JPS6254791B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides L-aspartyl-D-alanine, L-aspartyl-D-2- which is effective as a sweetener.
Aminobutyric acid, L-aspartyl-D-valine, L
-Related to intermediates for the production of new amides of aspartyl-D-norvaline.

The sweetening compounds ultimately obtained from the intermediates of the invention are L-aspartyl-D-amino acid dipeptide amides of the following formula and physiologically suitable cation salts and acid addition salts.

In the formula, R ^a is methyl, ethyl, n -propyl,
isopropyl, R is X is O, S, SO, SO ₂ , n and p are each 0 or 1, and when n is 0 and p is 1, X is O,
S, and when n and p are each O, X is S,
_SO2 .

The intermediate of the present invention is represented by the following formula: (In the formula, when n ₁ is 0 and p ₁ is 1, X ₁ is O, S, n ₁
When p ₁ is each 0, X ₁ is S, SO ₂ , etc.) Dipeptide amides of the above formula can be conveniently prepared using amino acid coupling methods. A good method for producing dipeptide amides of formula () is shown below.

(where n ₁ , p ₁ and X ₁ are as described above).

Q in the above-mentioned L-aspartic acid derivative is one of the known amino group protecting groups, and Advances is Organic by Boissonnas.
Chem., 3, 159-190 (1963). Particularly good amino-protecting groups are benzyloxycarbonyl, tertbutyroxycarbonyl. ^R10 has 1 to 4 carbon atoms
is an alkyl group or benzyl. D- used
Alanine, D-2-aminobutyric acid, D-valine, D
-Norvaline may be in the form of a free amino acid in which R ¹¹ is hydrogen, but preferably is a carboxylic acid derivative in which R ¹¹ has an ester residue such as methyl or ethyl. Silyl groups such as trialkylsilyl having 3 to 12 carbon atoms are also preferred. A particularly good example of such a group is trimethylsilyl. This is because it is economical and efficient.

In the above reaction step, diprotected L-aspartic acid is condensed with a suitable D-amino acid or carboxy-protected derivative to produce a diprotected dipeptide of formula (). In this step, diprotected aspartic acid is condensed in the presence of a reactive condensation agent such as dicyclohexylcarbodiimide, but it is preferable to use a carboxyl-activated derivative of diprotected aspartic acid.
Preferred examples of such carboxyl-activated derivatives include chloride, and examples of anhydrides include mixed anhydrides.
Particularly good in terms of efficiency are the diprotected L-
It is a mixed anhydride of aspartic acid and a chlorocarboxylic acid ester, especially the above-mentioned alkyl ester having 1 to 4 carbon atoms. Good mixed anhydrides are economically prepared from methyl and ethyl esters of chlorocarboxylic acids.

A particularly preferred method of preparing compounds of formula () involves reacting beta-benzyl-N-benzyloxycarbonyl-L-aspartic acid with ethyl chlorocarbonate in a conventional manner to give the corresponding mixed anhydride. Commercially available D-amino acid, R ^a CH in a separate container
(NH ₂ )COOH, or resolution of known racemic amino acids [Yamada et al., J. Org. Chem. , 38 , 4408
(1973)] is reacted with an equivalent amount of trimethylsilyl chloride in an inert solvent to prepare the trimethylsilyl ester. Suitable solvents for this purpose are, for example, pyridine,
dimethylformamide, dimethylacetamide,
etc., and a particularly good one is dimethylformamide.

