JPH10273486A - Production of 4-(2-alkenyl)-2,5-oxazolidinediones - Google Patents

Abstract

PROBLEM TO BE SOLVED: To efficiently obtain the subject compound useful as a synthetic raw material for peptides, etc., by reacting a specific α-amino acid 2-alkenyl ester with a chloroformylating agent in the presence of a base in a solvent and subjecting the reaction product to an intramolecular ring formation reaction. SOLUTION: An α-amino acid 2-alkenyl ester of formula I [R<1> to R<5> are each H, a 1-10C alkyl or aryl; R<6> is H or a (substituted) 1-10C alkyl; R<7> is H or a (substituted) alkyl, a (substituted) aryl, a 3-10C cycloalkyl, a 2-10C alkenyl, an acyl, an alkoxycarbonyl, an aminocarbonyl or a trialkylsilyl] is reacted with a chloroformylating agent in the presence of a base in a solvent to give an N-chlorocarbonyl α-amino acid 2-alkyl ester of formula II, which is subjected to an intramolecular ring formation reaction in the presence of a base in a solvent to give the objective 4-(2 alkenyl)-2,5-oxazolidinedione of formula III useful for a synthetic raw material for peptides, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing 4- (2-alkenyl) -2,5-oxazolidinediones. The above-mentioned 4- (2-alkenyl) -2,5-oxazolidinedione is one kind of α-amino acid derivative, but has a feature that an amino group is protected and a carboxyl group is activated. It is more useful as a raw material for synthesizing peptides and the like as compared with α-amino acids. Also,
4- (2-Alkenyl) -2,5-oxazolidinedione can be easily derived to the corresponding α-amino acid by hydrolysis or hydrogen reduction, for example, as shown in Reference Examples.

In particular, the present production method uses an α-substituted α-amino acid ester as an α-amino acid ester as a raw material, thereby deriving an α-amino acid having no hydrogen at the α-position, which has been conventionally difficult to produce. 4-substituted-4- (2
-Alkenyl) -2,5-oxazolines.

[0003]

2. Description of the Related Art Conventional 4- (2-alkenyl) -2,5
As a method for producing -oxazolidinedione, for example, there is a method described below.

[0004]: Journal of Chemical
al Society, 374, (1962) and J.
ownal of american chemical
al Society, 78, 5883, (1956) describes a method for obtaining 2,5-oxazolidineones in a yield of 60 to 85% by reacting an α-amino acid with phosgene in the presence of triethylamine. Have been. However, this method has a problem in that, when a 2,5-oxazolidineone having a substituent at the 4-position is synthesized, the corresponding α-substituted amino acid which is difficult to produce is required as a raw material. There was dissatisfaction with the standard manufacturing method.

[0005]: Journal of Organi
c Chemistry, 57, 2756, (199
2) A method for obtaining 2,5-oxazolidineones in a yield of 75% by reacting N-BOC-α-amino acid with bistrichloromethyl carbonate in the presence of triethylamine. Is described. However, this method is not applicable to 2,5-
In the case of synthesizing oxazolidinones, industrial production methods have been unsatisfactory in that an alpha-substituted N-BOC-amino acid, which is difficult to produce, is required as a raw material.

[0006]: Journal of Organi
c Chemistry, 61, 4400, (199
6) by oxidizing α-keto-β-lactams in an aqueous NaOCl solution in the presence of a catalytic amount of TEMPO (2,2,6,6-tetramethylpiperidyl-1-oxyl) , 5-Oxazolidineones, 95-
A method is described which gives a yield of 98%.

However, this method has been unsatisfactory as an industrial production method because it is difficult to industrially obtain α-keto-β-lactams as raw materials. ： Journal of American Che
medical Society, 85, 1839, (19
63) includes carbobenzoyl-L-glutamic acid
The 1,5-anhydride is opened by hydrogenation in the presence of a catalytic amount of Pd-carbon by hydrogenation and then recyclized to give N-carboxyl-L-glutamic anhydride. Are described in a yield of 68%.

[0008] However, this method is limited to compounds in which the starting amino acid is glutamic acid, and is unsatisfactory in that it cannot be applied to compounds in which the starting amino acid is another amino acid.

Therefore, in order to synthesize 2,5-oxazolidinediones in which the 4-position is substituted with a 2-alkenyl group, any of the known production methods and any of the known production methods,
The industrial production method has been unsatisfactory in that an operation of introducing an alkenyl group into each corresponding position of the raw material is required in advance.

[0010]

In order to solve the above-mentioned problems in the known production method, the present inventors have used α-amino acid 2-alkenyl ester as the starting α-amino acid ester and prepared a base (1) Is reacted with a chloroformylating agent in a solvent in the presence of a N-chlorocarbonyl α-amino acid 2-alkenyl ester represented by the general formula [III], and then, in the presence of a base (2), When an internal cyclization reaction is performed, 4- (2-alkenyl) -2,5
-The inventors have found that oxazolidinedione can be efficiently produced, and have completed the present invention.

Therefore, the present invention relates to an α-amino acid 2
Method for producing N-chlorocarbonyl α-amino acid 2-alkenyl esters using -alkenyl esters and 4- (2-alkenyl) -2,2 using N-chlorocarbonyl α-amino acid 2-alkenyl esters
An object of the present invention is to provide a method for producing 5-oxazolidinediones.

[0012]

Means for Solving the Problems The first production method of the present invention comprises a compound represented by the general formula [II]:

[0013]

Embedded image

Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵
Is the same or different and represents a hydrogen atom, a C ₁ -C ₁₀ alkyl group or an aryl group, R ⁶ represents a hydrogen atom, an optionally substituted C ₁ -C ₁₀ alkyl group, ⁷ is a hydrogen atom, an optionally substituted C ₁ -C ₁₀ alkyl group, an optionally substituted aryl group, a C ₃ -C ₁₀ cycloalkyl group, a C ₂ -C ₁₀ alkenyl group, It represents an acyl group, an alkoxycarbonyl group, an aminocarbonyl group, or a trialkylsilyl group. ) Is reacted with a chloroformate in a solvent in the presence of a base (1) to give a compound of the general formula [III]

[0015]

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Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁶ and R ⁷ have the same meaning as described above), and a process for producing N-chlorocarbonyl α-amino acid 2-alkenyl esters represented by the formula:

The second production method of the present invention has the general formula [II
I] N-chlorocarbonyl α-amino acid
General formula [I] characterized in that 2-alkenyl esters are subjected to an intramolecular cyclization reaction in a solvent in the presence of a base (2).

[0018]

Embedded image

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁶ and R ⁷ have the same meaning as described above), and a process for producing 4- (2-alkenyl) -2,5-oxazolidinedione represented by the formula:

The third production method of the present invention comprises a compound represented by the general formula [I
I]

[0021]

Embedded image

Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵
Is the same or different and represents a hydrogen atom, a C ₁ -C ₁₀ alkyl group or an aryl group, R ⁶ represents a hydrogen atom, an optionally substituted C ₁ -C ₁₀ alkyl group, ⁷ is a hydrogen atom, an optionally substituted C ₁ -C ₁₀ alkyl group, an optionally substituted aryl group, a C ₃ -C ₁₀ cycloalkyl group, a C ₂ -C ₁₀ alkenyl group, Represents an acyl group, an alkoxycarbonyl group, an aminocarbonyl group, or a trialkylsilyl group).
A 2-alkenyl ester and a chloroformate,
The reaction is carried out in a solvent in the presence of a base (1) to give a compound of the general formula
I]

[0023]

Embedded image

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁶ and R ⁷ have the same meanings as described above), and then subjected to an intramolecular cyclization reaction in a solvent in the presence of a base (2) in a general formula [I].

