JP2000026408A - Antipodally pure pyrrolidine derivative, its salt and their production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an antipodally pure pyrrolidine derivative composed of a specific hydroxymethylpyrrolidine derivative and a specific tartartic acid derivative and useful as a production intermediate for an antibacterial compound. SOLUTION: The objective compound is composed of a compound of formula I (R1 is H, a 1-6C alkyl or the like substitutable with a halogen or the like; R2 is H, a 1-6C alkyl or the like substitutable with a halogen or the like), etc., and a compound of formula II (R3 and R4 are each H or the like), etc., or formula III (R5 and R6 are each a 1-6C alkyl or the like substitutable with a halogen or the like), etc., preferably a compound expressed by formula IV (n1 and n2 are each >=1), e.g. (3S,4S)-3-amino-4-hydroxymethyl-1- benzyloxycarbonylpyrrolidine D-tartrate. The compound can be produced by treating a racemic material of the compound of formula I, etc., (e.g. cis-3- amino-4-hydroxymethyl-N-benzyloxycarbonylpyrrolidine) with an optically active compound of formula II (e.g. D-tartaric acid), etc., in a solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an intermediate for producing an antibacterial compound and a method for producing the intermediate.

[0002]

2. Description of the Related Art A 3-amino-4-fluoromethylpyrrolidinyl group is useful as a substituent of a quinolone compound. There are four types of stereoisomers resulting from the arrangement of groups. That is, there are two kinds, cis and trans, and each of them has four kinds of stereoisomers having an enantiomeric relationship. Of the four, the most useful is the (3S, 4S) -3-amino-4-fluoromethylpyrrolidinyl group in one of the cis configurations, which gives a quinolone with excellent safety:

[0003]

Embedded image It is. To introduce this (3S, 4S) -3-amino-4-fluoromethylpyrrolidinyl group, (3S, 4S) -3-amino-4-fluoromethylpyrrolidine (formula (Va)):

[0004]

Embedded image Alternatively, it is necessary to obtain a derivative thereof. And this (3S, 4
To obtain (S) -3-amino-4-fluoromethylpyrrolidine or a derivative thereof, (3S, 4S) -3-amino-4-hydroxymethylpyrrolidine (formula (IVa)):

[0005]

Embedded image Alternatively, it is easy to obtain a derivative thereof and introduce a fluorine atom into the derivative. However, conventionally, although racemic cis-3-amino-4-hydroxymethylpyrrolidine was known, a method for synthesizing (3S, 4S) -3-amino-4-hydroxymethylpyrrolidine was not known. Therefore, an object of the present invention is to obtain an excellent quinolone compound efficiently, a source of an excellent substituent, (3S, 4S) -3-amino-4-hydroxymethylpyrrolidine or an efficient derivative thereof. It is to provide a manufacturing method.

[0006]

As a result of intensive studies, the present inventors have found that a racemic cis-3-amino-4-hydroxymethylpyrrolidine derivative represented by the formula (II) can be converted into an optically active form in an appropriate solvent. By treating with a tartaric acid derivative, 3-
A salt of the amino-4-hydroxymethylpyrrolidine derivative with one enantiomer can be efficiently obtained, and this salt can be easily treated with a base to easily form one enantiomer, particularly (3
They have found that an (S, 4S) -3-amino-4-hydroxymethylpyrrolidine derivative can be obtained, and have completed the present invention.

That is, the present invention relates to the following formula (IIa)

[0008]

Embedded image Or formula (IIb)

[0009]

Embedded image And a compound represented by the formula (IIIa)

[0010]

Embedded image Or formula (IIIb)

[0011]

Embedded image Or a compound represented by the formula (IVa):

[0012]

Embedded image Or formula (IVb)

[0013]