In a typical reaction according to this method, a D-amino acid, such as D-alanine, is dissolved in dimethylformamide and an equivalent amount of trimethylsilyl chloride is added at room temperature. In a separate flask, betabenzyl N-benzyloxycarbonyl-L-aspartic acid and a 1 molar excess of acid binder (triethylamine is good) are dissolved in a mixture of dimethylformamide and tetrahydrofuran, and an equivalent amount of ethyl chlorocarbonate is dissolved in a mixture of dimethylformamide and tetrahydrofuran. Add at room temperature or lower (-25 to 25℃, especially -10 to 0℃ is good)
Prepare a mixture water. This is done by adding a solution of D-alanine trimethylsilyl ester at room temperature. The reaction is generally complete within 1 to 2 hours, after which the reaction mixture is poured into water or an acid such as hydrochloric acid, extracted with a water-insoluble solvent (such as chloroform, methylene chloride, ethyl ether) and extracted in the usual manner. isolate The diprotected dipeptide () is usually of sufficient precision to be used in the next step, but if necessary it can be further purified, for example by column chromatography.

In the second step of the method, the diprotected dipeptide () is reacted with an equivalent amount of a primary amine of formula _RNH2 to produce the corresponding diprotected dipeptide amide intermediate of formula (). R ^a , R, R ¹⁰ , Q are as defined above.

Intermediates of formula () can be prepared using a condensing agent, e.g. dicyclohexylcarbodiimide, in the carboxylic acid form of a compound of formula (), as in the first step; Conversion to activated derivatives such as chlorides, bromides, mixed anhydrides, etc. is advantageous. Mixed anhydrides are generally better. thus,
A mixed anhydride is prepared using a good compound of formula () where R ¹⁰ is benzyl and Q is benzyloxycarbonyl. As mentioned above, good anhydrides are made from chlorocarboxylic esters. Its methyl or ethyl esters are good. The mixed anhydride of formula () is prepared using the reactants and reaction conditions described in the first step of this process. Typically, approximately equivalent amounts of a compound of formula () and triethylamine are used, combined in an inert solvent (e.g., tetrahydrofuran), the mixture is cooled to about -10°C, and ethylchlorocarbonate is added to yield the mixed anhydride. . Then the equation of equivalent
_RNH2 or a solution thereof, for example in the same inert solvent, is added at -50 to 25<0>C. Generally -35~-
5°C is good. After adding the amine, the mixture is warmed to room temperature and maintained at this temperature until the reaction is complete. Usually 1 to 20 hours. The intermediate of formula () is then isolated and, if necessary, purified as described for the preparation of compounds of formula ().

In the final step of the process, the carboxyl protecting group R ¹⁰ and the amine protecting group Q are removed to produce the desired sweetener of formula ().

The method for removing protecting groups from dipeptide amides of formula () will vary depending on various factors. Two important factors are the protecting group R ¹⁰ , Q is the nature, and the nature of the amide substituent. For example, when R ¹⁰ , Q are each a particularly good group, benzyl, benzyloxy-carbonyl, and R does not contain a sulfur atom, a good method for removing the protecting group is hydrogenolysis.
However, when R ¹⁰ is benzyl or the alkyl defined above, Q is tert-butyroxycarbonyl and R is the various groups mentioned above, it is usually better to remove the protecting group by hydrolysis. R ¹⁰ is alkyl, Q
When is benzyloxycarbonyl and R does not contain a sulfur atom, it is preferable to use hydrolysis and hydrogenolysis together.

When hydrogenolysis is used to remove the protecting group from the intermediate of formula (), it is preferably carried out in an inert solvent in the presence of a metallurgical catalyst (palladium is good). Examples of such solvents include lower alkanols such as methanol, ethanol, isopropanol, and n-butanol; ethers such as tetrahydrofuran, ethyl ether, 1,2-dimethoxyethane, and diethylene glycol dimethyl ether; ethyl acetate, methylpropionate, and dimethyl These include esters such as succinate, and dimethylformamide. Particularly favorable such solvents are methanol and ethanol in terms of economy and efficiency. Hydrogenolysis can be carried out at high temperature and pressure, but room temperature and 1 to 10 atm is preferable in terms of economy and convenience. Normally 30 minutes to 6 at good temperature and pressure
After this time the catalyst is removed (generally by filtration), the solvent is distilled off and the product is purified, if necessary, according to conventional methods. For example, recrystallization or column chromatography.