[0025]

Embedded image

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁶ and R ⁷ have the same meanings as described above), and a process for producing 4- (2-alkenyl) -2,5-oxazolidinedione represented by the formula:

The present inventors have found that when a compound having a substituent which is not unsaturated at the 2-position, such as an α-amino acid alkyl ester, is used as a raw material and the same operation as in the reaction of the present invention is carried out, 5-alkoxy is obtained. It has been found that -2 (3H) -oxazolones can be obtained. (Japanese Patent Application Hei 8-3049
(See No. 30)

From the above, the reaction of the present invention is represented by the following reaction formula (1)

[0029]

Embedded image

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁷ and R ⁸ have the same meanings as described above). That is, represented by the general formula [III]
The class is 2- (2-alkenoxy) -2 (3H) -2, as represented by formula (V).
After passing through 5-oxazolones and immediately undergoing Claisen rearrangement, 4- (2-alkenyl)-represented by the general formula [I]
It is thought to produce 2,5-oxazolidinediones.

[0031]

BEST MODE FOR CARRYING OUT THE INVENTION In the production method of the present invention, an α-amino acid 2-alkenyl ester represented by the general formula [II] (hereinafter also referred to as compound (2)) is converted to a compound represented by the general formula [I
The reaction for synthesizing N-chlorocarbonyl α-amino acid 2-alkenyl esters [hereinafter, also referred to as compound (3)] represented by the following formula [II] is, for example, a reaction formula (2) described below.

[0032]

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(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁷ and R ⁸ have the same meanings as described above) (hereinafter, also referred to as the first step).

Α-amino acid represented by the general formula [II]
In 2-alkenyl esters, R ¹ , R ² , R ³ ,
Examples of the C ₁ -C ₁₀ alkyl groups represented by R ⁴ and R ⁵ include a methyl group, an ethyl group, a propyl group (including isomers), a butyl group (including each isomer), and a pentyl group (including each isomer). ), A hexyl group (including each isomer), a heptyl group (including each isomer), an octyl group (including each isomer), a nonyl group (including each isomer), or a decyl group (including each isomer) And a linear or branched alkyl group having 1 to 10 carbon atoms.

In the compound (2), R ¹ , R ² , R ³ ,
Examples of the aryl group represented by R ⁴ and R ⁵ include a phenyl group, a naphthyl group, an anthryl group and a phenanthryl group.

In the compound (2), the “optionally substituted C ₁ -C ₁₀ alkyl group” represented by R ⁶ is an “unsubstituted C ₁ -C ₁₀ alkyl group” or “substituted. C ₁ -C ₁₀ alkyl group ”.

Examples of the “unsubstituted C ₁ -C ₁₀ alkyl group” include a methyl group, an ethyl group, a propyl group (including isomers), a butyl group (including each isomer),
Pentyl group (including each isomer), hexyl group (including each isomer), heptyl group (including each isomer), octyl group (including each isomer), nonyl group (including each isomer) or A straight-chain or branched alkyl group having 1 to 10 carbon atoms such as a decyl group (including each isomer);
Preferred are a methyl group, an isopropyl group, a 2-methylpropyl group, and a 1-methylpropyl group.

"Substituted C₁~ C_TenArchi
And the like are, for example, hydroxymethyl group, 1-
Humans such as droxyethyl group and 2-hydroxyethyl group
C substituted with a droxy group₁~ C_TenAlkyl group; Merka
Ptmethyl group, 1-mercaptoethyl group, 2-mercap
C substituted by a mercapto group such as triethyl group₁~ C _Ten
An alkyl group; aminocarbokinylmethyl group, 2-amino
Nocarbokinylethyl group, 1-aminocarboquinylethyl
Substituted with an aminocarbokinyl group such as₁~ C
_TenAlkyl group; phenylmethyl group, 2-phenylethyl
Group, p-hydroxyphenylmethyl group, m-hydroxy
An optionally substituted group such as a cyphenylmethyl group
C substituted with a nyl group₁~ C_TenAn alkyl group of
Such as a lylmethyl group and a 3-indolyl-2-ethyl group
C substituted by "optionally substituted phenyl group"₁~
C_TenAnd the like, preferably an alkyl group of
Hydroxymethyl group, 1-hydroxyethyl group, merka
Pttomethyl group, aminocarbokinylmethyl group, 2-amido
Nocarbokinylethyl group, phenylmethyl group, p-hydrido
Roxyphenylmethyl group, 3-indolylmethyl group
You.

In the compound (2), the “optionally substituted C ₁ -C ₁₀ alkyl group” represented by R ⁷ is an “unsubstituted C ₁ -C ₁₀ alkyl group” or “substituted. C ₁ -C ₁₀ alkyl group ”.

Examples of the “unsubstituted C ₁ -C ₁₀ alkyl group” include a methyl group, an ethyl group, a propyl group (including isomers), a butyl group (including each isomer),
Pentyl group (including each isomer), hexyl group (including each isomer), heptyl group (including each isomer), octyl group (including each isomer), nonyl group (including each isomer) or A straight-chain or branched alkyl group having 1 to 10 carbon atoms such as a decyl group (including each isomer);
It is preferably an alkyl group having 1 to 6 carbon atoms, more preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group or a t-group.
ert-butyl group.

Examples of the substituent of the "substituted C ₁ -C ₁₀ alkyl group" include aryl groups such as phenyl group, 4-methylphenyl group, naphthyl group, anthryl group and phenanthryl group; Formyl group; acetyl group,
Acyl groups such as benzoyl; nitro; cyano;
Alkoxy groups such as methoxy group and ethoxy group; methoxycarbonyl group, benzyloxycarbonyl group, ter
Examples include an alkoxycarbonyl group such as a t-butoxycarbonyl group; and a trialkylsilyl group such as a trimethylsilyloxy group and a triethylsilyloxy group.

Specific examples of the "substituted C ₁ -C ₁₀ alkyl group" include benzyl, 1-phenylethyl, 1-phenyl-1-methyl-ethyl, diphenylmethyl and trityl. , 1-naphthylmethyl group, 1
-(1-naphthyl) ethyl group, 3-phenylpropyl group, 2-methoxyethyl group, 2-ethoxyethyl group, 2
-Benzyloxyethyl and the like are preferred.

The "optionally substituted aryl group" represented by R ⁷ in the compound (2) means an "unsubstituted aryl group" or a "substituted aryl group". .

Examples of the "unsubstituted aryl group" include a phenyl group, a naphthyl group, an anthryl group and a phenanthryl group.

Examples of the substituent of the "substituted aryl group" include an alkyl group such as a methyl group, an ethyl group, an isopropyl group and a tert-butyl group; a formyl group; an acetyl group and a benzoyl group. An acyl group such as an acyl group; a nitro group; a cyano group; an alkoxy group such as a methoxy group and an ethoxy group; an alkoxycarbonyl group such as a methoxycarbonyl group, a benzyloxycarbonyl group and a tert-butoxycarbonyl group; a trimethylsilyloxy group;
Examples thereof include a trialkylsilyl group such as a triethylsilyloxy group.

