JPS5826851A - Amides having branch chain of l-aspartyl- d-amino acid dipeptide - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to amides of the L-aspartyl-D-amino acid dibeptyl F of the formula:
;R is a branched group selected from the following group.

That is, fentyl, diimpropylcarvinylvinyl, 2-methylthio-2,4-dimethyl is
yl (R3, R4, in the formula) (at least 1 of 5, R6)
One is alkyl having 1 to 4 carbon atoms, and the rest is hydrogen or 1 carbon number.
~4 alkyl; X is o, s, so.

So2, G=O, CHOH; m is 0 or 1-4:n
and p are 0.1, 2, and 6, respectively, and pop is thicker than 3 (,) (3, R4, R5, and R6 are thicker than 6 (not). R3 and R4 or When both R5 and R6 are alkyl, alkyl is methyl or ethyl.) (R7, R8j (901 is alkyl having 1 to 4 carbon atoms).

The remainder is hydrogen or alkyl having 1 to 4 carbon atoms, R7, R8
゜The total number of carbon atoms in R9 is not greater than 6. m and q are the same or different, and each is as defined for m above. ) 13 (R12 and R13 are each methyl and ethyl; R12 is hydrogen R13 is alkyl having 1 to 4 carbon atoms, 2 is O or NHlt
is 1 or 2); (W is 1 to 4. R14, R16 C%h Number of carbons 1 to 4
Butylkyl R15 is H, OH, methyl, ethyl, R1
4°R1! , R16 has a total number of carbon atoms not greater than 6.

Both R14 and R15 are alkyl, methyl or ethyl): (R17 and R19 are alkyl having 1 to 4 carbon atoms) (
18゜R20 is H or alkyl having 1 to 2 carbon atoms, A is O
H, B are H, OH or (J3. A and B are bonded 0
0 0 o oo.

The total number of carbon atoms in Rlg, R19, and R20 is not greater than 6. (R17 and R18 or R19 and R20 are both alkyl, methyl or ethyl) Furthermore, the above-mentioned amides are better sweeteners than conventional ones, and edible compositions containing them, methods of use in foods, and production of the above-mentioned amides are provided. are associated with new amide intermediates that are useful for

The present invention relates to the L-aspartyl-D-serine one-character correction of the fault and the amides of L-aspartyl-D-0-methylserine, particularly for its use in food products due to its beneficial sweetness. The invention also relates to edible compositions.

In U.S. Pat. No. 3,492,131, several L-aspartyl-L-phenylalanine lower alkyl esters were found to be 200 times sweeter than sucrose, resulting in the bitterness found in conventional artificial sweeteners such as saccharin. It is stated that there is no These compounds have limited stability because diketobi forms radin in aqueous solution under neutral-acidic pH conditions.

Mazur et al., J, Med, Chem, 16
, 1284 (1973) reported that the lower alkyl ester of L-aspartyl-D-alanine and several of its congeners, especially L-aspartyl-D-alanine isopropyl ester, have a sweetness 125 times that of sucrose. ing.

5kehirO etc. are 5eikatsu Kagaku,
11.

9-16 (1977): Chem, Abst, r.
, 87.

168407h (1977), formula 1: L-
We report on the number 1 amyloid of aspartyl-D-alanine. R1 in the formula is methyl, ethyl, n-propyl, isopropyl, p-butyl, isobutyl, 5ec-7'tyl, cyclohexyl, or glycine, tan-alanine, ! - is the carbon residue in the methyl ester of alanine. The most active compound is a compound in which R1 is the above-mentioned butyl group or cyclohexyl,
They are 100 to 125 times more potent and 100 times more potent than sucrose, respectively.

n-Butylamide F is 125 times more than sucrose, isobutyl, 5e
Since c-butyramide is 100 times sweeter, the sweetening potency of these amyls is mainly influenced by the number of carbon atoms in the alkyl group R1, and structural isomers of the alkyl group are less sweet. It is thought that it does not affect the power.

Ar1yashi et al. Bull, phem, Soc
, Japan 47.326 (1974), the esters of L-aspartyl-D-serine and L-aspartyl-D-threonine are converted into L-aspartyl-D-threonine.
It has been reported that it has greater sweetening power than the corresponding esters of D-alanine and L-aspartyl-D-2-aminobutyric acid. The most salacious of these esters is L-aspartyl-D-serine nipropyl ester, which is 320 times more potent than the 5-sucrose reference; -D-aladinol and carboxylic acid, (2-methylbutyric acid,
Cyclopropanecarboxylic acid, cyclobutanecarboxylic acid,
2-methylcyclobutanecarboxylic acid). Cyclopropane- and cyclobutanecarboxylic acid esters are 200 times and 2 times more than sucrose, respectively.
It has 20 times the sweetening power. The ester of 2-methylcyclobutanecarboxylic acid has only 160 times the sweetening power. At the same time, L-aspartyl-D-serinol ester has also been described, the sweetening power of which is 160 times that of sucrose.

Methyl L-aspartylaminomalonate 2-methylcyclohexyl diester and the corresponding alkyl fenthyl diester are described in US Pat. No. 3.959.245 and 3.907.766, respectively. The former is described as being 6,600 times more active than sucrose, and the latter being 4,200 to 33,00 times more active.

Related literature by this inventor: Chem, Pharm, B
ull,.

24, 2112 (1976), a series of mono-asnortylaminomalonic acid diesters are reported, the esters being methyl, ethyl, and various other branched alkyl and cycloalkyl groups.

In the applicant's U.S. Patent Application No. 201745 (filed November 5, 1980), simply L-aspartyl-D-
It has been described that not only the size of the amide substituent in the alanine amide limits the high potency, but also the precise spatial arrangement of the amide substituent R. Aspartyl-D-alanine amides with a branched chain at the alpha carbon (the carbon attached to the nitrogen atom of the amide) and -
It has been found to be advantageous for one or both of the groups and groups to have branches.

The present invention is characterized in that: 1 new, branched L-as, J rutile-D-seri/, L-aspartyl-D-0-methyl serine, which has strong sweetness and has no undesirable taste at conventional usage amounts, is an amide of putido; provide similar supplies. They are very stable, both in solid form and in aqueous solution, at the pH ranges used in most food products, and are also stable at baking and food manufacturing temperatures.

The novel compounds of the present invention are L-asnozoruthyl-D-amino acids of the formula: C selected from the following group: fentyl, diisopropylcarbinyl, d-methyl-1-butylcarbinyl, d-
Ethyl-1-butylcarbinyl.

di-t-butylcarbinyl, 2-methylthio-2,4-
Dimethyl pancn-3-yl.

(At least one of R3, R4, R5, and R6 has 1 or more carbon atoms.
4 alkyl, the remainder is hydrogen or alkyl having 1 to 4 carbon atoms, X is o, s, so, So, c=o, CHOH:
m is 0.1, 2.6.4; n and p are 0, 1.2, respectively.
3 and 11 + TJ is not greater than 6: R, F1. F
l.

The total number of carbon atoms in R6 is not greater than 6. R and R4 or both R5 and R6 are alkyl, methyl or ethyl); (m is the one obvious above; one of R7, R8, and R9 is alkyl with 1 to 4 carbon atoms; the rest are hydrogen or carbon atoms) 1-4
Alkyl H'1. The total number of carbon atoms in R8 and R9 is 6
thicker (not); (m and q are the same or different numbers, as specified in m above,...) (Each of R12 and R13 is methyl, ethyl, or R12 is hydrogen R13 is carbon Alkyl number 1 to 4, 2 is ○ or NH
, t, is 1 or 2); (W is 0.1, 2.ro, 4; R%R is each carbon number 1 to 4
alkyl, R15 is water, OH.

Alkyl having 1 to 2 carbon atoms; R14, R15J (the total number of carbon atoms in 16 is greater than 6 (no, if both R14 and R15 are alkyl, methyl or ethyl): (R17, R1
9 is alkyl having 1 to 4 carbon atoms, R18 and R20 are hydrogen or alkyl having 1 to 2 carbon atoms, and A and B are bonded.
In this case, A is ○H and B is hydrogen.

OH, methyl; if A and B are bonded together.

The total number of carbon atoms in R17, HlB, R19, and R20 is not greater than 6. When both R and R or R19 and R20 are alkyl, methyl, ethyl. ) Good sweeteners of the present invention include L-asnoξlagic acid and D
--r/acid, RaCH(NH)COOH-
1! L-aspartyl- of formula 1) where one or both of the aspartyl or other amino acid (i.e. serine or 0-methylserine) residues are in racemic form as shown below. Mixtures of D-7 amino acids are also within the scope of this invention.

Namely.

DL-aspartyl-D-serinamide, DL-aspartyl-DL-serinamide F.

L-7 spartyl-DL-serinamide, L-aspartyl-DL-○-methylserinamide, DL-aspartyl-DL-0-methylserinamide, DL-aspartyl-D-0-methylserinamide F.

Compounds of formula 1i in which the aspartyl residue is completely D-configured or the other amino acid residues are completely L-configured have weak or no sweetening power.

A particularly good L-aspartyl-D-amino acid amide of formula I11 is where R is diimpropylcarbinyl.

It is an acyclic compound selected from tylcarvinyl.

Other suitable L-aspartyl-D-amino acid amino acids of the formula lit are compounds in which R is selected from the group:

R20) 719 <7') R3-R9, R12-R2O%A%B1X
,Z,rn.

n, p, q, t, w are clear above.

Further favorable compounds in the formula are compounds in which R is one of the first four types shown in the above diagram.

A particularly good amide in the formula is L-aspartyl-D-serinamide, ie the compound in which Ha is CH20H.

Better and more valuable L-aspartyl-D-amino acid amides of the present invention are those where R is:

(-) fenthyl, diisopropyl carbinyl, d-Methyl-1-butylcarbinyl.

di-t-butylcarbinyl, 2.6-dimethylcyclohexyl.

butyl to 2-methylcyclo, 2-Ethyl-6-methylcyclohexyl.

2-Ethylcyclohexyl.

2-methylcyclohexyl, 2.2-dimethylcyclohexyl, 2-ethylcyclo is butyl, 2-Methyl-6-isopropylcyclohexyl.

2,2.6.6-titramethylcyclohexyl.

2.2,4.4-Tetramethyltetrahyfuran-6
-il.

2.2.6-) IJ Methylcyclohexyl.

2-Inpropylcyclohexyl.

2,5-dimethylcyclo2-ethyl, 2.6-ymethylcyclohexyl.

2-Isopropylcyclononthyl.

2,2.5.5-Tetramethylcyclobutyl, t-butylcyclopropylcarbinyl, 2.2.4.4-tetramethylethane-ro-yl.

2.2,4.4-Tetramethyl-1,1-dioxochetan-3-yl.

2,2.4.4-Tetramethyltetrahydrothiophen-6-yl.

6.5-Dimethyltetrahydrothiapyran-4-yl.

2-1-Butylcyclohexyl, also hashcyclopropylcarbinyl; particularly good valuable sweeteners are the above-mentioned compounds in which R is

di-t-butylcarbinyl, 2.2.6-) Dimethylcyclohexyl.

2-1-Butylcyclohexyl.

2-isopropylcyclohexyl.

2.6-dimethylcyclohexyl, Butyl in 2.5-dimethylcyclo.

Butyl in 2-inpropylcyclo.

2,2.5.5-tetramethylcyclo is butyl, 2,2
．． 4.4-Tetramethyltetrahydrothiophene-6-
IL.

t-Butylcyclopropylcarbinyl.

Dicyclopropylcarbinyl, 2,2.4.4-tetramethylchetan-6-yl, or even 1% of the compound of formula +1) where R is a compound as described below.

Butyl in 2, 2.5.5-tetramethylcyclo.

2.2.4.4-Tetramethyltetrahydrothiophen-6-yl.

t-7'Tylcyclopropylcarbinyl.

2,2,4.4-Tetramethylchetan-6-yl.

2,2.4.4-tetramethyl-1,1-dioxochetan-6-yl; The compound of the best formula (11 is Ra7ri'-0H20H, Rcasiciclopropylcarbinyl, 2,2.4. 4-Tetramethylchetan-3-yl.

2,2.4.4-Tetramethyl-1,1-dioxochetan-6-yl.

') Compound '411 and f(a GH20CH3"'
C"Rka2,2,4.4-tetramethylchetane-6-
IL.

This compound has 200 to 1200 times the sweetening power of sucrose.

The present invention further provides compositions for sweetened food products characterized by a sweetening effect of a compound of the formula and a non-toxic carrier. The best composition is L-asuno and rutile-D-serine N-(dicyclopropylcarvinyl)amyl% L-
Aspartyl-D-serine N-(2,2,4,4-tetramethylchetan-6-yl)amiY and the latter 1,
It contains a 1-dioxo compound.

Further provided is a sweetened food composition featuring a food product and a sweetening effect amount of a compound of the invention.

Furthermore, a method for producing a sweet food composition is provided, characterized in that the compound of the invention is added in an amount that produces a sweetening effect.

The invention further provides a composition for making a sweetened food product characterized by a mixture of a sweetening effect amount of a compound of the formula and saccharin or a physiologically useful salt thereof.

Particularly good of such mixtures are H
a is CH20H, R is dicyclopropylcarbinyl, 2
,2,4.4-tetramethylchetan-6-yl or 2
．． The best one containing 2.4.4-tetramethyl-11-dioxochetan-6-yl is L-
It is a mixture of asnomorty-D-serine N-(2,2,4,4-tetramethylcetan-6-yl)amide and saccharin in a mixing ratio of 1:1 to 1:8.

By physiologically suitable salts of saccharin is meant salts of saccharin with physiologically useful cations, such as sodium, potassium, calcium, ammonium salts.

Physiologically appropriate cationic salts of the compounds of the present invention refer to salts prepared by neutralizing the carboxylic acid of the compound f in the formula with physiologically useful metals, ammonia, amines, and other bases. do. Examples of such metal salts include sodium,
Potassium, calcium.

Examples of amines include N-methylglucamine and ethanolamine.

Physiologically relevant acid addition salts refer to salts prepared between a free amine group in a compound of formula lit and a physiologically useful acid. Examples of such acids are acetic acid, benzoic acid, hydrobromic acid, hydrochloric acid, citric acid, fumaric acid, curconic acid, milk & maleic acid.

malic acid, nitric acid, phosphoric acid, saccharic acid, succinic acid,
It is tartaric acid.

The present invention further provides novel intermediates useful in the preparation of compounds of formula. This intermediate is a D-amino acid amide of the formula:

RCHCONHR' H2 where R& is as defined above and RC is selected from the following group. That is, fentyl, diimpropylcarbinyl, methyl-1-butyl-carbinyl, d-ethyl-t-butylcarbinyl, di-1-butylcarbinyl,
Cyclopropyl-keptylcarbinyl, cyclobenti-t-butylcarbinyl, dicyclopropylcarbinyl m1 is 1.2.3 When ml is 1, R30, R40, R50, R60 are each methyl.

When ml is 2, R30 is methyl, ethyl, isopropyl R4°, R50 and R60 are each hydrogen, or R and R are each methyl.

R40 and R60 are each hydrogen, If ml is 6.

fal R30 is inpropyl or t-butyl R
40, R50,, p, 6 Q is each hydrogen f'bl R30 is ethyl, R50 is methyl, R40
, R60 are each hydrogen.

Icl R30 and R40 are each methyl 1L.

R50J (60 is hydrogen or metal) Chill.

When R2 and □ are each 0, R41 and R61 are respectively methyl Sx2 is S, 5O2sC=0 or QHOH.

When R2 is o and R2 is 1, R41 and R61 are 6h methyl, x2 is Q, 3.302° When R2 and R2 are each 1, R41 and R61 are each hydrated, x2 is S, SO□.

"Carvinyl" as used herein means a -0H- residue. For example, diisopropylcarbinyl is (1-C3H
7) 2-CH-, dicyclopropylcarbinyl is (Δl
20H-NH2.

This di-buty-V amide can be conveniently produced industrially by a suitable condensation reaction of amino acids. A good method for producing (dipeptide amide) in the formula is shown below.

(Matamariki, activated form to ruboxy) Deprotection group 111 -> In the above-mentioned L-aspartic acid derivatives, Q is well known. One of the amine protecting groups, AdvanceSin Organic Cbem by Belss Onas
, 3 #159-190 (1963), which can be selectively removed. Particularly good amine protecting groups are
benzyloxycarbonyl and tert-butyroxycarbonyl. RIO is alkyl having 1 to 4 carbon atoms or indyl. above J+lL・D-serine or D-0
-For methylserine, a free amino acid in which R11 is hydrogen can be used, but a carboxy-protected form in which R11 is a methyl or ethyl ester residue is better.

Alternatively, a silyl group such as trialkylsilyl having 1 to 12 carbon atoms may be used. Especially good ones are economical.

Effectively, it is trimethylsilyl.

In the first step in the reaction process described above, the diprotected monoaspartic acid is condensed with the appropriate monoamino acid or carboxy-protected derivative to produce the diprotected dibutide of formula Ill. This step involves reacting with diprotected aspartic acid in the presence of a condensing agent such as dicyclohexylcarbodiimide.
Preferably, alpha carboxyl activated derivatives of diprotected aspartic acid are used. A good example of such activated derivatives is Chlorai F, bromide % acid anhydride 1% combined acid anhydride. The ones that are particularly good in terms of efficiency.

Among the above-mentioned mixed acid anhydrides formed from esters of diprotected L-aspartic acid and chlorocarboxylic acid, the esters are preferably alkyl esters having 1 to 4 carbon atoms. The best mixed acid anhydrides are those made from aq carbonated methyl and ethyl esters for economic reasons.

A good method for producing the compound of formula (1) is to react eta-indyl-N-benzyloxycarbonyl-L-asparagine with ethyl chlorocarbonate in a conventional manner to produce the corresponding mixed acid anhydride. Separate the amino acid racemic mixture commercially by hand or by conventional methods into containers (
Yamada et al. J.Org.Chem, 38.
4408 (1973)) by Ill D
-7mi/ff, RaCH (NH2) COOH wo!
-)limethylsilyl chloride in an inert organic solvent,
Reaction When Ha is CH20H, it is reacted with two equivalents of silylating agent to produce trimethylsilyl ester. Suitable solvents for this purpose are pyridine, dimethylformamide V1 dimethylacetamide V: especially dimethylformamide.

In a typical reaction according to this method, % D-amino acid such as D-0-methylserine is dissolved in dimethylformamide and an equivalent amount of trimethylchlorosilane is added at room temperature. In a separate flask, dissolve N-insiloxycarbonyl-L-asno-lagic acid and a 1 molar excess of acid binder (triethylamine is good) in a mixture of dimethylformamide and tetrahydrochloride. An equivalent amount of ethyl chlorocarbonate is added at or below room temperature to make the mixed anhydride. -25~25C, especially -10°
~DC is good. At the same temperature, for example, D-0
- Add a solution of methylserine trimethylsilyl ester. The reaction is usually complete in 1 to 2 hours and the mixture is poured into water or an aqueous acid such as hydrochloric acid and a water-insoluble solvent (e.g. chloroform, methylene chloride F or ether) is added.
The product of formula ill is extracted and isolated according to conventional methods.

This diprotected dipeptide is usually pure enough to be used in the next step and, if necessary, further purified by column chromatography.

In the second step of the method, the diprotected dibutide (1) is reacted with an equivalent amount of a primary amine of formula RNH2.

The corresponding diprotected sibutide amide intermediate of formula ill is prepared. Here, Ha, B R1O.Q are as defined above. The carboxylic acid form of one reactant as in the first step can be used to prepare intermediates of formula (II) using a condensing agent such as dicyclohexylcarbodiimide. However, one of formula (II) may be converted into carboxyl-activated derivatives, such as chloride F, bromide, or mixed acid anhydrides. In this case, mixed acid anhydrides are preferred. RIO is benzyl and Q is benzyloxy. Particularly good formulas that are carbonyl ([
Acid anhydride is prepared by mixing using compound 1. As mentioned above, good anhydrides are obtained from esters of chlorocarboxylic acids, especially their methyl and ethyl esters. Reactant 1 is prepared using the following reaction conditions. Typically, a compound of formula jul+ and triethylamine are used in aX equivalents of an inert reaction solvent (e.g., tetrahydrofuran).
The mixture is mixed in a vacuum, cooled to -10C, and ethyl chlorocarbonate is added and mixed to obtain an acid anhydride. To this is then added an equivalent amount of an amine of formula RN) 12, or a solution thereof, in the same inert reaction solvent at -50° to 25r (-35° to -5C is better). After the amine has been added, the mixture is brought to room temperature and kept at room temperature until the reaction is well established.

It usually takes 1 to 20 hours to complete. The intermediate of formula +Ill is then isolated and, if necessary, purified by the method of formula ill described above.

In the final step of the process, the carboxyl protecting group RIO and the amino protecting group Q are removed to yield the desired sweetener of formula ITI.

The method for removing the protecting group from the sibutide amide of formula will vary depending on a variety of factors that will be apparent to those skilled in the art. Two important factors in the selection of this method are the nature of the protecting group RIO,Q and the nature of the amide substituent H. For example, when RIO and Q are particularly good, benzyl and pensiloxycarbonyl, respectively, and R does not contain sulfur, the protecting group is usually removed by hydrogenolysis.

However, when R10 is alkyl or alkyl as specified above, Q is tert-butyroxycarbonyl, and R is many of those listed above, hydrolysis is usually used to remove the protecting group. When RIO is alkyl, Q is insiloxycarbonyl, and R does not contain sulfur, it is preferable to use hydrolysis and hydrogenolysis together.

When removing the protecting group from the intermediate of formula +11 by hydrogenolysis, one reaction is preferably carried out in an inert reaction solution in the presence of a catalytic amount of a noble metal catalyst (C radium is particularly good). Examples of solvents include methanol, ethanol, impropatol, and butanol.