If hydrolysis is used to remove one or both of the protecting groups R ¹⁰ and Q, good results are obtained using methods known for alkaline or acid hydrolysis of esters. However, if the protecting group R ¹⁰ has to be removed by hydrolysis, alkaline hydrolysis is preferred. Particularly favorable conditions use at least equivalent amounts of a strong base, such as sodium hydroxide, potassium hydroxide, water and a lower alkanol,
In particular, it is carried out at room temperature in the presence of methanol or ethanol. Under these conditions hydrolytic removal of the R ¹⁰ group is usually complete within a few hours.

When the amino protecting group Q is tert-butyloxycarbonyl, acid hydrolysis is suitable for its removal. Particularly good ones are heated to reflux with dilute hydrochloric acid in methanol or ethanol. Under these conditions, hydrolysis is usually complete within a few hours.

After removal of the protecting groups by hydrolysis as described above, the product of formula () is isolated by conventional methods. For example, after acid hydrolysis, the solvent is distilled off, the remaining aqueous solution is washed with a non-polar solvent that is insoluble in water, such as ethyl ether, chloroform, and the aqueous layer is made alkaline. , for example, by extraction with ethyl acetate and distilling off the solvent. If necessary, further purify by recrystallization or column chromatography. If alkaline hydrolysis is used to remove the protecting group R ¹⁰ followed by hydrogenolysis of the amino protecting group Q, the reaction mixture of the alkaline hydrolysis is neutralized with an acid, e.g. hydrochloric acid, and the mixture is treated as described above. It is hydrogenated and decomposed like this.

A second industrial method for producing formula () is as shown below.

R ^a , R, R ¹⁰ , Q are as defined above.

An equivalent amount of the amino group-protected D-amino acid or its carboxyl-activated derivative is prepared using the method and reaction conditions described for the production of intermediates () and ().
Amino group protection D of formula () by reaction with RNH ₂
-Produce amino acid amides. The protecting group Q is removed by hydrogenolysis or hydrolysis as described above, and the resulting free amino acid () is converted into a diprotected L-aspartic acid derivative, as described above in the preparation of the intermediate of formula (). or a carboxyl-activated derivative thereof to produce a diprotected dipeptide amide of formula () to obtain a sweetener of formula () as described above.

As an application of this method, in the formula (), R is cyclic,
or an intermediate having an acyclic sulfide residue (-S-) is oxidized to a sulfoxide or sulfone before being converted into an intermediate of formula () by the method described above, and R is a sulfoxide or sulfone of formula (I ) is produced.

The sweetness of the compound of formula () is determined by comparing the sweetness with sucrose. An aqueous solution of the compound of formula () diluted to an appropriate concentration range is compared with a standard sucrose by an expert taste tester. Comparisons are generally 7-9
% sucrose aqueous solution, i.e. 7-9 g/100 ml. At high concentrations, sucrose has a characteristic mouthfeel, and at low concentrations it does not exhibit a state that can be used normally. For example, a compound of formula (),
If a 0.014% solution is judged to have the same sweetness as a 7% sucrose solution, the sweetness of this compound is 7/0.014=500
×It is sucrose. All sweetness values for compounds of the invention presented here were determined by this method.
the lowest concentration (i.e., the concentration at which sweetness is first felt;
At sucrose (typically 2-3% concentrations), the potency of sweeteners such as the compounds of the present invention is generally twice that observed when comparing sweetness with 7-9% sucrose solutions.

