JPS6339896A - O-fenchyl ether of l-aspartylserine methyl ester - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R represents (-),alpha-fenchyl, (+),alpha-fenchyl or (+),beta-fenchyl]. EXAMPLE:L-Aspartyl-O-(-),alpha-fenchylserine methyl ester. USE:A sweetening agent useful for foods, medicaments, etc., as it has superior stability in an aqueous solution. PREPARATION:N-Carbobenzoxy-beta-benzyl L-aspartate expressed by formula II is condensed with O-(-),alpha-fenchylserine methyl ester expressed by formula III to afford the compound expressed by formula IV, followed by elimination of protecting groups by catalytic reduction.

Description

Detailed Description of the Invention - [Field of Industrial Application] The present invention provides a sweetener that has excellent sweetness properties and excellent stability in aqueous solutions, and can be widely used as a sweetener in foods, medicines, etc. This invention relates to a novel 7-ethyl ether of L-aspartyl-serine methyl ester.

[Conventional technology]

Gingerbread is most widely used as a good sweetener, and also contains sugars such as fructose, high fructose, glucose, toxose alcohols such as nlubitol and mannitol, natural sweeteners such as glycyrrhizin, stevioside, and thaumatin, sodium saccharin, Artificial sweeteners such as sodium ticlamate and aspartame have been used as sweeteners.

In recent years, the number of patients with obesity, diabetes, heart disease, hypertension, kidney disease, etc., which are mainly caused by tooth decay and excessive calorie intake, has been increasing, and low-calorie sweeteners are needed for these patients and to maintain their health. It has been sought after, many attempts have been made, and it has also appeared on the market as a regular product. However, artificial sweeteners are subject to various regulations due to toxicity issues, and natural sweeteners have drawbacks in the quality of sweetness and aftertaste, and are expensive, so none of them are satisfactory.

Recently, L-aspartyl-L-phenylalanine methyl ester (hereinafter referred to as APM) has been approved for use and is becoming the mainstream artificial sweetener.

The dipeptides represented by this APM are listed in the "Chemistry Review"
ノ忽14.85～+28 (+976); Ariyoshi, J.
Med, Chem, 24.572-585 (+9
8 1); IN entry MURA,
Chemzcal 5ensesand Flavo
r, 4 (2), + 4 + ~152 (197
9) More than 500 types have been reported by iA, Van clsr Heljdan et al., but there are very few that have a sweetness level 500 times or more than sucrose. In addition, these dipeptides are esters, which undergo hydrolysis in aqueous solution and dealcoholization reaction with the amine groups of aspartic acid residues to convert into diketopiperazine derivatives, resulting in loss of sweetness or deterioration in quality. There are many.

Among the dipeptide esters currently reported, the compound with the highest sweetness was reported by Fujino et al.
No. 50566, Chem, Pharm, Bull, 24
(9), 2112 (+976)), and its stability is inferior to APM at 80 tl', pi (4).On the other hand, in order to solve these problems, recently branched L-aspartyl-D-amino acid Chain amides (JP-A-56-
127559), (81-3-amino-4-((s
, s) -1-(1-hydroxyethyl)alkylaminoco-4-ochynebutyric acid compound ([JSP, 442502
9), but the sweetness level is 200 to 5.
00 times, which is not completely satisfactory.

[Problem that the invention seeks to solve]

An object of the present invention is to provide a dipeptide-based sweet compound that has a sweet taste similar to that of sucrose, has a high degree of sweetness, is low in calories, and is stable in an aqueous solution.

[Means for solving problems]

L-7 spartylaminomalonic acid diester and L-7, which the present inventors previously filed (Japanese Patent Application No. 42440/1982)
-7-ethyl alcohol tonoesters of aspartyl-〇-alanine (Patent Application No. 408/1988! 54) L-
It has been reported that ethers of aspartyl-2-methylserine methyl ester and fenthyl alcohol generally exhibit a high degree of sweetness. Furthermore, as an analogue of this, we synthesized 7-enthyl ether of L-aspartylserine methyl ester. As a result of repeated research on the isomers of the steric structure of the fenthyl group in L and -t, we found that (he), α-7-enthyl group, (to).

A compound having all α-7 enthyl groups and (t), β-7 enthyl groups has a sweetness that is 470 to 1,380 times higher than sucrose, and has sweetness characteristics similar to and superior to sucrose. It was discovered that the solubility and stability in aqueous solution were good, and the present invention was hereby completed.

That is, the present invention provides L-aspartyl-serine methyl ester represented by the following general formula % (11 (in the formula, R is (he), α-7 enter group, referred to as H3 BFS) f. 7-enthyl ether theal.

