JP4181233B2 - Method for producing pyrrolidine-2,4-dione derivative - Google Patents

Description

[0001]
[Industrial application fields]
The present invention relates to a compound useful as a raw material for synthesizing antibacterial compounds and a method for producing the same.
[0002]
[Prior art]
Formula (III)
[0003]
Embedded image
[0004]
[Wherein R^{twenty two}Means an amino-protecting group, R^Four And R^Five Each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms (provided that R represents^Four And R^FiveExcept when is simultaneously a hydrogen atom. ), Or together to form a polymethylene chain, may have the following structure:
[0005]
Embedded image
(In the formula, n means an integer of 2 to 5)]
(Hereinafter referred to as compound (III), the same applies to compounds represented by the other formulas) are useful as intermediates for the production of antibacterial compounds (Japanese Patent Laid-Open No. 5-1073). Gazette and JP-A-5-221947).
[0006]
As a production method thereof, there is a method using ethyl acetoacetate as a raw material (Japanese Patent Laid-Open No. 3-95176), but the yield is low and it is not suitable as an industrial production method. Further, there is a method using diketene as a raw material (JP-A-5-221947), but there are problems such as requiring many steps, and the industrial production still has room for improvement.
[0007]
[Problems to be solved by the invention]
The present inventor conducted intensive studies to solve the problems of the conventional techniques and find a production method for easily obtaining the compound (III). As a result, compound (II)
[0008]
Embedded image
[Wherein R¹ Means a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R^{twenty two}Means an amino-protecting group, R^Four And R^Five Each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms (provided that R represents^Four And R^FiveExcept when is simultaneously a hydrogen atom. ), Or together to form a polymethylene chain, may have the following structure:
[0009]
Embedded image
(In the formula, n means an integer of 2 to 5)]
As a production intermediate, it was found that compound (III) was easily obtained, and the present invention was completed.
[0010]
[Means for Solving the Problems]
The present invention relates to a compound of formula (I)
[0011]
Embedded image
[Wherein R¹Means a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R²And R^ThreeEach independently represents a hydrogen atomOr the following group:
Benzyl group, α-methylbenzyl group, trityl group, benzhydryl group, paranitrobenzyl group, paramethoxybenzyl group, t - Butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group , Butyroyl group, t - Butyroyl group, methoxyacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, and benzoyl group
Means a group selected from the group ² And R ^Three Except when is simultaneously a hydrogen atom. ),R^FourAnd R^FiveEach independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms (provided that R represents^FourAnd R^FiveExcept when is simultaneously a hydrogen atom. ), Or together to form a polymethylene chain, may have the following structure:
[0012]
Embedded image
(In the formula, n means an integer of 2 to 5)]
And a compound represented by formula (III-1)
[0013]
Embedded image
[Wherein R^{twenty one}IsFormyl group, acetyl group, propanoyl group, butyroyl group, t - Butyroyl group, methoxyacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, benzoyl group, t - Butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, or paranitrobenzyloxycarbonyl groupMeans R^FourAnd R^FiveEach independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms (provided that R represents^FourAnd R^FiveExcept when is simultaneously a hydrogen atom. ), Or together to form a polymethylene chain, may have the following structure:
[0014]
Embedded image
(In the formula, n means an integer of 2 to 5)]
It relates to the compound represented by these.
[0015]
Further, the formula (IV)
[0016]
Embedded image
(Wherein R¹Means a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R^{twenty one}Ist - Butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group , Butyroyl group, t - Butyroyl group, methoxyacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, or benzoyl groupMeans R³¹Is a hydrogen atom,Benzyl group, α-methylbenzyl group, trityl group, benzhydryl group, paranitrobenzyl group, paramethoxybenzyl group, t - Butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group , Butyroyl group, t - Butyroyl group, methoxyacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, or benzoyl groupMeans. And a compound represented by formula (V)
[0017]
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X¹ -(CH₂ )_n ―X²         (V)
(In the formula, n means an integer of 2 to 5, and X¹ And X² Each independently represents an atom or group leaving in a nucleophilic substitution reaction. )
Wherein the compound represented by formula (I-1) is treated in the presence of a base.
[0018]
Embedded image
(Wherein R¹Means a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R^{twenty one}Ist - Butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group , Butyroyl group, t - Butyroyl group, methoxyacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, or benzoyl groupMeans R³¹Is a hydrogen atom,Benzyl group, α-methylbenzyl group, trityl group, benzhydryl group, paranitrobenzyl group, paramethoxybenzyl group, t - Butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group , Butyroyl group, t - Butyroyl group, methoxyacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, or benzoyl groupAnd n means an integer of 2 to 5. It is related with the manufacturing method of the compound represented.
[0019]
Furthermore, the formula (IV)
[0020]
Embedded image
(Wherein R¹Means a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R^{twenty one}Ist - Butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group , Butyroyl group, t - Butyroyl group, methoxyacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, or benzoyl groupMeans R³¹Is a hydrogen atom,Benzyl group, α-methylbenzyl group, trityl group, benzhydryl group, paranitrobenzyl group, paramethoxybenzyl group, t - Butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group , Butyroyl group, t - Butyroyl group, methoxyacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, or benzoyl groupMeans. ) And a compound represented by formula (VI)
[0021]
Embedded image
R⁴¹―X^Three           (VI)
(Wherein R⁴¹Means an alkyl group having 1 to 6 carbon atoms, and X^Three Means an atom or group that is eliminated in a nucleophilic substitution reaction. )
Wherein the compound represented by formula (I-2) and / or formula (I-3) is treated in the presence of a base
[0022]
Embedded image
(Wherein R¹Means a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R^{twenty one}Ist - Butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group , Butyroyl group, t - Butyroyl group, methoxyacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, or benzoyl groupMeans R³¹Is a hydrogen atom,Benzyl group, α-methylbenzyl group, trityl group, benzhydryl group, paranitrobenzyl group, paramethoxybenzyl group, t - Butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group , Butyroyl group, t - Butyroyl group, methoxyacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, or benzoyl groupMeans R⁴¹Means an alkyl group having 1 to 6 carbon atoms. It is related with the manufacturing method of the compound represented.
[0023]
And formula (IV)
[0024]
Embedded image
(Wherein R¹Means a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R^{twenty one}Ist - Butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group , Butyroyl group, t - Butyroyl group, methoxyacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, or benzoyl groupMeans R³¹Is a hydrogen atom,Benzyl group, α-methylbenzyl group, trityl group, benzhydryl group, paranitrobenzyl group, paramethoxybenzyl group, t - Butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group , Butyroyl group, t - Butyroyl group, methoxyacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, or benzoyl groupMeans. ) And a compound represented by formula (VI)
[0025]
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R⁴¹―X^Three           (VI)
(Wherein R⁴¹Means an alkyl group having 1 to 6 carbon atoms, and X^Three Means an atom or group that is eliminated in a nucleophilic substitution reaction. )
Wherein the compound represented by formula (I-3) is treated in the presence of a base.
[0026]
Embedded image
(Wherein R¹Means a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R^{twenty one}Ist - Butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group , Butyroyl group, t - Butyroyl group, methoxyacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, or benzoyl groupMeans R³¹Is a hydrogen atom,Benzyl group, α-methylbenzyl group, trityl group, benzhydryl group, paranitrobenzyl group, paramethoxybenzyl group, t - Butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group , Butyroyl group, t - Butyroyl group, methoxyacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, or benzoyl groupMeans R⁴¹Means an alkyl group having 1 to 6 carbon atoms. It is related with the manufacturing method of the compound represented.
[0027]
Further, the formula (IV)
[0028]
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(Wherein R¹Means a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R^{twenty one}Ist - Butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group , Butyroyl group, t - Butyroyl group, methoxyacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, or benzoyl groupMeans R³¹Is a hydrogen atom,Benzyl group, α-methylbenzyl group, trityl group, benzhydryl group, paranitrobenzyl group, paramethoxybenzyl group, t - Butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group , Butyroyl group, t - Butyroyl group, methoxyacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, or benzoyl groupMeans. ) And a compound represented by formula (VI)
[0029]
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R⁴¹―X^Three           (VI)
(Wherein R⁴¹Means an alkyl group having 1 to 6 carbon atoms, and X^Three Means an atom or group that is eliminated in a nucleophilic substitution reaction. )
Wherein the compound represented by formula (I-2) is treated in the presence of a base.