The necessary amines of the formula RNH ₂ where R is as defined above can be obtained from their precursors. They are obtained by amination of the corresponding ketones under various conditions in a conventional manner. For example, using reductive amination via the Leuckhart reaction using formic acid and formamide as reducing agents (see, e.g., a review of Organic Reactions ).
Wiley, Sons; New York, Vol. 5, 301 (1949)). On the other hand, ketones can be reductively aminated using sodium cyanoboron hydride and ammonium acetate. See, eg, J. Amer. Chem. Soc. , 93 , 2897 (1971). Alternatively, it is carried out using ethanolic ammonia in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium. For example, Organic Reactions ,
4 , 174 (1948). Many amines of the formula RNH ₂ are obtained from oxime intermediates prepared by reacting the corresponding ketones with hydroxylamine or its salts in conventional manner. The oxime intermediate is reduced by catalytic hydrogenation or by heating and reaction with metallic sodium in a lower alkanol. A particularly good and useful method for reducing the oxime of sulfur-containing ketones is to reduce the oxime to 1 ml in ethanol.
The mixture is reduced by reacting with a molar excess of sodium metal at the reflux temperature.

Ketone precursors of amines RNH ₂ are commercially available and can be produced according to conventional methods. for example,
Ketones of formula (); (in which R ³ , R ⁴ , R ⁵ _, R ⁶ , Can be manufactured. Methylation is carried out, for example, under conditions in which a suitable methylating agent such as methyl halide or methyl sulfate is neutralized or made basic with a strong base such as sodium hydride or sodium amide. The compounds are prepared from the appropriate monoalkyl compound, but the unsubstituted alpha position is protected prior to alkylation and removed following alkylation.

A variant method for preparing ketones of formula () is the cyclization of acyclic precursors, for example Dzikmann condensation of dicarboxylate esters followed by hydrolysis and decarboxylation reactions. Modern
See Synthetic Reaction , WA Benjamin, Menlo Park, Cal., 1972, p.740. The resulting alpha ketone esters, especially those without other alpha substituents, can be alkylated, if desired, prior to hydrolysis and decarboxylation. This reaction can be used to prepare ketones () in which the carbon next to the carbonyl group is unsubstituted and can be alkylated as described above.

Certain ketones of formula () are also obtained from acyclic precursors derived from ketones of formula ().

For example, four-membered ring ketones of the formula () in which X is O or S can be obtained by brominating the formula () with 2 equivalents of bromine and cyclizing the alpha, alpha'-dibromo compound with, for example, sodium hydroxide to produce oxetanone or sulfurized Cyclization with hydrogen gives thietanone. The corresponding five-membered ring ketone () is first reacted with formaldehyde to obtain an intermediate alpha-hydroxymethyl compound, which is then brominated at the alpha' position and refluxed with sodium hydroxide or hydrogen sulfide to form X.
Compounds of formula () where is O or S are obtained, respectively.

Tetrahydropyran-4-one and tetrahydrothiapyran-4-one of formula () can be obtained by adding water or hydrogen sulfide to a substituted vinyl ketone.

Compounds where X is SO ₂ are prepared by oxidizing the corresponding compounds where X is S to sulfones using known reagents and reaction conditions. On the other hand, ketones of formula () where X is S or amines obtained from ketones as described above can be oxidized to sulfones prior to the condensation reaction to produce dipeptide amides of formula (). Good reagents and reaction conditions for sulfide oxidation are carried out using hydrogen peroxide in a solvent such as acetic acid or acetone. Using equimolar reactants, the product is the sulfoxide, which can be easily converted to the corresponding sulfone using an additional equivalent of hydrogen peroxide. Other good oxidizing agents are potassium permanganate or chromic acid and m-chloroperbenzoic acid for making sulfones. This latter is particularly advantageous since one equivalent of the above-mentioned thioketone () can be used to form the corresponding sulfoxide and two equivalents can be used to form the sulfone.

