JP2001064265A - Alkyl hydantoins - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound useful as an intermediate for effectively producing (L)-Boc-N-methyl-leucine and analogous compounds thereof and useful as a producing material for medical and agrochemical compounds. SOLUTION: This compound is represented by the formula (R1 is a 1-6C alkyl; R2 and R3 are each H or a 1-6C alkyl) e.g. 5-alkylidene-1-alkylhydantoin. The compound is obtained e.g. by reacting 1-substituted hydantoin with 0.8-1.5 molar times compound containing bromine (e.g. bromine or N- bromosuccinimide) in the presence of a solvent such as acetic acid at 70-120 deg.C to brominate 5-position of the hydantoin, then reacting the brominated product with 1-2 molar times phosphite based on the applied 1-substituted hydantoin and then reacting the resultant product with 1-5 molar times compound containing a carbonyl group (e.g. isobutly aldehyde) in a solvent e.g. ethanol in the presence of a base (e.g. triethylamine) at room temperature.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to alkylhydantoins useful as intermediates for the production of medicines and agricultural chemicals.

[0002]

2. Description of the Related Art WO 98/20891 discloses a compound represented by the following formula.

[0003]

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[0004] This compound is known to be useful as a medicament for maintaining the sensitivity of cells or for enhancing or restoring the sensitivity. The above publication contains (L) -Bo
c-N-methyl-leucine (Boc: tert-butoxycarbonyl) and N-benzyl- (3- (pyridin-4-yl) -1- (2- (pyridin-4-yl) ethyl) propyl) amine After the reaction, the Boc group is deprotected,
Furthermore, it is described that the target compound was synthesized by reacting with 3,4,5-trimethoxybenzoyl formic acid, but there is no specific disclosure about a method for producing (L) -Boc-N-methyl-leucine. .

[0005] The (L) -Boc-N-methyl-leucine is generally prepared, for example, by a known method (Canadian Journal).
al. Chemistry, 49, 1968, 1971), after introducing a protecting group into the amino group of leucine, followed by reaction with an alkyl iodide in the presence of sodium hydride. However, this method is not a practical method because the amounts of sodium hydride and alkyl iodide used are large and the yield of alkylation is low.

[0006]

An object of the present invention is to efficiently produce (L) -Boc-N-methyl-leucine and its analogous compounds which are useful as raw materials for producing pharmaceutical compounds and agricultural chemical compounds. The object of the present invention is to provide a production intermediate which can be used for the production. Another object of the present invention is to provide a method for producing (L) -Boc-N-methyl-
An object of the present invention is to provide a method for efficiently producing leucine and its analogous compounds.

[0007]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, the following general formula (I)
And alkylhydantoins represented by the general formula (II) were found to be useful as intermediates for producing (L) -Boc-N-methyl-isoleucine and its analogous compounds. The present invention has been completed based on the above findings.

That is, the present invention provides the following general formula (I):

[0009]

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Wherein R ¹ represents a C _1-6 alkyl group;
R ² and R ³ are each independently a hydrogen atom or C _1-6
Which represents an alkyl group). Further, the following general formula (III): (R ² ) (R ³ ) CH—CH (COOH) —N (R ¹ ) (R ⁴ ) (III) (wherein R ¹ , R ² and R ³ are as defined above) Is synonymous with R ⁴
Represents an amino-protecting group), which is an intermediate for producing the compound represented by the above general formula (I).

Also, an intermediate for producing the compound represented by the above general formula (I) or (III),
I):

[0012]

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(Wherein R ¹ , R ² and R ³ have the same meanings as described above).

From another viewpoint, a method for producing a compound represented by the general formula (III), comprising a step of hydrolyzing the compound represented by the general formula (I) and protecting an amino group; and After hydrolyzing the compound represented by the general formula (I) obtained by reducing the compound represented by the general formula (II), the method comprises the step of protecting an amino group.
A method for producing the compound represented by I) is provided.