Specific examples of the "substituted aryl group" include, for example, 4-methoxyphenyl group, 4-acetylphenyl group, 4-cyanophenyl group, 4-nitrophenyl group, 4-methoxyphenyl group , 2-methylphenyl group, 2,6-dimethylphenyl group, and 2,4,6-trimethylphenyl group.

[0047] In the compound (2) shown by R ⁷ "C ₃ ~
The cycloalkyl group "C _10, such as cyclopropyl group, and a cyclobutyl group, a cyclohexyl group, a cyclopentyl group, a cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group or a cyclodecyl group, preferably cyclopropyl Group, cyclobutyl group and cyclohexyl group.

The "acyl group" represented by R ⁷ in compound (2) includes, for example, formyl group, acetyl group, propionyl group, benzoyl group, phenylacetyl group, 2-methylpropionyl group, 2,2-dimethylpropionyl group and the like. Can be mentioned.

The "alkoxycarbonyl group" represented by R ⁷ in the compound (2) includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl or phenoxycarbonyl Examples include a carbonyl group.

The “aminocarbonyl group” represented by R ⁷ in compound (2) includes, for example, carbamoyl group, N-
Methylaminocarbonyl group, N-ethylaminocarbonyl group, N, N-dimethylaminocarbonyl group, N, N-
Examples thereof include a diethylaminocarbonyl group, an N-benzylaminocarbonyl group, and an N-phenylaminocarbonyl group.

The “trialkylsilyl group” represented by R ⁷ in the compound (2) includes, for example, trimethylsilyl, triethylsilyl, triisopropoxysilyl, dimethylisopropoxysilyl, tert-butyldimethylsilyl, tripentyl Examples thereof include a silyl group and a trihexylsilyl group.

In the compound (2), R⁷Is a general formula [I
V], a 1-arylalkyl group represented by R
⁸, R⁹, R^TenOptionally substituted aryl
Group, C ₁~ C_TenAlkyl group and C_Three~ C_TenCycloa
The alkyl group has the same meaning as described above.

The general formula [I] used in the production method of the present invention
Α-amino acid 2-alkenyl ester represented by the formula I)
In the class, such R¹, R^Two, R^Three, R^Four,
R^Five, R ⁶And R⁷Having the general formula [II]
Α-amino acid 2-alkenyl esters ”
Thus, the following compounds are preferred.

N-diphenylmethylglycine 2-propenyl ester, N-diphenylmethylglycine 1-
Methyl-2-propenyl ester, N-diphenylmethylglycine 2-methyl-2-propenyl ester, N
-Diphenylmethylglycine 2-butenyl ester, N
-Diphenylmethylglycine 1-methyl-2-butenyl ester, N-diphenylmethylglycine 1-ethyl-2-propenyl ester, N-diphenylmethylglycine 1,2-dimethyl-2-propenyl ester,
N-diphenylmethylglycine 3-methyl-2-butenyl ester, N-diphenylmethylglycine 2-pentenyl ester, N-diphenylmethylglycine 1
-Methyl-2-pentenyl ester,

N-diphenylmethylglycine 1-propyl-2-propenyl ester, N-diphenylmethylglycine 1-ethyl-2-methyl-2-propenyl ester, N-diphenylmethylglycine 1,3-dimethyl-2-butenyl Ester, N-diphenylmethylglycine 2-hexenyl ester, N-diphenylmethylglycine 1-methyl-2-hexenyl ester, N
-Diphenylmethylglycine 1-butyl-2-propenyl ester, N-diphenylmethylglycine 1-propyl-2-methyl-2-propenyl ester, N-diphenylmethylglycine 1-propyl-2-butenyl ester, N-diphenylmethyl Glycine 2-heptyl ester, N-diphenylmethylglycine 1-methyl-2-heptyl ester,

N-diphenylmethylglycine 1-pentyl-2-propenyl ester, N-diphenylmethylglycine 1-butyl-2-methyl-2-propenyl ester, N-diphenylmethylglycine 1-butyl-
2-butenyl ester, N-diphenylmethylglycine 2-octenyl ester, N-diphenylmethylglycine 3-phenyl-2-propenyl ester, N-diphenylmethylglycine 2-phenyl-2-propenyl ester, N-diphenylmethylglycine 1-phenyl-2-propenyl ester,

N-diphenylmethylalanine 2-propenyl ester, N-diphenylmethylalanine 2-
Butenyl ester, N-diphenylmethyl valine 2-
Propenyl ester, N-diphenylmethylisoleucine 2-propenyl ester, N-diphenylmethylserine 2-propenyl ester, N-diphenylmethylthreonine 2-propenyl ester, N-diphenylmethylcysteine 2-propenyl ester, N-diphenylmethylasparagine 2- Propenyl ester,
N-diphenylmethylglutamine 2-propenyl ester, N-diphenylmethyltryptophan 2-propenyl ester,

N-diphenylmethylglycine 2-propenyl ester, N- (1-phenylethyl) glycine 2-propenyl ester, N- (1- (1-naphthylethyl) glycine 2-propenyl ester, N-methylglycine 2-propenyl Propenyl ester, N-ethyl glycine 2-propenyl ester, N-propyl glycine 2-propenyl ester, N-isopropyl glycine 2-propenyl ester, N-tert-butyl glycine 2-propenyl ester, N-phenyl glycine 2-propenyl ester, N- (1-naphthyl) glycine 2-propenyl ester, N- (2-naphthyl)
Glycine 2-propenyl ester, N-trimethylsilylglycine 2-propenyl ester.

The first step in the production method of the present invention is a step of producing N-chlorocarbonyl α-amino acid 2-alkenyl esters represented by the general formula [III],
An α-amino acid 2-alkenyl ester represented by the general formula [II] is converted into a chlorocarbonylating agent and a base (1).
By carrying out the reaction in a solvent in the presence of

In the first step, examples of the chloroformate to be used include phosgene, trichloromethyl chloroformate and bistrichloromethyl carbonate, preferably phosgene or bistrichloromethyl carbonate. Preferably it is phosgene. The amount of use thereof is usually 1.0 to 1.5 equivalents in terms of phosgene relative to 1 mol of compound (2), and preferably 1.0 to 1.3 equivalents. is there.

The base (1) used in the first step may be any base that neutralizes HCl generated in the first step, and examples thereof include an organic base and an inorganic base. Examples of the organic base include tertiary amines such as triethylamine, tri-n-propylamine, tri-n-butylamine, diisopropylethylamine, N-methyl-piperidine or pyridine, and preferably triethylamine or tri-n-amine. Propylamine, and more preferably triethylamine.

The inorganic base used in the first step includes, for example, an alkali metal carbonate such as sodium carbonate or potassium carbonate, an alkali metal bicarbonate such as sodium hydrogen carbonate or potassium hydrogen carbonate, sodium hydroxide or water. Alkali metal hydroxides such as potassium oxide and the like can be mentioned, preferably a carbonate or a hydrogen carbonate, and more preferably sodium carbonate or potassium carbonate.

The amount of the base (1) used in the first step is usually 1 to 1 mol per mol of the compound (2).
2 equivalents can be mentioned, and preferably, 1.2 to 1.
It is a ratio of 7 equivalents.