Example 1 3-Amino-2,2,4,4-tetramethyltetrahydrofuran A 2,2,4,4-tetramethyltetrahydrofuran-3-one 25 g (0.1 mol) of 4-bromo-1-hydroxy-2. 2,4-trimethylpentane-3-
Dissolve On in 160ml of ethanol. to this,
Add a solution of 8 g (0.2 mol) of sodium hydroxide in 80 ml of water. Mix at room temperature for 30 minutes
Stir for a minute, dilute with water and extract with ethyl acetate. The extract is washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 17.7 g of 2,2,4-trimethylpentane-1,4-diol as a colorless oil. Identification by ^1H -NMR. Dissolve the diol in 50 ml of chloroform and add 1.5 ml of concentrated sulfuric acid dropwise. The mixture is heated to reflux for 3 hours. During this time, water/chloroform is steam distilled from the mixture. After standing overnight at room temperature, the reaction mixture is washed with water, the organic layer is dried (MgSO ₄ ) and the solvent is evaporated under vacuum to give 13.9 g of a colorless oil which is distilled to give 8.3 g of the desired product. BP70~72℃ (50mm), yield 58%.

B 8.0 g (0.056 mol) of the ketone obtained in Step A, 8.0 g (0.113 mol) of hydroxylamine hydrochloride,
2.3 g (0.113 mol) of sodium acetate are combined in 85 ml of ethanol and the mixture is heated to reflux for 48 hours. The mixture was diluted with water, extracted with ethyl acetate, washed with water, dried and evaporated to give 9.0 g of syn-
A mixture of anti-oxime and anti-oxime is obtained. ¹ H−
Identified by NMR.

1.3 g (8.28 mmol) of the oxime obtained above
was dissolved in 70 ml of dry ethanol, 1.9 g of sodium metal was added, and the mixture was warmed to reflux and maintained at this temperature for 15 minutes. Continue heating for another 2 hours and add metallic sodium twice in 1.9g portions. Water was carefully added to the reaction mixture and extracted with ethyl ether. The ether layer is extracted with hydrochloric acid, and the aqueous layer is made alkaline with sodium hydroxide and extracted with ether. The ether extract is dried (MgSO ₄ ) and distilled off, and the residue is distilled to obtain the desired amine. BP68
~69℃ (15mm). Precipitation of the hydrochloride salt from ethyl ether-methanol, basification of the salt and re-extraction with ether yields 0.87 g of 93% pure amine. Purity was determined by gas chromatography (OV-1 column).

Example 2 3-Amino-2,2,4,4-tetramethyltetrahydrothiophene A 1-Hydroxy-2,2,4-trimethylpentan-3-one Sodium made from 7.5 g sodium metal, 250 ml methanol 72.5g for methoxide
(2.4 moles) of paraformaldehyde is added followed by 250 g (2.2 moles) of diisopropyl ketone. Heat the mixture for 3 hours. The reaction is stopped by adding water, neutralized with hydrochloric acid, and extracted with ethyl ether. This is washed with water and brine, and the solvent is distilled off. The residual oil (90 g) was vacuum distilled,
28 g of desired product are obtained. Boiling point 92-98℃/16-
20mm. 314 at 107℃ for GLC using OV-1 column
Retention time in seconds, 96% purity.

The above procedure is repeated, the reaction mixture is refluxed for 16 hours, and the same amount of reaction is carried out, yielding 31 g of product, showing a purity of 96% by GLC.

B 4-bromo-1-hydroxy-2,2,4-
Trimethylpentan-3-one 69 g (0.48 mol) of 1-hydroxy-2.
A solution of 2,4-trimethylpentane in 500 ml of chloroform is stirred and brought to reflux. To this, 77g
A solution of bromine (0.48 mol) in 100 ml of chloroform is added dropwise. After the addition is complete, stir under reflux for 1 hour. This is cooled and left overnight at room temperature. The solvent was removed under reduced pressure to obtain 127 g of product. This is used in the next step without purification.

C 2.2.4.4-tetramethyltetrahydrothiophene-3-one 79 g (0.3 mol) of the product obtained in step B was added to 300 ml.
of dry pyridine and cooled to 0°C. 114
g (0.6 mol) of p-toluenesulfonyl chloride are added in several portions at 0°C. The mixture is stirred at this temperature for 3 hours and 15 minutes, poured into ice water and extracted with ethyl ether. The extract is washed with dilute hydrochloric acid, water, and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and 111g (98%)
crystalline tosylate is obtained.