From another viewpoint, the following general formula (I
V):

[0016]

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(Wherein R ¹ , R ² and R ³ are as defined above, and R ³¹ is a substituted or unsubstituted aralkyl group, a substituted or unsubstituted heteroarylalkyl group,
_1-4 represents an alkyl group; R ³² is a hydrogen atom, a substituted or unsubstituted aralkyl group, or a substituted or indicates unsubstituted heteroarylalkyl group; R ³³ is a substituted or unsubstituted aryl group, a substituted or unsubstituted A heteroaryl group, a substituted or unsubstituted aralkyl group, or a substituted or unsubstituted heteroarylalkyl group), the method comprising the following steps: (1) )), After hydrolyzing the compound represented by formula (III), protecting the amino group to produce the compound represented by the above formula (III); (2) the compound represented by the formula (III) obtained in the above step (1); ) And the following general formula (V): R ^33- (CH ₂ ) ₂ -CH (R ³² ) -NH-R ³¹ (V) (where R ³¹ , R ³² and R ³³ are As defined above) Extent; (3) The compound obtained in the above step (2) is deprotected, 3,
There is provided a method comprising reacting with 4,5-trimethoxybenzoyl formic acid.

In the method for producing the compound represented by the general formula (IV), the compound represented by the general formula (I) used in the step (1) is preferably represented by the general formula (II) The compound of the general formula (I) obtained by reducing the compound can be used.

[0019]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The terms used in the present specification have the following meanings. The “alkyl group” or the alkyl moiety of the substituent containing the alkyl moiety (eg, an aralkyl group) may be straight-chain or branched. C _{1-
6 As} an alkyl group, for example, a methyl group, an ethyl group,
n-propyl group, isopropyl group, n-butyl group, se
c-butyl group, isobutyl group, tert-butyl group, n
-A pentyl group, an isopentyl group, a cyclopentyl group, n
-A hexyl group, an isohexyl group or a cyclohexyl group can be used. As the “aryl group”, a monocyclic or condensed polycyclic aromatic group can be used. For example, a monocyclic or bicyclic aromatic group can be used. The number of carbon atoms of the aryl group is, for example, 6 to 12, preferably 6 to 10. Examples of the aryl group include a phenyl group and a naphthyl group, and a phenyl group can be preferably used. An aryl group can be attached at any position on the ring.

As the "heteroaryl group", one heteroatom such as a nitrogen atom, an oxygen atom, a sulfur atom or the like is used.
A monocyclic or fused polycyclic heteroaryl group containing two or more can be used. For example, a monocyclic or bicyclic heteroaryl group can be used. If they contain two or more heteroatoms, they may be the same or different. A heteroaryl group can be attached at any position on the ring. Examples of the heteroaryl group include a thienyl group, a furyl group, an imidazolyl group, a pyridyl group, an isoquinolyl group, and a quinolyl group. Of these, a pyridyl group or an imidazolyl group is preferable. More preferred is a pyridyl group, and a 3-pyridyl group or a 4-pyridyl group is particularly preferred.

As the "aralkyl group", C 1 to which one or more, preferably one, of the above-mentioned aryl groups are bonded.
_1-4 alkyl groups can be used, and preferably a benzyl group or a phenethyl group can be used. As the "heteroarylalkyl group", C 1 to which one or more, preferably one of the above heteroaryl groups is bonded
_{A 1-4} alkyl group can be used, and a pyridylmethyl group, a pyridylethyl group, an imidazolylmethyl group, an imidazolylethyl group, or the like can be preferably used.

In the compound represented by the above general formula, preferred substituents are as follows. As R ¹ , a methyl group can be preferably used. R ² is preferably an isopropyl group, and R ³ is preferably a hydrogen atom. R ³¹ is a benzyl group, p-
A chlorobenzyl group, a p-fluorobenzyl group, a 4-pyridylmethyl group, a 1H-imidazolyl-1-ylmethyl group or a methyl group can be used. Among these, a benzyl group, a p-chlorobenzyl group, a p-fluoro group and the like can be used. A benzyl group is more preferred. R ³² represents a hydrogen atom, a phenethyl group, a 3-phenylpropyl group, a 3- (3-pyridyl) propyl group, a 3- (4-pyridyl) propyl group,
-(3-pyridyl) ethyl group, 2- (4-pyridyl) ethyl group and the like can be used.
A pyridyl) ethyl group is more preferred. R ³³ includes a phenyl group, a pyridyl group, a benzyl group, a 3-pyridylmethyl group, a 4-pyridylmethyl group, and 1H-imidazolyl-1
A -yl group or the like can be used, and among these, a pyridyl group is more preferred, and a 4-pyridyl group is particularly preferred. As the amino protecting group represented by R ⁴ , various protecting groups can be employed (for example, Protective Groups in Organic
Synthesis, TW Greene, John Wiley & Sons, Inc.,
1981), for example, and a tert-butoxycarbonyl group (Boc group) and the like are preferable.