Contains lower alkanols such as tetrahydrofuran, ethyl ether, 1,2-dimethoxyethane, thiethylene glycol dimethyl ether, esters such as ethyl acetate, methyl propionate, and methyl succinate, and dimethylformamide. Particularly good solvents are economical and efficient.

Methanol and ethanol. Hydrocracking can be carried out at high pressure and high temperature, but 1 to 10 atmospheres or room temperature is preferable because it is economical and convenient. Using good temperature and pressure, the reaction is usually complete in 60 minutes to 6 hours. The catalyst is removed by filtration and the solvent is distilled off. If necessary, the product is prepared by conventional methods such as crystallization or column chromatography.

When hydrolysis is used to remove one or both of the protecting groups RIO, Q, good results are obtained using conventional methods such as alkaline or acid hydrolysis of the ester. However, when RIO is to be hydrolyzed, alkaline hydrolysis is preferred. at least 1
It is particularly effective to carry out the reaction at room temperature with a lower alkanol solution such as methanol or ethanol in the presence of water using an equivalent amount of a strong base such as sodium or potassium hydroxide. R10
The hydrolytic removal of is usually completed within a few hours under conditions as described above.

When the amine retention group Q is triphthyloxycarponyl Q, acid hydrolysis is suitable for its removal. In particular, it is preferable to reflux using dilute hydrochloric acid in the presence of methanol or ethanol. Under these conditions, it is usually completed within a few hours.

The product in the formula is isolated by a conventional method after removing the protecting group. For example, after acid hydrolysis, one reaction mixture is distilled off to remove the solvent, and the aqueous residue is washed with nonpolar, water-insoluble ethyl ether, chloroform, or the like.

Makes the aqueous layer an alkaline habitat. This is extracted with a water-insoluble solvent such as ethyl acetate and the solvent is distilled off. If necessary, the product is further purified by crystallization or column chromatography. When the protecting group RIG is removed by alkaline hydrolysis and the amino protecting group Q is subsequently removed by hydrogenolysis, the alkaline hydrolysis mixture is neutralized by adding an acid such as hydrochloric acid σ1, followed by hydrogenolysis as described above. .

Other suitable methods of preparing compounds in the formula are as shown below.

RaR & 1 +RNH21 D-QNHCHCOOHQNHCHCONHRRa,
H, RIO, Q are clear above.

D-amino acids or their carboxyl-activated derivatives were mixed with an equivalent amount of RNH2 and
not reacted using the method and conditions used in the production of Hr,
The amino-protected D-amino acid amide (■ is obtained. The protecting group Q is removed by hydrogenolysis or hydrolysis as described above. The resulting free amino acid amide is diprotected and the mono-aspartic acid derivative or its carboxyl activated Derivatives and 1 formula Tll
Condensation reaction as described for the preparation of + diprotected diprotected formula +11 produces butydoamide.

From this substance a sweetener of formula 1.1 is obtained as described above.

In a variation of this method, intermediates of formula +lVl in which R has a cyclic or acyclic sulfur residue (-8-) are oxidized to sulfoxides or sulfones before being converted to the intermediate group of formula (■).Next is reacted as described above to obtain a compound in which R is sulfoxide or sulfone.

A third method of preparing the compounds of the present invention is to react the D-aminoamide of formula 1 (■) with L-aspartic acid N-thio-carboxylic anhydride as described above directly to prepare the compound of formula 1i. To carry out this process, the intermediate (■) is mixed with an equivalent amount of L-asnoragic acid N-thiocarboxylic anhydride in a suitable solvent and a mild alkali at pH 9 between -25° and 10°C.
K and react.

A compound of formula (11) is obtained. The alkaline pH of this reaction is established with a strong base such as sodium hydroxide or potassium carbonate. A suitable solvent is required under the reaction conditions used (some of the reactants are dissolved, It is preferable to use a solvent that does not react with both reactants to a detectable extent and allows the product formed in one reaction to be isolated relatively easily. Examples of solvents for this reaction include water and tetrahydrofuran.

t2-dimethoxyethane, diethylene glycol dimethyl ether, dimethyl sulfoxide, dimethyl formamide, and mixtures thereof, but preferred are water and mixtures of water and tetrahydrofuran. A favorable pH range for this reaction is 8 to 10, with 9 being particularly favorable. Particularly good temperatures are -10 to DC.

Under the conditions described above, the reaction is usually complete in 1 to 2 hours. The product of formula +11 is then isolated by conventional methods, such as by pH testing the reaction mixture to the isoelectric point of the product. Normal pH 5
, 0 to 5.6, the product in the formula precipitates. The solvent is removed by distillation or filtration and slurried in a solvent such as methanol, ethanol, ethyl ether, ethyl acetate, or mixtures thereof.

The product of formula [11] is then isolated by K filtration. If necessary, further purify by recrystallization or column chromatography.

The sweetening power of the compound is determined by comparison of sweetness with sucrose.

An aqueous solution of the compound of formula (I) diluted to an appropriate concentration range is compared with a standard sucrose by an interrogating taste judge. Generally, a 7-9% sucrose aqueous solution (i.e. 7-9% in 100N)
Compare with Ji'). Higher concentrations of sucrose have a different mouth sensation that affects the results, and lower concentrations do not exhibit the conditions normally used. If it is determined that a 0.014% solution of the compound of formula i11 has a sweetness equivalent to that of a 7-sucrose solution, the sweetening power of this compound is 500 times that of sucrose (10.014). All sweetening power values given for compounds of the invention were determined by this method. At the threshold concentration (the lowest concentration at which a sweet taste is first felt, which is usually 2 to 3 ts for sucrose), the potency of sweeteners such as the compounds of the present invention is twice that of normal [7 to 9 ts] compared to the sweetness produced by sucrose solutions. be.

2RNH2 where R is the above-mentioned obvious ones are commercially available or can be obtained from readily available precursors.

%jt 2-alkylcyclohexylamine and 2.6
-Dialkylcyclohexylamines are obtained by catalytic reduction of the corresponding alkyl-substituted anilines. Many amines are prepared by conventional reductive amination of the corresponding ketone. For example, amination is carried out by Leuckhart reaction using formic acid and formamide F as reducing agents. For example, Organic Reactions, Wil
Eye and 5ons, New York.

See the review in Volume 5, page 301 (1949).
Suitable ketones can be reductively aminated using sodium cyanoborohyF-lye and ammonium acetate (see, eg, J. Amer.

(Raney nickel or platinum) can be aminated by reaction with ethanolic ammonia in the presence of a radium catalyst.
(Organic Reactives, 4 e
174 (1948)) Many amines of the formula RNH2 are obtained from intermediate oximes obtained by reacting the corresponding ketones with hydroxylamine or its salts in a conventional manner. This oxime is then reduced by catalytic reduction or by heating with lower alkaline earth metal sodium. A particularly good method, useful for reducing oximes of sulfur-containing ketones, is reduction with a 1 molar excess of sodium metal in ethanol at reflux.

The ketone precursor of amine RNH2 is commercially available or can be produced by conventional methods. For example, the formula ■ and the flat ketone: (■) (■) (R3, R', R5, R', X, m, n,
p is clear from above. However, in ■, the case where X is C=0 is excluded. ), R3, R4, R5, R6 are each hydrogen Q
) A compound can be alkylated to convert one of R, R, R, and H into a compound in which all of them are alkyl. Alkylation is carried out by using an alkylating agent such as a corresponding alkyl halide or alkyl sulfate, and making the reaction neutral or alkaline with a strong base such as sodium hydroxide or sodium amide. Formula (7) in which 1.2 or 3 of the alpha substituents of the ketone group are alkyl and formula (■ white compound, 2 of R, R, R, H
~4 can be converted into a compound where 4 is alkyl. Gem-dialkyl compounds of formula 2 and in which R3 and R4 or R5 and R6 are alkyl as defined above are obtained from the corresponding monoalkyl compounds by protecting the unsubstituted alpha position before alkylation and then removing the protecting group. I can do things.

For example, 2,2-dimethylcyclohexanone is prepared by condensing 2-methylcyclohexanone with ethyl formate in the presence of sodium methoxy V and alkylating the resulting intermediate as shown below.

Condensation of the corresponding alpha unsubstituted compound with a suitable aldehyde F or ketone under alkaline conditions.

An intermediate, alpha or alpha-alpha'-alkylidene ketone, is prepared and hydrogenolyzed.

One or more of R3 and R5 obtains a propyl or butyl formula, or a ketone.

The cyclocitanone required here is described by Gonia et al., Bull, Soc, Chim, France.
726 (1963) and Ccnia, Ind. C.
him, Belge, 31 e981 (19/)6
Another method for preparing the ketones of formulas 0 (1 and 2) prepared by the method described in 1.) is the cyclization reaction of an acyclic precursor.

If you feed it, it is good for dicarboxylic acid esters (known as Diec
kmann condensation followed by hydrocondensation membrane carbon i1! It is obtained by For example, Mod by W, A, Benj amin
ern 5yntheticReactions, M
Enlo Park, California.

1972, 740 see -. Alpha-ketoesters obtained here, if desired, especially those without other alpha substituents. can be alkylated before hydrolysis and decarboxylation. This reaction) can be used to produce ketones (2), which have no substituent on the carbon adjacent to the carbonyl group, and can be alkylated as described above.

To produce a compound in which X is C=0 in the formula (Company), the ketone group of the acyclic dicarboxylic acid ester precursor is
Before the nn condensation reaction, it is converted into a ketal or thioketal, such as dimethyl ketal, diethyl thioketal, ethylene dioxyketal, ethylene dithioketal. The ketoketal is prepared by hydrolysis and decarboxylation of the ester group, as described above, and converted to the corresponding aminoketal, followed by hydrolysis of the ketal group in a conventional manner. The resulting aminoketone is reduced, if necessary, by a conventional method. The corresponding hydroxylamine (X=CHOH)K can be obtained by
2,2.4.4-Tetraalkyl-6-hydroxycycloptylamine can be prepared from the corresponding 1,3-dione by the method of U.S. Pat. No. 3,125,569. I can do it.

Amines or their N-protected derivatives of formula: % formula % (wherein X is GHOH, R3-R6, n, p is as defined above), example t
For example, N-benzyloxycarbonyl, the derivative can be converted to the corresponding compound where Reaction with the compound derivative gives an intermediate compound of formula 0 in which R is a hydroxy-containing group, which can be oxidized with chromium trioxide to give the corresponding ketone. The ketone of formula [F] is converted to a compound of formula (II) in which R contains a ketone, as described above.

Ketones of formula (2) are obtained from acyclic intermediates obtained from ketones of formula (2).

RζR4, R5, and R6 are clear as described above. For example, the expression ■
The compound xfJ″-O or S is a four-membered ring ketone of (Vi
) is brominated with two equivalents of bromine, and the resulting alpha, alpha'-dibrome compound is subjected to ring-closing, for example with sodium hydroxide, to produce oxetanone, which is then reacted with % hydrogen sulfide to produce cetanone. The corresponding five-membered ring keto/target is (
2) was first reacted with formaldehyde to produce the intermediate alpha hydroxymethyl compound, and then brominated at the al-772 position.

React with sodium hydroxide or hydrogen sulfide to produce a compound in which X is 0 or S by ring closure.

TetrahyF ropyran-4-one and tetrahydrothiapyran-4-one of formula (1) are obtained by adding water or hydrogen sulfide to the corresponding substituted vinyl ketone.

The ketone intermediate 2m is converted to an amine via an oxime by the method shown below. R, R, R19, R20 are clear from above.

TXI (substituted acetoacetate ester) is condensed with formaldehyde F under alkaline conditions to form a hydroxymethyl intermediate (
1 is heated, for example in the presence of a mild acid or base, to remove ethanol and cause ring closure.

Bromination of an acetoacetate of formula (Xi) followed by reaction with sodium hydroxide produces a ketone of formula width, which is converted to the corresponding amine as described above.

11 (1973); Chem, Abstr.
78 135596e (1973) by reacting cyclobutane-1,6-dione with hydrogen peroxide.

As mentioned above, the dib tetramer (■) is reacted with an alkali hydroxide such as sodium hydroxide under mild conditions to produce the corresponding t6-hydroxyketone, which is then reacted with phosgene to form the t3-dioxane- 2,5-dione (XI)
can be manufactured.

(XI) The 5-oximino intermediate of (XI) is reacted with sodium metal as described above in ethanol to prepare the corresponding 5-amine compound.

A monobrominated ketone of formula (l) is reacted with, for example, ethyl malonate, followed by hydrolysis, decarboxylation, and esterification to produce an intermediate of formula (XIV). It is an intermediate of (XV).

(J QCXIV) (XV) The ketolactone (XV) is converted to the 4-amine compound as described above (eg, by reduction of the oxime).

t6-dimercaptoketone can be prepared by reacting 13-dibromoketone of formula (■) with at least two equivalents of sodium hydrogen sulfide as described above.

This dimercaptoketone is reacted with a reagent such as iodine, hydrogen peroxide, or hypochlorous acid under disulfide-forming conditions to obtain a ketone of formula (XVI).

This is converted into an amine by reducing the oxime using, for example, sodium metal in ethanol.

Amines of formula (XvID) can be prepared, for example, directly as follows by the method of Nagase et al.

(Shu K instead of formaldehyde in the first step in the diagram above.

The corresponding 3-amino-2-pyrone is obtained using ethylene oxide.

Lactam corresponding to the lactone intermediate on NH2 or
Xl, (XV), (Shu lactam is produced by reacting lactone with ammonia. For example, the above lactone is
Mixing with excess anhydrous ammonia in ethanol and stirring overnight at room temperature yields a compound of formula:

On the other hand, the lactam intermediate is manufactured by the following reaction step (Lj
tl 2siloN 5 ) 2 0 0 The resulting ketone is converted into an amine in the manner described above.

Ketolactam isomers are obtained according to the reaction scheme shown below.

The corresponding five-membered ring lactam is described in U.S. Pat.
Produce according to method 9.

A cyclic or acyclic alpha hydroxy ketone or alpha, alpha'-dihydroxy ketone of the formula (R14-R2O, m, A, B being clear above) can be brominated with 1 or 2 moles of bromine as described above. transformation,
It is prepared by reaction of a brome or dibrome intermediate with a hydroxide base such as sodium hydroxide, potassium hydroxide. The reaction steps are shown below.

For dicycloalkyl ketone (■) and alkylcycloalkyl ketone (X■), use an appropriate acid salt and Daligner's reagent under conventional conditions and reagents.

Manufactured by reaction. The feeling is as follows.

An amine of the formula RNH2 (where R is clear from above) can be prepared by combining a suitable carboxamide with an alkali metal hypochlorite and H
It can be obtained by carrying out an ofmann reaction.

The method is particularly useful for the production of cyclopropylamine. The corresponding cyclopropylamide can be prepared as shown below and converted to the amine.

The first step for producing a cyclopropylcarboxylic acid ester in the above production process is well known. For example, Ch.
em, Abstr, 54, 24436 (196
See 0).

A compound of formula I11 or an amide intermediate thereof in which R is
Alternatively, the compound S02 can be obtained by oxidizing the corresponding compound where X is S using known reagents and reaction conditions for converting sulfide to sulfoxide or sulfone. On the other hand, in the case of a ketone of Formula 1 (2) where X is S or an amine derived from the above-mentioned ketone, di in Formula 1 can be oxidized to a sulfoxide or sulfone before producing butydeamide. Good reagents and reaction conditions for the oxidation of Sulfi V use hydrogen peroxide in a solvent such as acetic acid or acetone. When equivalent amounts of reactants are used, sulfoxides are produced, and when one mole of hydrogen peroxide is used, sulfones can be easily produced. Other suitable oxidizing agents are potassium permanganate, sodium periodate, chromic acid and, for the production of sulfones, m-chloro-perbenzoic acid. m-Chloroperbenzoic acid is particularly useful in converting the Thioketone Co., Ltd., described above, to the sulfoxide, sulfone, using 2 equivalents of the oxidizing agent, by reacting with an equivalent of the present oxidizing agent.

Compounds of formula lit and physiologically beneficial salts thereof are.

It is useful as a sweetening agent because of its high activity, physical form, and stability. These are usually crystalline, non-hygroscopic, water-soluble solids. It has a good sweetness without undesirable unpleasant mouthfeel and bitterness, especially in normal usage amounts. These can be beneficially used as additives to sweeten foods. As used herein, "food" is any non-toxic substance that can be consumed by humans or other animals in solid or liquid form. Examples of these include foods, ready-made foods, chewing gum, beverages.1 Food additives (flavorings).

colorants, flavor enhancers) and medicinal preparations.

The compounds of the invention can be made into a variety of forms suitable for use as sweetening agents. Typically used are powders, tablets, granules, solids such as sugar-coated tablets, solutions, suspensions,
It is a good form for use in liquids such as white whelks, emulsions, and other foods in general. These forms may be comprised of a compound of formula il+, or a physiologically useful salt thereof, and a non-toxic sweetener carrier, i.e., a non-toxic substance commonly used in combination with sweeteners, either separately or in combination. I can do it. Suitable such carriers are water, liquids such as ethanol, sorbitol, chrycerol, citric acid, corn oil, bean oil, soybean oil, rice oil, propylene glycol, corn syrup, maple syrup, liquid paraffin, and lactose, cellulose.

Starches, dextrins, modified starches, polydextrose, etc. (e.g. U.S. Pat. No. 6.76 to 165 and 3)
．． 876.794), polydextrose, calcium phosphate (primary, secondary, tertiary) and calcium sulfate.

Similarly, compositions containing compounds of the invention in combination with sweeteners such as sucrose, saccharin, cyclamate, L-asnozoruthyl-L-phenylalanine methyl ester are also useful and well suited. In particular, formula I1
Mixtures of one compound with saccharin or a physiologically useful salt such as saccharin sodium, potassium, calcium, ammonium are useful. In mixtures with the above-mentioned saccharin, the compound of formula il+ reduces or completely eliminates the after-edible bitterness in saccharin.

Useful such sweetening compositions are those containing a compound of the formula til mixed with saccharin, containing a small amount (at least 40% of sucrose).
It has 0 times the sweetness. In particular, Ha is CH20HR is dicyclopropylcarbinyl, 2,2,4.4-tetramethylchetan-3-yl, 2.2.4.4-tetramethyl-
Preferred is 11-dioxochetan-6-yl. The best one is a mixture of saccharin and L-aspart-D-serine N-C22AA-tetramethylcetan-3-yl)amyl V, especially the latter formula
A mixture of compound t and saccharin at a weight ratio of 1:1 to 1:8 is preferred. These mixtures not only have a pleasant sweet taste, but also have a sweetness that is sufficiently enhanced to exceed the sum of the sweetness of the components in one individual mixture without bitterness after consumption. These have a synergistic effect that is 50% stronger than the calculated value. with saccharin or its salts.

L-aspartyl-D-serine N-(2,2,4,4
-tetramethylchetan-6-yl)amide, the synergistic effect is reduced if the mixing ratio is outside the above-mentioned weight ratio range.

The present invention also provides foods and sweeteners characterized by the use of -f amounts of the compound of formula (1), physiologically useful salts thereof, alone or in combination with non-toxic carriers or known sweeteners. Supplying food compositions. Examples of such foods are:
Fruits, vegetables, juices, meat products (such as ham, bacon, sausage), egg products, fruit concentrates: Gelatin:
Jam, jelly.

Gelatin-like foods such as sugared jam; Ice Cream Ichigo;
Dairy products such as sour creams and sherbet, confectionery sugar coatings, syrups containing molasses, corn, wheat, rye, soybeans, oats, rice, grains, barley products such as nosta, cakes and cake mixes, fish , cheese, cheese products, nuts, nut products; coffee, tea, carbonated drinks, non-carbonated drinks, beer, wine, and other beverages:
Confectionery such as candies, fruit flavored drops; edible foods.

seasonings such as sous sauce, spices; flavor enhancers such as monosodium glutamate; chewing gum.

This sweetener is also a dietary sweetener, a liquid sweetener, a granular flavor mix for reconstitution with water to control non-carbonated beverages, aJP
g pudding mix, instant coffee, tea, coffee white t-, fi-4 milk mix, k-t food,
Livestock feed, tobacco; ready-made packaged products such as mouthwash, cosmetics such as toothpaste, patented or non-patented drug products, other foods, drugs, and miscellaneous industrial products.

Particularly good ready-made sweet food compositions are carbonated beverages containing one or more instant sweeteners.

The aspartyl-D-amino acid of the present invention has the formula of U.S. Pat. Ethyl, n-propyl or isopropyl) butide amides are also useful in applications reported in the field regarding L-aspartyl-L-phenylalanine methyl ester and its congeners. For example, it has the same function as L-aspartyl-L-7 enylalanine methyl ester described in the patent shown below. These uses have been reported for butide esters. It has advantages not only in terms of strength but also in the aforementioned stability and efficacy.

U.S. Patent No. 3,642.491 3.97t857 3.865,
9575.76'1.288 to 3,982.0238
00,04<5 4,001,4563.818,07
7 4,004,0393.829.588 4.00
7,2883.875,311 4,031,2583
．． 875,312 4.03 to 9926.88 295
4.05t268 3.922,359 4.059,7063.934.
048 4,122,1956.94 600 4.
159,6663.955,000 4,143,17
06.95 be507 4.153.737 force nada patent number 1.02 to 987 1.027,113 1.028,197 i, 043.158 1.046,840 Dutch patent application number 73-04.314 73- 1t607 75-14,921 76-05,390 76-08,963 West German Patent Publication No. 2.438,317 2.456,926 2.509,257 2.518.302 2.609,999 2.646, 224 2.713,951 830.020 838.938 863.158 882.672 The invention is further illustrated in the following examples.