Embedded image Or a hydrate thereof, wherein R ¹ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms (a halogen atom and an alkoxyl group having 1 to 6 carbon atoms) May have one or more groups selected from the group consisting of the following as a substituent.), An aryl group (a halogen atom, a nitro group, an alkyl group having 1 to 6 carbon atoms and an alkoxyl having 1 to 6 carbon atoms) May have one or more groups selected from the group consisting of groups as substituents), or an aralkyl group (having a structure in which an aryl group is substituted on an alkyl group having 1 to 6 carbon atoms; The aryl group moiety is
The alkyl group moiety may have at least one group selected from the group consisting of a halogen atom, a nitro group, an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms; And at least one group selected from the group consisting of an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms. And R ² has, as a substituent, at least one group selected from the group consisting of a hydrogen atom, an alkyl group having 1 to 6 carbon atoms (a halogen atom and an alkoxyl group having 1 to 6 carbon atoms). And an aryl group (having, as a substituent, at least one group selected from the group consisting of a halogen atom, a nitro group, an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms). Aralkyl group (having a structure in which an aryl group is substituted on an alkyl group having 1 to 6 carbon atoms; the aryl group portion includes a halogen atom, a nitro group, an alkyl group having 1 to 6 carbon atoms and It may have one or more substituents selected from the group consisting of alkoxyl groups having 1 to 6 carbon atoms as substituents; the alkyl group portion is an alkyl group having 1 to 6 carbon atoms and 1 to 6 carbon atoms. Arco One or more groups selected from the group the group consisting of isoleucyl group which may have a substituent.),
An acyl group (which may be aliphatic or aromatic; in the case of an aliphatic group, is selected from the group consisting of an aryl group, a halogen atom and an alkoxyl group having 1 to 6 carbon atoms; The aryl group as a substituent on the aliphatic chain in the case of an aromatic or aliphatic group may be a halogen atom, a nitro group, a C1 to C6 group. May have one or more groups selected from the group consisting of an alkyl group and an alkoxyl group having 1 to 6 carbon atoms as substituents).
An alkyloxycarbonyl group having 2 to 7 carbon atoms (this alkyl group may have, as a substituent, at least one group selected from a group consisting of a halogen atom and an alkoxyl group having 1 to 6 carbon atoms); ), An aralkyloxycarbonyl group (where the aralkyl group has a structure in which an aryl group is substituted on an alkyl group having 1 to 6 carbon atoms; an aryl group portion includes a halogen atom, a nitro group, The alkyl group may have one or more groups selected from the group consisting of an alkyl group and an alkoxyl group having 1 to 6 carbon atoms as a substituent; It may have, as a substituent, one or more groups selected from the group consisting of 1 to 6 alkoxyl groups) or a substituted sulfonyl group (aliphatic or aromatic) Any one of aliphatic groups having 1 to 6 carbon atoms and having at least one group selected from the group consisting of an aryl group, a halogen atom and an alkoxyl group having 1 to 6 carbon atoms as a substituent; An aryl group as a substituent on the aliphatic chain in the case of an aromatic or aliphatic group may be a halogen atom, a nitro group,
It may have as a substituent one or more groups selected from the group consisting of an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms. ), R ³ and R ⁴
Each independently represents, as a substituent, one or more groups selected from the group consisting of a hydrogen atom, an alkyl group having 1 to 6 carbon atoms (a halogen atom and an alkoxyl group having 1 to 6 carbon atoms) Good), an aryl group (halogen atom,
Nitro group, alkyl group having 1 to 6 carbon atoms and 1 carbon atom
1 selected from the group consisting of
It may have the above groups as substituents. ), An aralkyl group (having a structure in which an aryl group is substituted on an alkyl group having 1 to 6 carbon atoms; an aryl group portion includes a halogen atom, a nitro group, an alkyl group having 1 to 6 carbon atoms, and an alkyl group having 1 to 6 carbon atoms). May have, as a substituent, one or more groups selected from the group consisting of alkoxyl groups of the formula: wherein the alkyl group moiety comprises an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms. The substituent may have one or more groups selected from the group consisting of groups), an acyl group (which may be aliphatic or aromatic; in the case of aliphatic, it has from 1 to 7 carbon atoms). May have, as a substituent, at least one group selected from the group consisting of an aryl group, a halogen atom and an alkoxyl group having 1 to 6 carbon atoms; On the fatty chain Aryl group as a substituent, a halogen atom,
Nitro group, alkyl group having 1 to 6 carbon atoms and 1 carbon atom
1 selected from the group consisting of
It may have the above groups as substituents. ) Or a substituted sulfonyl group (which may be aliphatic or aromatic; in the case of aliphatic, a group consisting of an aryl group, a halogen atom, and an alkoxyl group having 1 to 6 carbon atoms. And an aryl group as a substituent on the aliphatic chain in the case of an aromatic or aliphatic group may be a halogen atom, a nitro group, a carbon atom or a nitro group. R ⁵ and R ⁶ may have at least one group selected from the group consisting of an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms. Each independently represents an alkyl group having 1 to 6 carbon atoms (a halogen atom and 1 to 6 carbon atoms);
May have one or more groups selected from the group consisting of alkoxyl groups as a substituent. ), An aryl group (which may have at least one group selected from the group consisting of a halogen atom, a nitro group, an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms). ) Or an aralkyl group (having a structure in which an aryl group is substituted on an alkyl group having 1 to 6 carbon atoms; the aryl group portion includes a halogen atom, a nitro group,
May have, as a substituent, at least one group selected from the group consisting of an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms; It may have one or more groups selected from the group consisting of the alkoxyl groups of the formulas 1 to 6 as substituents. ). ].