Tosylate, 94 g (0.25 mol), is dissolved in 1 liter of pyridine, 180 g (0.75 mol) of sodium sulfide monohydrate is added and the mixture is heated to 75° C. and maintained at this temperature for 1 hour. Leave this at room temperature overnight. Add water and extract with ether. The extract is washed with hydrochloric acid, brine, and dried (MgSO ₄ ). The solvent was distilled off to obtain 35 g of the title compound. 89% yield. The product is silica gel
Ethyl acetate/hexane (1:4 vol.) by TLC,
A single point is indicated with R _f =0.5. The ¹ H-NMR spectrum matches the structure of the indicated compound.

D. Leuckart reduction of ketones 10.0 g (0.063 mol) of 2, 2, 4, 4-
Tetramethyltetrahydrothiophene-3-one, 15.2 ml (0.38 mol) formamide, 3.5 ml
(0.092 mol) of formic acid is added and the mixture is heated to reflux (163°C). During this time, water is separated and removed. The reaction mixture was kept at 160-180°C for 20 hours,
During this time, formic acid (10 ml) is added at intervals.
In this case the temperature rises to 200°C. The reaction mixture is extracted with ethyl acetate. The extract is evaporated under vacuum. The residue is refluxed with 20 ml of 6N hydrochloric acid for 2 hours, cooled and washed with ethyl ether. The aqueous layer is adjusted to pH 11 with an aqueous sodium hydroxide solution and extracted with ethyl ether. Dry the extract and distill it off to give 2g
3-amino-2,2,4,4-tetramethyltetrahydrothiophene is obtained. It was identified by ¹ H-NMR, and is also homogeneous by silica gel TLC.

TLC R _f 0.65 using a 7:4 mixture of ethyl acetate: hexane as the developing solvent: butanol: acetic acid: water using a 4:1:1 mixture as the developing solvent
TLC R _f 0.53. Positive ninhydrin reaction. The product is a yellow oil.

Reference example 1 L-aspartyl-D-alanine N-(2.
2,4,4-tetramethyltetrahydrothiophen-3-yl)amide: A 2.09 g (11
mmol) of N- t -butoxy-carbonyl-
Add 1.47 ml (10 mmol) of triethylamine to the D-alanine solution and cool the mixture to -10°C. At this temperature, add 0.96 ml (10 mmol) of ethyl chloroformate and stir for 15 minutes. −
1.6 g (10 mmol) dl − after cooling to 20 °C
3-Amino-2.2.4.4-tetramethyltetrahydrothiophene is added and the mixture is allowed to warm to room temperature. Add ethyl acetate and dilute the mixture
Wash with 5% (by weight) citric acid aqueous solution twice, 50 ml each, and then wash with sodium bicarbonate (1 x 50 ml).
ml) and saturated saline (1 x 50 ml). The organic layer was dried (Na ₂ SO ₄ ) and evaporated under reduced pressure to remove 3 g of N-(2,2,4,4-tetramethyltetrahydrothiophen-3-yl- t -butoxycarbonyl-D-alaninamide. Obtained as an oil. The structure of the product is confirmed by its ¹ H-NMR spectrum. It is essentially homogeneous by TLC on silica gel. The product is used in the next step without further purification.

B 5 ml of methanol to the product obtained from step A;
Add 30 ml of 1M hydrochloric acid and heat on a water bath for 30 minutes. Methanol is distilled off and the residue is extracted with ether. Discard the ether and adjust the aqueous layer to pH 11.0 with an aqueous sodium hydroxide solution. This was extracted with ethyl acetate, dried (Na ₂ SO ₄ ) and distilled off to give 1.0 g of N-
(2,2,4,4-tetramethyltetrahydrothiophen-3-yl)-D-alaninamide is obtained. This was identified using nuclear magnetic resonance spectroscopy.
Homogeneous by silica gel TLC.