Example 1 D-serine of L-7 Spartyl-D-serine N-(dicyclopropyl A, D-HOCH2CHCOOHHCb2 4.4110.042 mol) was dissolved 2
N Sodium hydroxide solution 211IE7! 5 to 10
After cooling and adjusting the concentrated hydrochloric acid tepHI to 0.0-11.5, 6.911 Ll (o, 048 mol) of nohensyl chloroformate is added in small portions over 1.5 hours. Meanwhile, the mixture is kept in the above pH range by continuously adding 2N sodium hydroxide solution. The mixture is stirred at room temperature overnight, washed with ethyl ether, and the aqueous layer is acidified with 6N hydrochloric acid (pH 2.5-3.0). After extraction with ethyl acetate and washing the extract with brine and drying (MgSO4), the product 3.
1411 was obtained as a colorless solid, which was recrystallized from 20 m ethyl acetate to give the product in a yield of 2.64 Jl).

RfO, 43 [Thin layer chromatography (TLC), ethyl acetate/hexane/acetic acid, 9:9:2, (volume)] 2-41/ (o, 01% le) NO obtained in step A
Cb2-D-serine was slurried with 75111 chloroform, and N-methylmorpholine 1.1111/
(0.01 mol) is added. The liquid becomes a clear solution and −
Cool for 12 c. Conorig liquid KO, 96MIC0,
01 mol) of ethyl chloroformate is added and the mixture is -
Stir at 100 for 5 minutes. 1111 (0,01+=l)nodicyclopropylamine in chloroform? Wi51
Add E/ and stir at -15r for 5 minutes. The reaction mixture was allowed to warm up to room temperature and washed with 0.5 N hydrochloric acid, 5% sodium bicarbonate, and water.
To leave. The washed aqueous layers are combined and extracted with ethyl acetate. The residue obtained by distilling off chloroform with an ethyl acetate extract was dissolved, and the ethyl acetate was dried (Mg5o4) and then distilled off under vacuum to obtain a white solid, which was dried overnight in an open vacuum to produce the desired product. Get 3.21 things. Rf(15
4 This substance will be used as is for the next step.

■N-Gb2-amide 52.9 (9,6
mmol) in 701L of methanol and added 10I of 5% Pa/C catalyst to 60 ps i (4,2 &
/ca2) for 60 minutes. The catalyst was removed by filtration, and P liquid #'i JE and T was distilled off.
The product is obtained as a soapy solid.

D, G6H3OH2OC0CH2Cf(CONHCH
(OH20H)CONHCH(E)25.4jl(9,
10117 (S'!
5 dimol) of N-methylmorpholine and 0.9 m(9,
A mixture of ethyl chloroformates of -1
Stir for 5 minutes at 5 to -10C, and add a solution of 1.9N (9.5 mmol) of D-serine N-dicyclopropylcarbinylamide obtained in step C in chloroform at -15C. Add. The reaction mixture was heated at 10C for 5
Stir for a minute, allow to warm to room temperature, and stir for an additional hour.

The solvent of the reaction mixture was distilled off under vacuum, and the residue was diluted with ethyl acetate (
250 II/), washed with 1N hydrochloric acid, 5% sodium bicarbonate, brine, and dried over anhydrous magnesium sulfate. The solvent is removed under vacuum to obtain a gelatinous solid. Dissolve this in 75 m hot ethyl acetate. Upon cooling, a crystalline solid is obtained which is dried under vacuum at 40r to obtain the desired 2-protected :) ibbutide amide as a fine white solid in a yield of 2.751. Rf Q, 30°E, 2-protected dibutyamide obtained in step 2.75
N, 200wLl of methanol, and 5% Pa/C of toy
The catalyst mixture was heated at 60 psi (4,2 kVc) for 1 hour.
Hydrogenate with 1L2). During this time, the product will precipitate.

Pass the catalyst/product mixture once, and the mass obtained is 1
The slurry is made into a slurry with 00-℃ hot water and heated again. The r liquids are combined and evaporated to dryness, water is added, kneaded, drained and dried under vacuum to obtain 260Iv product as a pure white fluffy solid. M, P 252-254C, Rf O, 5
8 (TLC, n-butanol/water/acetic acid 4:1=1, ninhydrin spray) The mass collected during hydrogenation was 5
The slurry was made with 0.1N hydrochloric acid and filtered through diatomaceous earth (Supercell). When dried on a vacuum, it becomes rough and sooM.
9 product is obtained. Overall yield 68%.

'v Soot vector (m/e) 313 (M'') Sweetness intensity: J! 700 times more than sugar Example 2 L-Asnolathy-D-serine N-(2,4-dimethyl-3-pentyl)amide mixed anhydride is prepared as follows: tO# (4.3 mol) of N-benzyloxycarbonyl-D-serine is dissolved in 50-g of tetrahydrofuran, cooled to -10C under nitrogen atmosphere, and then 0.47m17 (43
0.41 ml of N-methylmorpholint (mmol)
(4.3 mmol) of ethyl chloroformate is added. The mixture is stirred for 60 minutes at -10C.

2, dissolved in a small amount of chloroform in a solution of mixed anhydrides.
4-:) Methyl-6-aminotanthane 495~(4,6
After stirring at 10 tl' for 15 minutes, the mixture was allowed to warm to room temperature. 4Qm of ethyl acetate is added and the mixture is washed with 1N hydrochloric acid, sodium bicarbonate solution and brine, and the organic layer is dried over anhydrous magnesium sulfate.

When the solvent was distilled off, a colorless solid of 1.27.9 was obtained, which was mixed with ethyl ether and kneaded at ℃, then taken out and air-dried to obtain 1.0 g of a colorless product. RfO,7
7 (TLC, ethyl acetate/hexane, 7:6, vol., vanillin spray) 10 g of the product of step A was dissolved in 5 Qiu of methanol and 5% Pd/C catalyst 0. ! M and 50 psi (3,
52 kl/am ) until hydrogen absorption stops. After filtration and distillation of liquid f, 700 μm of the desired product is obtained.

\ 136, S' (3, EH!j mol) of beninobenzyl N-benzyloxycarbonyl-L-aspartate was dissolved in 10 d of tetrahydro7rane, cooled to -1 DC and 0.42 m (58 (mmol) of N-methylmorpholine is added. Ethyl chloroformate (KO, 36 MIC, 3.8 mmol) was added dropwise to this solution and stirred at -10C for 5 minutes. Then, a solution of 56611Iy (2,8 mmol) of D-serine N-(2,4-')methyl-6-pentyl)abad (obtained in step B) dissolved in a few milliliters of tetrahydrofuran was added dropwise. , and continue stirring for an additional 15 minutes. The reaction mixture is allowed to warm to room temperature and the solvent is distilled off under vacuum to obtain a solid residue. This was dissolved in ethyl acetate, washed with 1N hydrochloric acid, and the organic layer was washed with 5% sodium bicarbonate solution and brine, dried (MgSO3), and the solvent was distilled off to obtain 1661 as an amorphous solid. It will be used as is in the next process.

D, 15. 5% of f
A pd/c catalyst is added and the mixture is hydrogenated at 50 psi (3,52 kl/cm ) until no hydrogen gas is absorbed. The catalyst is removed by filtration and the FI is concentrated under vacuum to a small volume and left at room temperature. The precipitated product was filtered, collected and dried under vacuum to obtain 342 ml of colorless solid.

Sweetness, 180 times more than sucrose Example 3 L-7 Sunozo Lachiru D-Serine N-(2,2,4,
4-tetramethylchetan-3-yl)amide A, D-
HOcH20H(X)OH NHr, t, -5oc-Amino acid preparation qMoroder et al., Z
, Physiol, Chem, 357.1 (551(
197(S). Dioxane and sphagnum moss 10
2.18N (1 mole) of di-1- in 11I10 solution
butyl dicarbonate and 16117 (115 mol)
of triethylamine and 1.051 (10i%le)
Add cQD-*phosphorus. The mixture was stirred at room temperature for 60 minutes, and the dioxane was distilled off using nitrogen nitride. The remaining aqueous solution is cooled with ice, ethyl acetate is added thereto, and while the mixture is stirred, a dilute acidic potassium sulfate solution is added to adjust the pH to 2-3. The aqueous layer was separated and extracted twice with ethyl acetate, and the ethyl acetate layers were combined, washed with water, dried* (Na2SO4), and the solvent was distilled off to give the product as a sticky paste with a yield of t7J'. obtain.

The mixed anhydride is 2.85114ξ mol) of N-1-butoxycarbonyl-D-serine, 1.5511 Il! N of
-Methylmorpholine and ethyl chloroformate of 134d are dissolved in methylene chloride of -12 to -10c of 751 to obtain as described in Step B of Example 1. To this mixture 2.011i (14 mmol) of 3-amino-2
, 2,4,4-f-tramethylthietane and 12 tl
Stir for an additional 5 minutes at l'.

The product was isolated as described in Step BK of Example 1 and 4y
Leaves a sticky liquid residue. This residue was dissolved in 4°d of methylene chloride and 12ml of trifluoroacetic acid (d
= 1480) and the mixture was stirred at room temperature for 6 hours. The reaction mixture is made alkaline with 40% sodium hydroxide solution, the organic layer is separated, and the aqueous layer is made into a saturated solution with sodium chloride and then extracted with methylene chloride. The extracts were combined, dried (MgSO4), and then concentrated to dryness to give 2.211, an amorphous off-white solid. When crystallized from ethyl ether/hexane, 1.
The product 921 is obtained as a finely divided white solid.

2.3.9 (8.0 mmol) of Benigno-1-Butyl N
-t, -F'toxycarbonyl-L-7 snocrutate, 0.881 J (8.0 mmol) of N~methylmorpholine and 0.77 m (8.0 < υ mole) of ethyl chloroformate in 4Q+wj The mixture dissolved in methylene chloride is stirred at -12 tl' for 5 minutes. 18518.
A solution of 5d of D-serine N-(2,2,4,4-tetramethylchetan-6-yl)amide dissolved in the same solvent as 5d was added, and the mixture was further heated at -12 to -10C for 10
Stir for a minute. The mixture is allowed to warm to room temperature, stirred for a further hour at this temperature and the solvent is distilled off. The residue was dissolved in ethyl acetate, washed with dilute hydrochloric acid, sodium bicarbonate solution, and brine, dried (Mg5o4), and then the ethyl acetate was distilled off to obtain an amorphous solid of 5.5411. Crystallization from ethyl ether/hexane gives the product as a 2.91N colorless solid, Rf O,70 (ethyl acetate/hexane, 7:6) D, product obtained in step C 2.4 fI (4 , 78 mmol) in 60% chloroform, attach a gas inlet tube, and add anhydrous hydrogen chloride to the solution. Precipitation of solid is observed after 5 minutes. The introduction of hydrogen chloride is continued for a further 10 minutes, after which the mixture is stirred for 1 hour at room temperature and then evaporated to dryness under vacuum. After dissolving the residue in water and washing with chloroform, the pH
Wash with chloroform again according to 5.6, and remove water from the aqueous layer under vacuum. Add ethanol to the residue and evaporate to dryness under vacuum.

Dissolve the residual 25111 in hot water and leave to cool.

The precipitated product was collected and dried under vacuum. F (60
%) yield of M, P, 193-196
CRfO, 32 (n-butanol/water acid, 4:1:
1).

Elemental content ItrC14H25N, 05S Toshite total X value C
,48,39;H,7,25;N, 12.09;S,
9.23 actual value G, 46.77; H, 7:48;
N, 11.91; S, 8.82 Sweetness intensity 1 of sucrose
200 times Example 4 L-asuno ξrutile-D-serine N-(2,2,4
,4-tetramethyl-1,1-dioxochetane-6-
yl)amide A, 3-amino-2,2, 3-avano-2,2,4,4-tetramethylchetane-"1,1-dioxide 14.531! (0.1 mol)
4゜4-tetramethylchetane and 64.1711n, 3
mol) I) m-sodium periodate at 500W
11 in water and stirred overnight at room temperature. The reaction mixture was adjusted to pH 13 with a solution of sodium hydroxide and the precipitated sodium iodate was removed. The f solution was washed with 100-ml ethyl ether, and the aqueous layer was continuously extracted with methylene chloride for 18 hours. The extract was dried (MgSO4),
The solvent is distilled off by Muquangang. Recrystallization from the solid residue ethyl acetate gives the product 8.5I, M, P, 104-1
06.5r0 Obtain further 2.7y crystals from mother liquor, M
, P, 103-106C0 overall yield 66%.

B, D-serine N-(2,2,4,4-tetramethyl-1,1-sioxothietan-6-yl)abad Example 1, 1.33N (6.5 mmol) by the method of Step B ) of N-benzyloxycarbonyl-D-Se IJ 7.
0.7151L/(7)N-mey-rumorpho+)
7.0.621 of ethyl chloroformate and t15.9
(6.5 mmol) of 6-amino-2,2,4,4-tetramethylceta Z-1,1-dioxide.
N-benzyloxycarbonyl-D-serine N-(2
, 2°4.4-tetramethyl-1,1-dioquinochetan-3-yl)amide as a sticky liquid, Rf
0.37 (ethyl acetate/hexane, 7:6). This liquid is dissolved in methanol, 5% P a/c catalyst is added, and hydrogenated by the method of Example 1, Step C. After removing the catalyst by filtration, methanol was distilled off in vacuo and the afterflame was reduced to 1N.
Dissolve in hydrochloric acid and extract with chloroform.

The aqueous layer is made alkaline with sodium hydroxide solution saturated with IJium and extracted continuously with chloroform overnight. When the solvent is distilled off, the product 151' is obtained as a sticky liquid, which solidifies on standing, Rf O,32(n
-butanol/water/acetic acid, 4:1:1).

The second rule of thumb for the above structure is that the butide amide is prepared using the same method as in Example 1 on a scale of 4.7<IJ moles, i.e.
2p-benzylN-benzyloxycarbonyl-L-
Asunozo Lure) 1.7.9. N-methylmorpholine 0.511Ll, ethyl chloroformate 0.451
114 and D-serine N-(2,2,4,4-tetramethyl-1,1-dioxo-chetan-6-yl)amide 1
It is 24y. 2.4yM of product is obtained as a colorless amorphous solid. 2y of this material is purified by chromatographic methods using 60I silica gel. Elution with ethyl acetate gives an amorphous solid product of 1.2.9, Rf 0.30 (ethyl acetate/hexane, 7:6
).

D. Hydrogenate a mixture of the product purified in step C, 1.211 and 75-methanol, and 5% Pa/c of 0.611 at 80 psi (5,6 ψi). When hydrogen absorption has ceased, the catalyst is removed by filtration, and the r-liquid is distilled off to leave a colorless solid residue. Dissolve this afterflame in water.

After washing with chloroform, the aqueous layer is evaporated to dryness under vacuum.

When the solid residue is crystallized from ethanol, the desired di-butide amide is obtained as a finely powdered white solid at 255 ■.
P, 170-173. A further 180M9 product is obtained from the recovered mass during the Rf120° hydrogenation.

Sweetness intensity: 850 times that of sucrose Example 5 Add 59,55 N (0.5 mol) of a/-0-methylserine to 125- of water and add 2ON while stirring the mixture.
(0.5 mol) of sodium hydroxide is added.

The solution was cooled with ice and added through two addition funnels at the same time.
A solution of 019 sodium hydroxide dissolved in 125 g water and a solution of 47.8111<0.6 mol) chloroacetyl chloride are added over 1 hour. The rate of addition is adjusted to maintain the pH of the reaction mixture between 90 and 950. The reaction solution was washed twice with methylene chloride, and then acidified to pH 1.5 using concentrated hydrochloric acid while cooling with ice. The mixture is then saturated with sodium chloride and extracted several times with chloroform. After the extracts are combined and dried (MgSO3), the solvent is chromatically distilled off. When ethyl ether was added to the afterflame and stirred, a yellow solid product precipitated, which was then removed and dried, 69.38 N (71%).

M, P, 104-107tl', RfQ, 23 (ethyl acetate/hexa//acetic acid, 9:9:2, molypide/phosphoric acid spray).

Add sodium chloride to the aqueous layer and extract with chloroform. Distilling off the chloroform gives a 3.65N product. Overall yield 75%.

B, N-chloroacetyl-D-0-methylserine 35
73.0311C (0.67 mol) of N-chloroacetyl-methylserine is added to 6,000 - of -37C water, and the pH of the mixture is adjusted to 7.18 by adding concentrated ammonium hydroxide solution.

Add water to bring the total volume to 6700. This solution contains N-acyl abanoic acid amide hydrolase, a commercially available pig kidney abanoylase; EC3゜5.1.14ff
+ Lase I), 1845 units/Iv (1 unit I
d Add 171 kl of N-acetyl-L-)f-one (defined as the amount that can hydrolyze 1 micromole in 1 hour at pH 7,0125C). The amount of enzyme added is more susceptible to hydrolysis (calculated to be able to hydrolyze the isomer within 6 hours).

The solution is kept at 37-38t:'' for 28 hours, with occasional additions of ammonium hydroxide to maintain the pH between 7.1 and 12. After 24 hours, an additional 5M9 of enzyme is added. The hydrolyzed mixture is diluted with glacial acetic acid to pH 4. 5 acidic, Q,
It is filtered through a 6μ shoulder cut bore filter (BD type), and the f liquid is distilled off under vacuum at 65C or less until the total amount becomes 100 to 150d. The residual sound mixture is diluted with hydrochloric acid to pH 2.00.
Then, extract with ethyl vinegar and chloroform several times.

After each organic layer was washed with water and dried (Mg5o4), the -X2T solvent was distilled off to obtain a yellow liquid. Add hexane and distill off to crystallize. Ethyl acetate extract contains 16.6719 (46%) N-chloroacetyl-D
-0-Methylserine, M, P, 95-96C.

[Alpha]D-15,5 (C=1,1NNaOH).

M, P, 9O-94c (chloroacetic acid odor), the same product of chloroform extract II'i4.611i (13%).

Both products are single spots on thin layer chromatography on silica gel plates, R4Q, 55;
9:9:2 ethyl acetate/hexane/acetic acid, molybdenum phosphate spray.

Add 25 m of 2N hydrochloric acid to N-chloroacetyl-D-0-methylserine (C, 16,6710,085 mol)
Heat to reflux for an hour. The reaction solution is concentrated under vacuum, and further water is added and concentrated to drive out traces of chloroacetic acid. When the solid residue was washed with ethyl ether and removed, 12.311i
(93%) of D-0-methylserine hydrochloride, M,
P, 188-190tl'; [Alpha, 1D-16
, 7° (C = 0.7. 0H30H) Example 6 D-0 of L-aspartyl-D-0-methylserine N-(dicyclopropylcarvinyl)amide A, D-CH30CH2CHOOOH 12,3110,079 mol) - Methylserine is dissolved in 4 ONl of water containing 6.311 (0.158 mol) of sodium hydroxide and cooled to 5-1 Or. 1174 iu (0,0806 mol) of pendyl chloroformate and 4M sodium hydroxide were added to the solution at the same time, and the pH was adjusted to
8-9. The reaction mixture remains p without the addition of further base.
Stir until H is maintained at 8. After washing with methylene chloride, the aqueous layer is acidified with concentrated hydrochloric acid and extracted four times with methylene chloride. After drying (Mg5O4), JE
The 4T solvent is distilled off. When hexane is added to the remaining sticky liquid and stirred, a precipitate is formed, so when f is removed, the product is obtained with a yield of 18.6F (96%), [Alpha] 9-2.7
°(C:=1.Na0H), Rf O, 43°3.8
0. To a solution of F (0,015 mol) N-benzyloxycarbonyl-D-0-methylserine dissolved in 75 methylene chloride was added 168 ml (0,015 mol) of N-methylmorpholine, and the mixture was cooled to -15C. To this solution was added 1.4311/(0,[]115 moles of ethyl chloroformate, stirred at -20 to -15C for 10 minutes, and further added 1.68 g (0,015 moles) of dicyclopropyl-carbinyl. The amine is added. The mixture is allowed to warm to room temperature and stirred for an additional 2 hours. The reaction is washed twice with 1N sodium hydroxide, twice with 1N hydrochloric acid and dried over magnesium sulfate. The solvent is evaporated in vacuo. , 5.1 # (98%) of target substance obtained, Rf 0
．． 59, silica gel TLC, 1:1 ethyl acetate/hexane, molybdenum phosphate spray.

The structure of the product was confirmed by H-NMR spectrum.

N-benzyloxycarbonyl-D- obtained in the above step B
0-Methy1〆serine N-(dicyclopropylcarvinyl)amide5. Hydrogenation of IIi by the method of Step C of Example 1 yielded 2.96 g (95%) of D-〇-methylseri/N
-()cyclopropyl-carbinyl)amide is obtained as a liquid substance, Riy O, 39; C alpha] D
-23,2° (C=O, NHCl.Structure is 'H
- Confirmed with NMR spectral.

D, C6H3GH20COCH2CH(NHCb2)C
ONHCH 4.97 g (13.9 mmol) of betabenzyl N-benzyloxycarbonyl-L-asbaldate and 1.55111 J (13.9 mmol) of N-
Methylmorpholine! = 1.3311/(13,9 mmol) of ethyl chloroformate mixture in Example 1
When reacted according to the method described in the process step, Z 43 f
9 (97%) of the di-protected dibeptide compound, which is recrystallized twice from ethyl acetate to give a colorless product of 4.25 J', Rf Q, 45 (7:!l
ethyl acetate/hexane). The structure was verified by 'H-NMR.