The solvent used in the first step is not particularly limited as long as it does not directly participate in the present reaction, and may be an organic solvent alone or “organic solvent + water”.

Examples of the organic solvent include aromatic hydrocarbons such as benzene, toluene and xylene, chlorobenzene, dichlorobenzene, methylene chloride, chloroform,
Chlorinated hydrocarbons such as carbon tetrachloride and 1,2-dichloroethane; esters such as methyl acetate, ethyl acetate and butyl acetate; and ethers such as diisopropyl ether, dibutyl ether, dimethoxyethane, tetrahydrofuran and dioxane. And are preferably aromatic hydrocarbons or ethers, and more preferably toluene.

The organic solvent in “organic solvent + water” includes the above-mentioned organic solvents. The mixing ratio of “organic solvent + water” is free.

The amount of the organic solvent or “organic solvent + water” to be used is usually 0.1 to 1 mol of compound (2).
The range is from 1 to 6.0 liter, preferably from 0.2 to 3.0 liter. It is possible to use more solvent than this upper limit, but there is no advantage. When using an organic base as the base,
An organic solvent alone is preferable, and when an inorganic base is used, a mixed solvent of “organic solvent + water” is preferable.

The reaction temperature varies depending on the type of the compound (2), chlorocarbonylating agent, base (1) and solvent, but can be usually from 0 to 80 ° C., preferably from 0 to 80 ° C.
５０50 ° C. The reaction time varies depending on the reaction temperature and the like, but is usually 0.5 to 10 hours, preferably 0.5 to 5 hours.

The reaction may be carried out in the presence of an inert gas such as nitrogen, argon, helium and the like.

Compound (3) produced in the present invention is
All are defined by the corresponding compound (2). The method for obtaining the reaction mixture containing the compound (3) produced in the present invention may be carried out by a combination of a usual washing operation and a separation operation. For example, the produced salt is removed by a filtration operation, and the filtrate is washed with water and dried. A crude product of compound (3) is obtained by a dehydration operation with an agent, a removal operation by concentration of an organic solvent, or the like. In the case of further purification, purification may be performed by a known means such as column chromatography and recrystallization.

The compound (3) of the present invention can also be obtained by applying the specific production methods described in Examples.

In the production method of the present invention, the compound represented by the general formula [III]
From the compound (3) represented by the formula (4)
The reaction for synthesizing-(2-alkenyl) -2,5-oxazolidinedione [hereinafter, also referred to as compound (1)]
For example, the reaction formula (3) described below

[0073]

Embedded image

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁷ and R ⁸ have the same meaning as described above) (hereinafter, also referred to as a second step).

The second step is a step of producing the compound (1). The compound (3) is dissolved in a solvent in the presence of a base (2).
This is achieved by performing an intramolecular cyclization reaction.

When the compound (3) of the first step is used as a raw material of the second step, the compound (3) may or may not be isolated. In the case of a mixed solvent of “organic solvent + water”,
The process can be transferred to this step as a solution of an organic solvent obtained by separating an aqueous layer by a liquid separation operation. Further, if necessary, washing of the solvent with water, dehydration of the organic solvent with a drying agent, and the like may be incorporated.

When the organic solvent is used alone, the generated hydrochloride of the base is removed by filtration or the like, and the solution is washed with water,
An operation such as dehydration with a desiccant may be incorporated.

As a method for carrying out the second step, the base (2) is added to the organic solvent mixture containing the compound (3) obtained in the first step and reacted with or without heating, or the base ( The organic solvent mixture containing the compound (3) obtained by using an organic base as the 1) in an amount of 2 equivalents or more with respect to the compound (2) is heated, or the organic solvent of the compound (3) obtained in the first step is used. The mixture may be added to an organic solvent solution containing the base (2) and reacted with or without heating. In this case, the amount of the solvent used to dissolve the organic base is 0.1 to 0.5 liter per 1 mol of the compound (3). Further, the organic solvent mixture containing the compound (3) obtained in the first step is concentrated, the compound (3) is isolated, and an organic solvent and a base (2) are added thereto and reacted with or without heating. Good. The organic solvent used in this case is the same as the organic solvent used in the first step and the amount used.

In the second step, the base (2) used
Is required for the intramolecular cyclization of compound (3). As the base (2) to be used, for example, an organic base such as a tertiary amine such as triethylamine, tri-n-propylamine, tri-n-butylamine, diisopropylethylamine, N-methyl-piperidine or pyridine, sodium carbonate or Alkali metal carbonates such as potassium carbonate, alkali metal hydrides such as sodium hydride,
Examples thereof include alkali metal amides such as sodium amide, lithium diisopropylamide, and lithium bistrimethylsilylamide, and tertiary amines are preferable.

The amount of the base (2) to be used is generally in the range of 1.0 to 5.0 equivalents, preferably 1.0 to 3.0 equivalents, per 1 mol of compound (3). Range.

The reaction temperature depends on the base (2) used. When using an alkali metal amide such as the above sodium amide, lithium diisopropylamide, and lithium bistrimethylsilylamide, it is usually from -78 to
150 ° C., preferably in the range of room temperature to 120 ° C.
When the above-mentioned organic base, alkali metal carbonate or alkali metal hydride is used, it is usually in the range of 80 to 150 ° C, preferably 80 to 120 ° C.

The reaction time can be appropriately selected depending on the reaction temperature, but can be generally selected in the range of 1 to 12 hours. The reaction may be performed in the presence of an inert gas such as nitrogen, argon, and helium.

In the case where the second step is performed without separating the compound (3), the amount of the base (2) used is 1
It is usually in the range of 1.0 to 5.0 equivalents to mol,
Preferably, it is in the range of 1.0 to 3.0 equivalents, and the amount of the organic solvent used is 0.1 to 1.0 mol per 1 mol of the compound (2).
A range of 6.0 liters can be mentioned, and a preferable range is 0.2 to 3.0 liters.

The compound (1) produced in the present invention is
All are defined by the corresponding compound (3). The method for obtaining the reaction mixture containing the compound (1) produced in the present invention may be carried out by a combination of a usual washing operation and a separation operation. For example, the produced salt is removed by a filtration operation, and the filtrate is dried at the head and dried. A crude product of compound (1) can be obtained by a dehydration operation using an agent, a removal operation by concentration of an organic solvent, or the like. In the case of further purification, purification may be performed by a known means such as column chromatography and recrystallization.

The compound (1) of the present invention can also be obtained by applying the specific production methods described in Examples.

[0086]

According to the present invention, an α-amino acid 2-alkenyl ester is reacted with a chlorocarbonylating agent in a solvent in the presence of a base (1) to obtain a compound (3). Compound (3) or compound (3) isolated
Is reacted with an intramolecular cyclization reaction in the presence of a base (2) to give 4- (2-alkenyl) -2,5.
-Oxazolidinedione can be obtained in high yield. The obtained 4- (2-alkenyl) -2,5-oxazolidinediones are useful as drug substances, intermediates and raw materials.