The compound of the above formula (I) wherein R ¹ is a C _1-6 alkyl group and R ² and R ³ are hydrogen or a C _1-6 alkyl group is a novel compound. Isomers (eg, optical isomers, diastereoisomers, geometric isomers) of these compounds, arbitrary mixtures of the isomers, and racemates are also included in the scope of the present invention. Furthermore, hydrates or solvates of these compounds are also included in the scope of the present invention.

The method of the present invention comprises: (A) a step of hydrolyzing the compound represented by the above general formula (I) and then protecting the amino group.
(B) a method for producing a compound represented by the general formula (II), wherein the compound represented by the general formula (I) obtained by reducing the compound represented by the general formula (II) is hydrolyzed; The above general formula (III) including the step of protecting
(C) A method for producing a compound represented by the above general formula (IV), comprising the following steps: (1) A method for producing a compound represented by the above general formula (I) A step of producing a compound represented by the above general formula (III) by protecting the amino group after hydrolysis; (2) a step of preparing a compound represented by the general formula (III) obtained in the above step (1); The following general formula (V): R ³³ — (CH ₂ ) ₂ —CH (R ³² ) —NH—R ³¹ (V) (wherein R ³¹ , R ³² and R ³³ are as defined above). (3) deprotecting the compound obtained in the above step (2),
(D) a method comprising the step of reacting with 4,5-trimethoxybenzoylformic acid; and (D) a method for producing a compound represented by the above general formula (VI), wherein the compound represented by the general formula (I) used in the step (1) is used. The compound represented by the general formula (I) includes a method using a compound represented by the general formula (I) obtained by reducing the compound represented by the general formula (II).

From the compound represented by the formula (II), the compound represented by the formula (V)
As a method for producing the represented compound, R^FourIs a Boc group
The following scheme shows the production method in such a case. R¹,
R³¹, R ³², And R³³Is as defined above. Less than,
The method of the present invention will be described based on this scheme.
The method of the invention is a specific production method shown in the scheme below.
It is not limited to. The reaction conditions and reagents
The method can be appropriately selected by those skilled in the art and described below.
Should be understood that appropriate alterations and modifications are possible
is there.

[0026]

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First, 5-alkylidene-1-alkylhydantoin (IIa) can be produced by condensing an alkylaldehyde or ketone with an alkylhydantoin or a derivative thereof. As a method of the condensation, (1) a method of brominating the 5-position of the corresponding hydantoin, reacting it with a phosphite, and further reacting with a carbonyl group-containing compound in the presence of a base (Journal of Organic Chemistry, Vol. 56, 24) No. 6897, 1991), (2) A method of reacting a carbonyl group-containing compound with a 1-substituted hydantoin in the presence of a base using acetic acid or acetic anhydride as a solvent (JP-A-56-156).
268), and in the case of the present compound, (1) can be suitably used. In the method of (1),
The bromination is carried out by reacting the 1-substituted hydantoin with a bromine-containing compound. Examples of the bromine-containing compound include bromine and N-bromosuccinimide. The amount of the bromine-containing compound to be added is 0.8 to 1.5 times, preferably 0.9 to 1,4 times the mol of the 1-substituted hydantoin.

As a solvent used in the reaction, a compound containing a carboxylic acid such as acetic acid or acetic anhydride, or an ether compound such as diethyl ether or tetrahydrofuran can be used. The amount of the solvent used is 1 to 50 times by volume, preferably 5 to 30 times by volume, based on the charged alkylhydantoin. The reaction temperature varies depending on the solvent used.
To 120 ° C, preferably 70 to 100 ° C. The thus obtained 5-bromine-1-substituted hydantoin is
The 5-substituted phosphoric acid-1- was further reacted with a phosphorus-containing compound.
Convert to substituted hydantoin. Phosphorous esters (methyl phosphite, ethyl phosphite) are preferably used as the phosphorus-containing compound. The amount of the phosphorus-containing compound to be used is 1 to 2 moles, preferably 1 to 1.5 moles, relative to the charged 1-substituted hydantoin. As a solvent used in the reaction, a compound containing a carboxylic acid such as acetic acid or acetic anhydride, or an ether compound such as diethyl ether or tetrahydrofuran can be used. The amount of the solvent used is 1 to 50 times by volume, preferably 5 to 30 times, based on the charged 5-bromine-1-substituted hydantoin.
It is twice the capacity. The reaction temperature is usually around room temperature. In the presence of the thus obtained 5-substituted phosphoric acid-1-substituted hydantoin, a carbonyl group-containing compound and a base,
Reaction gives a 5-substituted olefin-1-substituted hydantoin of formula (IIa).