E. The purified di-protected dipeptide ide of 4,25j' obtained in the above step is hydrogenated by the method described in Example 10 Step E to obtain the desired dipeptide amide of 2.4J9 (95%). M, P, 215-2170 (decomposition): [Alpha] +37.6° (C=0.8.1,2NHC
j); Rf Q, 41° sweetness intensity, 85 times that of sucrose Example 7 L-Aspartyl-D-0-methylserine A, D-C
To a solution of H30CH2CHCOOH2,89Ii (18,6 mmol) of D-0-methylserine hydrochloride in 11 iu of water, 6.48 MIC46,5 mmol) of triethylamine, 5.1ON (20,7 mmol) of 2-( t-Butoxycarbonyloxyimino)-2-phenylacetonitrile (Boc-ON”) and 11'IL
Add 1 liter of tetrahydrofuran. The mixture is stirred overnight at room temperature, 2511/ml of water is added and washed with ethyl acetate. The aqueous layer is brought to pH 1.8 with 1M hydrochloric acid and extracted with ethyl acetate (3x75m), dried (Mg5O4) and evaporated to give 4.29 product as a sticky liquid. Rf 0165 (9:9:2 ethyl acetate/hexane/acetic acid, molybdenum phosphate spray) B, N t Boc-D-0-methylseri/N
-(2,2,4゜4-f tramethylchetan-3-yl)amide 4.2 N (1B, 6 mol) of N-
2.08117 N-methylmorpholine is added to a solution of D-0-methylserine dissolved in 9011 Lt of methylene chloride, cooled to -15C, and 178-ethyl chloroformate is added. -20 to 8 at 15C
After stirring for a minute, 2,701 (18,6 mmol) of 3
-amino-2,2,4,4-tetramethylchetane 1
A solution dissolved in 0 m of methylene chloride is added at the same temperature and then left to warm to room temperature.

After stirring for 2 hours, the reaction mixture was washed with dilute sodium hydroxide solution and dilute hydrochloric acid, dried over magnesium sulfate, and the solvent was distilled off under vacuum to obtain a colorless solid with a yield of 6.04 JF (94%), Rr O, 35 (3 near ethyl acetate/hexane, molybdenum phosphate spray).

The structure was verified by H-NMR.

C0D-0-methylserine N-(2,2,4,4-
Butramethylchetan-6-yl amide 6.04 g (17,4 mol) of Nt-Boc-D
-0-methylserine Fluoroacetic acid (sp, gr, 1480
) and stirred at room temperature for 6 hours. Further, a solution of 1- and 2- in methylene chloride was continuously added and stirred for 1 hour. The reaction mixture is made alkaline with 40% (wt) sodium hydroxide solution, the organic layer is removed and the aqueous layer is extracted several times with fresh methylene chloride. Combine the extracts and dry (M
g5O4) After distilling off the solvent, a crude liquid product of 4.29.9 is obtained. This was dissolved in 201 liters of 1N hydrochloric acid, washed with ethyl ether, the aqueous layer was made alkaline with sodium hydroxide solution (40% yield), saturated with sodium chloride, and extracted with methylene chloride. The extract is distilled off to obtain the target substance (3.21175%), RfO
, 41; (alpha)D-19,8° (C=0.8
, INHC/). The structure of this product was confirmed by IH-NMR spectrum.

The 3,76N product obtained in Step C above was reacted using the method of Step C of Example 6 at a scale of 13 mmol using 50d methylene chloride as the solvent, yielding 5.0 g (74
%) of the desired 2-protected dipeptide amide as a friable foam, Rf O,40 (ethyl acetate/hexane, 1:1: molybdenum phosphate spray). The structure of the product was confirmed by H-NMR spectroscopy.

E, 2 of 5,019.7<IJ mol) obtained in the above step
Anhydrous hydrogen bromide gas is passed through the solution of the protected dibutamide and the mixture is stirred at room temperature for 1 hour. The reaction mixture is evaporated to dryness and the resulting yellow solid residue is dissolved in water.
Washed twice with ethyl ether and once with methylene chloride;
The aqueous layer was adjusted to pH 5.8 with sodium hydroxide solution and then evaporated to dryness under vacuum. When the solid remains 101!7 in 95% ethanol and ethyl ether is added, the title compound precipitates in two groups at once.

1.66LC Alpha]. +16.4° (C=0.9.
1.2NHC1, M, P, 85-90C; 1, 20
．． 9, [Alpha] +16.9° (C=0.8.1.
2NHCJ).

Each cluster is determined by the Rf of the target substance in thin layer chromatography.
In addition to the Rt value of 0.51, it also contains a small amount of material exhibiting an Rt value of 0.44.

1.69 g (3
, 85 mmol) and 0.66N (3,83<lmol) of p-)luenesulfonic acid are added to 1 Qiu of water. The dissolved bath solution is stirred at room temperature for 2 hours. One portion of the resulting precipitate was taken and washed with a small amount of water to obtain 0.941 p-1 luenesulfate salt.
A mixture of 6 yt of hexane and 21 yt of water was stirred for 2 hours. The aqueous layer was separated, washed with hexane, and then evaporated to dryness under vacuum to obtain 0.72 g of an off-white solid.
H(41); Rfα4 & sweetness intensity 620 times that of diM sugar. Because it has no scent and the sweetness hits quickly, it was able to judge sweet tastes with unusual accuracy.

■Rohm and Haas Go, registered trademark example 8 L-as/ξrutile-D-0-methylserine N-(
75 iu of N-benzyloxycarbonyl-D-0-methylserine of 2,2゜4.4-tetramethyl-1,1-dioxochetane-3-y3.819 (15 iu mol)
of methylene chloride, added N-methylmorpoline (1,681R1), and cooled to -15 cK.
Add 43m of ethyl chloroformate. Reaction solution #'
After stirring for 8 minutes with 1-15U 2.18. S+(15i
u mol) of 6-avano2.2.4.4-tetramethylchetane are added and allowed to warm to room temperature.

After further stirring for 2 hours, the reaction mixture was diluted with dilute hydroxide l-
After washing with 1g of solution and dilute hydrochloric acid and drying (Mg5O4), all the solvent was distilled off to obtain 6.11g of liquid product.
Rf O,58 (ethyl acetate/hexane, 1:1; molybdenum phosphate spray).

The product 6.11.9 obtained in step A above is dissolved in 75111 chloroform, and 7.12 II m-chloroperbenzoic acid is added little by little under ice cooling. The reaction mixture was allowed to warm to room temperature and stirred for 6 hours. Chloroform (751
LI3) was further added and the solution was dissolved in 5% (wt/vol) sodium carbonate solution, 0.5N thiosulfate) IJium,
Wash each portion twice with 1N hydrochloric acid.

After drying the organic layer (MgSO4) and distilling off the solvent, 6.2
The product of 4y is obtained as a sticky liquid, Rf O,22
(Ethyl acetate/hexane, 1:1, molybdenum phosphate spray) This contains starting materials and traces of sulfoxide. 'H-NMR spectra matched the structure of the target sulfone containing a small amount of chloroform.

6.119 N-benzyloxycarbonyl-p-〇-
Methylserine N -(2,2,4,4-tetramethyl-
1,1-dioxochetan-6-yl)amide, 250
1 methanol and 6. 50 psi (3,52 kl/cx2) of Oy 5 ξ radium-carbon catalyst mixture
Hydrogenate for 2 hours. Touching gjE, is removed by r passing, f
The solvent of the solution was distilled off under vacuum, and the remaining amount was dissolved in 1N hydrochloric acid. The acidic solution is washed six times with chloroform, then made alkaline with solid sodium hydroxide, saturated with sodium chloride, and then extracted six times with 5 Qil of chloroform. The extracts are combined and dried (MgSO4) and the solvent is distilled off under vacuum to yield 6.37 g (80%) of the alpha adanamide product as a colorless liquid, Rf O,29; [alpha) D-15,7°. (C=0.8, INH(,/). The structure was confirmed by H-NMR spectrum.

D, C6H5CH20COCH2CH(NHCb2)C
ONHCH 3.37 g of the product obtained in step C above (12C
The desired 2-proof sibutide amide is obtained as a transparent glassy substance by the process of Example 1 using 6.73 JF (91%), Rfo, 28 (ethyl acetate/hexane, 70: 30).

The IH-NMR spectral was in good agreement with this structure.

E, 6.73N dinobenzyl N-Cb-L-aspartyl-D-0-methylserine N-(2,2°4.4
-Tetramethyl-1,1-dioquincetan-3-1) 7mi)', 250R1f) meta/- and 2. 5 of OI
The mixture of %Pa/G catalyst is hydrogenated as per step C above. The residue left after evaporation of the solvent was stirred in ethyl ether overnight, and the solid product was taken and dried in a vacuum oven to give 3.3.9 (77
%) with a yield of Rf O,23;M,P,140-
150C (decomposition); [Alpha]. +20.3° (C=
1.1.2NHC/).

Sweetness intensity: 200 times more than sucrose Example 9 L-asuno ξ rutile D-seriyN-(aJ-cis.

2.11 trans-2,6-cystylcyclohexanone oxime is dissolved in 5OII7 dry ethanol and heated to reflux. Add 6.1 g of sodium metal in portions to this solution. When the addition is complete, reflux is continued for an additional 60 minutes, and then allowed to cool to room temperature. The reaction solution becomes a gel, so it is dissolved in water, adjusted to pH 2.0 with hydrochloric acid, and washed with ethyl ether. The aqueous layer is made alkaline with sodium hydroxide and extracted with ether. Dry the extract (Mg
5O4) After distillation, the desired amine is obtained as a colorless liquid.

B, D-serine N-(see, trans-2,6-
cystylcyclohexyl)amide 147II (6,
15 barimole) N-Cb2-D-serine, 77511
d of 19 (6,15 barimole)! -cis, trans-2
, 6-cystylcyclohexylabane is reacted with an equal amount of N-methylmorpholine and ethyl chloroformate, and the amino protecting group is removed by catalytic reduction to obtain 0.70I of the desired D-serinamide as a white solid. Rf Q, 64
(Ethyl acetate/hexane, 7:6).

c, D-serine-N-(az
--, y, z, , ) The corresponding beninobenzyl N-benzyloxycarbonyl-L-aspartyl-D was prepared by following the steps of Example 1 using lance-2,6-cystylcyclohexyl)amide. - 1.2 g of serine amide are obtained as a colorless solid. When recrystallized from isopropyl ether, 1. Get OI. R1,35 (ethyl acetate/hexane, '7:3).

D, 2-protected dibezotide amide (1,0
Catalytic reduction of JF) by the method of Example 1, Step E in the presence of 0.61 5% palladium/carbon catalyst in methanol affords the title compound as an off-white crystalline solid 4
Obtained with a yield of 651v.

Sweetness intensity: 200 times that of sucrose Example 10 Betabenzyl N-benzyloxycarbonyl-b
2 D-0-Methylserine (6,65 L 56.1 mol) was dissolved in 1001111 N,N-dimethylformamide (
6.741 (62.4 mmol) of trimethylchlorosilane is dissolved in DMF) and fed at room temperature. Betabenzyl N-benzyloxycarbonyl-L in a separate flask.
- aspartate (18,0L50.4-?remol),
Add triethylamine (12,35 I, 1221 v mol), DMF and 110,111 each of tetrahydro7ran and cool to -15C. Ethyl chloroformate) in this solution
(5-9!M, 55.1 mlJ mol) is added and the reaction mixture is stirred at -10C for 10 minutes. The previously prepared DMF solution of silylated D-0-methylserine is added dropwise to this solution while maintaining the temperature of the reaction solution at -5 to -10C. After stirring the reaction mixture at -5C for 1 hour, 0.2N hydrochloric acid was added until the reaction mixture became acidic, and the mixture was extracted several times with chloroform. Combine the chloroform extracts and wash with diluted hydrochloric acid several times,
Remove remaining DMF.

Removal of the solvent in vacuo yields the title compound.

If you perform the same operation using D-serine instead of D-0-methylserine and doubling the amount of trimethylchlorosilane, you will get the same results! -Benzyl N-Cb2-L-aspartyl-D
-Serine is obtained in the same way.

Example 11 Betamethyl-N-benzyloxycarbonyl-L-
Aspartyl-D-Se1 80.7.9 (0.78 mol) of D-Seri/200d
The suspension in DMF was cooled to 10C, and 181'(
1.70 mol) of trimethylchlorosilane was added little by little, and the mixture was stirred at 25C for 1 hour.

In a separate flask, dissolve 158F (0.86 mol) of beta-methyl L-a, spalagate hydrochloride in 1 liter of water. To this solution was added 34.5j' (186 mol) of sodium hydroxide followed by 80 g of hydrogen carbonate and stirred vigorously. 1611I after cooling to 5-10C
(0.94 mol) of benzylox7carbonyl chloride is added little by little and stirring is continued at this temperature for an additional 2 hours. The reaction mixture was washed with 100 ml of ethyl acetate, made acidic by adding 8 Qm of concentrated hydrochloric acid, and extracted with ethyl acetate (45 M twice). This extract (900 m) contained 218. ! 9 (0.78 mol 90% yield) and used in the next step without further purification.

The ethyl acetate extract was cooled to -20C and 16511 (1
, 63 mol) of triethylamine and 84y (0.78 mol) of ethyl chloroformate are added. This solution-
After stirring for 30 minutes at 15-20C, the previously prepared DMF solution of silylated D-serine is quickly added, and the mixture is allowed to warm to room temperature and stirred for over 1 hour. The reaction mixture was washed with water (500ml 15 times), and the organic layer was dried over sodium sulfate and evaporated under vacuum to obtain the title compound.

By using D-0-methylserine instead of D-serine, halving the amount of trimethylchloro7rane, and repeating the same procedure at °C, beta-methyl N-Cb-L-asunolthyl-D-0-methylserine is obtained.

In Examples 10 and 11, DL-Seri/or DL-0
-Methylserine yields a 2-polymer #L-asnorthyl-DL-amino acid dipeptide with the corresponding structure:

In the formula, cb2uocα3H2CsHs Thea Q, Rtf
iH mata tria (3 soshite R10 ha CH3 or ha CH2C
6H5 Theal.

Example 12 L-aspartyl-D-serine N-(trans-2-
Beta methyl of methylcyclohexyl) ado A, 228.5' (0.62 mol)
Dissolve N-benzyloxycarbonyl-L-asnocerthy-D-serine in 1 liter of ethyl acetate, and dissolve 69F
(0.68 mol) of triethylamine are added, the mixture is cooled to -20C and 67 g (0.62 mol) of ethyl chloroformate are added. After stirring the reaction mixture at -15 to -20C for 60 minutes, 76.5 g (0.68 mol) of trans-2-methylcyclohexylapine was added and stirring continued for a further 60 minutes. After being allowed to warm to room temperature, the mixture is washed twice with 500 ml of water containing 15 m concentrated hydrochloric acid, followed by twice with a 5% sodium bicarbonate solution and then with water. The organic layer was dried (Na2SO4) and concentrated to a X2T of approximately 200'111, and 400 d of hexane was added to give rutvatermethyl-N-benzyloxycarbonyl-
L-asnozorutyl-D-serine N-()lansu 2-
methylcyclohexyl)abad precipitates.

B, 24II was added to a solution of 230.9 (0.50 mol) of the product obtained in step A above dissolved in 500 methanol.
A solution of (0.60 mol) sodium hydroxide in 5001 g water is added. The mixture is stirred at 50C for 1 hour, neutralized with dilute hydrochloric acid to about pH 7, and then placed in an autoclave. Add 2g of 5% palladium/carbon catalyst and heat at 25C.
, 3, 5! Hydrogenate at I/cR (50 pst) for 1 hour. 200m7 of catalytic liquid removed under vacuum! When the solution is concentrated to 100% and concentrated hydrochloric acid is added to make an acidic solution with a pH of 5.2, particulate matter is formed in 1 hour at 5C. The precipitate is collected by filtration, the wet mass is dissolved in a mixture of water and concentrated hydrochloric acid, treated with activated carbon, and the filtrated liquid is brought to pH 5.2 with 50% (weight/coulometric) sodium hydroxide solution. After precipitating the particulate matter at 5C, it is collected, washed with cold water, and dried to obtain the target substance.

Other beta-methyl-N-Cb2-L-aspartyl-
With D (or DL)-amino acid dipeptides, dipeptide peptides corresponding to the structures shown below can be obtained in the same manner by the above method.

Raha CH20H and #1CH20CH3 Teal.

Example 13 L-aspartyl-D-0-methylserine N-(a/
-t-butylcyclopropylcarvinyl) abad: cyclopro7ξ carbonyl chloride and cuprous chloride each 0
．． To a solution of 5 mol of 5001 in dry ethyl ether was added 2381 L ((0.5 mol) of 2.I
A solution of Mt-butylmagnesium chloride dissolved in the same solvent is added dropwise at -10C. The reaction mixture was heated to 250-
Pour into a mixture of 3M hydrochloric acid and 7001 ice, separate the organic layer, wash with water, hydrogen carbonate solution, and saline, and then dry over anhydrous magnesium sulfate. The ether was distilled off under reduced pressure and the residue was distilled under normal pressure to give 45 g (72
%) of butyl cyclopropyl ketone. B, P
, 145-153C0 4El (0.36 mol) of the ketone in ethanol/water 1
: Hydroxylazun hydrochloride and sodium acetate are reacted in the solution of 1 according to the method of Preparation Q.

After heating under reflux overnight, the reaction solution was cooled, and the precipitated oxime was collected and washed with cold ethanol to give 2i5.
9 of y-butylcyclopropyl ketoxime is obtained. An additional 7.7 N is obtained from the mother liquor. Both are combined and recrystallized from a 1:1 ethanol/water solution. ! =25.21? (
50%) of the oxime, M, P, 113.5-11
4C0 5,0N (0,035 mol) of oxime is dissolved in 80-mole of ethanol, and 8.01 (0,35 mol) of oxime is dissolved in 8.01 (0,35 mol) of oxime.
3.31. Crude 1-butylcyclopropylcarbinylamine of F is obtained.

This is distilled at normal pressure to obtain 2.01N (45%) of a product with a boiling point of 153-155C.

250 with stopper, thermometer, drying tube, and magnetic rotor.
2.82 JI (6.6 mmol) of <2p-benzyl-N-benzyloxycarbonyl-L-aspartyl-D-0-methylserine in a 1+117 6-diameter flask;
Add 501 Lt of tetrahydrofuran and toid (7.0 mmol) of triethylamine.

The mixture is cooled to =1 DC, 0.69117 (7.0 mol) of ethyl chloroformate is added and stirred for 20 minutes. Further cooled 135UK, Q-761CC1,66
mmol) of dd-t, -7' tylcyclopropylcarbinylamine. The reaction mixture is allowed to warm up gradually and is stirred at room temperature overnight. The mixture was poured into 100 ml of water, extracted with 170 d of ethyl acetate, and the organic layer was diluted with 5% hydrogen carbonate.IJum solution (50 d, twice), 6M hydrochloric acid (50
117, twice) and brine (703,117, once), and dried over anhydrous magnesium sulfate. The dried extract is distilled off under vacuum to obtain a crude product of 2-protected dipeptide ide, which is purified by silica gel column chromatography.

C5 2.33 jl of the purified material obtained in Step B is hydrogenated using a C radium-carbon catalyst in the manner described in Step E of Example 1 to yield the desired dibeptide i.

The compound a(20H can also be obtained from the corresponding diprotected dipeptide.

Example 14 The following L-alpartyl mono-amino acid amide is similarly obtained by using the appropriate aban having the structural formula RNH2 in the manner described in the previous examples.

2.2-:) Methyl-5-1-butylcyclo to methyl 2
-inbutylcyclohexyl 2-n7'thyl-6-nitylcyclohexyl 2,2-dimethylcyclohexyl 2-t, -1thyl-6-methylcyclohexyl 2A-
diethyl-2,4-dimethylgtrahydrofuran-3-
yl 2,4-dimethyltetrahydrofuran-6-yl 2
．． 2.4.4-Tetramethyltetrahydrofuran-3-
yl 3.5-:) methyltetrahydropyran-4-yl 3.3,5.5-r tramethyltetrahydropyran-
4-yl2.2,4.4-tetramethyltetrahydropyran-6-yl4,4-dimethyltetrahydropyran-
6-yl2.2- :) Methyltetrahydropyran-6
-yl3,3.5.5-tetramethyloxenozo/-4
-yl 2,3-diinopropyl cyclopropyl 2-1
-butylcyclopropylimprobylcyclopropylcarbinyl d-meth route
-Butylcarbinyldiisoprobylcarbinyldi-butylcarbinylL-7Enthyl2.2.5-trimethyl-6-cycloR-rentenyl RRR H2CH3 Example 15 L-Aspartyl-D-0-Methylserine N-(3 ，
5-Dimethyltetrahydrothiopyran-4-yl)amide A mixture of 2 g of sodium acetate and 25 m of ethanol is saturated with hydrogen sulfide gas. Add 7,0.9 (
0,063 mol) of diimpro adds nylketone.

During this time, cool in a water bath until the heat generated by the reaction disappears.

The mixture was stirred at room temperature for 4 hours while passing hydrogen sulfide gas through it, and then left overnight. Ethanol and excess H2S were distilled off, the remaining amount was dissolved in ether, water, potassium carbonate solution,
Wash with dilute hydrochloric acid and water in that order. Dry the ether extract (N
a2S04) and distilled off to obtain 6,8I oil. This was passed through a Vi greaux column of Muji J10cIt at ℃
Distillate, yield 1.67.9 products, B, P, 8
Re-86C/910I is used in the next step without further purification.

B, 4-oxybanor 6,5-dimethyltetrahydrothiopyran 67 g (0,011 mol) of the cyclic ketone obtained in Step A,
1.6. F (0,023 mol) of hydroxylamine hydrochloride and 1.9.9 (0,023 mol) of sodium acetate in 601 parts of water and 101 LI! The mixture of P dissolved in ethanol was heated under reflux for 6 hours, and the precipitated P was then collected.

Recrystallization from methanol-water 1:1 yields 1.5 g of oxime as a white solid. M, P, 6O-85C.