An example of the production of the compound of the present invention (AFS) is as follows.

First, 7-ethyl alcohol is chloromethylated, then condensed with dimethyl malonate, and then mixed with a half ester. Next, this phenyloxymalonic acid methyl ester was subjected to a Curtius rearrangement reaction, and by deprotection, j
l) O-H, α-7 enthylserine methyl ester was obtained. Further, this ester is condensed with N-carboxy-β-benzyl-aspartic acid, and the protecting group is removed by fused reduction to obtain the target FS.

This reaction process will be explained in detail below using formulas.

1) Synthesis of o-(he), α-7 ethyl serine methyl ester Uti, , F/1 CH3(VD 0H3
Chem, 45, 2222-2229 (+98
0)] to obtain [1, then condensation with dimethyl malonate to obtain (F/l), and use an equivalent amount of caustic soda to form a half ester (VB). Next, this fentyloxymalonic acid The methyl ester was prepared by a known method [O
he+++, Pharm, Bull.

221611598-1404 (+974)] That is, a Curtius-type rearrangement reaction using diphenylphosphoric acid azide (DPPA), triethylamine, and pendyl alcohol was carried out (as Wl, and by deprotection, O-H, α-
7 Entylserine methyl ester (obtains Tsukasa).

+1) O of L-aspartylserine methyl ester
-Synthesis of fenthyl ether Z-NH-CH-GOOH+HN-0H-OH2-0-
Fen(Sat.Z-NH-OH-GONH-(JCH20-Fan(Summer) 0-H, α-7 Enthylserine Methyl Ester("l:
By condensing N-carbobenzoxy-β-benzyl-L-aspartic acid and then removing the protecting group by catalytic reduction, the 0-7-enzyme of L-aspartylserine methyl ester, which is the target product, is obtained. You can wander around Luether.

The O-7 ethyl ether of L-aspartylserine methyl ester of the present invention thus obtained is a colorless and odorless powder that easily dissolves in water.

The diluted aqueous solution has a sweetness characteristic very similar to that of sucrose, and causes almost no unpleasant sensations such as bitterness, sarcasm, or bad aftertaste.

The compounds of the present invention are widely used in various foods, beverages, toothpastes, cigarettes, cosmetics, etc. in which sweeteners are generally added, regardless of their form. For example, soft drinks including fruit juices, juices, cider, etc., lactic acid bacteria drinks, carbonated drinks, powdered drinks of these, alcoholic beverages such as sake, synthetic alcohol, fruit wine, and mijin, frozen desserts such as ice cream, sherbento, etc. fruits in syrup, miso, soy sauce, sauces, edible vinegar, dressings, mayonnaise, ketchup and other seasonings, American and British food, bread, Western sweets, biscuits, crackers and other sweets, chocolate, chewing gum, jelly, yokan,
Jam, marmalade, powdered milk, various types of tsukudani, canned goods, agricultural and livestock meat delicacies, meat products such as bacon, ham, and sausage, fish meat such as kamaboko and chikuwa a! Examples include spices, compound seasonings, lipstick, and oral medicines.

The compound of the present invention can be used in the form of a powder or in the form of a solution using an appropriate solvent.The amount added depends on the compound of the present invention to be used, the intended use, target The addition means, the sweetener used in combination, the type and amount of seasoning, etc. can be selected depending on the trap PM.

Example Next, the present invention will be explained in detail using examples and usage examples.

Example-1
Synthesis of H1α-7 ethyl alcohol 50 # (0,525
mole), +, 3.5- trioxane + 5.7, ?
(0,+74 mol) was dissolved in 100 groups of benzene, and 1
At 5C or lower, hydrogen chloride gas was added and the mixture was reacted for 5 hours.

The reaction mixture was poured into f + 50 rnl of water and the benzene layer was extracted. The organic layer was washed twice with water and then dried with anhydrous sodium sulfate. Benzene was distilled off under reduced pressure, and the residue was distilled under reduced pressure to obtain B, P, 70~BsC (tmH
g) The target product 48.9.9 (yield 74%) was obtained.

Example-2 H1α-phentyloxymethylene malonic acid dimethyl ester (Kaku synthesis under anhydrous conditions, oily 60% sodium hydride 1.6051
6.0.9 (45 mmol) of dimethyl malonate was added dropwise to a 100α suspension of (40 mmol) in ether with stirring at room temperature. The sodium salt of dimethyl malonate forms within a few hours after the dropwise addition. This was obtained in Example-1.