[0030]
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(Wherein R¹Means a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R^{twenty one}Ist - Butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group , Butyroyl group, t - Butyroyl group, methoxyacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, or benzoyl groupMeans R³¹Is a hydrogen atom,Benzyl group, α-methylbenzyl group, trityl group, benzhydryl group, paranitrobenzyl group, paramethoxybenzyl group, t - Butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group , Butyroyl group, t - Butyroyl group, methoxyacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, or benzoyl groupMeans R⁴¹Means an alkyl group having 1 to 6 carbon atoms. It is related with the manufacturing method of the compound represented.
[0031]
Furthermore, the formula (IV)
[0032]
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(Wherein R¹Means a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R^{twenty one}Ist - Butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group , Butyroyl group, t - Butyroyl group, methoxyacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, or benzoyl groupMeans R³¹Is a hydrogen atom,Benzyl group, α-methylbenzyl group, trityl group, benzhydryl group, paranitrobenzyl group, paramethoxybenzyl group, t - Butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group , Butyroyl group, t - Butyroyl group, methoxyacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, or benzoyl groupMeans. ) And 1 equivalent of the formula (VI) with respect to the compound of the formula (IV)
[0033]
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R⁴¹―X^Three           (VI)
(Wherein R⁴¹Means an integer having 1 to 6 carbon atoms, and X^Three Means an atom or group that is eliminated in a nucleophilic substitution reaction. )
Is treated in the presence of a base, followed by formula (VII)
[0034]
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R⁵¹―X^Four           (VII)
(Wherein R⁵¹Means an alkyl group having 1 to 6 carbon atoms, and X^Four Means an atom or group that is eliminated in a nucleophilic substitution reaction. )
Wherein the compound represented by formula (I-4) is treated in the presence of a base.
[0035]
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(Wherein R¹Means a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R^{twenty one}Ist - Butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group , Butyroyl group, t - Butyroyl group, methoxyacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, or benzoyl groupMeans R³¹Is a hydrogen atom,Benzyl group, α-methylbenzyl group, trityl group, benzhydryl group, paranitrobenzyl group, paramethoxybenzyl group, t - Butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group , Butyroyl group, t - Butyroyl group, methoxyacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, or benzoyl groupMeans R⁴¹Means an alkyl group having 1 to 6 carbon atoms and R⁵¹Means an alkyl group having 1 to 6 carbon atoms. It is related with the manufacturing method of the compound represented.
[0036]
Alternatively, formula (II)
[0037]
Embedded image
[Wherein R¹Means a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R^{twenty two}IsBenzyl group, α-methylbenzyl group, trityl group, benzhydryl group, paranitrobenzyl group, paramethoxybenzyl group, t - Butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group , Butyroyl group, t - Butyroyl group, methoxyacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, or benzoyl groupMeans R^FourAnd R^FiveEach independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms (provided that R represents^FourAnd R^FiveExcept when is simultaneously a hydrogen atom. ), Or together to form a polymethylene chain, may have the following structure:
[0038]
Embedded image
(In the formula, n means an integer of 2 to 5)]
Wherein the compound represented by formula (III) is treated in the presence of a base or an alkylaluminum reagent.
[0039]
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[Wherein R^{twenty two}IsBenzyl group, α-methylbenzyl group, trityl group, benzhydryl group, paranitrobenzyl group, paramethoxybenzyl group, t - Butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group , Butyroyl group, t - Butyroyl group, methoxyacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, or benzoyl groupMeans R^FourAnd R^FiveEach independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms (provided that R represents^FourAnd R^FiveExcept when is simultaneously a hydrogen atom. ), Or together to form a polymethylene chain, may have the following structure:
[0040]
Embedded image
(In the formula, n means an integer of 2 to 5)]
It relates to the manufacturing method of the compound represented by these.
[0041]
Furthermore, the formula (II)
[0042]
Embedded image
[Wherein R¹Means a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R^{twenty two}IsBenzyl group, α-methylbenzyl group, trityl group, benzhydryl group, paranitrobenzyl group, paramethoxybenzyl group, t - Butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group , Butyroyl group, t - Butyroyl group, methoxyacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, or benzoyl groupMeans R^FourAnd R^FiveEach independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms (provided that R represents^FourAnd R^FiveExcept when is simultaneously a hydrogen atom. ), Or together to form a polymethylene chain, may have the following structure:
[0043]
Embedded image
(In the formula, n means an integer of 2 to 5)]
Wherein the compound represented by formula (III) is treated under heating:
[0044]
Embedded image
[Wherein R^{twenty two}IsBenzyl group, α-methylbenzyl group, trityl group, benzhydryl group, paranitrobenzyl group, paramethoxybenzyl group, t - Butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group , Butyroyl group, t - Butyroyl group, methoxyacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, or benzoyl groupMeans R^FourAnd R^FiveEach independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms (provided that R represents^FourAnd R^FiveExcept when is simultaneously a hydrogen atom. ), Or together to form a polymethylene chain, may have the following structure:
[0045]
Embedded image
(In the formula, n means an integer of 2 to 5)]
It relates to the manufacturing method of the compound represented by these.
[0046]
The substituents used in the present invention will be described below.
[0047]
Examples of the amino-protecting group include an acyl group, an alkoxycarbonyl group, an aralkyloxycarbonyl group, and an aralkyl group.
[0048]
Examples of the acyl group include formyl group, acetyl group, propanoyl group, butyroyl group, t-butyroyl group, methoxyacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, and benzoyl group. An aliphatic or aromatic acyl group such as
[0049]
Examples of the alkoxycarbonyl group include a t-butoxycarbonyl group, a methoxycarbonyl group, an ethoxycarbonyl group, and a 2,2,2-trichloroethoxycarbonyl group.
[0050]
Examples of the aralkyloxycarbonyl group include a benzyloxycarbonyl group, and the phenyl group moiety includes a lower alkyl group such as a methyl group and an ethyl group, a lower alkoxyl group such as a methoxy group and an ethoxy group, a nitro group, A halogen atom or the like may be substituted, and examples thereof include a paramethoxybenzyloxycarbonyl group and a paranitrobenzyloxycarbonyl group.
[0051]
Examples of the aralkyl group include a benzyl group, an α-methylbenzyl group, a trityl group, a benzhydryl group, and the like. The phenyl group moiety includes a lower alkyl group such as a methyl group and an ethyl group, a methoxy group, an ethoxy group, and the like. The lower alkoxyl group, nitro group, halogen atom and the like may be substituted, and examples thereof include a paranitrobenzyl group and a paramethoxybenzyl group.
[0052]
Examples of the atom or group eliminated in the nucleophilic substitution reaction include a halogen atom such as chlorine, bromine or iodine, a sulfonyloxy group such as p-toluenesulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, or dimethylsulfonium. And a dialkylsulfonium group. In the case of a dialkylsulfonium group, a halogen anion may be accompanied as a counter anion.
[0053]
The substituents of the compounds in the present specification will be described in detail below.
[0054]
First, the substituent R of the compound (I) of the present invention¹ Is preferably an alkyl group having 1 to 6 carbon atoms, particularly preferably a methyl group or an ethyl group. Substituent R² And R^Three As the amino-protecting group, an aralkyl group, an alkoxycarbonyl group, an aralkyloxycarbonyl group and an acyl group are preferable, and a formyl group, an acetyl group, a benzyl group, a t-butoxycarbonyl group and a benzyloxycarbonyl group are particularly preferable. Substituent R^Four And R^Five As R^Four And R^Five Together form a polymethylene chain with the following structure:
[0055]
Embedded image
(Wherein n represents an integer of 2 to 5) is preferred, and those in which n is 2 or 3 and those in which n is 2 are particularly preferred.
[0056]
Substituent R of the present compound (III-1)^{twenty one}As formyl, acetyl, propanoyl, butyroyl, t-butyroyl, methoxyacetyl, fluoroacetyl, difluoroacetyl, trifluoroacetyl, chloroacetyl, pivaloyl, benzoyl, t-butoxy A carbonyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, a benzyloxycarbonyl group, a paramethoxybenzyloxycarbonyl group, and a paranitrobenzyloxycarbonyl group are preferable, particularly a formyl group, an acetyl group, A t-butoxycarbonyl group and a benzyloxycarbonyl group are preferred. Substituent R^Four And R^Five As R^Four And R^Five Together form a polymethylene chain with the following structure:
[0057]
Embedded image
(Wherein n represents an integer of 2 to 5) is preferred, and those in which n is 2 or 3 and those in which n is 2 are particularly preferred.