[0087]

【Example】

Example 1: 3-diphenylmethyl-4- (1-methyl-
Synthesis of 2-propenyl) -2,5-oxazolidinedione 1.48 g (5.0 mmol) of N-diphenylmethyl-glycine crotyl ester was dissolved in 5 ml of toluene to obtain a toluene solution. To the obtained toluene solution, an aqueous solution obtained by dissolving 0.33 g of anhydrous sodium carbonate in 7 ml of water was added, and while stirring at room temperature, 0.5 g of phosgene gas was added.
9 g (6 mmol) were blown into the reaction. After the phosgene gas injection was completed, the mixture was further stirred for 1 hour.

After completion of the reaction, an aqueous layer was separated from the obtained reaction mixture (1), the toluene layer was dried over anhydrous magnesium sulfate, filtered, and 2.00 g (2%) of triethylamine was added to the filtrate.
0.0 mmol), and the mixture was heated at 120 ° C. for 8 hours to be reacted. After completion of the reaction, insolubles were separated by filtration from the obtained reaction mixture (2), 10 ml of a saturated aqueous solution of ammonium chloride was added, and the mixture was separated. The organic layer was washed with 10 ml of a saturated aqueous solution of sodium chloride. After dehydration with anhydrous magnesium sulfate and filtration, the filtrate was concentrated to give 3-diphenylmethyl-4- (1-methyl-2-propenyl) -2,
5-oxazolidinedione (two diastereomers-
58:42) 1.24 g (3.85 mmol)
Was obtained as a brown oil. [Yield based on N-diphenylmethyl-glycine crotyl ester = 77%]

(Mixture) MS (CI, i-C ₄ H ₁₀ )
m / z 322 (MH ⁺ ) (main product) ¹ H-NMR (δ, CDCl ₃ ): 1.12 (d, J =
6.8 Hz, 3H), 2.48 (m, 1H), 4.19
(D, J = 2.9 Hz, 1H), 4.98 (dd, J =
1.0 Hz, 18.1 Hz, 1 H), 5.19 (d, 1
0.3Hz, 1H), 5.65 (ddd, J = 7.3H)
z, 10.3 Hz, 18.1 Hz, 1H), 6.00
(S, 1H), 7.25-7.41 (m, 10H) (By-product) ¹ H-NMR (δ, CDCl ₃ ): 0.99 (d, J =
6.8 Hz, 3H), 2.30 (m, 1H), 4.25
(D, J = 3.4 Hz, 1H), 4.91 (d, J = 1
7.1 Hz, 1H), 5.07 (d, 10.3 Hz, 1
H), 5.79 (ddd, J = 7.8 Hz, 10.3 H)
z, 17.1 Hz, 1H), 6.12 (s, 1H),
7.25-7.41 (m, 10H)

Example 2: 3-diphenylmethyl-4-
Synthesis of (1-methyl-2-propenyl) -2,5-oxazolidinedione N-diphenylmethyl-glycine crotyl ester 4
99 mg (1.7 mmol) and triethylamine 172
mg (1.7 mmol) was dissolved in 5 ml of toluene to obtain a toluene solution. At room temperature, 590 mg of bistrichloromethyl carbonate was added to the obtained toluene solution.
A solution in which (2.0 mmol) was dissolved in 5 ml of toluene was added dropwise over 0.5 hour, and the mixture was further stirred for 1 hour to react.

After completion of the reaction, the obtained reaction mixture (1) was washed with 10 ml of a saturated aqueous solution of sodium chloride. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered, and 726 mg (7.2 mmol) of triethylamine was added to the filtrate.
l) was added, and the mixture was stirred and reacted at 100 ° C. for 13 hours and at 120 ° C. for 8 hours. After completion of the reaction, insolubles were filtered off from the obtained reaction mixture (2), and then 10 ml of a saturated aqueous solution of sodium hydrogen carbonate and 1 ml of a saturated aqueous solution of sodium chloride
After washing with 0 ml, a washed organic layer was obtained. The obtained washed organic layer was dehydrated with anhydrous magnesium sulfate, filtered,
The filtrate was concentrated to give 3-diphenylmethyl-4-
434 mg (1.4 mmol) of (1-methyl-2-propenyl) -2,5-oxazolidinedione (a mixture of two diastereomers 69:31) were obtained as a brown oil. [Yield based on N-diphenylmethyl-glycine crotyl ester = 80%]

Example 3: 3-diphenylmethyl-4-
Synthesis of (2- [E] -butenyl) -2,5-oxazolidinedione N-diphenylmethyl-glycine 1-methyl-2-propenyl ester 768 mg (2.6 mmol) and triethylamine 606 mg (6.0 mmol) in 10 ml of toluene To give a toluene solution. At room temperature, 590 mg (2.0 mmol) of bistrichloromethyl carbonate was added to 10 ml of toluene in the obtained toluene solution.
Was added dropwise over 0.5 hours, and the mixture was further reacted by stirring for 1.5 hours.

After the completion of the reaction, the obtained reaction mixture (1) was washed with 20 ml of a saturated aqueous solution of sodium chloride. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered, and 726 mg (7.2 mmol) of triethylamine was added to the filtrate.
l) was added, and the mixture was stirred at 120 ° C. for 7 hours to be reacted. After completion of the reaction, insolubles were filtered off from the obtained reaction mixture (2), and then washed with 20 ml of a saturated aqueous solution of sodium hydrogencarbonate and 20 ml of a saturated aqueous solution of sodium chloride to obtain a washed organic layer. The obtained washed organic layer was dried over anhydrous magnesium sulfate, filtered, and then the filtrate was concentrated.
3-diphenylmethyl-4- (2- [E] -butenyl)
643 mg of -2,5-oxazolidinedione (2.0 m
mol) was obtained as a brown oil. [Yield based on N-diphenylmethyl-glycine 1-methyl-2-propenyl ester = 77%]

MS (CI, i-C ₄ H ₁₀ ) m / z 32
2 (MH ⁺ ) ¹ H-NMR (δ, CDCl ₃ ): 1.62 (dd, J
= 1.5 Hz, 6.4 Hz, 3H), 2.14 (m, 1
H), 2.40 (m, 1H), 4.24 (dd, J =
3.4 Hz, 5.9 Hz, 1 H), 5.18 (m, 1
H), 5.39 (m, 1H), 6.09 (s, 1H),
7.13-7.41 (m, 10H)

Example 4: 3-diphenylmethyl-4-
Synthesis of (2- [E] -butenyl) -2,5-oxazolidinedione N-diphenylmethyl-glycine 1-methyl-2-propenyl ester 260 mg (0.88 mmol) and pyridine 158 mg (1.7 mmol) were added to toluene 3 .
It was dissolved in 3 ml to obtain a toluene solution. At room temperature, 196 mg (0.67 mmol) of bistrichloromethyl carbonate was added to 3.3 ml of toluene in the obtained toluene solution.
Was added dropwise over 0.5 hours, and the mixture was further reacted by stirring for 1.5 hours.