α-7 Enthyloxymethylene chloride 8.1.9'
(40 mmol) was added dropwise at room temperature. - After stirring overnight, it was poured into water +00*. Separate the ether layer,
After washing twice with 50% of water, it was dried with anhydrous sodium sulfate. The ether was distilled off under reduced pressure, and the residue was distilled under reduced pressure to obtain B, ? ,
120-130C colorless oil y, +5.9 (yield 70%)'f: obtained.

Example-5 Synthesis of H1α-7 Enthyloxymethylene Malonic Acid Monomethyl Ester (V) H2α-7 Enthyloxymethylene Malonic Acid Dimethyl Ester 7.15II (24 mmol) obtained in Example-2
was dissolved in a mixture of 20 d of acetone, 18 M of methanol, and 9 M of water, and 12 m of 2 N -NaOH (2
4 mmol) was added dropwise. After the dropwise addition was completed, the reaction solution was returned to room temperature and further stirred for 1 hour. After concentrating the reaction product under reduced pressure, 50M water was added to the residue, and the mixture was washed twice with ether 20d. The aqueous layer was adjusted to pHs, a with citric acid, and extracted with methylene chloride 5 (1 g Lt). The methylene chloride layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to produce a colorless oil of monomethyl ester. 8I (yield 86%) was obtained.

Example-4 N-carbobenzoxy-〇-H, α-phentylserine methyl ester (obtained in Synthesis Example-3 of ■l)
, α-phentyloxymethylene malonic acid monomethyl ester 4.701 (+6.6 mmol), triethylamine 2.021 (20 mmol) and diphenyl phosphoric acid azide 4,70.9 (17 mmol) total benzene 8
The solution was dissolved in 0 ml and heated under reflux for 2 hours in a nitrogen stream.

After that, return to room temperature and use benzyl alcohol 2.55.9
(2+, 6 mmol) was added and heated to reflux - overnight. After concentrating the reaction product under reduced pressure, 60M ether was added to the residue, which was washed twice with 10% citric acid water, 4% sodium bicarbonate water, and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain a colorless oil of N-carbobenzoxy-Q-i→, α-phentylserine methyl ester. 2.679 (yield 63%) was obtained.

Example-5 Carbobenzoxy-β-benzyl-L-aspartyl-
〇-(he), α-7 Enthylserine methyl ester Synthesis Example-4 U-carbobenzoxy-0-day, α-
7 Enthylserine methyl ester 2.67.9 (+
(0.5 mmol) in total methanol group 50, and catalytic reduction was performed at normal pressure for 4 hours in the presence of palladium black. After filtering off the contact, methanol was distilled off under reduced pressure. Dioxane 5011Lt was added to the obtained oily substance to dissolve it, and on day 1, a solution of α-7 enthylserine methyl ester was prepared. Separately, carbobenzoxy-L-asharachic acid-β-benzyl ester 5,579 (+0.
0 mmol) was dissolved in 50M dioxane, 1.79 g (10.0 mmol) of L,N-hydroxy-5-fulbornene-2,3-dicarboximide was added, and under water cooling,
While stirring, dicyclohexylcarbodiimide 2.06
, P (+ 0.0 mmol). After returning to room temperature and continuing stirring for 4 hours, the generated dicyclohexyl urea was d! Separately, add the previously prepared O-H, α-
While cooling the 7-enthylserine methyl ester solution on ice, add 1
・Added to the eel while stirring. The mixture was returned to room temperature and stirred day and night to complete the reaction. After distilling off the solvent, the residue was dissolved in 60 ml of ethyl acetate, 10% aqueous citric acid, 4% aqueous sodium bicarbonate,
It was washed with saturated saline in this order. After drying with anhydrous sodium sulfate and distilling off the solvent, the residue was purified by silica gel chromatography to obtain carbobenzoxy-β-benzyl-L-7.
Subarthyl-H,α-phentylserine methyl ester oil 5.15! ! (yield 85%).

Example-6 Synthesis of L-aspartyl-〇-(→,α-phethylserine methyl ester)Carbobenzoxy-β-benzyl-L obtained in Example-5
-Aspartyl-〇-H, α-7 Enthylserine Methyl Ester5. +59 (8,0 mmol) was dissolved in 50 mK of methanol, and catalytic reduction was performed at normal pressure and room temperature for 4 hours in the presence of palladium black. The catalyst is filtered off and methanol is distilled off under reduced pressure. An appropriate amount of n-hexano was added to this residue to obtain 2.90 g of crystals of the title compound (yield 90.5%).
I got it.

The characteristic values of this compound are as follows.