[0058]
Substituent R of Compound (IV)¹ Is preferably an alkyl group having 1 to 6 carbon atoms, particularly preferably a methyl group or an ethyl group. Substituent R^{twenty one}As these, an alkoxycarbonyl group and an aralkyloxycarbonyl group are preferable, and a t-butoxycarbonyl group and a benzyloxycarbonyl group are particularly preferable. Substituent R³¹As a hydrogen atom and an aralkyl group, a hydrogen atom and a benzyl group are particularly preferable.
[0059]
N in the compound (V) is preferably 2 or 3, particularly 2 and means an atom or group which is eliminated in the nucleophilic substitution reaction.¹ And X² Is preferably a halogen atom, particularly preferably a bromine atom.
[0060]
R of compound (VI)⁴¹X is preferably a methyl group or an ethyl group, and means an atom or group that is eliminated in a nucleophilic substitution reaction.^Three Is preferably a halogen atom, particularly preferably a bromine atom.
[0061]
R of compound (VII)⁵¹X is preferably a methyl group or an ethyl group and means an atom or group that is eliminated in a nucleophilic substitution reaction.^Four Is preferably a halogen atom, particularly preferably a bromine atom.
[0062]
Substituent R of Compound (II)¹ Is preferably an alkyl group having 1 to 6 carbon atoms, particularly preferably a methyl group or an ethyl group. Substituent R^{twenty two}As these, an aralkyl group, an alkoxycarbonyl group, an aralkyloxycarbonyl group and an acyl group are preferable, and a formyl group, an acetyl group, a benzyl group, a t-butoxycarbonyl group and a benzyloxycarbonyl group are particularly preferable. Substituent R^Four And R^Five As R^Four And R^Five Forms a polymethylene chain and has the following structure:
[0063]
Embedded image
(Wherein n represents an integer of 2 to 5) is preferred, and those in which n is 2 or 3 and those in which n is 2 are particularly preferred.
[0064]
Next, the manufacturing method of this invention is demonstrated for every process.
[0065]
First, the process for producing compound (I-1) by reacting compound (IV) with compound (V) will be described.
[0066]
Compound (I-1) can be obtained by treating compound (IV) and compound (V) in a solvent in the presence of a base.
[0067]
The reaction solvent is not particularly limited as long as it is inert to the reaction, but a preferable one may be selected according to the base to be used. Alcohol-based, ether-based, halogenated hydrocarbon-based, amide-based, etc. , Dimethyl sulfoxide, acetonitrile, acetone, acetate ester, water and the like can be used. Moreover, these can also be used as a mixed solvent.
[0068]
Of these solvents, amides such as dimethylformamide and acetone are preferred.
[0069]
While the reaction temperature varies depending on the type of base and the solvent used, it may be in the range of −78 ° C. to the boiling point of the solvent, preferably in the range of room temperature to the boiling point of the solvent.
[0070]
The base may be either organic or inorganic, alkali metal or alkaline earth metal, for example, sodium, potassium, lithium, magnesium, calcium and other hydroxides, carbonates, bicarbonates and alkoxides, Metal hydrides such as sodium hydride, potassium hydride, lithium hydride, alkyllithium reagents such as n-butyllithium, methyllithium, lithium diisopropylamide, tertiary amines such as triethylamine, N, N-diisopropylethylamine, etc. 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,8-diazabicyclo [4.3.0] non-5-ene (DBN), dimethylaniline, N-methylmorphol Heterocyclic compounds such as phosphorus can be used.
[0071]
In order to accelerate the reaction, in the presence of quaternary ammonium salts such as tetrabutylammonium bromide and benzyltriethylammonium chloride, alkali metal or alkaline earth metal iodides such as potassium iodide and sodium iodide, and crown ethers. Sometimes it is done.
[0072]
Of these bases, metal carbonates such as potassium carbonate and sodium carbonate, and metal hydrides such as sodium hydride and potassium hydride are preferable.
[0073]
The amount of the base used is usually in the range of 1 to 30 equivalents relative to compound (IV), but the reaction efficiency is higher when an excess amount is used, preferably about 2 to 16 equivalents.
[0074]
Compound (IV) can be derived from a commercially available product or glycine having an amino group protected.
[0075]
Next, the process for producing compound (I-2) and / or (I-3) by reacting compound (IV) with compound (VI) will be described.
[0076]
Compound (I-2) and / or compound (I-3) can be obtained by treating compound (IV) and compound (VI) in a solvent in the presence of a base.
[0077]
The reaction solvent is not particularly limited as long as it is inert to the reaction, but a preferable one may be selected according to the base to be used. Alcohol-based, ether-based, halogenated hydrocarbon-based, amide-based, etc. , Dimethyl sulfoxide, acetonitrile, acetone, acetate ester, water and the like can be used. Moreover, these can also be used as a mixed solvent.
[0078]
While the reaction temperature varies depending on the type of base and the solvent used, it may be in the range of −78 ° C. to the boiling point of the solvent, preferably in the range of room temperature to the boiling point of the solvent.
[0079]
The base may be either organic or inorganic, alkali metal or alkaline earth metal, for example, sodium, potassium, lithium, magnesium, calcium and other hydroxides, carbonates, bicarbonates and alkoxides, Metal hydrides such as sodium hydride, potassium hydride, lithium hydride, alkyllithium reagents such as n-butyllithium, methyllithium, lithium diisopropylamide, tertiary amines such as triethylamine, N, N-diisopropylethylamine, etc. 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,8-diazabicyclo [4.3.0] non-5-ene (DBN), dimethylaniline, N-methylmorphol Heterocyclic compounds such as phosphorus can be used.
[0080]
In order to accelerate the reaction, in the presence of quaternary ammonium salts such as tetrabutylammonium bromide and benzyltriethylammonium chloride, alkali metal or alkaline earth metal iodides such as potassium iodide and sodium iodide, and crown ethers. Sometimes it is done.
[0081]
Of these bases, metal carbonates such as potassium carbonate and sodium carbonate, and metal hydrides such as sodium hydride and potassium hydride are preferable.
[0082]
In this step, the amount of compound (VI) used and / or the amount of base used varies depending on the target compound.
[0083]
That is, when the target compound is (I-3), compound (VI) may be reacted using 1 equivalent, or may be reacted in the presence of 1 to 1.2 equivalents of base. When 1 equivalent of compound (VI) is used (in theory, 1 equivalent may be used, but in the case of actual reaction, it may be used in a slightly excessive amount), the amount of the base should be 1 equivalent or more. Is preferably 1 to 1.2 equivalents. When 1 to 1.2 equivalents of a base are used, the amount of the compound (VI) may be 1 equivalent or more, but 1 equivalent (theoretically 1 equivalent is sufficient, but in the actual reaction, it is somewhat May be used in excess).
[0084]
When the target compound is (I-2), 2 equivalents or more of compound (VI) and a base may be used.
[0085]
Next, a process for producing compound (I-4) by reacting compound (VII) with compound (VII) after reacting compound (IV) with compound (IV) with one equivalent of compound (VI) will be described. The amount of compound (VI) may theoretically be 1 equivalent, but may be used in a slightly excessive amount when actually reacting.
[0086]
Compound (I-4) is prepared by treating compound (IV) and compound (IV) with one equivalent of compound (VI) in a solvent in the presence of a base, and then adding compound (VII). Can be obtained by processing.
[0087]
The reaction solvent is not particularly limited as long as it is inert to the reaction, but a preferable one may be selected according to the base to be used. Alcohol-based, ether-based, halogenated hydrocarbon-based, amide-based, etc. , Dimethyl sulfoxide, acetonitrile, acetone, acetate ester, water and the like can be used. Moreover, these can also be used as a mixed solvent.
[0088]
While the reaction temperature varies depending on the type of base and the solvent used, it may be in the range of −78 ° C. to the boiling point of the solvent, preferably in the range of room temperature to the boiling point of the solvent.
[0089]
The base may be either organic or inorganic, alkali metal or alkaline earth metal, for example, sodium, potassium, lithium, magnesium, calcium and other hydroxides, carbonates, bicarbonates and alkoxides, Metal hydrides such as sodium hydride, potassium hydride, lithium hydride, alkyllithium reagents such as n-butyllithium, methyllithium, lithium diisopropylamide, tertiary amines such as triethylamine, N, N-diisopropylethylamine, etc. 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,8-diazabicyclo [4.3.0] non-5-ene (DBN), dimethylaniline, N-methylmorphol Heterocyclic compounds such as phosphorus can be used.