After the completion of the reaction, the obtained reaction mixture (1) was washed with 7 ml of a saturated aqueous solution of sodium chloride. After the obtained organic layer was dehydrated with anhydrous magnesium sulfate and filtered,
158 mg (1.7 mmol) of pyridine was added to the filtrate,
The mixture was reacted by stirring at 120 ° C. for 6 hours. After completion of the reaction, insolubles were filtered off from the obtained reaction mixture (2), and then washed with 7 ml of a saturated aqueous solution of sodium hydrogencarbonate and 7 ml of a saturated aqueous solution of sodium chloride to obtain a washed organic layer. The obtained washed organic layer is dehydrated with anhydrous magnesium sulfate,
After filtration, the filtrate was concentrated to give 245 mg (0.76 mmol) of 3-diphenylmethyl-4- (2- [E] -butenyl) -2,5-oxazolidinedione as a brown oil. [Yield based on N-diphenylmethyl-glycine 1-methyl-2-propenyl ester = 87%]

Example 5 3-Diphenylmethyl-4-methyl-4- (1-methyl-2-propenyl) -2,5-
Synthesis of oxazolidinedione 148 mg of bistrichloromethyl carbonate (1.5 mg)
mmol) was mixed with 5 ml of toluene to obtain a toluene solution. After cooling the obtained toluene solution to 0 ° C, N-
Diphenylmethyl-alanine crotyl ester 309
mg (1.0 mmol) and 152 mg of triethylamine
(1.5 mmol) in 5 ml of toluene was added dropwise over 1 hour, and the mixture was further stirred for 2 hours to obtain a mixed solution. The obtained mixed solution was heated to 60 ° C., stirred, and repeatedly heated to 20 ° C. every 2 hours.
Finally, the temperature was raised to 120 ° C, and the reaction was carried out by stirring at 120 ° C for 1 hour.

After completion of the reaction, the resulting reaction mixture (1)
After cooling to room temperature, bistrichloromethyl carbonate
148 mg (1.5 mmol) and triethylamine 3
04 mg (3.0 mmol) was added dropwise, the temperature was raised to 100 ° C., and the mixture was stirred and reacted for 1 hour. After completion of the reaction, insolubles were filtered off from the obtained reaction mixture (2), and then washed with 10 ml of a saturated aqueous solution of sodium hydrogencarbonate and 10 ml of a saturated aqueous solution of sodium chloride to obtain a washed organic layer. The obtained washed organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to give 3-diphenylmethyl-4-methyl-4- (1-methyl-2-propenyl) -2,5-. Oxazolidinedione (mixture of two diaztereomers 81:19) 319 mg (0.
95 mmol) was obtained as a brown oil. [Yield based on N-diphenylmethyl-alanine crotyl ester = 95%]

(Mixture) MS (CI, i-C ₄ H ₁₀ )
m / z 336 (MH ⁺ ) (main product) ¹ H-NMR (δ, CDCl ₃ ): 1.13 (d, J =
6.8 Hz, 3H), 1.70 (s, 3H), 2.63
(Dq, J = 7.6 Hz, 6.8 Hz, 1H), 4.8
4 (dd, J = 1.0 Hz, 17.1 Hz, 1H),
5.08 (dd, J = 1.0 Hz, 10.3 Hz, 1
H), 5.41 (s, 1H), 5.50 (ddd, J =
6.8Hz, 10.3Hz, 17.1Hz, 1H),
7.18-7.51 (m, 10H) (By-product) ¹ H-NMR (δ, CDCl ₃ ): 0.83 (d, J =
6.8 Hz, 3H), 1,62 (s, 3H), 2.53
(Dq, J = 9.3 Hz, 6.8 Hz, 1H), 5.1
2 (dd, J = 1.5 Hz, 10.7 Hz, 1H),
5.13 (d, J = 17.1 Hz, 1H), 5.42
(S, 1H), 5.90 (ddd, J = 9.3 Hz, 1
0.7 Hz, 17.1 Hz, 1H), 7.18-7.
51 (m, 10H)

Example 6: Synthesis of 3-((S) -1-phenylethyl) -4- (2-propenyl) -2,5-oxazolidinedione 450 mg (1.5 mg) of bistrichloromethylcarbonate
mmol) was mixed with 10 ml of toluene to obtain a toluene solution. After cooling the obtained toluene solution to 0 ° C.,
A solution obtained by dissolving 658 mg (3.0 mmol) of-((S) -1-phenylethyl) -glycine 2-propenyl ester and 364 mg (3.6 mmol) of triethylamine in 10 ml of toluene was added dropwise over 1 hour.
The reaction was further stirred for one hour.

After completion of the reaction, the resulting reaction mixture (1)
Was washed with 20 ml of a saturated aqueous solution of sodium chloride. The obtained organic layer was dried over anhydrous magnesium sulfate and filtered, and then 606 mg of triethylamine (6.0 mm) was added to the filtrate.
ol) and heated at 120 ° C. for 9 hours to react. After the completion of the reaction, insolubles were removed by filtration from the obtained reaction mixture (2), and then a saturated aqueous solution of sodium hydrogencarbonate 20 m
and 20 ml of a saturated aqueous solution of sodium chloride. The obtained washed organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated.
486 mg (2.0 m) of ((S) -1-phenylethyl) -4- (2-propenyl) -2,5-oxazolidinedione (a mixture of two diastereomers 57:43)
mol) was obtained as a brown oil. [N-((S)
-1-phenylethyl) -glycine 2-propenyl ester yield = 66%]

(Mixture) MS (CI, i-C ₄ H ₁₀ )
m / z 246 (MH ⁺ ) (main product) ¹ H-NMR (δ, CDCl ₃ ): 1.78 (d, J =
12.9 Hz, 3H), 2.27 (m, 1H), 4.2
8 (dd, J = 3.4 Hz, 5.4 Hz, 1H);
95 (dd, J = 1.5 Hz, 17.1 Hz, 1H),
5.02 (q, J = 7.3 Hz, 1H), 5.10
(D, J = 10.3 Hz, 1H), 5.34 (ddt,
J = 10.3 Hz, 17.1 Hz, 7.3 Hz, 1
H), 7.16-7. 46 (m, 5H) (by-product) ¹ H-NMR (δ, CDCl ₃ ): 1.75 (d, J =
7.3 Hz, 3H), 2.56 (m, 1H), 3.94
(Dd, J = 3.9 Hz, 5.4 Hz, 1H), 5.1
5 (dd, J = 1.5 Hz, 17.1 Hz, 1H),
5.22 (d, J = 10.3 Hz, 1H), 5.28
(Q, J = 7.3 Hz, 1H), 5.6 (ddt, J =
10.3Hz, 17.1Hz, 7.3Hz, 1H),
7.16-7.46 (m, 5H)

Example 7: 3-((S) -1-phenylethyl) -4- (1-methyl-2-propenyl) -2,5
Synthesis of oxazolidinedione bistrichloromethyl carbonate 225 mg (0.7 mg)
5 mmol) was mixed with 7.5 ml of toluene to obtain a toluene solution. After cooling the obtained toluene solution to 0 ° C., N-((S) -1-phenylethyl) -glycine was added.
A solution in which 350 mg (1.5 mmol) of crotyl ester and 228 mg (2.3 mmol) of triethylamine were dissolved in 7.5 ml of toluene was added dropwise over 1 hour, and the mixture was further stirred for 1 hour to react.