This is a mixture of isomers that is sufficiently pure to be used in the next step.

C, trans/trans and cis/trans-4-amino-6,5-dimethyltetrahydrothiopyran 1.45 Jil (0,009 mol) of the oxime obtained in Step B
Sodium 51 is added little by little to a solution of 5i1 dissolved in ethanol, and then 25]1/ethanol is added, and the reaction mixture is heated under reflux for about 60 minutes.

The reaction mixture is diluted with water, extracted with ethyl ether and the extract is washed with water. Next, the ether layer is extracted with dilute hydrochloric acid, and the aqueous layer is washed with fresh ether. The aqueous layer is made alkaline by adding sodium hydroxide solution and extracted again with ether.

After drying the organic layer (Mg5O4), the ether was distilled off to give 1
．． 1 g of colorless oil is obtained. Gas chromatography (ov)
-1 column to raise the temperature from 80 to 100C).
It was shown that they were contained at a ratio of 0/40. IH-N
MR (CDC73) Fi, this product is 4-amino-
It was suggested that it was a mixture of 6-trans-5-trans-dimethyltetrahydrothiobilane and the corresponding 6-cis-5-trans-isomer.

D,N(3,5-dimethyltetrahydrothiopyran-4
-yl) -t, -7'Toxycarbonyl-D-0-methyl t961 (8
A mixture of Nt-Boc-D-0-methylserine (1.9El (19ξmol)) of triethylamine and 4om of tetrahydrofuran is cooled to -100. To this was added dropwise 0.96 g (8.9 mol) of ethyl chloroformate and the mixture was stirred at 1'OU for 20 minutes. To this solution was added 1.1 g (7.5 golimol) of the mixture of isomers of 4-amino-6,5-dimethyltetrahydrothiobilane obtained in Step C, and the reaction mixture was stirred at -10C for 10 minutes. , leave to warm to room temperature.

The reaction mixture is diluted with water and extracted with ethyl acetate.

The organic layer is washed with hydrogen carbonate) I) Washed with rum, diluted hydrochloric acid, water, and brine, dried (Na2S04), and the solvent is distilled off under reduced pressure to obtain the desired product.

E, N-(3,5-dimethyltetrahydrothiobilane-
4-yl)-D-0-methylserine adsorbent was mixed with 1511% ethanol and 511% ethanol.
Dissolve Lt in a mixture of concentrated hydrochloric acid and add lQt/ of water. The liquid was heated under reflux for 50 minutes, and then the ethanol was removed by distillation under vacuum. After washing the aqueous residue with ethyl acetate, it is made alkaline with sodium hydroxide solution and extracted with ether, and the extract is dried (Na2SO4). When the solvent is distilled off, the desired aminoamide is obtained.

E, D-0-methylserine amide obtained in step E of condensation of D-0-methylserinamide and L-asnozolagic acid N-thiocarboxylic anhydride 1.2515.1? Dissolve 5 parts of tetrahydrofuran and add 5111 parts of water. The clear solution was cooled on ice and 0.89. ! ?
(5-1ξ mol) of L-asnozolagic acid N-thiocarboxylic anhydride is added at once. Add 0.5M sodium hydroxide to this solution if necessary to bring the mixture to pH 9.
Keep it. After stirring for 30 minutes, the reaction mixture is washed with ethyl ether and ethyl acetate, and the washings are discarded. The aqueous layer was acidified to pH 5.6 with dilute hydrochloric acid and evaporated to dryness under reduced pressure.

Hot methanol (10 Qiu) was added to the residue, filtered, and methanol was distilled off. Hot methanol was added to the residue again and filtered, and the P solution was decolorized with activated carbon and filtered through a diatomaceous filter.
A crude product is obtained by distilling off liquid f. The crude product was dissolved in hot water (1
1117) and treated with water, 5+a under a nitrogen stream.
7! When concentrated and cooled with ice, a precipitate is formed, which is removed and dried.

In the above steps, instead of t-Boc-D-0-methylserine, tBoc-D-serine, t-Bo
N- produced using a-DL-0-methylseri/
±-Machidari = D (also FiDL) - When the amino acid is processed and reacted by methods E and F, compounds corresponding to each of the structural formulas (D are obtained. However, R is 6,5-dimethyltetrahydrothiopyran-4- Iru de RaU CH20H and u 0H
20CH3-c-t,, le.

Example 16 L-aspartyl-D-serine N (2,2,4,
4-7''tramethyltetrahydrothiophen-6-yl)abado: To a solution of 2.26 g (11 < 9 mol) of N-t-zthoxycarbonyl-D-serine in 75 d of tetrahydrofuran was added 1. 47117 (10? Rimol)
of triethylamine is added and the mixture is cooled to -1 DC. At this temperature 0.96 MIC (10 mmol) of ethyl chloroformate is added and stirring is continued for 15 minutes. -2
i, 511 (io mmol) glue-6 after cooling to DC
-Amino-2,2,4,4-tetramethyltetrahydrothiophene is added and the mixture is allowed to warm to room temperature. Add ethyl acetate and mix the mixture twice with 5% of 11 Lt.
(Weight) Citric acid solution, sodium hydrogen carbonate solution (50
d. 1 time) Wash with saturated saline (50'111.1 times). The organic layer was dried (Na2S04) and evaporated to dryness under reduced pressure to obtain N-(2,2°4.4-tetramethyltetrahydrothiophen-6-yl)-1-,/toxycarbonyl-D-serinamide. This product is used in the next step without purification.

The product of 3Ii obtained in step A was mixed with 5-methanol and 60
Add 1M hydrochloric acid and heat the mixture on a steam bath for 60 minutes. Methanol is distilled off and the residue is extracted with ether.

Discard the ether and hydroxylate the aqueous layer) Adjust the pH to 11.0 with an IJ solution and extract with ethyl acetate. When the extract was dried (Na2S04) and evaporated to dryness, D-serine N
-(2,2,4,4-tetramethyltetrahydrothiophen-6-yl)amide is obtained.

Condensation step B to C, dipeptide amide 1.03 g (4,25
517 mol) was mixed with 101 water, cooled with ice, and then 0.5N
Adjust to pH 9.2 with sodium hydroxide solution.

Add 0.8 N (4.25 mmol) to this while stirring.
of L-aspartic acid N-thiocarboxylic alhydride was added little by little while adding sodium hydroxide solution (0,5
N) to maintain the pH of the mixture at 9. Once the addition was complete, the mixture was stirred at DC for 45 minutes and adjusted to pH 5 with hydrochloric acid.
2 and then evaporated to dryness under vacuum. The residue is slurried with methanol, precipitated solids are removed by r-filtration, and methanol in the P solution is distilled off under reduced pressure. The crude product thus obtained is purified by column chromatography on silica gel.

Example 17 Using the methods of Examples 6.7.8.15 and 16 the corresponding L-asylthyl-D-amino acid ξ-dos (I
), in its structure Ra is CH20H or CH2O
CH3, R having the structure shown below, is synthesized from an appropriate starting material via the intermediate D-Ra-CH(NH2)CONHR. Corresponding L-aspartyl-DL-
Similarly, for the athanoic acid ε-do, instead of the D-enantiomer, t
Synthesized using -Boc-DL-azunoic acid. Using DL-aspartic acid N-thiocarboxyanhydride in the condensation step, co-workers obtained compounds of structure (I), DL-D or Fi, DL-DL.

HOOCCH2CHCONHCHCONHR...(
I)(I H2Ra In the formula, Ra=CH20H or HCH20CH3RRR CH3 RRR RRR RRR RRR Q((CH3)2 Example 18 L-7Snoξrutyl-D-serine N-(2-,,1 thio-2, 4-dimethyl(ethyl)amide A, 2-methylthio2,4-dimethylpentane-9,
200M containing 29 (0,40 mol) of metallic sodium
A methanolic solution of A is cooled in a water bath and saturated with gaseous methyl mercaptan. To this solution, 77.210.40 mol) of 2-bromo-2,4-dimethylintan-3-one are added at room temperature and the mixture is stirred for 2 hours. The reaction mixture was diluted with water [7. Extracted with ethyl ether, the extract was washed with water and brine, and dried over anhydrous sodium sulfate.

Distill the ether and distill the residue under vacuum.50.4.9
Get the objective. B, P, 76° (20+m).

B, 2-methylthio-2,4-dimethyl-6-aminotinthane,! 2-methylthio-2,
A solution of 4-dimethylintan-6-one, 9.9° formamide and 261 g of 100% formic acid is heated to reflux, while the water produced by the reaction is removed by a fractionating head. 12
Time later [2,5,! Add formic acid (No. 9) and heat to reflux for 241 yen F in the same manner. At that time, the temperature of the reaction mixture is 1
It reaches 90C. Cool the mixture.

After diluting with water, extract with ethyl acetate. The extract was washed with water and evaporated to dryness under reduced pressure to obtain a residual oil of 5.511. This oil is refluxed with 43 m of 6N hydrochloric acid for 6 hours, diluted with water, washed with ether, and the aqueous layer is made strongly alkaline with sodium hydroxide. After extraction with ethyl ether, the extract was distilled off to obtain 3 g (56%) of colorless amine. This one uses a 6 foot 0V-1 column to
Gas chromatography at c gives a single peak; Kiri time 412 seconds.

C,D-serine N-(2-methylthio-2,4-3,
4,710,017 mol) of N-t-butoxycarbonyl-D-serine and 2.51 (0,017 mol) of triethylamine were dissolved in 100 N tetrahydrofuran (90 mol) [-15C, 1.631 M ethyl chloro] Add formate. After stirring for 15 minutes t7 2.49.9 (
0,017 mol) of 2-methylthio-2.4-dimethyl-3-amine was added to the solution and the mixture was stirred for 1 hour. The reaction mixture is diluted with ethyl acetate and washed with water, 5% citric acid solution (1 volume/volume, sodium bicarbonate solution, 1 brine). The organic layer is evaporated to dryness. Remaining V10011
t of methanol, 60r! 11 of concentrated hydrochloric acid is added and the mixture is refluxed for 1 hour. After distilling off the methanol, add water to the residue.

Wash with ether and adjust the aqueous layer to pH 12 with sodium hydroxide.
and extract with ether. Distill the extract to obtain the desired D
- Based on serine amide.

D, A solution of 5,3410.013 mol of D-serine amino 1 obtained in step C in 3Qm acetone and 17mA water was adjusted to pH 9.9 with a hydroxide solution, and -2C Cool to 278g (0,01
3 mol) of L-aspartic acid N-thiocarboxylic anhydride was added little by little over 20 minutes.
Maintain the pH at 99 with lithium (XIN hydroxide). After the addition is complete, the mixture is stirred at 12 C for 0 minutes, washed with ethyl acetate, acidified with hydrochloric acid to pH 2, and washed again with ethyl acetate.

The ice layer is then adjusted to pH 5.2 and evaporated to dryness. Add the remaining residue to methanol to form a slurry and take 1 portion of crude di-R-butide amide. The crude product was prepared by preparative thin layer chromatography on silica gel spray (20 x 20 x 2 fl), and the developing solution was butanol/water/ Acetic acid, 4:1:1, incubate at 5°. Cut out the product band and elute with methanol to give ah L-asno-ξrutile-D-serine amide.

A substance produced in the same manner by using N-t-butoxycarbonyl-D-0-methylserine instead of N-t-Boc-D-serine used in the method of Step C was used in the above-mentioned method. I responded by telling him to react, and Asuno ξ
Obtain rutile-D-0-methylserinamide.

L-Aspartyl-D-serine N-(2-hydro,xy-2,4-dimethyl-ro-hamethyl)amide A, 2-hydroxy-2,4-dimethyl-6-o tanthanone 283 (0,2 Stir a solution of 2,4-dimethyl-6-tantanone dissolved in 100 mt of chloroform, and add dropwise a solution of bromine (10.3a10.2 mole) dissolved in the same solution of 30 mt. The mixture was pressed for several minutes, and the solvent was distilled off under vacuum, leaving behind 1QQ'm.
1 of ethanol. Add 5 IM of water and 5 Dmt of 10M sodium hydroxide. Stir this mixture and
Reflux for 1 hour 1. After that, dilute with 200'rlLl of water,
Extract 5 times with 53 m ethyl ether. The extract was dried (MgSO4) and then evaporated to dryness, and the residue was distilled to give 15.9
! M (61%) of hydroxy-ketone is obtained. b, p,
6O-62C71B failure.

B, 3-amino-2-hydroxy-2,4-dimethylsyntane 15 g (0,115
4.5.9 mol) was reduced by refluxing with a mixture of formamide and formic acid in the manner described in step f) K of Example 13.
(30%) of hydroxyamine moat is obtained. b, p,
8O-8IC/171n.

C,2 protected dibutyamide 2.22 g (5.0 mmol) betabenzyl-
N-benzyloxycarbonyl-L-aspartyl-D
- A solution of serine in 55 mmol of tetrahydrofuran was cooled to 15 °C, 55 °C (5.0 mmol) of N-methylmorpholine and 3.48 mm (50 mmol) of N-methylmorpholine.
of ethyl chloroformate. This mixture -1
Stir for 2 minutes at 5 to 10 tZ' and 0.66.9 (
6-amino-2-hydroxy-2,
Add 4-dimethyl ester.

The mixture was allowed to warm to room temperature and stirred overnight.

When the post-treatment described in Step B of Example 16 is carried out, 2-ho turret R
Butideamide is obtained, which is used as such in the fifth step.

D. Dissolve the product obtained in step C above in 250 ml of methanol, and use 1.0 IIf7) 5% Pd/C to prepare 60 Ps.
Hydrogenate for 2 hours at 17 kF/Crn''. Remove the catalyst and evaporate the solvent in vacuo. Dissolve the residue in methanol and slowly add ethyl ether with stirring. Example 20 L-aspartyl-D-0-mercerin N-(DL-
2-Amino-6,3-dimethyl-4-hydroxybutanoic acid lactone)amide A, synthesized by the method of DL-2-amino-6,6-dimethyl-4-hyde.

6.5 g of 2-keto-3,3-dimethyl-4- and droxybutyric acid lactone are neutralized with dilute sodium hydroxide and the aqueous solution is evaporated to dryness under vacuum. The remaining vC1QQim was added to hot ethanol, filtered through KI while still hot, and added to a bath prepared by bathing 700~ of metallic sodium in 10-component cucotanol containing 2& of hydroxylamine hydrochloride. 5 g of the sodium salt of 6,3-dimethyl-4-hydroxy-2-oxyiminobutyric acid lactone precipitates, which is recrystallized from methanol.

The sodium salt is decomposed in 2Nm acid and the oxime slowly crystallizes from the solution (filtration. Recrystallization from benzene-hexane, M, P, 160"C.

259θ) In a solution of oxime dissolved in 1001 Wl of ethanol, 55' platinum oxide was suspended in 1501 2N Hanjo.1. The mixture was hydrogenated at normal pressure for 2 days.6 The catalyst was removed by distillation, and the I liquid was distilled off.
When 500 ml of ethyl ether is added, DL-2-amino-6,3-dimethyl-4-hydroxybutyric acid lactone hydrochloride is precipitated.
Recrystallized from ethanol/ether to give 22 g4 filters, M,
P, 208-212C.

■1.65 g of aminolactone hydrochloride obtained in Step A (0,
010 mol) in 10d of methylene chloride and an equivalent amount of triethylamine and using the method of Example 16σ) Step B, C6Hs CH20COCH2cHcONHcH(CH
20cH3) CONH-NHCO2CH-2C6H5 1) is obtained.

C0 Upper period process B raw product Iy (2,5,9) 200
1 in methanol and hydrogenated as described in Example 13, Step C with addition of 0.29 in 5% Pd/C catalyst.

Isolation of the product yields the desired di-butide amide. Example 21 ■7-, aspartyl-D-serine N-(2,
2,4.

4-tetramethyl-6-hydroxycyclobutyl)amide A.

N-indyloxycarbonyl-〇-serine (01 mol) was prepared by the method of Example 8q) Step A in cis/trans-
2. '；'． 4. Reaction with 4-tetramethyl-6-hydroxycyclobutylamine yields N-Cb2-'serinamide.

B. Hydrogenation of N-Cb2-serinamide by the method of Example 80 Step C yields the corresponding 2-amine compound.

D-serine N-(2.2.4.4-tetramethyl-6-hydroxycyclobutyl)amide is obtained. This compound was subjected to the steps of Example 8. Conversion using method E gives the top compound.

Corresponding monoasunoξrutile-D-0-methylserine
Amide is obtained in the same manner. Example 22 L-aspartyl-D-serine N-(2,2,4-
Tetramethyl-6-oxycyclobutyl)amide N-pendyloxycarbonyl-D-serine N-(2.2,4.4-tetramethyl-3-hydroxycyclobutyl)amide 36, which was completed in Step A of Example 21. 4
, 10.10 mol) in 1500 IR1 acetone and cooled to -10C under a dry nitrogen atmosphere.

2.42 liters of dilute sulfuric acid solution of 67M chromic anhydride (0.11
mol). After stirring for 15 minutes at -10C, the solvent is removed in vacuo and the mixture is poured into an ice-water mixture (hydroxylated).
After neutralizing with IJum solution, extracting with ethyl ether. Dry the ether extract (wSO4).

Evaporation to dryness gives the crude product, which if desired is purified by column chromatography on cedarica gel.

B. The product obtained in Step A above is hydrogenated by the method of Step C of Example 8 to obtain D-serine N-(2,2,4,4-tetramethyl-6-oxocyclobutyl)amide.

This is converted to the title compound as described in Example 80, Step E.

Example 2 A compound of structural formula (1) was synthesized in the same manner as described above using an appropriate amine having the structure of RN)T2, except that R
a is CH20H or CH2OCH3.

H2 Ra RR RR RR RR G (3 RR RR RR rxi 3n-C3) J7 RR C2H5 (CH3) 2 RR (CH3) 2 RR RR (173) RR RR Example 24 Carbonated cola beverage The carbonated cola beverage is described below. Made with the same composition. The drink is 1
The intensity of sweetness is compared using a 1% sucrose drink as a control.

Ingredients %, Oki amount caffeine (1% aqueous solution) 0
．． 700 concentrated cola flavoring
o, o s.

Phosphoric acid (50% aqueous solution) 0
．． 040 citric acid (50% water incorrectly)
0.066 Sodium citrate (25% aqueous solution)
0.210 force lamel colorant (25% water soluble fV
i,) 0.370 lemon oil extract
(1,012 lime oil extract
0021 Carbonated water (3.5 volumes of carbon dioxide) q, s.

Instead of N-(72,) lance-2,6-dimethylcyclohexyl)amyl, [0,090% of 10% to7spartyl-D-serine N-(dicyclopropylcarvinyl)amide aqueous solution]1. The same negative carbonated cola beverage is also obtained using a 65% aqueous solution of 10% L-aspartyl-D-0-methylserine N-(dicyclopropylcarvinyl)abad.

Example 25 Hard candy is prepared by the following treatment and method: Water
4.00FD and C red No. 40 (10% aqueous solution)
0.30 Thierry fragrance
0.60 citric acid
6.00 Polydextrose* 420.
00 water
180.00 Dissolve sweetener in water and 1 coloring agent in a small beaker.

Add the fragrance and citric acid (mix and dissolve. In another beaker, mix the polydextrose and water. While stirring, add the
Heat to 40C and then cool to 120-125C. Add the ingredients from the small beaker to this and stir thoroughly. Transfer this mass to a hard, oiled plate;
Leave to cool to 75-8 DC. Pull the lump out through an oiled stamping roller.

L-Aspartyl-D-serine 0.49 as a sweetener instead of N-(dicyclopropylcarbinyl)amide
g Noshiichi Asuno ξ Rutiru 〇-Se177N -(2,2
,4,4-tetramethyl-1,1-dioquinchetane-
The same results are obtained using 3-yl)amide or 2.33.9-aspartyl-D-serine N-(2,2,4,4-tetramethyl-6-zunthyl)amide.

*U, S, 3,766.165 Example 26 A gelatin dessert is made using the following composition and 11 hours by hand.

Ingredients Grams Gelatin 225 White Flour Z522 Citric Acid
1.848 Sodium citrate 1.296 Strawberry flavoring
[1,298L-Aspartyl-
D-serine N-0,036 boiling water
240.000 cold water 24
0.000 491.000 First, mix the 5th ingredients from the top, add boiling water and stir until completely dissolved. Add cold water and stir vigorously. Transfer the portion to a serving plate and refrigerate until firm.

Example 27 A low calorie cooking sweetener is made using the following recipe.

A8 Make a powdered sweetener by mixing the following ingredients.

Crystal sorbitol 495
2 Dextrin (10 equivalents of dextrose) 50
．． 00 Monosodium glutamate [0,02 Glucono-delta-lactone 0.
02 Sodium citrate
0.02 Rain 0.00 1 gram of sweetness of this blend is equivalent to approximately 3 grams of sucrose.

B. Prepare liquid sweetener for cooking as follows.

Ingredients %1 honor water
9973
Sodium benzoate 0
．． 10i o o, o.

The sweetness of 1 gram of this solution corresponds to approximately 1.2 grams of crystalline sucrose.

In the above step A, the sweetener of structural formula (1) is 0.86 g.
Noshiichi alpartyl-D-serine N-(2,2゜4.
Similar results are obtained with a 1:4 mixture of 4-tetramethylchetan-5-yl)amide and saccharin.

Similarly, in the above step B, instead of L-aspartyl-D-serine N-(dicyclopropylcarbinyl)amide, the same compound of 03411 and saccharin sodium 1
A similar liquid cooking sweetener is obtained with a mixture of :6(m,t).

A vanilla sugar-free frozen dessert is made according to the following recipe.