[0090]
In order to accelerate the reaction, in the presence of quaternary ammonium salts such as tetrabutylammonium bromide and benzyltriethylammonium chloride, alkali metal or alkaline earth metal iodides such as potassium iodide and sodium iodide, and crown ethers. Sometimes it is done.
[0091]
Of these bases, metal carbonates such as potassium carbonate and sodium carbonate, and metal hydrides such as sodium hydride and potassium hydride are preferable.
[0092]
The base may be used in an amount of 2 to 30 equivalents, preferably 2 to 16 equivalents, relative to compound (IV) from the beginning of the reaction. The step of reacting compound (VI) and the step of reacting compound (VII) May be used in two separate steps. In the step of reacting compound (VI), 1 equivalent or more, preferably 1 to 1.2 equivalents of base is used, and in the step of reacting compound (VII), 1 equivalent or more of base may be used.
[0093]
In the reaction to obtain this compound (I-4), the compound (VI) is treated in the presence of a base in the presence of a base, the compound obtained is isolated once, and then the compound and the compound (VII) are added to the base in the solvent. It can also be obtained by processing in the presence.
[0094]
R in this reaction⁴¹And R⁵¹In the case of producing compounds having different Rs, the one having more carbon atoms (in the same case, the branched one) is selected as R⁴¹Then, the one with the smaller carbon number (in the same case, the straight chain) is R⁵¹It is preferable to react as follows.
[0095]
Compound (III) can be obtained by ring-closing compound (II). Specifically, it can be obtained by treating compound (II) in a solvent in the presence of a base. Compound (III) can also be obtained by treating compound (II) in a solvent in the presence of an alkylaluminum reagent.
[0096]
The solvent is not particularly limited as long as it is inert to the reaction, but a preferable solvent may be selected according to the base and alkylaluminum reagent to be used. Alcohol-based, ether-based, halogenated hydrocarbon-based, amide Acetate, aromatic hydrocarbon, others, acetonitrile, acetone, acetate ester, water, etc. can be used. Moreover, these can also be used as a mixed solvent.
[0097]
Of these solvents, ethers such as tetrahydrofuran (THF), halogenated carbons such as methylene chloride, and aromatic hydrocarbons such as toluene are preferable.
[0098]
While the reaction temperature varies depending on the type of base and the solvent used, it may be in the range of −78 ° C. to the boiling point of the solvent, preferably 0 ° C. to the boiling point of the solvent. The reaction proceeds at room temperature, but the reaction may be promoted by heating.
[0099]
The amount of the base used is usually in the range of 1 to 15 equivalents, preferably about 1 to 5 equivalents, relative to compound (II).
[0100]
Examples of the alkylaluminum reagent include trimethylaluminum, triethylaluminum, triisobutylaluminum, dimethylaluminum chloride, diethylaluminum chloride, methylaluminum dichloride, ethylaluminum dichloride, and trimethylaluminum is particularly preferable.
[0101]
The amount of alkylaluminum reagent used is usually in the range of 1 to 15 equivalents, preferably about 1 to 5 equivalents, relative to compound (II).
[0102]
Furthermore, compound (III) can also be obtained by treating compound (II) in a solvent under heating.
[0103]
The solvent is not particularly limited as long as it is inert to the reaction, but alcohol, ether, halogenated hydrocarbon, amide, aromatic hydrocarbon, others, acetonitrile, acetone, acetate, water Etc. can be used. Moreover, these can also be used as a mixed solvent.
[0104]
Of these solvents, ethers such as tetrahydrofuran (THF), halogenated carbons such as methylene chloride, and aromatic hydrocarbons such as toluene are preferable.
[0105]
Although the reaction temperature varies depending on the solvent used, it may be carried out in the range of 40 ° C. to the boiling point of the solvent, and is preferably carried out under heating and reflux.
[0106]
Compound (II), which is a reaction raw material, is R among compounds (I).² Is an amino protecting group R^Three May be a hydrogen atom, but R² And R^Three Protecting group R of amino group of compound (I) in which both are protecting groups of amino group^Three Can also be obtained by deprotection using conventional methods (see “Protective Group in Organic Synthesis” such as TWGreen). It is done. For example, R^Three Is an acyl group by hydrolysis, and when it is an alkoxycarbonyl group or an aralkyloxycarbonyl group, by treatment with an acid in the absence or presence of a cation scavenger in a solvent or in a solvent, and In the case where the phenyl group is a lower alkyl such as methyl or ethyl, a lower alkoxy such as methoxy or ethoxy, nitro, or a benzyl group optionally substituted by a halogen, in a solvent in the presence of an acid or an alkali using a catalyst. Alternatively, it can be deprotected by hydrogenolysis in the absence.
[0107]
When the protecting group of the amino group is an acyl group, the reaction is carried out using an acid or alkali, acid such as hydrochloric acid or sulfuric acid is used for acidic hydrolysis, and sodium hydroxide, potassium hydroxide or sodium is used for alkaline hydrolysis. An alkali such as alcoholate can be used for the deprotection reaction as an aqueous solution of these acids or alkalis, or an alcohol organic solvent such as methanol or ethanol, or a solution containing a water-containing organic solvent. Performed at the boiling point.
[0108]
When the amino-protecting group is an alkoxycarbonyl group or an aralkyloxycarbonyl group, there is no particular limitation as long as it is inert to the deprotection reaction as a solvent, but alcohol-based, ether-based, halogenated hydrocarbon-based In addition, aromatic hydrocarbons, other solvents such as acetonitrile, acetone, acetic acid ester, water, acetic acid and the like, or mixed solvents thereof can be used. Examples of the cation scavenger include anisole and thioanisole. Examples thereof include p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, hydrobromic acid, trifluoroacetic acid and the like. The reaction temperature is from under ice cooling to the boiling point of the solvent.
[0109]
In addition, in hydrogenolysis of benzyl groups which may be substituted with lower alkyl such as methyl and ethyl, lower alkoxy such as methyl and ethyl, lower alkoxy such as methoxy and ethoxy, and optionally halogen, inert to the reaction as a solvent There is no particular limitation as long as it is anything, but alcohols, amides, aromatic hydrocarbons, and others such as acetonitrile, formic acid, and acetic acid can be used. Examples of the catalyst include metal-containing compounds such as 5% palladium carbon, 10% palladium carbon, 20% palladium carbon, and Raney nickel. Examples of the acid or alkali include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid. And mineral acids such as sulfuric acid and phosphoric acid, organic acids such as p-toluenesulfonic acid and methanesulfonic acid, and inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide and aqueous ammonia. The reaction temperature may be in the range of room temperature to 200 ° C., and the hydrogen pressure is in the range of normal pressure to 150 atm.
[0110]
The solvent used in each step of the present invention will be described.
[0111]
Examples of aromatic hydrocarbons include benzene, toluene, xylene and the like. Examples of alcohols include methanol, ethanol, propanol, isopropanol (IPA), butanol, t-butanol and the like. Examples of the ether type include diethyl ether, tetrahydrofuran (THF), dimethoxyethane, 1,4-dioxane and the like. Examples of the amide system include dimethylformamide (DMF) and dimethylacetamide (DMAc). Examples of halogenated hydrocarbons include chloroform, methylene chloride, 1,2-dichloroethane (EDC), and the like.
[0112]
The compound (III) obtained here can be led to an antibacterial synthetic intermediate by the methods described in JP-A-3-95176 and JP-A-4-149174. EXAMPLES Hereinafter, although an Example and a reference example are given and this invention is demonstrated further more concretely, this invention is not limited to these.
[0113]
【Example】
Example 1:ethyl 4- [ (Tert-Butoxycarbonyl) amino ] 2-cyclopropyl-3-oxobutyrate
Ethyl 4-[(tert-butoxycarbonyl) amino] -3-oxobutyrate (822.0 mg) and 1,2-dibromoethane (1.86 g) were dissolved in acetone (33 ml). At room temperature, potassium carbonate (2.74 g) was added with stirring, and the reaction was heated to reflux for 9 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography (ethyl acetate-toluene = 1: 3) to obtain 653.8 mg of a crude product. Further, the crude product was subjected to silica gel column chromatography (ethyl acetate-normal hexane = 1: 3) to obtain 547.4 mg of the title compound as a colorless oil.