After completion of the reaction, the resulting reaction mixture (1)
Was washed with 15 ml of a saturated aqueous solution of sodium chloride. The obtained organic layer was dried over anhydrous magnesium sulfate and filtered, and then the filtrate was added with 303 mg of triethylamine (3.0 mm).
ol) and heated at 120 ° C. for 8 hours to react. After completion of the reaction, insoluble materials were filtered off from the obtained reaction mixture (2), and then a saturated aqueous sodium hydrogencarbonate solution (15 m) was added.
and 15 ml of a saturated aqueous solution of sodium chloride. The obtained washed organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated.
((S) -1-phenylethyl) -4- (1-methyl-
2-propenyl) -2,5-oxazolidinedione (4
326 mg (1.3 mmol) of a mixture of species diastereomers (40: 33: 12: 15) were obtained as a brown oil. [N - ((S)-1-phenyl-ethyl) - glycine black Yield = 84% relative to chill ester] (mixtures) MS (CI, i-C 4 H 10) m / z 26
0 (MH ⁺ )

Example 8: Synthesis of 3-benzyl-4- (1-methyl-2-propenyl) -2,5-oxazolidinedione 148 mg (0.5 mg) of bistrichloromethyl carbonate
mmol) was mixed with 5 ml of toluene to obtain a toluene solution. After cooling the obtained toluene solution to 0 ° C, N-
Benzyl-glycine crotyl ester 219mg
(1.0 mmol) and 152 mg of triethylamine
(1.5 mmol) in 5 ml of toluene was added dropwise over 1 hour, and the mixture was stirred and reacted for 2 hours.

After completion of the reaction, the resulting reaction mixture (1)
Was washed with 20 ml of a saturated aqueous solution of sodium chloride. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered, and then 237 mg (3.0 mmol) of pyridine was added to the filtrate, followed by heating at 120 ° C. for 18 hours to cause a reaction. After completion of the reaction, insolubles were filtered off from the obtained reaction mixture (2), and then washed with 20 ml of a saturated aqueous solution of sodium hydrogencarbonate and 20 ml of a saturated aqueous solution of sodium chloride. The obtained washed organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to give 3-benzyl-4-.
147 mg (0.60 mmol) of (1-methyl-2-propenyl) -2,5-oxazolidinedione (mixture of two diastereomers 74:26) were obtained as a brown oil. [Yield based on N-benzyl-glycine crotyl ester = 60%]

(Mixture) MS (CI, i-C ₄ H ₁₀ )
m / z 246 (MH ⁺ ) (main product) ¹ H-NMR (δ, CDCl ₃ ): 1.20 (d, J =
7.3 Hz, 3H), 2.83 (m, 1H), 3.98
(D, J = 3.4 Hz, 1H), 4.51 (m, 2
H), 5.17 (d, J = 17.6 Hz, 1H);
24 (d, J = 10.3 Hz, 1H), 5.67 (d
dd, J = 6.8Hz, 10.3Hz, 17.6H
z, 1H), 7.22-7.41 (m, 5H) (By-product) ¹ H-NMR (δ, CDCl ₃ ): 1.06 (d, J =
6.8 Hz, 3H), 2.76 (m, 1H), 4.00
(D, J = 3.4 Hz, 1H), 4.65 (m, 2
H), 5.13 (d, J = 17.1 Hz, 1H);
16 (d, J = 10.2 Hz, 1H), 5.85 (dd
d, J = 7.3 Hz, 10.2 Hz, 17.1 Hz, 1
H), 7.22-7.41 (m, 5H)

Example 9: 3- (p-toluylmethyl)-
4-methyl-4- (1-methyl-2-propenyl)-
Synthesis of 2,5-oxosazolidinedione 3.71 g (15.0 mmol) of N- (p-toluylmethyl) -glycine crotyl ester in 15 m of toluene
to give a toluene solution. An aqueous solution in which 0.88 g of anhydrous sodium carbonate was dissolved in 20 ml of water was added to the obtained toluene solution, and 1.63 g (16.5 mmol) of phosgene gas was blown therein while stirring at room temperature to cause a reaction. After the phosgene gas injection was completed, the mixture was further stirred for 1 hour.

After completion of the reaction, an aqueous layer was separated from the obtained reaction mixture (1), the toluene layer was dried over anhydrous magnesium sulfate, filtered, and 3.03 g (3.
0 mmol) and heated at 120 ° C. for 2 hours to react. After completion of the reaction, from the obtained reaction mixture (2),
After filtering off insolubles, a saturated aqueous solution of ammonium chloride 15
Then, the organic layer was washed with a saturated aqueous solution of sodium chloride (15 ml). Dehydrate with anhydrous magnesium sulfate,
After filtration, the filtrate was concentrated to give 3- (p-toluylmethyl) -4-methyl-4- (1-methyl-2-propenyl) -2,5-oxosazolidinedione (two diastereomers). 77:23) 3.07 g (1
1.2 mmol) was obtained as a brown oil. [N-
(Yield based on (p-toluylmethyl) -glycine crotyl ester = 75%]

(Mixture) MS (CI, i-C ₄ H ₁₀ )
m / z 274 (MH ⁺ ) (main product) ¹ H-NMR (δ, CDCl ₃ ): 1.16 (d, J =
7.3 Hz, 3H), 1.34 (s, 3H), 2.34
(S, 3H), 2.65 (m, 1H), 4.21 (d,
J = 15.4 Hz, 1H), 4.70 (d, J = 1
5.4 Hz, 1 H), 5.10 (dd, 1.5 Hz,
16.9 Hz, 1 H), 5.20 (d, 10.3 Hz,
1H), 5.59 (ddd, J = 8.1 Hz, 10.
3 Hz, 16.9 Hz, 1H); 13-7.28
(M, 4H) (By-product) ¹ H-NMR (δ, CDCl ₃ ): 0.91 (d, J =
6.6 Hz, 3H), 1.32 (s, 3H), 2.34
(S, 3H), 2.45 (m, 1H), 4.33 (d,
J = 15.4 Hz, 1H), 4.60 (d, J = 15.
4 Hz, 1 H), 5.11 (m, 2 H), 5.87 (d
dd, J = 8.8 Hz, 10.3 Hz, 16.9 Hz,
1H), 7.13-7.28 (m, 4H)

Example 10: 3-benzyl-4-methyl-
Synthesis of 4- (1-methyl-2-propenyl) -2,5-oxosazolidinedione 148 mg (0.5 mg) of bistrichloromethylcarbonate
0 mmol) was mixed with 5 ml of toluene to obtain a toluene solution. After cooling the obtained toluene solution to 0 ° C.,
-Benzylalanine crotyl ester 233 mg
(1.0 mmol) and 152 mg of triethylamine
(1.5 mmol) in 5 ml of toluene was added dropwise over 0.5 hour, and the mixture was further reacted for 1 hour with stirring.