M, P,: 112-114C NMR ((, D300) J: Q, 88.1. OS, +, 06 (5) I, S,
Fenthyl group Cwa,) 2.65 (2H, m, containing spβ-c!2) 5.75
(5H, S, co2cu3)4.6 5 (+
H, m, input spa -CH)M
S (m/θ): 37 1 (M -1-1), 325, 31 1.
217.136, 150, 102 (base), 88
, Examples-7 to 18 L-aspartyl-〇-(t)α-7-enthylserine methyl ester (DAFS) i Examples-7 to 12, L-
Aspartyl-o-H-1β-7 Enthylserine Methyl Ester (BFS) i Examples 15 to 18 are shown as tables.

L-aspartyl-〇-f-+-1 obtained in Example-12
The characteristic values of α-7 enthylserine methyl ester (DAFS) are as follows.

u, p,: ++o ~ 112 C NklR (CD50D) δ: 0.89.1.05, +, o 8 (5H, S, 7
Enthyl group C! (3) 2.61 (2H, m, Aspβ-C)+2)5.
75 (5H, S, C02CH,,)4.66 (
+ H, m, A! II) d -CH) M S (
ln/a): 571(M+1), 552.325.511.217.
156.102.81.51 (bass) Example-18
The characteristic values of 7'(L-aspartyl-〇-(←), β-7 enthylserine methyl ester (BFS)) obtained in Example 1 are as follows.

u,p, :too~105C N105CN,00)δ: 0.90.1.02,+,05(!Sl(,S,;71
-inter group C! (5) 2.64 (2H, m, +Lspβ-G!2)3.
72 (5H, S, co,, c!3)4.66 (
I H, m, ASp ex-CH) M S (
m/e, ): 57 + (M” +1), 521.311.217
．． 156, 150, 102, 88, 81.70, 5 1
(base) Example-19 In Example-6, L-7 Spartilu 0-(-1゜α-
7 Entylserine methyl ester (AFS), Example-
L-aspartyl-〇-(a) obtained in 12.

α-7 Entylserine methyl ester (DAFS), L-aspartyl-o-(++) obtained in Example-18.

β-7 Enthylserine Methyl Ester (BFS) and A
PM and sucrose were dissolved in water, and the threshold values were determined using the limit method using a panel of 5 experienced flavorists. The results are shown in Table 1.

Table 1 Example of use Example 6 (AFS) for ease of use.

Example-+2 (DAFS) and Example-18 (BF
1 g each of compound S) was added to 99.9 g of glucose. This was mixed well in a jil and used as a powder sample with a concentration of 1%. The amount of bone added to the compound of the present invention in the usage examples is the amount of this 1% concentration product.

Usage example-1 Fruit juice-free carbonated drink Glucose 200g Citric acid 1.5g Lemon essence 2, d Compound of the present invention AFS
Water was added to 24 g to make 400M, and 1600M carbonated water was added to make a carbonated beverage.

The quality of sweetness is good and hot, similar to sugar.

Use fll-2 Ice, confectionery powder starch syrup 1801 Thickener 3fI Citric acid 2g Salt 0.19 Strawberry essence 1 Go FS containing the present compound 281i Add water to the above and add 1000
．． It was set as 9.

Make a stock solution according to the above recipe and freeze it to get a strawberry frozen dessert. It had a refreshing sweet taste and was delicious.

Usage Example-5 Sherbento Compound of the Invention DkFB 5811 Powdered Starch syrup 210y Stabilizer 5y Citric acid 1g Yellow No. 5 Appropriate amount Orange flavor 1!9 Add water to the above + ooo, v and Toshitomo.

The formulation was placed in the freezer to make a sorbet according to the above recipe. Using caster sugar, the taste was comparable to that of regular sherbet.

Usage example-4 Toothpaste calcium hydrogen phosphate 500g carboxymethylcellulose + 19ndium lauryl sulfate 15g glycerin
250y Compound of the present invention BIPS O, 6jl Two paste flavor 9.59 Sodium benzoate 0.5! 9 Add water to the above to make +ooo, p.

Next, mix all the ingredients in a blender according to the above recipe to make toothpaste. When used, good results were obtained, with no bitterness and a refreshing sweet taste.

〔Effect of the invention〕

The present invention provides novel 0-7 ethyl ethers of L-aspartylserine methyl ester,
It has a sweet taste similar to that of sucrose, has a high degree of sweetness, and is stable in aqueous solutions, so it can be used in a wide range of fields without any restrictions on its use as a sweetener.

Claims (1)

[Claims] 1. The following general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) (wherein, R is (-), α-phentyl group, (+), α-
A fenthyl group and (+), a β-fenthyl group are shown. ) Fenthyl ether of L-aspartyl-serine methyl ester.