[0114]
¹H-NMR (CDCl_Three ) Δ: 1.29 (3H, t, J = 7.0 Hz), 1.45 (9H, s), 1.57 (4H, s), 4.21 (2H, q, J = 7.0 Hz) , 4.49 (2H, d, J = 5.0 Hz), 5.30 (1H, brs)
MS (m / z): 272, 216, 172, 170, 57
[0115]
Example 2:ethyl 4- [ (Benzyloxycarbonyl) amino ] 2-cyclopropyl-3-oxobutyrate
Ethyl 4-[(benzyloxycarbonyl) amino] -3-oxobutyrate (558.6 mg) and 1,2-dibromoethane (1.10 g) were dissolved in acetone (20 ml). At room temperature, potassium carbonate (1.66 g) was added with stirring, and the reaction was heated to reflux for 9 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography (ethyl acetate-toluene = 1: 3) to obtain 227.7 mg of a crude product. Further, the crude product was subjected to silica gel column chromatography (ethyl acetate-normal hexane = 1: 3) to obtain 189.9 mg of the title compound as a colorless oil.
[0116]
¹H-NMR (CDCl_Three ) Δ: 1.29 (3H, t, J = 7.0 Hz), 1.58 (4H, s), 4.21 (2H, q, J = 7.0 Hz), 4.59 (2H, d, J = 5.0 Hz), 5.12 (2H, s), 5.46 (1H, brs), 7.46-7.39 (5H, m)
MS (m / z): 306, 262, 91
[0117]
Example 3:ethyl 4- [ Benzyl (tert-butoxycarbonyl) amino ] 2-cyclopropyl-3-oxobutyrate
Ethyl 4- [benzyl (tert-butoxycarbonyl) amino] -3-oxobutyrate (100.0 mg) and 1,2-dibromoethane (69.8 mg) were dissolved in N, N-dimethylformamide (6 ml). At room temperature, potassium carbonate (98.6 mg) was added with stirring, and the mixture was stirred at that temperature for 15 hours 30 minutes. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography (ethyl acetate-toluene = 1: 3) to obtain 75.2 mg of a crude product. Further, the crude product was subjected to silica gel column chromatography (ethyl acetate-normal hexane = 1: 3) to obtain 55.7 mg of the title compound as a colorless oil.
[0118]
¹H-NMR (CDCl_Three ) Δ: 1.19 (3H, t, J = 7.2 Hz), 1.38 to 1.60 (4H, m), 1.46 (9H, s), 4.13 (2H, q, J = 7.2 Hz), 4.40, 4.45 (2H, s × 2), 4.48 (2H, s), 7.20-7.38 (5H, m)
[0119]
Example 4:ethyl 4- [ Benzyl (tert-butoxycarbonyl) amino ] 2-cyclopropyl-3-oxobutyrate
Ethyl 4- [benzyl (tert-butoxycarbonyl) amino] -3-oxobutyrate (100.0 mg) and 1,2-dibromoethane (167.5 mg) were dissolved in acetone (6 ml). At room temperature, potassium carbonate (246.5 mg) was added with stirring, and the reaction was heated to reflux for 6 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography (ethyl acetate-toluene = 1: 3) to obtain 84.3 mg of a crude product. Further, the crude product was subjected to silica gel column chromatography (ethyl acetate-normal hexane = 1: 3) to obtain 75.8 mg of the title compound as a colorless oil. The NMR spectrum was consistent with that obtained in Example 3.
[0120]
Example 5:5-t-Butoxycarbonyl-4,7-dioxo-5-azaspiro [2.4] heptane
Ethyl 4-[(tert-butoxycarbonyl) amino] -2-cyclopropyl-3-oxobutyrate (200.0 mg) was dissolved in tetrahydrofuran (30 ml). While stirring with ice cooling, 60% sodium hydride (43.8 mg) was added and stirred at the same temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography (ethyl acetate-normal hexane = 1: 3) to give 23.4 mg of the title compound as white crystals.
[0121]
Melting point 103-105 ° C
¹H-NMR (CDCl_Three ) Δ: 1.57 (9H, s), 1.75 to 1.87 (4H, m), 4.29 (2H, s)
Elemental analysis value: C₁₁H₁₅NO_Four As
Theoretical value (%): C 58.66; H 6.71; N 6.22
Analytical value (%): C 58.39; H 6.58; N 6.06
[0122]
Example 6:5-t-Butoxycarbonyl-4,7-dioxo-5-azaspiro [2.4] heptane
Ethyl 4-[(tert-butoxycarbonyl) amino] -2-cyclopropyl-3-oxobutyrate (137.1 mg) was dissolved in toluene (10.1 ml) under an argon stream. While stirring under ice cooling, 1.01 M trimethylaluminum normal hexane solution (1.10 ml) was added, and the mixture was stirred at the same temperature for 21 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography (ethyl acetate-normal hexane = 1: 3) to give 46.0 mg of the title compound as white crystals. Various spectral data were consistent with those obtained in Example 5.
[0123]
Example 7:5-Benzyloxycarbonyl-4,7-dioxo-5-azaspiro [2.4] heptane
Ethyl 4-[(benzyloxycarbonyl) amino] -2-cyclopropyl-3-oxobutyrate (200.0 mg) was dissolved in toluene (13.1 ml) under an argon stream. While stirring with ice cooling, 1.01 M trimethylaluminum normal hexane solution (1.30 ml) was added, and the mixture was stirred at the same temperature for 21 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was subjected to silica gel column chromatography (ethyl acetate-normal hexane = 1: 3) to give 35.7 mg of the title compound as white crystals.
[0124]
Melting point 126-128 ° C
¹H-NMR (CDCl_Three ) Δ: 1.76 to 1.88 (4H, m), 4.35 (2H, s), 5.34 (2H, s), 7.28 to 7.36 (5H, m)
Elemental analysis value: C₁₄H₁₃NO_Four As
Theoretical value (%): C 64.86; H 5.05; N 5.40
Analytical value (%): C 64.66; H 5.05; N 5.37
[0125]
Example 8:ethyl 4-Benzylamino-2-cyclopropyl-3-oxobutyrate
Ethyl 4-[(benzyloxycarbonyl) amino] -2-cyclopropyl-3-oxobutyrate (131.5 mg) was dissolved in methylene chloride (1 ml) under an argon stream. While stirring under ice cooling, trifluoroacetic acid (1.82 ml) was added. The reaction was stirred at room temperature for 1 hour 30 minutes. The reaction mixture was evaporated, 1N aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporating the solvent, 84.9 mg of the title compound was obtained as a colorless oil. This product was used in the next step without purification.
[0126]
¹H-NMR (CDCl_Three ) Δ: 1.24 (3H, t, J = 7.2 Hz), 1.51 (4H, s), 3.77 (2H, s), 4.01 (2H, s), 4.16 (2H) , Q, J = 7.2 Hz), 7.20-7.43 (5H, m)
[0127]
Example 9:5-Benzyl-4,7-dioxo-5-azaspiro [2.4] heptane
A crude product of ethyl 4-benzylamino-2-cyclopropyl-3-oxobutyrate (84.9 mg) was dissolved in toluene (5 ml), and the reaction solution was heated to reflux for 30 minutes. After the reaction solution was distilled off, the obtained residue was subjected to silica gel column chromatography (ethyl acetate-toluene = 1: 4) to obtain 56.3 mg of the title compound as white crystals.
[0128]
Melting point 92-94 ° C
¹H-NMR (CDCl_Three ) Δ: 1.60 to 1.79 (4H, m), 3.79 (2H, s), 4.68 (2H, s), 7.26 to 7.42 (5H, m)
Elemental analysis value: C₁₃H₁₃NO₂ As
Theoretical value (%): C 72.54; H 6.09; N 6.51
Analytical value (%): C 72.41; H 6.03; N 6.46
[0129]
Reference example 1:ethyl 4- [ (Tert-Butoxycarbonyl) amino ] -3-Oxobutyrate
Under an argon stream, 350 mg of Nt-butoxycarbonylglycine was dissolved in tetrahydrofuran (10 ml). 1,1'-Carbonyldiimidazole (356.7 mg) was added to the reaction solution with stirring under ice cooling, followed by stirring at room temperature for 1 hour. Separately from this reaction solution at −78 ° C., a tetrahydrofuran solution of lithium enolate prepared from ethyl acetate (0.78 ml), 1.6 M n-butyllithium normal hexane solution (5 ml) and diisopropylamine (1.12 ml) ( 10 ml) was added dropwise and stirred at the same temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. After the solvent was distilled off, the residue was subjected to silica gel column chromatography (ethyl acetate-normal hexane = 1: 1) to obtain 185.6 mg of the title compound as a colorless oil.