Condensation for producing C dipeptide amide 0.97 g of D-alanine amide obtained in step B
(4.25 mmol) is mixed with 10 ml of water, cooled in ice and brought to pH 9.2 with 0.5N aqueous sodium hydroxide solution. To this, 0.8 g (4.25 mmol) of L-aspartic acid N-thiocarboxylic anhydride is added in portions while stirring. During this time, the pH of the mixture was maintained at 9 with an aqueous sodium hydroxide solution (0.5N). After the addition was complete, the mixture was stirred for 45 min at 0°C and
Adjust the pH to 5.2 and evaporate under vacuum. The residue is slurried with methanol, filtered to remove the precipitate, the liquid is evaporated under reduced pressure, and ethyl ether is added to form a solid. It is filtered, reslurried with ethyl ether, and the filtered solid is recrystallized from 8 ml of water. After drying in a vacuum oven 1 g of product is obtained. A second product is obtained from the mother liquor.
Sweetening potency 500 times that of sucrose.

Levorotatory 3-amino-2.2.
4,4-tetramethyltetrahydrothiophene was used in place of the racemic amine in the method described above to obtain L-aspartyl-D-alaninamide;
This is 800 times more sweetening than sucrose.

Example 3 3-Amino-2,2,4,4-tetramethylthietane A 2,4-dibromo-2,4-dimethylpentan-3-one 136 g (1.2 mol) of diisopropyl ketone with 2 ml of tribromide Add phosphorus and cool the mixture to 10°C. To this is added dropwise 384 g (2.4 mol) of bromine. The mixture is warmed to room temperature for 2 hours and then heated at 55-60°C for 1 hour, cooled and partitioned between chloroform and water. Discard the water and wash the organic layer with aqueous sodium carbonate until neutralized. The organic layer was dried (MgSO ₄ ) and the solvent was distilled off to give 316 g.
(97%) of the desired product is obtained.

B 2.2.4.4-Tetramethyl-3-oxothiethane 23 g (1.0 mol) of sodium metal are dissolved in 500 ml of dry methanol and the mixture is cooled to 10°C. Hydrogen sulfide gas is introduced into the mixture to saturate it. Next, 136 g (0.5 mol) of dibromoketone obtained in step A is added. During this time, hydrogen sulfide gas is continued to be introduced. After the dropwise addition, the mixture was stirred at 10°C for 2 hours, warmed to room temperature, and stirred overnight. The reaction mixture is poured into water and extracted with ethyl ether. Wash the extract with dilute hydrochloric acid and saline. After drying over magnesium sulfate, the ether is distilled off and the residue is made into a slurry with methanol. After cooling this, 46g
(64%) of solid matter is obtained. This is used in the next step without purification.

C Reductive amination of ketones 4.5 g (0.031 mol) in 75 ml dry methanol
of 2,2,4,4-tetramethyl-3-oxothiethane, 23.9 g (0.31 mol) ammonium acetate, and 1.36 g (0.0217 mol) sodium cyanoborohydride. The mixture is heated to reflux for 4 hours. Add more sodium cyanoborohydride (1.36 g) and reflux for 3 days, then add more of the same reagent at the beginning of the 3rd day. The mixture is brought to pH 2 with hydrochloric acid. This is distilled off using a rotary evaporator under reduced pressure. Dissolve the residue in water, wash with ethyl ether, adjust the aqueous layer to pH 11 with aqueous sodium hydroxide solution, and extract with ethyl ether. The extract is washed with brine, dried (MgSO ₄ ) and evaporated to yield 1.9 g (42%) of the desired amine as a crystalline solid. The structure of the product was confirmed by its ¹ H-NMR spectrum. Melting point approx.
45℃, boiling point 90℃ (20mm) D 3-amino-2,2,4,4-tetramethylthiethane-1,1-dioxide 550ml of 29g (0.2mol) of the amine obtained in Step C
Dissolve in acetonitrile and add 250ml of water. Keep the mixture at PH10 with sodium hydroxide
Add 35.8 g (0.21 mol) of carbobenzoxy chloride over 30 minutes. The mixture was stirred for 1 hour, filtered, washed with water, and dried under vacuum at 50°C.
NCbz-amine is obtained. R _f 0.7 (hexane/ethyl acetate 4:1, V/V, phosphomolybdic acid spray), 52.1 g (93.4%), dissolved in 700 ml of methylene chloride, 77 g (0.372 mol)
Add m-chloroperbenzoic acid slowly at a temperature below 45°C. (20-42°C) The precipitate is filtered and the solution is washed with 1N hydrochloric acid and sodium bicarbonate solution, dried (MgSO ₄ ), and the solvent is distilled off. The residue was crystallized from acetone-water to give 42 g (73
%) of Cbz-protected amine 1,1-oxide. R _f 0.7 (hexane/ethyl acetate, 1:
1, V/V, phosphomolybdic acid spray).