After completion of the reaction, the resulting reaction mixture (1)
Was washed with 10 ml of a saturated aqueous solution of sodium chloride. The obtained organic layer was dried over anhydrous magnesium sulfate and filtered, and then the filtrate was added with 303 mg of triethylamine (3.0 mm).
ol) and heated at 100 ° C. for 6 hours to react. After the completion of the reaction, insolubles were filtered off from the obtained reaction mixture (2), and then 10 m
and 10 ml of a saturated aqueous solution of sodium chloride. The obtained washed organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to give 3-benzyl-4-methyl-4- (1-methyl-2-propenyl).
230 mg (0.89 m) of -2,5-oxosazolidinedione (mixture of two diastereomers 79:21)
mol) was obtained as a brown oil. [Yield based on N-benzylalanine crotyl ester = 89%]

(Mixture) MS (CI, i-C ₄ H ₁₀ )
m / z 260 (MH ⁺ ) (main product) ¹ H-NMR (δ, CDCl ₃ ): 1.17 (d, J =
6.8 Hz, 3H), 1.35 (s, 3H), 2.66
(M, 1H), 4.26 (d, J = 15.6 Hz, 1
H), 4.74 (d, J = 15.6 Hz, 1H), 5.
10 (dd, J = 1.0 Hz, 17.1 Hz, 1H),
5.20 (dd, 1.0 Hz, 10.3 Hz, 1H),
5.59 (ddd, J = 8.3 Hz, 10.3 Hz, 1
7.1 Hz, 1H), 7.31-7.38 (m, 5H) (By-product) ¹ H-NMR (δ, CDCl ₃ ): 0.91 (d, J =
6.8 Hz, 3H), 1.33 (s, 3H), 2.45
(M, 1H), 4.38 (d, J = 15.6 Hz, 1
H), 4.64 (d, J = 15.6 Hz, 1H) 5.1
0 (dd, J = 1.0 Hz, 17.1 Hz, 1H),
5.13 (dd, J = 1.0 Hz, 10.3 Hz, 1
H), 5.87 (ddd, J = 9.3 Hz, 10.3 H)
z, 17.1 Hz, 1H), 7.31-7.38 (m,
5H)

Example 11 Synthesis of N-benzyl-N-chlorocarbonyl-glycine crotyl ester Bistrichloromethyl carbonate 297 mg (3.0 mg)
mmol) was mixed with 10 ml of toluene to obtain a toluene solution. After cooling the obtained toluene solution to 0 ° C.,
-Benzyl-glycine crotyl ester 439 mg
(2.0 mmol) and 304 mg of triethylamine
(3.0 mmol) in 10 ml of toluene was added dropwise over 1 hour, and the mixture was further reacted by stirring for 2 hours.

After completion of the reaction, the resulting reaction mixture (1)
Was washed with 20 ml of a saturated aqueous solution of sodium hydrogen carbonate. The obtained organic layer is dehydrated with anhydrous magnesium sulfate,
After filtration, the filtrate was concentrated to give 532 mg of N-benzyl-N-chlorocarbonyl-glycine crotyl ester.
(1.89 mmol) was obtained as a brown oil.
[Yield based on N-benzyl-glycine crotyl ester = 95%]

¹ H-NMR (δ, CDCl ₃ ): 1.7
2 (m, 3H), 4.01 (s, 1H), 4.07
(S, 1H), 4.56 (m, 2H), 4.66 (s,
1H), 4.81 (s, 1H), 5.55 (m, 1
H), 5.79 (m, 1H), 7.25-7.39
(M, 5H)

Reference Example 1: Synthesis of isoleucine (3-diphenylmethyl-4- (1-methyl-2-propenyl)
Amino acid derivation of -2,5-oxazolidinedione) 3-Diphenylmethyl-4- (1-methyl-2-propenyl) -2,5-oxazolidinedione (diastereomer; mixture of 60:40) 321 mg (1.0 mmol)
l) was mixed with 10 ml of a saturated aqueous solution of sodium hydrogen carbonate to obtain an aqueous solution. The obtained aqueous solution was stirred and reacted at room temperature (20 ° C.) for 16 hours.

The obtained reaction mixture (1) was filtered, and the crystals on the filter paper were washed with 10 ml of toluene and then dried under reduced pressure to obtain washed crystals. The washed crystals obtained are methano-
And mixed with 5 ml of water. In the resulting mixture,
70 mg of Pd (OH) ₂ / carbon (containing 20 wt% of Pd) was added, and the mixture was stirred at room temperature (20 ° C.) in a hydrogen atmosphere for 5 hours to react.

The obtained reaction mixture (2) was filtered, and the insoluble matter on the filter paper was washed with 10 ml of purified water. The filtrate and washing solution are mixed and concentrated, and DL-alloisoleucine and DL
Mixture with isoleucine (60:40) 70.5 (m
g) (0.54 mmol) was obtained as white crystals.
[Yield based on 3-diphenylmethyl-4- (1-methyl-2-propenyl) -2,5-oxazolidinedione = 54%]

Claims (7)

[Claims] 1. A compound of the general formula [II] [Wherein, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same or different and represent a hydrogen atom, a C ₁ -C ₁₀ alkyl group or an aryl group, R ⁶ represents a hydrogen atom, substituted an alkyl group optionally C ₁ -C ₁₀ also, R ⁷ is a hydrogen atom, an optionally substituted C ₁ -C ₁₀ alkyl group, optionally substituted ants - le groups, C cycloalkyl group ₃ -C _10, alkenyl group of C ₂ -C _10, acyl group, alkoxycarbonyl group, aminocarbonyl group, alpha-amino acid 2-alkenyl esters represented by showing a trialkylsilyl group) and chloro A formylating agent is reacted in a solvent in the presence of a base (1) to give a compound of the general formula [III] Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷
Has the same meaning as described above.) A method for producing an N-chlorocarbonyl α-amino acid 2-alkenyl ester represented by the formula: 2. A compound of the general formula (III) wherein an N-chlorocarbonyl α-amino acid 2-alkenyl ester represented by the formula (III) is subjected to an intramolecular cyclization reaction in a solvent in the presence of a base (2). [I] Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷
Has the same meaning as described above). 4- (2-alkenyl) -2,5-oxazolidinedione 3. A compound of the general formula [II] [Wherein, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same or different and represent a hydrogen atom, a C ₁ -C ₁₀ alkyl group or an aryl group, R ⁶ represents a hydrogen atom, substituted an alkyl group optionally C ₁ -C ₁₀ also, R ⁷ is a hydrogen atom, an optionally substituted C ₁ -C ₁₀ alkyl group, optionally substituted ants - le groups, C cycloalkyl group ₃ -C _10, alkenyl group of C ₂ -C _10, acyl group, alkoxycarbonyl group, aminocarbonyl group, alpha-amino acid 2-alkenyl esters represented by showing a trialkylsilyl group) and chloro A formylating agent is reacted in a solvent in the presence of a base (1) to give a compound of the general formula [III] Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷
Has the same meaning as described above) [II
I], followed by an intramolecular cyclization reaction in a solvent in the presence of a base (2). Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷
Has the same meaning as described above). 4- (2-alkenyl) -2,5-oxazolidinedione 4. The process according to claim 1, wherein the chloroformate is phosgene, trichloromethyl chloroformate (trichloromethyl chloroformate) or bistrichloromethyl carbonate (bistrichloromethyl carbonate). 5. A compound of the formula [IV] wherein R ⁷ is (Wherein, R ⁸ , R ⁹ and R ¹⁰ are at least one optionally substituted aryl group, an optionally substituted aryl group, a hydrogen atom, C ₁ -C ₁₀ An alkyl group of
A substituent selected from the group consisting of cycloalkyl group having C ₃ -C _10. The method according to claim 1, 2, or 3, which is a 1-aryl ester represented by the formula: 6. The process according to claim 1, wherein R ⁷ is a 1-aryl ester represented by a diphenylmethyl group, a 1-phenylethyl group or a benzyl group. 7. The process according to claim 1, wherein the base is the same or different and is a trialkylamine, pyridine or an alkali metal carbonate.