[0130]
¹H-NMR (CDCl_Three ) Δ: 1.28 (3H, t, J = 7.2 Hz), 1.45 (9H, s), 3.49 (2H, s), 4.13 (2H, d, J = 5.0 Hz) , 4.21 (2H, q, J = 7.2 Hz), 5.30 (1H, brs)
MS (m / z): 246, 190, 146, 144, 57
[0131]
Reference example 2:ethyl 4- [ (Tert-Butoxycarbonyl) amino ] -3-Oxobutyrate
Under an argon stream, Nt-butoxycarbonylglycine (1.75 g) was dissolved in tetrahydrofuran (20 ml). 1,1'-Carbonyldiimidazole (1.95 g) was added to the reaction solution with stirring under ice cooling, and then stirred at room temperature for 1 hour. This reaction solution was separately added dropwise to a tetrahydrofuran suspension (15 ml) of magnesium malonate prepared with ethyl potassium malonate (2.55 g) and magnesium chloride (920 mg) at room temperature and stirred at the same temperature for 20 hours. . A saturated aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. After the solvent was distilled off, the residue was subjected to silica gel column chromatography (ethyl acetate-normal hexane = 1: 1) to give 1.86 g of the title compound as a colorless oil. Various spectral data were consistent with those obtained in Reference Example 1.
[0132]
Reference Example 3:ethyl 4- [ (Benzyloxycarbonyl) amino ] -3-Oxobutyrate
Under an argon stream, N-benzyloxycarbonylglycine (418.4 mg) was dissolved in tetrahydrofuran (10 ml). 1,1'-Carbonyldiimidazole (356.7 mg) was added to the reaction solution with stirring under ice cooling, followed by stirring at room temperature for 1 hour. Separately from this reaction solution at −78 ° C., a tetrahydrofuran solution of lithium enolate prepared from ethyl acetate (0.78 ml), 1.6 M n-butyllithium normal hexane solution (5 ml) and diisopropylamine (1.12 ml) ( 10 ml) was added dropwise and stirred at the same temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. After the solvent was distilled off, the residue was subjected to silica gel column chromatography (ethyl acetate-normal hexane = 1: 1) to obtain 216 mg of the title compound as a colorless oil.
[0133]
Melting point: 22-23 ° C
¹H-NMR (CDCl_Three ) Δ: 1.28 (3H, t, J = 7.2 Hz), 3.48 (2H, s), 4.20 (2H, q, J = 7.2 Hz), 4.22 (2H, d, J = 5.0 Hz), 5.12 (2H, s), 5.44 (1H, brs), 7.31-7.38 (5H, m)
[0134]
Reference example 4:ethyl 4- [ (Benzyloxycarbonyl) amino ] -3-Oxobutyrate
Under an argon stream, N-benzyloxycarbonylglycine (2.09 g) was dissolved in tetrahydrofuran (20 ml). 1,1'-Carbonyldiimidazole (1.95 g) was added to the reaction solution with stirring under ice cooling, followed by stirring at room temperature for 2 hours. This reaction solution was separately added dropwise to a tetrahydrofuran suspension (15 ml) of magnesium malonate prepared with ethyl potassium malonate (2.55 g) and magnesium chloride (920 mg) at room temperature and stirred at the same temperature for 20 hours. . A saturated aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. After the solvent was distilled off, the residue was subjected to silica gel column chromatography (ethyl acetate-normal hexane = 1: 1) to give 2.42 g of the title compound as a colorless oil. Various spectral data were consistent with those obtained in Reference Example 3.
[0135]
Reference example 5:N-benzyl-N- (tert-butoxycarbonyl) glycine
Benzylglycine (606 mg) was dissolved in methanol (60 ml). At room temperature, a tetrahydrofuran solution (10 ml) of triethylamine (8.36 ml) and ditert-butyl dicarbonate (1.31 g) was added to the reaction solution. The reaction solution was stirred for 20 hours at the same temperature. After the reaction solution was distilled off, a saturated aqueous potassium hydrogen sulfate solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. After the solvent was distilled off, the residue was subjected to silica gel column chromatography (chloroform-methanol = 20: 1) to obtain 1.04 g of a standard compound as white crystals.
[0136]
Melting point: 100-102 ° C
¹H-NMR (CDCl_Three ): 1.48 (9H, s), 3.81, 3.97 (2H, s × 2), 4.53 (2H, d, J = 8.9 Hz), 7.20 to 7.39 ( 5H, m), 10.59 (1H, brs)
[0137]
Reference Example 6:ethyl 4- [Benzyl (tert-butoxycarbonyl) amino] -3-oxobutyrate
Under an argon stream, N-benzyl-N- (tert-butoxycarbonyl) glycine (500.0 mg) was dissolved in tetrahydrofuran (5 ml). 1,1'-Carbonyldiimidazole (458.9 mg) was added to the reaction solution with stirring under ice cooling, and then stirred at room temperature for 2 hours. This reaction solution was separately added dropwise to a tetrahydrofuran suspension (7 ml) of magnesium malonate prepared with ethyl potassium malonate (481.1 mg) and magnesium chloride (173.3 mg) at room temperature, and left at that temperature for 16 hours. Stir. A saturated aqueous potassium hydrogen sulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. After the solvent was distilled off, the residue was subjected to silica gel column chromatography (ethyl acetate-normal hexane = 1: 3) to obtain 530.8 mg of the title compound as a colorless oil.
[0138]
¹H-NMR (CDCl_Three ) Δ: 1.25 (3H, t, J = 7.2 Hz), 1.46, 1.47 (9H, s × 2), 3.34, 3.41 (2H, s × 2), 3. 93, 4.07 (2H, s × 2), 4.16 (2H, q, J = 7.2 Hz), 4.46, 4.51 (2H, s × 2), 7.26 to 7.38. (5H, m)

Claims (28)

Formula (I)
[Wherein R ¹ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R ² and R ³ each independently represent a hydrogen atom or the following group:
Benzyl, alpha-methylbenzyl, trityl, benzhydryl group, p-nitrobenzyl group, p-methoxybenzyl group, t - butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, Benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group, butyroyl group, t - butyroyl group, methoxyacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoro Acetyl, chloroacetyl, pivaloyl, and benzoyl groups
R ⁴ and R ⁵ are each independently a hydrogen atom or an alkyl group having 1 to 6 carbon atoms (except when R ² and R ³ are simultaneously hydrogen atoms). (Provided that R ⁴ and R ⁵ are simultaneously hydrogen atoms), or together form a polymethylene chain, which may have the following structure:
(Wherein n represents an integer of 2 to 5)]. In formula (I), R ¹ is an ethyl group, R ² is a benzyl group, R ³ is a t-butoxycarbonyl group, and R ⁴ and R ⁵ are combined to form an ethylene chain in which n is 2. The compound according to claim 1, wherein In formula (I), R ¹ is an ethyl group, R ² is a t-butoxycarbonyl group, R ³ is a hydrogen atom, and R ⁴ and R ⁵ are combined to form an ethylene chain in which n is 2. The compound according to claim 1, wherein In the formula (I), R ¹ is an ethyl group, R ² is a benzyloxycarbonyl group, R ³ is a hydrogen atom, and R ⁴ and R ⁵ are combined to form an ethylene chain in which n is 2. The compound according to claim 1, wherein In the formula (I), R ¹ is an ethyl group, R ² is a benzyl group, R ³ is a hydrogen atom, and R ⁴ and R ⁵ are combined to form an ethylene chain in which n is 2. The compound of claim 1. Formula (III-1)
[Wherein R ²¹ is formyl, acetyl, propanoyl, butyroyl, t - butyroyl, methoxyacetyl, fluoroacetyl, difluoroacetyl, trifluoroacetyl, chloroacetyl, pivaloyl, benzoyl , t - butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, means a benzyloxycarbonyl group, para-methoxybenzyloxycarbonyl group or a para-nitrobenzyloxycarbonyl group,, R ⁴ and R ⁵ each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms (except when R ⁴ and R ⁵ are simultaneously hydrogen atoms), or together, polymethylene It may form a chain and have the following structure:
(Wherein n represents an integer of 2 to 5)]. The compound according to claim 6, wherein in formula (III-1), R ²¹ is a t-butoxycarbonyl group, and R ⁴ and R ⁵ are combined to form an ethylene chain in which n is 2. . The compound according to claim 6, wherein in formula (III-1), R ²¹ is a benzyloxycarbonyl group, and R ⁴ and R ⁵ are combined to form an ethylene chain wherein n is 2. Formula (IV)