5 g of Cbz-amine in 250 ml of methanol, 5 ml of concentrated hydrochloric acid, 2 g of 5% Pd/C (50%
Protecting groups are removed by hydrogenolysis using a wet solution. The product is isolated using conventional methods. Yield 2.4g
(85%), R _f 0.6. In gas chromatography using a 1 meter OV-1 column, the holding time was 1.3 minutes at 180°C. 3-amino-2, 2, 4, 4
-Overall yield of 3 steps starting from tetramethylthietane is 65%.

Reference example 2 L-aspartyl-D-alanine N-(2.
2,4,4-tetramethylthietan-3-yl)amide: A To a solution of 0.9 g (11 mmol) N-t-butoxycarbonyl-D-alanine in 75 ml of tetrahydrofuran is added 1.47 ml (10 mmol) of triethylamine. The mixture was cooled to -10°C, 0.96 ml (10 mmol) of ethyl chloroformate was added, and the mixture was stirred for 10 minutes, then cooled to -20°C.
1.70 g (11 mmol) of 3-amino-2.2.
Add a solution of 4,4-tetramethylthietane in 5 ml of tetrahydrofuran. Warm the reaction mixture to room temperature and add ethyl acetate. 5% (weight) of this
Wash with citric acid solution (2 x 50 ml), wash with sodium bicarbonate solution until neutralized and then with saline. Dry the organic layer (Na ₂ SO ₄ ) and evaporate the solvent to yield 27 g (78%) of the desired solid product. The ¹ H-NMR spectrum of the product is consistent with the expected values. 1:1 for silica gel TLC
When developed with ethyl acetate/hexane, the product shows homogeneity. R _f 0.77.

B The t-Boc-D-alanine amide prepared here was hydrolyzed to produce free alpha-aminoamide at 43
% yield. The product is homogeneous by silica gel TLC and the ¹ H-NMR spectrum is consistent with its structure.

C Condensation for producing dipeptide amide Alpha aminoamide produced in step B above
Mix 0.7 g (3.2 mmol) with 10 ml of water and adjust the pH
Adjust the temperature to 10.1, cool in an ice bath, and add 0.567 g (3.2 mmol) of L-aspartic acid N-thiocarboxylic anhydride in portions. During this time, add 0.5N sodium hydroxide solution to keep the pH at 9.0. The mixture is then stirred at 0° C. for 45 minutes to a pH of 5.2 and evaporated under vacuum. Slurry the residue with methanol,
The solids are removed by filtration and the liquid is distilled off. to the residue
Add 150 ml of ethyl ether and filter off the precipitated product. This is dried in a vacuum oven overnight to obtain 1.5 g of crude material. After slurrying twice more with ethyl ether, 0.9 g of product is obtained (85%). Sweetening potency, 2000 times more than sucrose.

Claims (1)

[Claims] 1 Formula: compound. (In the formula, when n ₁ is 0 and p ₁ is 1, X ₁ is O or S, and when n ₁ and p ₁ are each 0, X ₁ is S or
SO ₂ )