4-nitrophenylcarbamoyl)-L-aspartic acid 2.97 fl was mixed with acetic acid 8 cc and acetic anhydride 1.28 ml.
The mixture was added to a mixed solution of p and stirred at room temperature overnight. Add hexane ether to the reaction slurry and filter it.
Colorless crystals of (4-nitrophenylcarbamoyl)-L-aspartic anhydride 2.60.9 were obtained. Yield 96
．． 6%.

(C)N-(4-nitrophenylcarbamoyl)-α-
L-7Snomorutile-4-nitroanilide N-(4-nitrophenylcarbamoyl)-L-amic acid/4' line acid anhydride 2.60.9 was suspended in ethyl acetate 80a, and 4-nitroaniline was suspended in ethyl acetate 80a. 1638g was added. At room temperature,
After standing for 8 days, the reaction solution was washed with dilute hydrochloric acid. The ethyl acetate layer was concentrated and the residue was chromatographed (
Merck, silica glue plate Art5717
．． Developing solution (chloroform: methanol: acetic acid = 30:5
:1).

The fraction corresponding to the Rf value of 0.46 was eluted with ethyl acetate and concentrated to dryness to obtain 0.11 yellow crystals of the desired product.
I got g. Yield 28.0%, m, p, 191'c (decomposition).

Implementation 91J 10 N -(4-cyanophenylthiol lupamoyl-alpha-L-as/rutyl-4-chloroanilide (4) 4-cyanophenyl isothiocyanate 4-Schiff/7niline 6゜01 tl-I N HC
Thiophosgene 6.5
y was added to a suspension of 100 cc of water, and the mixture was stirred for 3 and a half hours at room temperature.

The precipitated crystals of 4-cyanophenyl thiocyanate were separated by suction filtration, washed with a small amount of water, and then dried in vacuo in the presence of phosphorus pentoxide. Dry weight 7.25.9,
Yield 88%.

(B) N-(4-cyanophenylthiocarbamoyl)-α-L-asnorthyl-4-chloroanilide α-
L-7 Snocurtil-4-chloroaniline 0.24II
was dissolved in 50 g of water containing 0.06.9 g of anhydrous sodium carbonate. To this was added 20 cc of an ethanol solution containing 0.16.9 4-cyanophenyl inthiocyanate, and the mixture was stirred at room temperature for 1 hour.

The reaction solution was concentrated under reduced pressure, water was added, and the mixture was washed and extracted with ether. Hydrochloric acid was added to the water until the pH reached 2.5, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous sodium sulfate. By distilling off ethyl acetate under reduced pressure, 0.29.9 (i-) of pale yellow crystals of the target product were obtained. Yield 71.8%, mp, 147-150°C.

Practical MA Example 11 N-(4-nitrophenylcarbamoyl)-α-L-asno9rutile-4-methylanilide (4) α-L-as/4'rutile-4-methylanilide (4) of Example 1, ( By the same method as B), 9L-
It was synthesized from as-yaragic acid and p-)ruinone. Yield 7.2%.

(B) N-(4-nitrophenylcarmoyl)-α
-L-asuno 4-rutile-4-methylanilide α-L-7 spalty-4-methylanilide 0.44J
From F and 0.32.9 fc of 4-nitrophenyl isocyanate, 0.44.9 fc of yellow crystals of the target product were obtained by the same operation as in C) of Example 1. Yield 57.0%%nap, 2
08°C (decomposition).

Claims (2)

[Claims] (1) A novel amino acid derivative represented by general formula (I) and a salt thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I) In the formula, R_1 and R_3 are hydrogen, halogen, CN, NO_2
, R' (alkyl having 1 to 6 carbon atoms), CO_2R'' (R
" is alkyl having 1 to 4 carbon atoms), R"CO, methyl halide, R"O, CONHR", SO_2R", SOR
", R_2 is oxygen or sulfur atom, n is 0, 1 or 2
and the structure -HNCH-CO- containing C at position * represents an amino acid residue in the L or DL form (CH_2)_n-CO_2H. (2) A sweetener containing a novel amino acid derivative represented by the above general formula (I) or a salt thereof as an active ingredient.