The base used in the reaction is a pKa value indicating the strength of the base, for example, Advanced Orange.
9 or more, preferably 10 or more can be used, as exemplified in Volume 4 of the Nick Chemistry.
Specifically, tertiary amines (triethylamine, pyridine, etc.), alkoxides (sodium methoxide, sodium ethoxide, etc.), alkali metal hydroxides (lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.) are exemplified. . The amount of the base to be used is 1 to 3 moles, preferably 1 to 2 moles relative to the charged 5-substituted phosphoric acid-1-substituted hydantoin. Examples of the solvent used for the reaction include nitrile compounds (eg, acetonitrile), alcohols (eg, ethanol, methanol), and water.
When condensing with a compound such as acetone, it can be used also as a solvent. When a solvent is used, the amount of the solvent used is the charged 5-substituted phosphoric acid-1-
The volume is 1 to 50 times, preferably 5 to 30 times the volume of the substituted hydantoin. The amount of the corresponding carbonyl group-containing compound used in the reaction is 1 to 5 moles, preferably 1 to 3 moles, based on the charged 5-substituted phosphoric acid-1-substituted hydantoin. The reaction temperature is usually suitably around room temperature. The alkylhydantoin used as a raw material can be easily produced by reacting a compound represented by R ¹ —NH—CH ₂ —COOH (R ¹ represents a C _1-6 alkyl group) with KCNO.

By reducing the compound represented by the formula (IIa), 5- (alkyl) -1-alkylhydantoin (Ia) can be produced. The reduction can be generally performed by catalytic reduction. Examples of the catalyst include a palladium catalyst (palladium carbon, palladium alumina, palladium hydroxide carbon, palladium acetate, etc.), a platinum catalyst (platinum carbon, platinum carbon sulfide, etc.), a rhodium catalyst (rhodium carbon, rhodium alumina, rhodium triphenylphosphine). Complex), a ruthenium catalyst (such as ruthenium carbon), a nickel catalyst (such as Raney nickel) and the like, but preferably a palladium catalyst,
A rhodium catalyst or a platinum catalyst can be used.

The amount of the catalyst is not particularly limited, but is 1 to 50 mol%, preferably 1 to 20 mol%, in terms of metal, based on compound (IIa). As the solvent, for example, formic acid, acetic acid, methanol, ethanol, ethyl acetate, tetrahydrofuran, dimethylformamide and the like can be used, and preferably acetic acid, tetrahydrofuran, ethyl acetate and dimethylformamide can be used.
You may use these solvents in mixture of 2 or more types. The reaction temperature can be arbitrarily selected from the room temperature to the boiling point of the solvent. The reaction pressure is from normal pressure to 2 MPa, preferably from normal pressure to 1 MPa.

Compound (Ia) is hydrolyzed to give compound (Ia-
After 1), compound (IIIa) can be produced by introducing a Boc group as a protecting group. The hydrolysis can be usually performed under alkaline conditions. As the alkali, a general alkali can be used,
For example, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, or the like can be used, and preferably, calcium hydroxide, barium hydroxide, or the like can be used. The amount of the alkali used is an equimolar to 20-fold molar amount relative to compound (Ia),
Preferably it is about equimolar to about 10-fold molar.

The hydrolysis reaction can be performed in water, but can also be performed using an auxiliary solvent. As the auxiliary solvent, for example, dimethylsulfoxide, dimethylformamide, acetonitrile, methanol and the like can be used. When an auxiliary solvent is used, compound (Ia)
1 to 50 times by volume, preferably 5 to 30 times by volume, and two or more auxiliary solvents may be used in combination. The reaction can be usually performed at any temperature in the range from room temperature to the reflux temperature of the solvent, and can be preferably performed at the reflux temperature of the solvent. The reaction can be performed under pressure, but when the reaction is performed under pressure, 2MP
a, preferably a pressure of about 1 MPa is suitable.