(In the formula, R ¹ is a hydrogen atom or an alkyl group having a carbon number of 1 to 6, R ²¹ is t - butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, Benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group, butyroyl group, t - butyroyl group, methoxyacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoro An acetyl group, a chloroacetyl group, a pivaloyl group, or a benzoyl group means R ³¹ is a hydrogen atom, a benzyl group, an α-methylbenzyl group, a trityl group, a benzhydryl group, a paranitrobenzyl group, a paramethoxybenzyl group, t − Butoxycarbonyl group, methoxyca Rubonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group, butyroyl group, t -. the butyloyl, methoxyacetyl group, trifluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group or means a benzoyl group), compounds represented by the formula (V)
(Wherein n represents an integer of 2 to 5, and X ¹ and X ² each independently represents an atom or group that is eliminated in a nucleophilic substitution reaction). Formula (I-1) characterized by processing below
(In the formula, R ¹ is a hydrogen atom or an alkyl group having a carbon number of 1 to 6, R ²¹ is t - butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, para-methoxybenzyloxycarbonyl group, para-nitrobenzyloxycarbonyl group, a formyl group, an acetyl group, a propanoyl group, butyroyl group, t - butyloyl, methoxyacetyl group, trifluoroacetyl group, difluoroacetyl group, trifluoroacetyl An acetyl group, a chloroacetyl group, a pivaloyl group, or a benzoyl group means R ³¹ is a hydrogen atom, a benzyl group, an α-methylbenzyl group, a trityl group, a benzhydryl group, a paranitrobenzyl group, a paramethoxybenzyl group, t − Butoxycarbonyl group, methoxyca Rubonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group, butyroyl group, t - butyloyl, methoxyacetyl group, trifluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, means a pivaloyl group or a benzoyl group,, n is represented by) represents an integer of 2 to 5. A method for producing a compound. The production method according to claim 9, wherein X ¹ and X ² are halogen atoms. The process according to claim 9, wherein R ¹ is an ethyl group, R ²¹ is a t-butoxycarbonyl group, R ³¹ is a benzyl group, n is 2, and X ¹ and X ² are bromine atoms. The process according to claim 9, wherein R ¹ is an ethyl group, R ²¹ is a t-butoxycarbonyl group, R ³¹ is a hydrogen atom, n is 2, and X ¹ and X ² are bromine atoms. The process according to claim 9, wherein R ¹ is an ethyl group, R ²¹ is a benzyloxycarbonyl group, R ³¹ is a hydrogen atom, n is 2, and X ¹ and X ² are bromine atoms. Formula (IV)
(In the formula, R ¹ is a hydrogen atom or an alkyl group having a carbon number of 1 to 6, R ²¹ is t - butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, para-methoxybenzyloxycarbonyl group, para-nitrobenzyloxycarbonyl group, a formyl group, an acetyl group, a propanoyl group, butyroyl group, t - butyloyl, methoxyacetyl group, trifluoroacetyl group, difluoroacetyl group, trifluoroacetyl An acetyl group, a chloroacetyl group, a pivaloyl group, or a benzoyl group means R ³¹ is a hydrogen atom, a benzyl group, an α-methylbenzyl group, a trityl group, a benzhydryl group, a paranitrobenzyl group, a paramethoxybenzyl group, t − Butoxycarbonyl group, methoxyca Carbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, para-methoxybenzyloxycarbonyl group, para-nitrobenzyloxycarbonyl group, a formyl group, an acetyl group, pro Panoiru group, butyroyl group, a t - butyroyl group, a methoxyacetyl group, a fluoroacetyl group, a difluoroacetyl group, a trifluoroacetyl group, a chloroacetyl group, a pivaloyl group, or a benzoyl group ) and a compound represented by the formula (VI)
(Wherein R ⁴¹ represents an alkyl group having 1 to 6 carbon atoms, and X ³ represents an atom or group that is eliminated in a nucleophilic substitution reaction). In the presence of a base, the compound represented by Formula (I-2) and / or Formula (I-3)
(In the formula, R ¹ is a hydrogen atom or an alkyl group having a carbon number of 1 to 6, R ²¹ is t - butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, para-methoxybenzyloxycarbonyl group, para-nitrobenzyloxycarbonyl group, a formyl group, an acetyl group, a propanoyl group, butyroyl group, t - butyloyl, methoxyacetyl group, trifluoroacetyl group, difluoroacetyl group, trifluoroacetyl An acetyl group, a chloroacetyl group, a pivaloyl group, or a benzoyl group means R ³¹ is a hydrogen atom, a benzyl group, an α-methylbenzyl group, a trityl group, a benzhydryl group, a paranitrobenzyl group, a paramethoxybenzyl group, t − Butoxycarbonyl group, methoxyca Rubonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group, butyroyl group, t - butyloyl, methoxyacetyl group, trifluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, means a pivaloyl group or a benzoyl group,, R ⁴¹ denotes an alkyl group having 1 to 6 carbon atoms. The manufacturing method of the compound represented by this. Formula (IV)
(In the formula, R ¹ is a hydrogen atom or an alkyl group having a carbon number of 1 to 6, R ²¹ is t - butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, para-methoxybenzyloxycarbonyl group, para-nitrobenzyloxycarbonyl group, a formyl group, an acetyl group, a propanoyl group, butyroyl group, t - butyloyl, methoxyacetyl group, trifluoroacetyl group, difluoroacetyl group, trifluoroacetyl An acetyl group, a chloroacetyl group, a pivaloyl group, or a benzoyl group means R ³¹ is a hydrogen atom, a benzyl group, an α-methylbenzyl group, a trityl group, a benzhydryl group, a paranitrobenzyl group, a paramethoxybenzyl group, t − Butoxycarbonyl group, methoxyca Carbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, para-methoxybenzyloxycarbonyl group, para-nitrobenzyloxycarbonyl group, a formyl group, an acetyl group, pro Panoiru group, butyroyl group, a t - butyroyl group, a methoxyacetyl group, a fluoroacetyl group, a difluoroacetyl group, a trifluoroacetyl group, a chloroacetyl group, a pivaloyl group, or a benzoyl group ) and a compound represented by the formula (VI)
(Wherein R ⁴¹ represents an alkyl group having 1 to 6 carbon atoms, and X ³ represents an atom or group that is eliminated in a nucleophilic substitution reaction). Formula (I-3) characterized by
(In the formula, R ¹ is a hydrogen atom or an alkyl group having a carbon number of 1 to 6, R ²¹ is t - butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, para-methoxybenzyloxycarbonyl group, para-nitrobenzyloxycarbonyl group, a formyl group, an acetyl group, a propanoyl group, butyroyl group, t - butyloyl, methoxyacetyl group, trifluoroacetyl group, difluoroacetyl group, trifluoroacetyl An acetyl group, a chloroacetyl group, a pivaloyl group, or a benzoyl group means R ³¹ is a hydrogen atom, a benzyl group, an α-methylbenzyl group, a trityl group, a benzhydryl group, a paranitrobenzyl group, a paramethoxybenzyl group, t − Butoxycarbonyl group, methoxyca Rubonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group, butyroyl group, t - butyloyl, methoxyacetyl group, trifluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, means a pivaloyl group or a benzoyl group,, R ⁴¹ denotes an alkyl group having 1 to 6 carbon atoms. The manufacturing method of the compound represented by this.   The process according to claim 15, wherein the amount of the compound of formula (VI) is 1 equivalent relative to the compound of formula (IV). Formula (IV)
(In the formula, R ¹ is a hydrogen atom or an alkyl group having a carbon number of 1 to 6, R ²¹ is t - butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, Benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group, butyroyl group, t - butyroyl group, methoxyacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoro An acetyl group, a chloroacetyl group, a pivaloyl group, or a benzoyl group means R ³¹ is a hydrogen atom, benzyl group, α-methylbenzyl group, trityl group, benzhydryl group, paranitrobenzyl group, paramethoxybenzyl group, t − butoxycarbonyl group, Metokishika Rubonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group, butyroyl group, t -. the butyloyl, methoxyacetyl group, trifluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group or means a benzoyl group), compounds represented by the formula (VI)
(Wherein R ⁴¹ represents an alkyl group having 1 to 6 carbon atoms, and X ³ represents an atom or group that is eliminated in a nucleophilic substitution reaction). Formula (I-2) characterized by