Ingredients %, N amount Heavy cream (tJ containing 65% butterfat) 23.00 Skimmed milk powder 10.50 Mono- and diglycerin emulsifier 0.25
Polydextrose* 11.
20 water
54.49 Gelatin (225 white flour) 0.50 100.00 Extra U, S, 3,766.165 Example 29 Wash, peel, core, and slice fresh pears, 0.05% by weight An aqueous solution containing ascorbine 2 [
Soak. Place the thinly sliced fruit in a wide mouth bottle with a screw cap and fill the bottle with syrup containing the primary ingredient.

%, '11 Ayanlubitol 25.
n 00 citric acid
0.125 water
q, s.

ioo, oo.

Loosely cap the wide-mouth bottle, place it in an autoclave filled with hot water, and autoclave at 1 ooc for 45 minutes. Take out the wide mouth bottle.

Immediately tighten the cap tightly to seal and leave to cool.

Example 30 Ingredients %, 1
J Responsible Citric Acid
3 ; 1.7 s sodium citrate
5.08 Strawberry flavoring
5Z72 Strawberry FD and ci colorant
0.54 Carboxymethyl cellulose 2.44i o o, o.

Mix all ingredients in a mixer until homogeneous. When using, use 4 ounces of 1.769 concentrated powdered beverage (
1113d) dissolved in water.

Example 1 A very popular vanilla confectionery is made using the following method.

Emulsified shortening 16.0
9 water
20.83 eggs
23.00 Sodium bicarbonate
1.10 vanilla extract
0.28 Gluconode tarlactone 1.75 Polydextrose*
, 70% aqueous solution 80.00 Skimmed dry milk
2.50 flour
56.20 Powdered whole milk
0.80 wheat starch
1.40204.0
0 Skimmed dry milk and powdered whole milk, yt? Combine IJ dextrose solution and emulsified shortening. Add the eggs and mix vigorously with a whisk to get a homogeneous, creamy mixture (about 6 minutes, stirring slowly until the mixture is creamy and smooth). Dissolve the sweetener in water and add to the creamy consistency.
Mix for 2-3 minutes.

Add remaining ingredients and mix until creamy and smooth (3-5 minutes). Place 120g of dough in a small oiled pan and bake at 350F, (17671:') for 60 minutes.

*U, S, 3,766.165 Example filtration 2 L-aspartyl-D-serine N -(2,2,4゜4-tetramethylchetan-6-yl)amide CH3C
H3 A mixture of L-aspartyl-D-serine N-(2,2,4゜4-tetramethylchetan-6-yl)amide and saccharin sodium was prepared and its taste acceptability and sweetness compared with a standard sucrose aqueous solution were investigated. The strength was evaluated. Saccharin and the compound he invented were 600 times and 12 times that of Wutang, respectively.
00 times and this value was used to calculate the theoretical sweetness of the mixture. Evaluation by a series of taste examiners tested an aqueous solution of the experimental mixture with a 6 to 12% sucrose solution and 0.
．． 033% saccharin sodium solution. The results are shown in the table below.

9 proportion of mixture is weight [1, Ra=CH20H.

(CH3)2 Sweetness intensity 1: 1 7501125 50 Refreshing, not sweet or bitter 1: , 2 60 [) 900
50 same 1: 4 480 72
0 50 Same 1: 6 430
580 Ro5 Same % synergy was calculated according to the following formula:

Here, A is the actual sweetness determined by averaging the results of taste testers and examiners, and T is the theoretical sweetness determined from the composition of the mixture by weight. For example, the theoretical sweetness of a 1:4 mixture is (IAX1200) + Rihe x 300) = 48
From the results an unexpected increase in sweetness intensity of 30-50% was observed from the 1:1 to 8 mixture. The synergy at higher ratios could not be accurately determined due to the interference of the metallic taste caused by saccharin.

Moreover, the well-known bitter aftertaste of saccharin is completely hidden by mixing from 1:1 to 1=6, and L-aspartyl-D-serine N-(2,2,4,4-tetramethylcerine) Tan-ro-yl)amide is 1. +7um effectively masked bitterness up to 8 mixtures.

L-aspartyl-D-serine N-(2,2,4-
A 0.0192% (wt/vol t) solution of a 8-ratio mixture of Tetramethylchetan-6-yl) esteramide/saccharin sodium is a 10% (wt/vol) sucrose solution or a 1:10 saccharin/sodium solution. 0.1177% of Siframate
It was found to have the same sweetness as a solution of (t weight/t volume).

For further sensory evaluation, trained taste testers were asked to test the above invention compound/saccharin sodium 1.
:3 consisting of a 0.0192% aqueous solution of a mixture of 8 and a 0.1177% solution of 1=10 saccharin/siframate.
Three samples were given and a triangular test was conducted. The examiner was asked to put two identical samples together and to see if there was a pail of water he preferred. 7-10 taste testers were accurate [could not distinguish between the two sweetener mixtures].

People who put the same samples together also said the degree of difference between the two mixtures was "very slight" or "barely perceptible."
It was evaluated as follows.

These results show that there is no meaningful difference between the invention compound/saccharin 8 mixture and the saccharin/siframate 1:10 mixture.

Even if the above procedure is repeated using an inventive compound having the following structure, lil-like results are obtained.

In structural formula (1), Ra: CH20CH.

(CH3)2 Example Roro L-aspartyl-D-phosphorus N-(dicyclo, 12
．． To a solution of 9 (0.01 mol) of L-aspartyl-D~ ~serine N~ (dicyclopropylcarvinyl)amide dissolved in 1001 of ethanol is added 21 of 5N sodium hydroxide. The mixture is stirred in the chamber for 10 minutes and evaporated to dryness under vacuum.

Knead the erosion with absolute ethanol, filter it for 1 time, and air dry.

When an equal amount of potassium hydroxide, calcium hydroxide, magnesium hydroxide or ammonium hydroxide is used in place of IJium (hydroxide used above), the corresponding potassium, calcium, magnesium and ammonium salts are formed in the same way. do.

The remaining butydoamide of structural formula (1) is similarly converted to the carboxylic acid salt as described above.

Example 64 Acid addition salt Noshi-aspartyl-D-amino acid dibutide amide of structural formula (1) is slurried with a small amount of water and an equal amount of acid is prepared, such as hydrochloric acid, phosphoric acid, sulfuric acid, maleic acid, fumaric acid, lactic acid. , add tartaric acid, citric acid, gluconic acid or sugar acid. The mixture is stirred for 15-30 minutes and evaporated to dryness, or precipitated by adding methanol or ethanol as a co-solvent.

Production example A alkylcycloalkylcarbinylamines and r,
A mixture of 11s, sy (1.0 mol) of cyclobutylcarbonyl chloride and 99 g (1.0 mol) of cuprous chloride was dissolved in 1000 IIL of dry ether under a nitrogen atmosphere in 478 columns (1.0 mol) of 2 Mt. - Butylmagnesium chloride dissolved in the same solvent is added dropwise. The dropping is carried out at -5--1 DC. The mixture is poured into 500 rILt of 6M hydrochloric acid and 700 g of ice, and the organic layer is separated, washed with water, sodium bicarbonate solution, brine, and dried (wSO4). The dried ether extract is distilled off under reduced pressure, and the residue is distilled to obtain t-butylcyclobutylkatone.

11, 1o 5j? (0.75 mol) of the ketone was added to hydroxylamine hydrochloride 38. , l' (1,16 mol)
, sodium acetate (12,311.50 moles), add enough water until it becomes a solution, and heat on a water bath for 1 hour.

The mixture is cooled and adjusted to pH 75 with sodium hydroxide solution. After extracting the mixture with ether, the extract is dried (wSO4) and evaporated to dryness to yield the oxime. The oxime is dissolved in absolute ethanol (approximately 2 liters per mole of oxime) and the solution is refluxed. Metallic sodium (
(approximately 10 moles per mole of oxime) is added in small portions at a rate sufficient to maintain the reflux temperature. Once all the sodium has been added, cool the mixture and add 200 d of ethanol followed by 300 d of water. Acidify the mixture with hydrochloric acid,
Ethanol is distilled off, and the residue is made alkaline (pH 12-13) with 10M sodium hydroxide.

The alkaline mixture was extracted several times with ether.

Combine the extracts and dry (FiuSO+). Dry hydrogen chloride gas is passed through the dry extract until complete formation of the precipitate. The precipitated hydrochloride is collected, washed with ether, and air-dried. This salt is neutralized with sodium hydroxide solution, extracted with ethyl ether, and the extract is distilled off to convert it into the free base. The product, t-butylcyclobutylcarbinylamine, is of sufficient purity to make the inventive amide, but can be further purified if desired, for example by distillation or column chromatography.

111. The following amine can be obtained in a similar manner by using an appropriate acid halide 1 and Grignard reagent in place of cyclobutylcarbonyl chloride and t-butylmagnesium chloride in the above step.

m R7R8R9 0HH) 1 0 CH3HH OCR3CH3H OCH3CH2CH3CH2CH3CH20CH3n
-C4H7H O(CH3)2CH(CH3)2CHHOCR3CH3
C(CH3)3 1 CH3CH2CH3C)12
HI n-C3H7HH I CH3CH3'H I CH3n-C4H7H l n-C3H7n-C3H7HI C
H3CH2 (CH3)3CH2CH3CH3CH3* 2 CH3CH2HH m R7R8R9 2CH3CH2CH3CH2CH3CH22CH3HH 2CH3CH3H 2n-CaK7 (CH3)2CHH2CH3CH
2n -C4H7PI 3 CH3CH3CH3 3n-C3H7HH 3CH30H3H 4CH3HH 4CH3CH3CH3 4CH3CH2CH3CH2H *B, P, 8O-901Z', (21+1111
．． ) IV, amines having the following structural formulas are also obtained in a similar manner.

1 2 3 4 1 2 6 4 2 6 4 6 4 4 The following amines are also obtained in this way.

2.2-Dimethyl-6-aminotinol, B, P.

123-126c, normal pressure 2.2.4-) Limethyl-ro-aminohantan, B, P
.

149-150tr, normal pressure production example B 13.5.9 (0.25 mol) of sodium methoxy)
Add 30.89 (0.28 mol) of 2-methylcyclohexanone and 20.3.9 (0.28 mol) of ethylpolmate to the tuna suspended in 500 Fill(r) ethyl ether. Bring the mixture to room temperature. Stir for 12 hours under a nitrogen atmosphere, wash the resulting solid with ethyl ether and dry in a vacuum oven at 751°C.The dried mass is ground with a mortar and pestle until a fine powder is obtained at 17.51°C.
43%) of 2-formylcyclohexanone, which is now used in the fifth step.

The above compound ii 17511 (0.11 mol), 2,8
8 g (0.13 mol) granules of metallic sodium, 500 d
of anhydrous ammonia and about 0.1 g of ferric chloride. The gray suspension is cooled to -45 tl' and stirred for 1 hour at the reflux temperature of the thread. 20.86g for this
(0.15 mol) of methyl iodide is added and the mixture is stirred at reflux for 6 hours, allowed to warm to room temperature and evaporate by standing overnight. The residue is suspended in 3001d ethyl ether and refluxed to drive off traces of ammonia, and water is added to dissolve the solids. Ether to water (
103 m (3 times), solid sodium hydroxide of 611 was added to the combined aqueous layer, and the ketone was steam distilled. The steam distilled product was extracted with ethyl ether, the extract was washed with brine, and after drying, the ether was distilled off.
-2.0g of dimethylcyclohexanone as a colorless liquid
obtain.

11. The ketone obtained as above was subjected to step 1 of Production Example A.
Conversion to the oxime as in 1 and reduction with sodium in ethanol yields 6.1 g of 2,2-dimethylcyclohexylamine.

The following 2,2-disubstituted ketones are synthesized by the method described above and converted to amines.

2.2-dimethylcyclo is nthanone 2.2-diethylcyclopentanone 2.2-cy n-furobylcyclo is nthanone 2.2-diethylcyclohexylamine 3.3-dimethylchepan-4-one filtrate, 3-dimethylcyclopentanone Xenon-4-one 4.4-Dimethyloxepan-5-one Preparation Example C 50% sodium hydride suspended in mineral oil14.
6 g (0.30 mol) suspended in tetrahydrofuran,
Decant the liquid and resuspend the solid in tetrahydrofuran and decant again to remove the oil.

Then 15 g (0.12 mol) of 2,6-dimethylcyclohexanone was added, followed by dropwise addition of a mixture of 111i' t-butanol and 201 tetrahydrofuran (with intense hydrogen evolution) until the mixture was completely free of hydrogen evolution. Reflux until finished. 37.810.30 mol in this liquid)
of methyl sulfuric acid is added dropwise and the mixture is heated to reflux for 24 hours. After diluting with water, it was extracted with ethyl ether, the extract was washed with water, and after drying, the solvent was distilled off at below 40C.
of tetramethylketone is obtained. Distill this and 14. <
Obtain l of product. B, P, 62-641T (151
111).

11゜ 2,2,6,6-titramethylcyclohexanone (8 g) obtained as above was added to Step '1 of Production Example A.
oxime by method 1, and reduce the compound to 1.4g
The desired amine was obtained as a colorless liquid with sufficient purity as an intermediate.

Production example D 2.0 mol of sodium hydride in tetrahydrofuran was made into a slurry and the oil was removed by washing), 19'0m
1 (2.0 mol) of methyl sulfate is added at a rapid rate. At the same time, a solution of 35.7 g (0,425 mol) of cyclo-tantanone in 50 mt of the same solvent is added at a slow rate. The reaction mixture is allowed to warm slowly and gently to reflux, resulting in vigorous hydrogen evolution.

Once the addition is complete, the mixture is left stirring at room temperature overnight. Next, the mixture was heated under reflux for 2 hours or more, a mixture of t-butanol dissolved in tetrahydrofuran was added, and the mixture was further refluxed for 3 hours. The reaction mixture was diluted with water and extracted with ethyl ether. The extract was washed with water and brine, dried over anhydrous MgSO4, and the solvent was distilled off to obtain 48.2 g of crude product. When this is distilled, 24.2. The tetramethyl ketone of li' is obtained. B, P6 Loichi 68C143m.

When methyl sulfate is used in a lower molar ratio than cyclo-ncun, 2-methylcyclo can be converted to ntanone, 2,5
-Dimethylcyclo is 2.2.5゜5) 1) Methylcyclo is nthanone.

11. The following ketones can be obtained in the same manner as in Step 1 and Production Example C using other suitable starting materials. Alpha-propyl and alpha-butyl ketones may be synthesized, for example, by using the appropriate argyl bromide as an alkylating agent.

2.2.6-Dolimethylcyclohequinanone 2-Ethylcyclopentanone 2,2.4.4-Tetramethylcyclobutanone 2-Methylcyclobutanone 2.2-Dimethylcyclobutanone 2.4-Diimprocyclobutanone 2-t- 7'
Tylcyclotakutentanone 2.2-dimethyl-5-t-butylcyclotontanone 2.5-diisopropylcyclopentanone 2-sec-
Butylcyclo is phthanone 2-isobutylcyclohexanone 2-methylcycloheptanone 2-t-butylcycloheptanone 2.7-dimethylcycloheptanone 2.7-diituprobylcycloheptanone, 5-dimethyltetrahydro-4H- Pyran-4-one 6,5-diinpropyltetrahydro-4H-pyran-
4-one 3,3.5.5-tetramethyltetrahydro-4H-pyran-4-one 6-methyl-5-t-butyltetrahydro-4H-pyran-4-one 3,3.5.5-tetramethyl Tetrahydro-4H-thiapyran-4-one 6-isoprobyltetrahydro-4H-thiapyran-4
-one 6.5-diisopropyltetrahydro-4H-thiapyran-4-one 3-t-butyltetrahydro-48-thiaoran-4
-one 2-methyltetrahydro-4H-thiapyran-3-one 2,4-dimethyltetrahydro-4H-thiapyran-6
-one 2-methylchepan-3-one 4-methylchepan-3-one 2,4-diinpropylchepan-6-one 6,5-dimethylchepan-4-one 3,3.5.5-tetramethylchepan-3-one Pan-4-on 4-
Methyltetrahydro-4H-pyran-6-one 4-see-7' methyltetrahydro-4H-pyran-3
-one 2-inpropyltetrahydro-4H-pyran-3-one 2,4-diisopropyltetrahydro-4H-pyran-
6-one 2.4-dimethyltetrahydro-4H-pyran-6-one 2-methyloxepan-6-one 4-methyloxepan-3-one 2.4-dimethyloxepan-6-one 2,2. 4.4
-tetramethylcyclonozone 6-methyloxepan-4-one 5-methyloxepan-4-one 3.5-dimethyloxepan-4-one 3, 3.5.5
-Tetramethyloxepan-4-one 5.5-diisopropyloxepan-4-one 3-t-butyloxepan-4-one 5-t-butyloxepan-4-one The ketones listed above are compatible. by conversion to the oxime followed by reduction with sodium in ethanol as described in Preparation A, step 11, or by Leuckart reduction of the ketone as described in Preparation G, step iiK.

Convert.

Production example E Mineral oil 3510 with 40% sodium dispersed in a flask
．． 61 mol). Remove the oil by washing with ethyl ether and decanting. Adding 4001 ether to this sodium, the method of Coffman et al., J. Am., Che.
A mixture of 2.8 (0.20 mol) of 2.2.5.5-tetramethyladiponitrile and 400 mt. of tetrahydrofuran is slowly added. 4 of the mixture
After stirring for an hour at room temperature, excess sodium is decomposed by dropwise addition of saturated aqueous ammonium chloride solution. The organic layer was washed with water, dried (Na2SO4) and evaporated 25.
1 g of crude 2.2.5.5-tetramethylcyclo yields methylimine. This imine is dissolved in 751 ethanol and added dropwise to a flask containing 26.3 g (1 mol) of sodium metal particles. Add another 75 d of ethanol,
The mixture is heated to reflux until the remaining sodium metal is completely consumed. The reaction mixture was diluted with water and adjusted to pH 1 with concentrated hydrochloric acid.
After washing with ether and hydroxide), make it strong basic by adding IIum. The organic layer is extracted with ether, washed with brine, dried (NazSO4) and evaporated to dryness. - Distill the residue under vacuum to 6.6gk23
%) of the desired amine. B, P, 6060-6IC
(20゜Production example F 2-alkyl- and 2,6-dialkylcyclohex 259
A solution of 2.6-dipropylaniline dissolved in 250 portions of ethanol and water KioI! of dry 5% ruthenium-carbon catalyst is added. This mixture was heated in an autoclave at 100 C, 1000 ps i (7(j,4'
Hydrogenate with VA Go) until hydrogen absorption stops. The catalyst was removed by filtration, and the solvent of liquid f was distilled off. The residue was distilled under vacuum to give 11.2 g of 2,6-diimpro B,=P,
122-12411? , 22nd order.

Using a suitable 2-alkylaniline or 2,6-dialkylaniline as a starting material and hydrogenating it in the manner described above, the following cyclohexylamines are obtained.

2-Methyl-6-ethylcyclohexylamine.

B, P, 82-87C, 19m+11 (yield 50%)
:2-Methyl-6-isopropylcyclohexylamine, BJp, s6°, 14m (yield 45%):2-n-butylcyclohexylamine:2-xthyl-6-n-
Ethylcyclohexylamine; 2-methyl-6-n-butylcyclohexylamine; 2-t-butylcyclohexylamine: 2,6-dimethylcyclohexylamine: trans-2-ethylcyclohexylamine.

B, P, 77-78tl' (231! II); 2.6-
) Ethylcyclohexylamine, B, P.

96tl'(17a) Nidorans-2-isopropylcyclohexylamine; 2-inbutylcyclohexylamine; 2-methyl-6
-n-ethylcyclohexylamine.

Production example G 2-t, 'Tylcyclohexylamine i, 2-t-7''Tylcyclohexanone 31.2510
．． 20 mol) of 1-butylcyclohexanol to 801
Dissolve in ethyl ether.

Cool to 10C. Stir into this solution.

21.0. ? (0.07 mol) of sodium dichromate dihydrate and 15.75 mt (0.30 mol) of concentrated sulfuric acid
The temperature of the reaction mixture was 25C.
Add to keep it below. The mixture was warmed to room temperature, stirred for 2 hours, poured into water-water, the ether layer was separated, the aqueous layer was further extracted with ether, the extracts were combined, and washed with water and hydrogen carbonate solution. Drying (lli7L9so4)
Sur. -c-f water distillation, 30. tl (99%)
to obtain the desired ketone.

2-t-i methylcyclohexanone 30.6g (0,2
0 mol), formamide 50 Wlt (1,2 mol) and Gil! i! The mixture of (1[1au) is heated to reflux, during which time the water produced by the reaction is removed, while the ketone is allowed to return to the reaction vessel. Formic acid (1CJIILI) is added to decompose the ammonium carbonate in the cooler. After 4 hours the reaction temperature reached 197C, at which point the distillation was stopped. The mixture is cooled, diluted with water (501M) and extracted with ethyl acetate (7Fl/). The organic layer is distilled off, concentrated hydrochloric acid (50a per 100d remaining) is added and boiled overnight. After cooling, wash with 5Qm ethyl ether. The aqueous layer was made pi-111 with sodium hydroxide, and cooled with ether (400
1d twice) and dry the extract with sodium hydroxide grains. The solvent is distilled off and the residue is distilled through a 10C1n sheath column to yield 21.93.171%) of the title amine as a mixture of cis and tra72 isomers. B,
P, 86-88C (211EI+).

iii. az-fenchone and t-fenchone are also reduced to the corresponding fenthylamine by the Leuckart reduction method in step ii above. (-) Phentylamine is obtained as a colorless liquid, B, P, 55-5'0U (6 sleeps).