As a method for introducing a Boc group into the compound (Ia-1), for example, Protective Groups in Organic
Synthesis, TWGreene, John Wiley & Sons, Inc., 19
The method specifically described in 81 or the like may be adopted. Various reagents can be used as the reagent for introducing the Boc group, and for example, ditert-butyl dicarbamate and the like can be used. P for performing the reaction
As H, generally, alkaline conditions can be selected. As the deoxidizing agent used for pH control, for example, sodium hydroxide, potassium hydroxide, ammonia and the like can be used, but an organic amine such as triethylamine and diisopropylethylamine may be used.

As the solvent, for example, methanol, acetonitrile, dioxane, ethyl acetate, tetrahydrofuran, methylene chloride and the like can be used, but the reaction may be carried out in a water-containing system. The amount of the solvent to be used is, for example, 1 to 50 times by volume, preferably 5 to 30 times by volume, relative to the compound (Ia-1). When water is used, the amount of the solvent is based on the compound (Ia-1). 1 to 50 times the volume, preferably 5
It is about 30 times the volume. The reaction can be performed at a temperature ranging from room temperature to the reflux temperature of the solvent. Compound (II
The production of compound (Va) from Ia) can be carried out, for example, according to the reaction conditions described in Examples 3 to 6 of International Publication WO98 / 20891.

[0036]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited to the following Examples. Example 1 25.0 g of methylhydantoin was added to 50 mL of acetic acid at 90 ° C.
After dissolving in, 35.0 g of bromine (1 mol per mol of charged methylhydantoin) was added over 1.5 hours. After stirring for 1 hour, the temperature was lowered to room temperature, and the mixture was stirred overnight. The obtained crystals were filtered and dried. To the dried crystals, 100 ml of diethyl ether was added, and at room temperature, 36.5 g of ethyl phosphite (1 mol per mol of methylhydantoin charged) was added over 1 hour. After the obtained crystals were filtered, they were recrystallized from hexane and tetrahydrofuran. The obtained crystals were filtered and dried to obtain 2-diethylphosphate-1-methylhydantoin (29.4 g, yield 53).
%). ¹ H-NMR (DMSO-d ₆ ) δ (ppm)
22 (m, 6H), 2.85 (s, 3H), 4.10
(M, 4H), 4.75 (s, 1H), 11.10
(S, 1H)

Example 2 5-Diethylphosphoric acid ester-1-obtained in Example 1
To 28.4 g of methylhydantoin, 50 mL of ethanol and 12.0 g of isobutyraldehyde (1.5 times the molar amount of the charged 5-diethylphosphate-1-methylhydantoin) were added, and at room temperature, 11.6 g of sodium ethoxide ( Charged 5-diethyl phosphate-
An ethanol solution (80 ml) of 1-methylhydantoin (1.5 times mol) was added over 1 hour. After stirring for 1 hour, ethanol was distilled off under reduced pressure. The obtained residue was crystallized by adding 150 ml of water. The obtained crystals were filtered and dried to obtain 16.7 g (88% yield) of 5-isobutylidene-1-methylhydantoin. ¹ H-NMR (DMSO-d ₆ ) δ (ppm)
00 (d, 6H, J = 0.67 Hz), 2.90 (s,
3H), 3.60 (m, 1H), 5.31 (d, 1H,
J = 1.0Hz)

Example 3 To 16.7 g of 5-isobutylidene-1-methylhydantoin obtained in Example 2 was added 150 mL of ethanol and 5%
7.79 g of palladium carbon (2 in metal conversion based on charged 5-isobutylidene-1-methylhydantoin)
Mol%), and the reaction was performed under a hydrogen atmosphere. 1
After stirring for 2 hours, the catalyst was removed by filtration, and ethanol was distilled off under reduced pressure. The obtained crystal was recrystallized from hexane and ethanol to obtain 16.2 g (yield 95%) of the target 5-isobutyl-1-methylhydantoin. ¹ H-NMR (DMSO-d ₆ ) δ (ppm)
87 (m, 6H), 1.60 (m, 2H), 1.77
(M, 1H), 2.75 (s, 3H), 3.28 (s,
1H), 3.31 (s, 1H), 3.98 (t, 1H,
J = 0.26 Hz)