(In the formula, R ¹ is a hydrogen atom or an alkyl group having a carbon number of 1 to 6, R ²¹ is t - butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, para-methoxybenzyloxycarbonyl group, para-nitrobenzyloxycarbonyl group, a formyl group, an acetyl group, a propanoyl group, butyroyl group, t - butyloyl, methoxyacetyl group, trifluoroacetyl group, difluoroacetyl group, trifluoroacetyl An acetyl group, a chloroacetyl group, a pivaloyl group, or a benzoyl group means R ³¹ is a hydrogen atom, a benzyl group, an α-methylbenzyl group, a trityl group, a benzhydryl group, a paranitrobenzyl group, a paramethoxybenzyl group, t − Butoxycarbonyl group, methoxyca Rubonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group, butyroyl group, t - butyloyl, methoxyacetyl group, trifluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, means a pivaloyl group or a benzoyl group,, R ⁴¹ denotes an alkyl group having 1 to 6 carbon atoms. The manufacturing method of the compound represented by this.   The process according to claim 17, wherein the amount of the compound of formula (VI) is 2 equivalents or more based on the compound of formula (IV). Formula (IV)
(In the formula, R ¹ is a hydrogen atom or an alkyl group having a carbon number of 1 to 6, R ²¹ is t - butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, Benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group, butyroyl group, t - butyroyl group, methoxyacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoro An acetyl group, a chloroacetyl group, a pivaloyl group, or a benzoyl group means R ³¹ is a hydrogen atom, a benzyl group, an α-methylbenzyl group, a trityl group, a benzhydryl group, a paranitrobenzyl group, a paramethoxybenzyl group, t − Butoxycarbonyl group, methoxyca Rubonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group, butyroyl group, t - butyloyl, methoxyacetyl group, trifluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, to a pivaloyl group or means a benzoyl group compound represented by) a compound of formula (IV),. 1 equivalent of formula (VI)
(Wherein R ⁴¹ represents an integer having 1 to 6 carbon atoms, and X ³ represents an atom or a group that is eliminated in the nucleophilic substitution reaction) and is treated in the presence of a base. Followed by formula (VII)
(Wherein R ⁵¹ represents an alkyl group having 1 to 6 carbon atoms, and X ⁴ represents an atom or group that is eliminated in a nucleophilic substitution reaction). Formula (I-4) characterized by
(In the formula, R ¹ is a hydrogen atom or an alkyl group having a carbon number of 1 to 6, R ²¹ is t - butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, para-methoxybenzyloxycarbonyl group, para-nitrobenzyloxycarbonyl group, a formyl group, an acetyl group, a propanoyl group, butyroyl group, t - butyloyl, methoxyacetyl group, trifluoroacetyl group, difluoroacetyl group, trifluoroacetyl An acetyl group, a chloroacetyl group, a pivaloyl group, or a benzoyl group means R ³¹ is a hydrogen atom, a benzyl group, an α-methylbenzyl group, a trityl group, a benzhydryl group, a paranitrobenzyl group, a paramethoxybenzyl group, t − Butoxycarbonyl group, methoxyca Rubonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group, butyroyl group, t - butyloyl, methoxyacetyl group, trifluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, means a pivaloyl group or a benzoyl group,, R ⁴¹ denotes an alkyl group having 1 to 6 carbon atoms, R ⁵¹ represents an alkyl group having 1 to 6 carbon atoms.)   The process according to claim 19, wherein when the compound of formula (IV) and the compound of formula (VI) are treated, the amount of base used is 1 to 1.2 equivalents relative to the compound of formula (IV). Formula (II)
[Wherein R ¹ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R ²² represents a benzyl group, an α-methylbenzyl group, a trityl group, a benzhydryl group, a paranitrobenzyl group, a paramethoxybenzyl group, t - butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, para-methoxybenzyloxycarbonyl group, para-nitrobenzyloxycarbonyl group, a formyl group, an acetyl group, A propanoyl group, a butyroyl group, a t - butyroyl group, a methoxyacetyl group, a fluoroacetyl group, a difluoroacetyl group, a trifluoroacetyl group, a chloroacetyl group, a pivaloyl group, or a benzoyl group , and R ⁴ and R ⁵ are each independently Or hydrogen atom or 1 carbon It means 6 alkyl group (excluding the case where R ⁴ and R ⁵ do not simultaneously hydrogen atoms.), Or together form a polymethylene chain, may serve as a following structure.
(Wherein n represents an integer of 2 to 5)] is treated in the presence of a base or an alkylaluminum reagent.
Wherein, R ²² is benzyl, alpha-methylbenzyl, trityl, benzhydryl group, p-nitrobenzyl group, p-methoxybenzyl group, t - butoxycarbonyl group, a methoxycarbonyl group, an ethoxycarbonyl group, 2,2, 2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group, butyroyl group, t - butyroyl group, methoxyacetyl group, fluoroacetyl group , Difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, or benzoyl group , and each of R ⁴ and R ⁵ independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms ( However, R ⁴ and R ⁵ are the same Unless a hydrogen atom.), Or together form a polymethylene chain, it may serve as a following structure.
(Wherein n represents an integer of 2 to 5)]. The production method according to claim 21, wherein the amino-protecting group for R ²² in formula (II) is an alkoxycarbonyl group or an aralkyloxycarbonyl group. A compound in which R ¹ is an ethyl group, R ²² is a t-butoxycarbonyl group, and R ⁴ and R ⁵ are combined to form an ethylene chain in which n is 2, is treated in the presence of a base. The production method according to claim 21. In the presence of an alkylaluminum reagent, R ¹ is an ethyl group, R ²² is a t-butoxycarbonyl group, and R ⁴ and R ⁵ together form an ethylene chain in which n is 2. The manufacturing method of Claim 21 processed into. In the presence of an alkylaluminum reagent, R ¹ is an ethyl group, R ²² is a benzyloxycarbonyl group, and R ⁴ and R ⁵ together form an ethylene chain in which n is 2. The manufacturing method according to claim 21 to be processed. Formula (II)
[Wherein R ¹ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R ²² represents a benzyl group, an α-methylbenzyl group, a trityl group, a benzhydryl group, a paranitrobenzyl group, a paramethoxybenzyl group, t - butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, para-methoxybenzyloxycarbonyl group, para-nitrobenzyloxycarbonyl group, a formyl group, an acetyl group, A propanoyl group, a butyroyl group, a t - butyroyl group, a methoxyacetyl group, a fluoroacetyl group, a difluoroacetyl group, a trifluoroacetyl group, a chloroacetyl group, a pivaloyl group, or a benzoyl group , and R ⁴ and R ⁵ are each independently Or hydrogen atom or 1 carbon It means 6 alkyl group (excluding the case where R ⁴ and R ⁵ do not simultaneously hydrogen atoms.), Or together form a polymethylene chain, may serve as a following structure.
(Wherein n represents an integer of 2 to 5)], and the compound represented by the formula (III)
Wherein, R ²² is benzyl, alpha-methylbenzyl, trityl, benzhydryl group, p-nitrobenzyl group, p-methoxybenzyl group, t - butoxycarbonyl group, a methoxycarbonyl group, an ethoxycarbonyl group, 2,2, 2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group, butyroyl group, t - butyroyl group, methoxyacetyl group, fluoroacetyl group , Difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, or benzoyl group , and each of R ⁴ and R ⁵ independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms ( However, R ⁴ and R ⁵ are the same Unless a hydrogen atom.), Or together form a polymethylene chain, it may serve as a following structure.
(Wherein n represents an integer of 2 to 5)]. Process according to claim 26 in Formula (II), the protecting group of the amino group of R ²² is an aralkyl group. 27. The process according to claim 26, wherein R ¹ is an ethyl group, R ²² is a benzyl group, and R ⁴ and R ⁵ are combined to form an ethylene chain in which n is 2.