[Alpha] 1)-21,9? Collection 60% - Production example H 2,4-dimethyl-6-amino is 0 in the bottle
．． Add 2 g of platinum dioxide and 10 fills of water. Hydrogenate this slurry at 50 psi (3.5 to 7 cm) for 15 minutes.
64.26 g (0.30 mol) of 2,4-dimethyl-ro-R-Ntanone, 20.010.37 mol) of ammonium chloride, 225 g (0.30 mol) of ammonia-saturated methanol and 25 m
Add 1 part of concentrated ammonium hydroxide to 6 parts of the slurry.
Hydrogenate for 20 hours at 0 psi (4,2 KtI/an") and room temperature. Filter, reflux for 1 F#, and cool. The mixture is brought to pH 2,0 with concentrated hydrochloric acid and evaporated under reduced pressure to reduce the volume. After washing with 75au of ethyl ether, the aqueous solution is oxidized to 10M hydroxide).
! Extract 6 times with ILt in ether. Combine the extract liquid,
After drying with anhydrous M#SO4, it is saturated with hydrogen chloride gas. The precipitated amine hydrochloride is stripped of P, air-dried, and decomposed with 75 mt of 10M sodium hydroxide solution. The oily amine layer is separated and distilled at normal pressure to obtain 176ji. B-P
, 129-132C.

Production example ■ A 6-diameter flask [contains a solution of 5.0 g of metallic sodium dissolved in 250 g of dry ethanol, containing 61.24 g.
Add (0.20 mol 5) of 2-carboethoxycyclotantanone. 18.4 mA (0,23
mol of ethyl iodide is added dropwise and the mixture is heated to reflux for 2 hours. Next, add 250 shochu worth of food and 5 QmA of water and extract the mixture with ethyl ether (1001172 times). After drying (MJ7SO4), the solvent was distilled off and 66.
5f/C99%) of 2-ethyl-2-carboethoxycyclo gives tantanone.

Scary 200#! A mixture of concentrated hydrochloric acid and water of i[][11m] is heated to reflux to decarboxylate. After refluxing for 4 hours, the evolution of carbon dioxide ceases. After cooling the mixture, it is saturated with sodium chloride, extracted with ethyl ether, the extract is dried (MES04), and the ether is distilled off. Distill the residue 12. ．． 62.9 (56%) of 2-ethylcyclotonthanone'& obtain eB, P, 97-98C (100 order).

11. The 4-paraboloid obtained above is converted by the method of Step 11 of Preparation Example A to obtain trans-2-ethylcyclopentylamine with a yield of 65%, B, P, 150-151tr
Identification of the product was carried out by IH-Shodensu Kutle.

The appropriate 2-carboethogycycloalkanone or the corresponding heterocyclic ketone (synthesized from the well-known Dieckmann'JR reaction of various dicarboxylic acid esters, e.g. H,0,House"Modern
Synthetic Reactions “+ W, A
-Benjamin.

Menlo Park, Ca1.1972. p, 7
40) and the appropriate alkyl halide in place of ethyl iodide, the following structural formula RN
H2-carrying amines are similarly synthesized, considering V 1 C)(3 1C2H5 t-C4H9 2CH3 2sec-C4Hg 4 CH3 4t-c,,u,.

Here R is R3 and ＼ X dan dan is also 0
1 0 2-CH3010
4-CH3 0102-t-C4H9 0022-CH3 0024-CH3 0024-locus-C4H9 0022-i-C3H7 0032-CH3 0034-CH3 0123-CH3 0125-CH5 Q 12 5-j-C4H901
23-t-C4H9 5O12-CH3 S O14-CH3 S 1 1
1-C3H780211t-C4Hg 5 O22-cH3 S O filter
2-CH5SO64-CH3 Production example J trans-2-isopropylcyclobentylua 10.9
100F (1.19 mol) of cycloR nthanone and 6
A mixture of 0 g (1.03 mol) of acetone is added dropwise and the mixture is refluxed for 1.5 hours.

The solvent was distilled off under vacuum, the residue was dissolved in ether, 6M hydrochloric acid (200 #17.5 times), 5% sodium hydrogen carbonate (
200M, 3 times) +3[Water (200+d, 11'
101) Wash and dry (W7SO4). Distill the ether without heating it up to 97. ? You will get a black liquid. This was distilled under vacuum to yield 55I! 2-inzolobylidenecyclopentanone is obtained. B, P, 96-100
C (2,7111).

12.75 g of the above product was dissolved in 250 U of methanol, 2.0 g of 5% palladium-carbon catalyst was added and the mixture was heated to 50 psi (51/C+++' to 3,5).
Hydrogenate with After 1 hour, hydrogen absorption is completely completed. Remove the catalyst and evaporate the solvent under vacuum, 12.75.9
A colorless liquid is obtained. This was distilled to obtain 964 g of 2-isopropylcyclobutanone. 'B, P, 74-7
6CC201HII).

2-Isopropylcyclo is butanone in Step 1 of Production Example A.
1 to give the corresponding amine in 31% yield. B, P, 167° (normal pressure).

Production Example K 2. Into a flask of 2-dimethyl-3-aminobutane 5001, 10.0. lO, 10 mol) of 2,2-dimethyl-6-butanone, 250 methanol, 76.94.11.0 mol) of sodium acetate and 4
．． Add 67 g (0.07 mol) of sodium cyanoborohydride and stir the mixture at room temperature for 24 FI? Stir for f.

Adjust the pH to 2.0 with concentrated hydrochloric acid and remove methanol under reduced pressure (
. The solid residue was dissolved in 5 IQd of water.

Washed 3 times with 1001d ether and adjusted the pH of the aqueous layer to 10.
Adjust to 16 with M sodium hydroxide and extract 6 times with 100 ml of ether. Combine the extracts and anhydride ■804
It is dried, filtered through f, and the solvent is distilled off.

Distilling the residue at normal pressure yields amine (2,49) with 10
Distill at 2-103tZ'.

Racemic forms of amines have been described by Bruck et al., J. Che.
The dispensable amine was separated by crystallization from 70:30 methanol/water (by volume) using the polarimetric control method of M, Soc, +921 (1956). , the left-handed amine is obtained with a purity of 80±4%.

2. Instead of 2-dimethyl-ro-butanone, an equivalent amount of 2,
Using 2-dimethyl-3-a-butanone, the above procedure can be used in 2.2. -dimethyl-6-amino yields butano, which can be resolved into its enantiomers.

Production Example L-Aspartic Acid N-thiocarboxyanhydride A, 350.9 g (8,
58 mol) of 50% sodium hydroxide solution.

Add as quickly as possible a solution of methyl methylxanthi (550 L, 4.51 mol) in 405 methanol. The mixture is kept at 45C for 1.5 hours, cooled to room temperature and then washed twice with methylene chloride. The methylene chloride is discarded and the aqueous layer is acidified with concentrated hydrochloric acid over OC. This solution was extracted 6 times with ethyl acetate,
The combined extracts are washed with brine and dried over anhydrous magnesium sulfate.

The solvent is evaporated under vacuum to give a yellow oil which is crystallized by adding ethylene dichloride and n-hexane. One portion of N-methoxy-thiocarbonyl-L-aspartic acid was washed with fresh n-hexane and dried (420
．． 9.47%).

M, P, 128-150tZ': "H-NMR (
DMSO-d6).

(Delta) 2.73 (d, 2H, J=6Hz), 3.6
3 (8°3H), 4.43 (dt, IH, J=6
Hz, 8Hz), 6.63(d, IH, J=8H
z); Infrared spectrum (KBr) 1715.1515c
m-”.

B, N-Methoxythiocarbonyl-thio-aspartic acid (207.0 g, 1.00 mol) was dissolved in 12001 ethyl acetate with OC and phosphorus tribromide (471 d.

0.50 mol) at once. The cooling bath is removed and the temperature is gradually raised to 35 C. The solution is stirred for 10 minutes, resulting in the formation of a granular white precipitate. The reaction mixture is cooled to 0-5C and the product is poured, washed with a little ether and dried. Analytically pure mono-aspartic acid N-thiocarboxyanhydrin is obtained with a yield of 157.4.9 (90%).

M, P, 200-205 U (decomposition); [Alpha] 65=109.5° (C=1.THF); Infrared speed
< Kutle (KBr) 3225.17ro 9.1724.1
653.1399Crn-':'H-NMR (DMSO
−d6) ppm (delta > 2.83 (d, 2H.

J=5.0Hz), 4.70 (t, IH, J=
5.0Hz), 9.23 (b s.

2H, ex); mass is kutle (m/e) 175
(M”).

87, 60 Production example M 1, ethyl 2.2.3.3-tetramethylcycloprod
(1960) method is used. A mixture of 19 g (0,226 mol) of 2,6-dimethyl-2-butene and 2I #L copper acid was refluxed and 51. lO, 447 mol) of ethyl
Diazoacetate and 19.9 2,3-dimethyl-2-
Add the butene mixture. The mixture was heated under reflux for 3 hours, then filtered and distilled to obtain 198 g (26%) of the desired cyclized ester. B, P.

7 low 77° (15m+11).

ii. To the ethanolation of 6001ILt containing 4oIi of ammonia is added 17 g of the ester obtained above and the mixture is left to stand overnight. After heating under reflux for 1 hour, ethanol was distilled off under vacuum to obtain 2.2.3.3-tetramethylcyclopropanecarboxamide.

A solution of amide (2.82, 10.02 mol) dissolved in 8 parts of tetrahydrofuran and 4 parts of water was cooled to 5C and 1
Drop 0 solution of 2M sodium hypochlorite, then 8m
20% (t/3t) of sodium hydroxide is added dropwise. The two-layer mixture is stirred at 5C for 30 minutes, followed by 1 hour. The organic layer is extracted with ether, the ether layer is extracted with 2M hydrochloric acid (2011L6 3 times), the acidic aqueous layer is made strongly alkaline with sodium hydroxide, and then extracted with ether. Dry the extract (Na2SO4)
Distilled at °(501111) to 0.7719 (25%)
2.2. filtration to obtain 6-titramethylcycloprobylamine. IH-NN4R (CDC43) (Delta): 99m 0.95 (6H, single line); 1.00 (6H, single line)
: 1.8 (1R1 multiplet) : 1.7 (2H, multiplet) 1 (10th-order substituted cyclopropylamines are also synthesized from appropriate olefins in a similar manner.

Q(3HCH3H CH3HHH i-CH2R3HHH i-C3H7H1-C5H7H CH3CH3HH t-C4H9HHH CH3CH3t-C4H9H Production example N 6-amino-2,2,4,4-tetramethyloxeta 1
3.6.9 (0.12 mol) of diimpropyl ketone [0.2 #I/phosphorous tribromide are added. This [101r
So 38.4! 7 (0.24 mol) of bromine are added dropwise and the mixture is warmed to 55-60' and kept at that temperature for 1.5 hours.

After cooling and partitioning between chloroform and water, the organic layer was washed with sodium carbonate solution until neutral, and after drying, the solvent was distilled off to give 2,4-dibromo-2,4-dimethylpentane-
6- Get onwo.

Dissolve 0.1 mole of dibromoketone in 1601d of ethanol, and dissolve 8g of sodium hydroxide in 80! A solution of L1 in water is added and the mixture is stirred for 0 minutes at room temperature. After diluting with water, the reaction mixture is extracted with ethyl ether, and the extract is washed with water, brine, and dried (MgSO4). The ether was distilled off to give 2,4-dihydroxy-2,
Obtain 4-dimethyl-6-pentane. This was dissolved in 50 chloroform [1.5 mA]. Add phosphoric acid dropwise. The reaction mixture is heated to reflux for 5 hours and the amount of water is removed as an azeotrope with chloroform. When no water is generated, the reaction mixture is washed with water and the organic layer is dried (w
SO4) and evaporation of the solvent yields 2.2.4.4-tetramethyloxetan-3-one, which is purified by distillation.

The ketone is converted into an oxime in Step 11 of Step 11 of Production Example A,
Reduce with sodium/ethanol.

Production example O Lodihydroxy-lo-methyl-2-butanone, 0.20
mol, is reacted with an equal amount of bromine at room temperature, and the mixture is
Stir for an hour. Add chloroform to the mixture, wash with sodium carbonate solution until neutral, and after drying, the solvent is distilled off to give 1-promo-3-hydroxy-6-methyl-2-butanone.

Dissolve 0.1 mol in 160 IM of ethanol, add a solution of 4I sodium hydroxide in 80 ml of water,
The mixture is stirred at room temperature for 60 minutes. The mixture is diluted with water, extracted with ether, and the extract is washed with water, brine, and dried (wSO4). The solvent is distilled off and 50 chloroform is added to the afterflame.

1.5-ml concentrated sulfuric acid is added dropwise thereto, the reaction mixture is heated to reflux, and that amount of water is removed as an azeotrope with chloroform→7. Once water evolution has ceased, the resulting ketone is isolated and converted to the desired amine as described in Preparation N.

Preparation Example P The following amines are similarly synthesized using the method of Preparation Examples N and O, starting in each case from the appropriate ketone or alpha hydroxy ketone.

Black μ Mayuri (“H3HHH OT3 Ht-C4Hc+ HC)T3
C2H5 "3 C2H3CH3HCH3H CI (3ch3C2H5C2H5 I -C3HHHHH I -C3H7H1 -C3H7H C2H5C2H5HH manufacturing Example Q Missichloproproprophlcalbinyl Amine 5001 round bottom flask 41.7 g (0, 60 molits) Hydroxylamine hydrochloride and 83m Add water. While stirring, add 10M sodium hydroxide solution and 44.49 (0.40 mol) of dicyclopropyl ketone. The mixture is stirred under reflux for 6 hours. Then add 60 WLl of methylene chloride. and stir the mixture until all the oxime is dissolved. Separate the methylene chloride layer and dry over anhydrous magnesium sulfate.

The solvent was removed by distillation under reduced pressure, and the residue was recrystallized from 55 ml of hexane to obtain dicyclopropyl ketoxime in a yield of 40.0#. M, P, 69-72C.

18.8.9 (0,15
mol) of dicyclopropyl ketoxime and 153 rnl of absolute ethanol. 19.2g with light stirring
Add (0.83 mol) of spherical metal +7 um little by little as quickly as possible. Once the sodium has dissolved, the reaction solution is cooled to 60C and water from 601 is added. Next, add 78 liters of #hydrochloric acid dropwise while stirring. Distill the ethanol under reduced pressure and add 50 d of water to dissolve the salt. mix 10
Adjust the pH to 16 with IJ solution and extract 6 times with 40ml of methylene chloride. The extracts are combined, dried over anhydrous magnesium sulfate, filtered, and the solvent is distilled off under reduced pressure. The remaining amine was converted into 88-90C/95111
Distill at 1Hg to obtain the desired product with a yield of 11.0#.

Production example R 2-amino-6,6=dimethyl-gamma-butyro 17.
398 (1969).

2.2-Dimethylhydroacrylaldehyde C3til
ler et al., J. Am. Chem. Soc.
62.

1785 (19"40), synthesized from 5ee-butyraldehyde V and formaldehyde by the method of 5.11
．． A solution of 9 in methanol (251d) was stirred, and a bath solution of 2.94 g of ammonium oxide and 2.9 g of sodium cyanide dissolved in water (40d) was added dropwise.

After stirring for 6 hours, the mixture was saturated with ammonia gas.

Leave at room temperature overnight. The reaction mixture is concentrated under vacuum to a small volume and 40-m concentrated hydrochloric acid is added. After the mixture was refluxed for 6 hours, it was evaporated under vacuum and the residue was crystallized from ethanol-ethyl ether and then from ethanol.
．． 2 g of the title compound are obtained. M, P, 214-2151
? (Decomposition) Using a homolog of 2,2-dimethylhydroacrylaldehyde in the above method, a corresponding compound having the following structure is obtained.

Here, one of R12 and R13 is an alkyl group having 1 to 4 carbon atoms, and the other is hydrogen or an alkyl group having 1 to 4 carbon atoms.

Production example S 4-amino-ro, 3.5.5-tetramethyl-tetra 1,5-hydroxy-2,2,4,4-tetramethyl 1
72,! i' (1.0 mol) of 2.2.4-) methyl riftyl-6-ketovalerate, 5.4.9 (0.10 mol) of sodium methoxide and 33 g (0.56 mol) of para A mixture of formaldehyde dissolved in 250 methanol is heated to reflux for 8 hours. The mixture is cooled by adding water, neutralized with hydrochloric acid, extracted with ethyl ether, washed with water and brine, and the solvent is distilled off. The residue is cleaved by vacuum distillation or chromatography on silica gel to give a clean product.

i[,2,2,4,4-tetramethyl-2,4-dioxo101 l! (0,50 mol) of the above product in 200
A solution dissolved in Niji's methanol and 20 companies' concentrated hydrochloric acid was heated under reflux for 2 hours, poured into ice-water after cooling, extracted with ethyl ether, and the extract was washed with sodium bicarbonate solution and water, dried, and then evaporated. Dry. Remain under vacuum 8O-1001
Heating at r for 2 hours yields the desired product with sufficient purity for use in the next step.

The ketolactone obtained above 1116 is reduced to a convective 4-oximino derivative by the method of Preparation Q to give the title compound.

Production example T 4-amino-3,3,'5.5-)stramethyl-2-
Pinilydone 1,5-dibenzylamino-2,2,4,4-tetra8
6 g (0,50 mol) of 2.2.4-1-rifutyl-3
-Methyl ketovalerate, 11710.64 mol) of dibenzylamine hydrochloride and 19.8 (0.22 mol) of paraformaldehyde was heated with 1 powder of concentrated hydrochloric acid at 150 mA.
of 95% ethanol was added and the mixture was diluted with
Heat to reflux for an hour. The mixture is filtered once with 500 m/ml of hot acetone and the mixture is cooled and refrigerated overnight. One portion of the precipitated product is washed with acetone and dried.

++, 6. 5,5-tetramethylbi-lysine-2,
The above hydrochloride of 4-dione is partitioned between 0.1N hydroxide solution and ethyl ether. Dry the ether extract (IV
L! i'5O4) L, evaporate to dryness and dissolve the residue in methanol. This methanol solution [1,! 10% of 9
Is hydrogen absorption completely VC by adding p d/C? V: Hydrogenate at 6-4 times atmospheric pressure until the mixture is completely dissolved. The catalyst was removed and the mixture was heated at 7O-80C for 2 hours under a liquid atmosphere. The remaining product is purified by chromatography on silica gel.

111, the above-obtained pyridine is converted from lysinedione into a 4-oximino derivative by the method of Preparation Example Q, and this is reduced to give the title 4-amine compound.

Production example U Ro, Ro, 5,5-tetramethyl-0 Loridine-2,4-
Dione U, S, Ro, 80 g of 2.2.4.4-tetramethyl-1,ro-dichlorobutanedione monooxime synthesized by the method of 125.569 and 25 Q tnl of 98% (7M amount by weight) of sulfuric acid. The mixture is warmed to 50-60C for 1 hour and then left at room temperature overnight. The reaction mixture was poured into ice at 800F, extracted with methylene chloride, and the extract was washed with sodium bicarbonate solution and water, and dried (MESO4).
The solvent is then removed by distillation. The remaining product mixture is purified by column chromatography on silica gel and the fractions containing the title compound are evaporated to dryness.

The ketolactam thus obtained is converted to 6-amino-6,ro,5,5-tetramethyl-2-pyrrolidone by the method previously described.

Production example ■ 6-amino-2,2,4,4-tetramethylchetane and its 1,1-dioxide A, 2,4-dibromo-2,4-dimethylpentane-1
To 66 g (1.2 moles) of diisopropyl ketone are added 2 molar phosphorus bromide and the mixture is cooled to IOr.

384 for this. ! i' (2.4 mol) of bromine was added dropwise.
The mixture is allowed to warm to room temperature. After 2 hours at this temperature, warm to 55-60C for 1 hour and cool.

Partition between chloroform and water. The aqueous layer is discarded and the organic layer is washed with sodium bicarbonate solution until neutral.

The organic layer was dried (MgSO4), the solvent was distilled off, and 61
6I (97%) of the desired product is obtained.

B. 2,2,4,4-Tetramethyl-6-oxochetane 23 g (1.0 mol) of total sodium are dissolved in 500 g of dry methanol and cooled to 10 tZ'.

Hydrogen sulfide gas is passed through the mixture until saturation.

136 g (0.5 mol) of dibromoketone obtained in step A are added dropwise, while hydrogen sulfide gas is passed through the reaction mixture. After the addition was completed, the mixture was stirred at 10C for 2 hours, warmed to room temperature and stirred overnight.The reaction mixture was poured into water and extracted with ethyl ether.

Wash the extract with dilute hydrochloric acid and saline. After drying with anhydrous #r and magnesium acid, the ether was distilled off, and the residue was made into a slurry with methanol, cooled, and filtered once to give 46 g (64%
) is obtained, which is used in the next step without further purification.

C, Reductive Amination of Ketones 75% in dry methanol 4.510. 2.2.4.4-tetramethyl-ro-oxochetane,
23.9. 10.0217 mol) of ammonium acetate and 6.10.0217 mol) of sodium cyanoborohydride are added and the mixture is heated to reflux for 4 hours.

Furthermore, sodium cyanoporohydride (1.56 g) was added, reflux was continued for 6 days, and the 6th leaf expansion using the same reagent was started on the 6th day of the month. The reaction mixture was made acidic to pH 2 with hydrochloric acid and evaporated to dryness in a vacuum-bottom tally evaporator. The residue was dissolved in water, washed with ethyl ether, and the aqueous layer was adjusted to pH 11 with sodium hydroxide solution and extracted with ethyl ether. The extract was washed with saline and dried (M,
9SO4) and then evaporated to dryness to obtain 1.9.142%) of the desired amine as a crystalline solid. The structure of the product is IH
- demonstrated by NMR spectra.