Example 4 The Boc group was introduced after hydrolyzing 5-isobutyl-1-methylhydantoin obtained in Example 3 according to a conventional method. The obtained (L) -Boc-N-methyl-leucine was converted to N-benzyl-N- [3- (pyridin-4-yl) according to the method described in Example 5 of International Publication WO98 / 20891. -1- (2- (pyridin-4-yl)-
Ethyl) propyl] amine and Example 5 of the publication
(S) -N-benzyl-2- (N-methyl-N-tert-butoxycarbonyl) amino-3- (isobutyl) -N- (3- (pyridine- 4-yl) -1- (2- (pyridin-4-yl) ethyl) propyl) propionamide is treated with trifluoroacetic acid, and the obtained deprotected product is further processed by the method described in Example 6 of the publication. By reacting with 3,4,5-trimethoxybenzoylformic acid according to the method of (S) -N-benzyl-3- (isobutyl) -2- (methyl- (2-oxo-
2- (3,4,5-trimethoxyphenyl) acetyl)
Amino) -N- (3- (pyridin-4-yl) -1-
(2- (pyridin-4-yl) ethyl) propyl) propionamide (compound 1 described in Table 1 of the international publication)
6) was obtained.

[0040]

The alkylhydantoins of the present invention are useful as intermediates for producing pharmaceutical compounds and agricultural chemical compounds. Further, according to the method of the present invention using the above-mentioned alkylhydantoins, (L) -Boc-N-methyl-4-chlorophenylalanine and its analogous compounds useful as raw materials for producing pharmaceutical compounds and agricultural chemical compounds can be efficiently produced. Can be manufactured.

Claims (7)

[Claims] 1. The following general formula (I): (Wherein R ¹ represents a C _1-6 alkyl group; R ² and R ³
Each independently represents a hydrogen atom or a C _1-6 alkyl group). 2. The following general formula (III): (R ² ) (R ³ ) CH—CH (COOH) —N (R ¹ ) (R ⁴ ) (III) (wherein R ¹ , R ² and R ³ is as defined above; R ⁴
Is an intermediate for the production of the compound represented by the formula (I), wherein the compound is represented by the general formula (I). 3. The following general formula (II) which is an intermediate for producing a compound represented by the general formula (I) according to claim 1 or the general formula (III) according to claim 2. ] (Wherein, R ¹ , R ² and R ³ are as defined above). 4. A compound represented by the general formula (III) according to claim 2, comprising a step of protecting the amino group after hydrolyzing the compound represented by the general formula (I) according to claim 1. A method for producing a compound. 5. A compound represented by the general formula (I) according to claim 1, which is obtained by reducing the compound represented by the general formula (II) according to claim 3, and hydrolyzing the amino compound The method for producing a compound represented by the general formula (III) according to claim 2, comprising a step of protecting the group. 6. The following general formula (IV): (Wherein, R ¹ , R ² and R ³ are as defined above, and R ³¹
Represents a substituted or unsubstituted aralkyl group, a substituted or unsubstituted heteroarylalkyl group or a C _1-4 alkyl group; R ³² represents a hydrogen atom, a substituted or unsubstituted aralkyl group or a substituted or unsubstituted heteroarylalkyl R ³³ represents a substituted or unsubstituted aryl group;
A substituted or unsubstituted heteroaryl group, a substituted or unsubstituted aralkyl group or a substituted or unsubstituted heteroarylalkyl group), the method comprising the following steps: A step of producing the compound represented by the general formula (III) according to claim 2 by hydrolyzing the compound represented by the general formula (I) according to 1 and then protecting the amino group; (2) The compound represented by the general formula (III) obtained in the above step (1) and the following general formula (V): R ^33- (CH ₂ ) ₂ -CH (R ³² ) -NH-R ³¹ (V) ( Wherein R ³¹ , R ³² and R ³³ are as defined above); (3) deprotecting the compound obtained in the above step (2),
A method comprising the step of reacting with 4,5-trimethoxybenzoyl formic acid. 7. The method according to claim 6, further comprising the step of reducing the compound represented by the general formula (II) according to claim 3 to produce the compound of the general formula (I) before the step (1). the method of.