D, Ro-amino-2,2,4,4-tetramethylchetane-1,1-dioxide 29 g (0.2 mol) of the amine obtained in the above step C was added to 50 ml of
Dissolve Ll in acetonitrile and add 250 ml of water; while keeping the mixture at pH 10 with sodium hydroxide, add 35.8.9 (0.21 mol) of carbobenzoxy chloride over 30 minutes; The mixture is stirred for 1 hour, filtered, and the precipitate is washed with water and dried under vacuum at 50C to give N-Cb2-amine. Rfo, 7 (hexane/ethyl acetate; 4:1. molybdenum phosphate spray)
, 52.1 g (93.4%). This was dissolved in methylene chloride rVC of 7001, and 779 (0,372 mol)
of m-chloroperbenzoic acid at a temperature below 45C (20-4
Add slowly to maintain the temperature at 2C). The precipitated solid is removed, the fi liquid is washed with 1N hydrochloric acid and sodium bicarbonate solution, and after drying (MgSO4) the solvent is distilled off.

Recrystallization of the residue from acetone-water yields 42 g (73%) of cb2-protected amine 1,1-dioxide, RfO
, 7 (hexane/ethyl acetate 1:1 vol/vol, molybdenum phosphate spray).

5g of cb2-amine to 250rrLt(1) meta,/
- 2g of 5% Pb/C (5d) dissolved in 5d of concentrated hydrochloric acid;
Protecting groups are removed by water-purple addition at 0% wetness).

The product is isolated by conventional methods. Yield: 2.4g (
85%), Rf Q, retention time at 180C is 1.3 minutes by gas chromatography using a 661 meter 0-1 column. 3-amino-2,2°4.4
Starting from -tetramethylchetane, the overall yield over 6 steps is 65%.

Using equal amounts of amine and m-chloroperbenzoic acid in the above method similarly yields the corresponding sulfoxides.

E, instead of diisopropyl ketone [R3R4CHCO
Using a suitable ketone having the structural formula CHR5R6, the corresponding amine with the following structure is obtained by the method of Steps A-C.

CH3HCH3H CH3HHH C2H5HHH i -C3H7HHH i-C3H7H1-C3H7H t-C4Hg HHH t-C4Hg Ht-C4H9H n-C4H9Hn-C4H9H C2H5Hc2 get

Creation example W Lo-Amino2.2.4.4-Tetramethyltetrahydrothiophene A, 1-hydroxy-2,2,4-trimethylpancn-3-one Made from 7,59 metallic sodium and 2501 methanol Sodium methoxide, followed by 250 g (2°2
mol) of diisopropyl ketone are added and the mixture is heated to reflux for 3 hours. Stop the reaction with water, neutralize with hydrochloric acid, extract with ethyl ether, and extract with water.

After washing with brine, the solvent is distilled off. Remaining oily substance (90
g) was distilled under vacuum to give 92-98t at 16-200:'
28 g of desired product are obtained which is distilled off at .

GLC with 0V-1 column at 107C, retention time 6
14 seconds, 96% pure.

Carrying out the above procedure on the same scale but with reflux of the reaction mixture for 16 hours yielded 61 g of 96% pure product by GLC.
can get.

B, 4-promol 1-hydroxy-2,2,4-tri6
While stirring and refluxing a solution of 1-hydroxy-2,2,4-trimethyl R-tan-3-one (910.48 mol) dissolved in 50 []m of chloroform, 77 g (0,4
A solution of 8 moles of bromine dissolved in 100 moles of chloroporm is whitened. After the addition is complete, the mixture is stirred and refluxed for an additional hour, allowed to cool, and stirred overnight at room temperature. The solvent was distilled off under reduced pressure to obtain 127 g of product. This is used in the next step without further purification.

C,2,2,4,4-tetramethyltetrahydrothiophene-6-one 79. obtained in step B. ! ? (0,,1S mol) of product is filtered out.

- Dissolve chu in dry pyridine, cool to oc and 1 oc.
14. 1O, 6 mol) of p-)luenesulfonyl chloride is added in portions. The mixture is stirred at that temperature for 6 hours and 15 minutes, poured into water/water and extracted with ethyl ether. The extract is washed with dilute hydrochloric acid/brine and dried over anhydrous magnesium sulfate.

Distill the solvent, 111! A crystalline tosylated product of j (98%) is obtained.

94, lO, 25 mol) of tosylated '&11] liter of pyridine, 18010.75 mol) of sodium sulfide monohydrate was added, the mixture was heated to 750 °C and kept at this temperature for 1 hour. After that, leave it at room temperature overnight. Water is added and the mixture is extracted with ether.

Wash the extract with hydrochloric acid and brine, dry (MESO4)
Afterwards, the solvent was distilled off to obtain 5 g of the title compound, yield 8.
9%. The raw acid was developed on silica gel TLC with ethyl acetate/hexane (1:4, RfO, 5) showing a single spot. IH-NMR spectra confirmed the structure of the title compound.

D, 100 with Leuckart reduction stirrer for ketones, thermometer and condenser with fractionation head.
10.0.9 (0,063 mol) of 2.2.4.4-tetramethyltetrahydrothiophene-6-one, 15.2rn1.d in a 6-diameter round bottom flask. (0.38 mol)
of Formamide F and 6.51M (0,092 mol) of formic acid were added, and the mixture was heated to reflux (163r) while removing water.
do.

The reaction mixture is kept at 160-1800 for 20 hours, during which time formic acid (IQd) is added. At the end of this period the temperature of the reaction vessel reaches 200C. After cooling the reaction mixture, water was added and extracted with ethyl acetate. Evaporate the extract under vacuum. The residue was refluxed with 20-6N hydrochloric acid for 2 hours, and the mixture was then washed with ethyl ether.
The aqueous layer was adjusted to pH 11 with sodium hydroxide solution and extracted with ethyl ether. When the extract is dried and distilled off, 2I
6-amino-2,2,4,4-tetramethyltetrahydrothiophene was obtained, which was identified by IH-NMR,
It was found to be single by silica gel TLC.

E. If appropriate ketones are used as starting materials in place of dicyclopropyl ketone in the above method and surface preparation example X, the following amines are similarly obtained.

S CH3HCH3H 8HHCH3H 8CH3CH2HCH3CH2H 8(CH3)2CHH(CH3)2CH,H8CH3C
H3HH OCH3CH2HCH3CH2) ( OCH3HCH3H OHHCH3H OCH3HH)1 0 HH(CH3)3CH OCH3CH2Hn-C4Hg HOCH3CH3
CH2CH3CH3CH2 When tetrahydrothiophenes of the above structure are reacted with equal amounts of hydrogen peroxide or chloroperbenzoic acid, the corresponding sulfoxides (X=S
O) is generated. Reaction of the same starting material or its sulfoxide with a 1 molar excess of the same reagent or potassium permanganate gives the corresponding sulpon (X=so2).

Production example
, 2,2,4.4-Tetramethyltetrahydrofuran-6-one 4-bromo-1-hydroxy-2,2,4-trimethylsyntan-6-one (as described in Steps A and B of Preparation W) 8. Dissolve 25,10.1 mol) of 25,10.1 mol) in 160 powder of ethanol. A solution of 80 ml of sodium hydroxide (1O, 2 mol) in 80 molar water is added. The mixture was stirred for 60 minutes at room temperature.

Dilute with water and extract with ethyl ether. Add the extract to water,
Wash with saline and dry with anhydrous magnesium sulfate. The solvent was distilled off and 177.9 2.2.4. -) Limethyl produces butane-1,4-diol as a colorless liquid, which is identified by IH-m. The diol was dissolved in 501 Lt of chloroform, and 1.5 liters of concentrated sulfuric acid was added dropwise. The mixture is heated under reflux for 6 hours, during which time the water/chloroform azeotrope is distilled off from the mixture. After leaving it at room temperature overnight 1
Wash the reaction mixture with water and dry the organic layer (M19SO4)
L. The solvent was distilled off under vacuum to obtain 13.9 g of a colorless liquid. With distillation I-.

8.6 g of desired product are obtained. B, P, 70-72° (50m) 58% of all vehicles collected.

B, ketone obtained in step A (8.0 JlO, 056 mol),
Hydroxylamine hydrochloride (8,010.11 s mol) and sodium acetate 2.3 g (0,113 mol) are placed in 85% ethanol and the mixture is refluxed for 48 hours.

It was diluted with water, extracted with ethyl ether, washed with water, dried and the solvent was distilled off, yielding a mixture of syn- and anti-oxime with a concentration of 9.0, ? Samurai in the yield of 100%, which was identified by IH-merization.

Oxime 1.3.9 (8,28
1.9 mmol) was dissolved in 70 liters of dry ethanol.
Add IJum and warm the mixture until it begins to reflux and hold at that temperature for 15 minutes.

Heating was continued for 2 hours, during which time 1.9 g of metallic sodium was added twice. Carefully dilute the reaction mixture with water and
Extract with ethyl ether, extract the ether layer with dilute hydrochloric acid, hydroxylate the aqueous layer) Make alkaline with IJum, extract again with ether, dry the extract CMiSO4)
L is evaporated to dryness and the residue is distilled to obtain the desired amine.

B, P, 68-69CC15raR). Ethyl erthyl was precipitated as a hydrochloride from methanol, and the salt was made basic and extracted again with ether.
The amine has a purity of 0.87.94%.

Patent fi'XM agent Pfizer Incorporated Patent attorney Kyo Yuasa 3-7.

Claims (1)

Claims: 1. L-asnomorty-D-amino acid di-R-butide amide of the formula and its physiologically suitable cation salts and acid addition salts. [wherein Ra CH20H or CH2OCH3; R is a branched group selected from the following group: fenthyl, diisopropylcarbinyl. 5-Methyl-su-butylcarbinyl, 9-ethyl-su-
Butyl carbinyl, di-butyl carbinyl, 2-methylthio-2,4-dimethylpentan-6-yl, and the rest is hydrogen or alkyl having 1 to 4 carbon atoms; X is 0, s, so, so2, C:=:O or CHOH;
and p are respectively zero, 1.2, or 3, and the sum of n and p is 6.
Not bigger than. The total number of carbon atoms in R3, R<, Rs and R6 does not exceed 6. When both R3 and R4 or R5 and R6 are alkyl, the alkyl is methyl or ethyl) (
One of R7, R8, and R9 is alkyl having 1 to 4 carbon atoms, and the rest are hydrogen or alkyl having 1 to 4 carbon atoms, and the total number of carbon atoms in R7, RζR9 is not greater than 6. ) (m and q are the same or different numbers, each of which is 0 for the above m (R12, l' (13 is each methyl or ethyl, or R12 is hydrogen and R13 is alkyl having 1 to 4 carbon atoms: Z is 0 or NH; t is 1 or 2) (W is 1.2.6 or 4; R14 and R16 are each alkyl having 1 to 4 carbon atoms; R15 is hydrogen, OH1 or alkyl having 1 to 2 carbon atoms. Available: R14, R15゜R
The sum of the 16 carbons is not greater than 6. R14 and R1
When both of 5 are alkyl, the alkyl is methyl or ethyl. ) (R17, R19 are alkyl having 1 to 4 carbon atoms, R18,
) (20 is alkyl having 1 to 2 carbon atoms, when A and B are separate, A is OH, B is hydrogen, 0H7lj methyl. When A and B are bonded together, A and B are OO. The total number of carbon atoms of R, R, R, and H is less popular than 6, and R
17, R18 or Hl9. When both H20 are alkyl, the alkyl is methyl or ethyl. ,H6,H7,H8,R9,F
? 12, R13, R14, R15, R16, Hl 7.
R1B, R19, R20, A, B, X, Z,
m, n, p, q, t, and W are each the same as defined above) 3. R is diisopropylcarbinyl, d-methyl-
The compound of claim 1 which is t-butyl-carbinyl or di-t-butylcarbinyl. 4. R is (R17, R18, R19, R20 are each methyl, A is OH, B is hydrogen, OH or methyl, or
The compound of claim 2 which is 0. 5, R is (R15 is 0H1R14, R16 is each methyl, w is 2
or 6) in Claim 2]J. The compound according to claim 2, which is The compound according to claim 2, wherein Z R is (R7, R8, R9 are each methyl). The compound according to claim 2, which is 9 When R is (m is 2: R3-R6 are each methyl: R3, R
4, R5 is each hydrogen, R6 is methyl, ethyl, isopropyl or t-butyl; or R3J (5 is each hydrogen and R4J (6 is each methyl; when m is 6, R3 is hydrogen or methyl, R4゜R5,
R6 is each methyl; R3, R4, R5 are each hydrogen R6 Cainprohy6 or t-butyl: R3 and R5 are each hydrogen) (4 is methyl; R6 is methyl, ethyl, impropyl: or R3, R4 are each hydrogen , ) (5, R6 is methyl or ethyl). 10. When R is (n is 1. p is zero: R3-R6 are each meth A
/, xhao, S MatahaSOz; When watop is each 1, 2R3 and R5 are hydrogen, R4,
The compound of claim 2, wherein each R6 is methyl X is S or 802). 11. The above compound is L-asnozorutyl-D-serine N-(2,2,5,
5-tetramethylcyclotactyl)amide, L-aspartyl-D-serine N -(2,2,4,4
-tetramethyltetrahydrothiophen-6-yl)amide. L-7 Spartyl-D1 Serine N-(t,-butylcycloprobyl)carbinylamide. L-Aspartyl-D-serine N-(dicyclopropylcarvinyl)amiF. lucicloprovir (rubinyl) amide. L-Aspartyl-D-0-methylserine N-(dicyclopropylcarvinyl)amide. The compound according to claim 1, which is 12, L-aspartyl-D-serine N-(dicyclohexylcarvinyl)amide, thyl-1,1-dioxochetan-6-yl)amide. The compound according to claim 11, which is 13°. 14. A composition for sweetening foods, characterized by a sweetening effect amount of a physiologically suitable cationic salt or acid addition salt of a compound of the following formula: and an autotoxic carrier. R is a branched group selected from the following group: fentyl, diisopropylcarbinyl. d-methyl-1-butylcarbinyl, d-ethyl-t-
i-thylcarbinyl, di-t-butylcarbinyl, 2-methylthio-2,4-dimethylintan-3-yl. (Here, at least one of R'', R', H5, H6 is an alkyl having 1 to 4 carbon atoms, and the rest are hydrogen or alkyl having 1 to 4 carbon atoms: X is O, S, So, 802 c= o or C
HOH: m is zero, 1.2, 6 or 174: 11 and p are each zero, 1.2 or 3 and the sum of n and p is not greater than 6. The total number of carbon atoms in R3, R4, R5, and R6 does not exceed 6. When both R3 and R4 or R5 and R6 are alkyl, this alkyl is methyl or ethyl) (One of R, R, and H is an alkyl having 1 to 4 carbon atoms, and the remaining are hydrogen or carbon is an alkyl number 1 to 4
The total number of carbon atoms in R7, H8, and H9 is not much larger. ) (m and q are the same or different numbers and are the values shown for m above.) 13 (R12 and R13 are each methyl or ethyl, or R12 is hydrogen and R13 has 1 to 4 carbon atoms.) Alkyl: Z
k-10 or NH: t is 1 or f! 2) (W is 1,2
．． 3 or 4: R14 and R16 are each alkyl having 1 to 4 carbon atoms; R15 is hydrogen. OH1 or alkyl having 1 to 2 carbon atoms; R14, R
The total number of carbon atoms in 15 and R16 is not greater than 6. R1
When both 4 and R15 are alkyl, the alkyl is methyl or ethyl. ) (R17 and R19 are alkyl having 1 to 4 carbon atoms, RlB,
R20 is alkyl having 1 to 2 carbon atoms, when A and B are separate, A is OH, B is hydrogen, OHt+ is methyl, and when A and B are bonded together, A, R, R %R,
The total number of carbon atoms in H is not greater than 6, R17, R1g
or when both R19 and R20 are alkyl, the alkyl is methyl or ethyl)] 15. A sweetening amount of the compound of the following formula or a physiologically appropriate cation salt or acid addition salt thereof and saccharin or a physiologically appropriate amount. A composition for sweetening foods, characterized in that it consists of a mixture with naso salt. In the formula C, R is a branched group selected from the following group: fentyl, diisopropylcarbinyl, he-methyl-3-butylcarbinyl, ethyl-i- t-1-lcarvinyl, di-t-1-lcarvinyl, 2-methylthio-2,4
-dimethylpentan-6-yl. (n) where R3, R4, R5, R6 (one of them is alkyl having 1 to 4 carbon atoms, and the rest are hydrogen or alkyl having 1 to 4 carbon atoms)
Nofurkyl; X)t O,S, So, So2.
C=O or CHOH: m is zero, 1.2.6 e.g. 4:0 and p are each zero, 1%2 or 3 and the sum of D and p is not greater than 6. The total number of carbon atoms in H3, H4, R5, and R6 does not exceed 6. When both R3 and R4 or R5 and R6 are alkyl, this alkyl is methyl or ethyl) (one of R, RlH has 1 carbon number)
~4 alkyl, the remainder being hydrogen or alkyl having 1 to 4 carbon atoms, and the total number of carbon atoms of R7, R8, and R9 is not greater than 6. ) (m and q are the same or different numbers and are the values shown for m above.) (R12 and R13 are each methyl or ethyl, or R12 is hydrogen and R13 is a carbon number of 1 to 4. Alkyl: Z
is O or NH; t is 1 or 2) (W is 1.2, 3 or 4: R14 and ""6 are each alkyl having 1 to 4 carbon atoms: R15 is hydrogen, OH1 or 1 to 2 carbon atoms) is alkyl, and the total number of carbon atoms of R, R, and H is not greater than 6. When both R and H are alkyl,
The alcohol is methyl or ethyl. ) (R17, R19, are alkyl having 1 to 4 carbon atoms, R18
, E (20 is alkyl having 1 to 2 carbon atoms, when A and B are separate, A is 0H1B is hydrogen, OH or IJ methyl, and when A and B are bonded together, A and B is 0
0 0 The total number of carbon atoms in R17, R18, R19, and R20 is not greater than 6, and when R17%R18 or both R19 and R20 are alkyl, the alkyl is methyl or ethyl)]i 6. Compound KaL-asunolthyl-D-serine N-(2,2,4,4-tetramethylchetane-6
-yl)amide according to claim 15. 1Z The weight ratio of the above compound and saccharin is 1:1 to 1
:B. 18. A sweet food composition comprising a food and a sweetening amount of a compound of the following formula, or a physiologically appropriate cation salt or acid addition salt thereof. Formula % Formula % R is a monobranched group selected from the following group: fenthyl, diisopropylcarbinyl. d-methyl-t-butylcarbinyl, d-ethyl-t-
-jf carbinyl, di-t-butylcarbinyl, 2-
Methylthio-2,4-dimethyl is nthan-6-yl, (wherein one of R3, R4, R5, R6 is an alkyl having 1 to 4 carbon atoms, and the rest are hydrogen or alkyl having 1 to 4 carbon atoms. , a; xhao, s, so, so2, G=
O ma or Ql (OH: m is zero, 1.2.6 e (4 years old)
+n and p are each zero 1.1.2 or 6, and the sum of D and p is not greater than 6. The total number of carbon atoms in R3, R4, R5, and R6 does not exceed 6. When both R3 and R4 or R5 and R6 are alkyl, this alkyl is methyl or ethyl) (One of R7, H8, and H9 is an alkyl having 1 to 4 carbon atoms, and the rest are hydrogen or 1 carbon alkyl.) ~4 alkyl,
The total number of carbon atoms in R, R, H is not greater than 6. ) (m and q are the same or different numbers, each having the value shown for m above.) (R%R is each methyl or ethyl, or. R12 is hydrogen and R13 has 1 to 4 carbon atoms. alkyl; Z is O or NH; t, is 1 or 2) (W is 1.2.6 or 4; R" and R16'
L% is alkyl having 1 to 4 carbon atoms; R15 is hydrogen, OH,
or alkyl having 1 to 2 carbon atoms; R14, R15,
The total number of carbon atoms in R16 is not greater than 6. R14 and R
When both of 15 are alkyl, the alkyl is methyl or ethyl. ) (Hl7.R19 is alkyl having 1 to 4 carbon atoms Hl8
゜If A and B are bonded together, A and B are R1
7, R1: Hl 9. The total number of carbon atoms in R20 is not greater than 6, and when R17, Rlg or both R19 and R20 are alkyl, the alkyl is methyl or ethyl)]19.Claim 18, wherein the above-mentioned food is a carbonated beverage. sweet food composition. Formula 201: % Formula % (D-amino acid amide compound of .
C (selected from D iI, i.e., fenthyl, diisophthyl carbinyl, cyclophthyl t-
Butyl carbinyl, dicyclopropyl carbinyl. (11134 in the formula is 1, 2 or 6; when ml is 1, 2R
30R40, R51% R6° each has 2 methyl sml
When: R30 is methyl, ethyl or isopropyl and R4
0, R50, R60it % k hydrogen, AluihaR
", 'R50b"21? ``Methyl, R4O, R6
When 0 is each hydrogen and m+ is O: Ial R30 is isopropyl or t-butyl. 1 (4Q, R2O, R60 are each hydrogen, Ibl R3
0 is ethyl, R50 is methyl, R40 and R60 are each hydrogen, lcl Rho, p (40 is each methyl, R5ζR6
0 is each hydrogen or methyl): (When R2 and TJ2 in the formula are each zero, R4ζR61 is each methyl, X2 is S, So, C=Q or CH
When OH, R2 is zero and R2 is 1. R41 and R61 are each methyl, X2 is 0, S or SO3
; 112 is 1. When R2 is 1, R41 and R61 are each hydrogen, and X2 is S or SO2. ) 21, F (0 cyclopropylcarvinyl. 2,2.4.4-butramethylethane-3-yl, or 2,2.4.4-tetramethyl-1,1-dioxo-chetane-3 The compound according to claim 20, which is -yl. The compound according to claim 21, wherein 22 and Ra are CH20H.