Further, the present invention relates to each of the following. Formula (IIa) below

[0015]

Embedded image Or formula (IIb)

[0016]

Embedded image And a compound represented by the formula (IIIa)

[0017]

Embedded image Or formula (IIIb)

[0018]

Embedded image And a hydrate thereof (wherein the definitions of R ¹ , R ² , R ³ and R ⁴ are the same as those defined above); and the following formula ( Ia)

[0019]

Embedded image Or formula (Ib)

[0020]

Embedded image And hydrates thereof, wherein R ¹ and R ²
Is the same as defined above, and n ¹ and n ² each independently represent an integer of 1 or more. ); A compound represented by the following formula (Ia), and a hydrate thereof:

[0021]

Embedded image (Wherein, the definition of R ¹ , R ² , n ¹ and n ² is the same as the above definition.); The above compound wherein n ¹ and n ² are both 1; R ¹ is a hydrogen atom R ² is an acyl group (which may be either aliphatic or aromatic; in the case of aliphatic, it has 1 to 7 carbon atoms, an aryl group, a halogen atom and 1 to 6 carbon atoms. May have one or more groups selected from the group consisting of alkoxyl groups as a substituent; the aryl group as a substituent on the aliphatic chain in the case of an aromatic or aliphatic group is a halogen atom; May have, as a substituent, at least one group selected from the group consisting of an atom, a nitro group, an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms.)
To 7 alkyloxycarbonyl groups (this alkyl group may have, as a substituent, one or more groups selected from the group consisting of a halogen atom and an alkoxyl group having 1 to 6 carbon atoms) and aralkyl. An oxycarbonyl group (where the aralkyl group has a structure in which an aryl group is substituted on an alkyl group having 1 to 6 carbon atoms; an aryl group portion includes a halogen atom, a nitro group,
May have, as a substituent, at least one group selected from the group consisting of an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms; It may have one or more groups selected from the group consisting of the alkoxyl groups of the formulas 1 to 6 as substituents. The above compound is a group selected from the group of radicals consisting of); R ² is an alkyloxycarbonyl group (the alkyl group of a carbon number of 2 to 7, the group consisting of an alkoxyl group having from 1 halogen atom and carbon atoms 6 And may have one or more groups selected from the groups described above as a substituent.)
And an aralkyloxycarbonyl group (where the aralkyl group has a structure in which an aryl group is substituted on an alkyl group having 1 to 6 carbon atoms; the aryl group portion is a halogen atom, a nitro group, an alkyl group having 1 to 6 carbon atoms. And at least one group selected from the group consisting of an alkoxyl group having 1 to 6 carbon atoms as a substituent; the alkyl group portion includes an alkyl group having 1 to 6 carbon atoms and an alkyl group having 1 to 6 carbon atoms. . from a group selected from one or more of the groups may have a substituent) of the group consisting of group selected from the group of radicals consisting of 6 alkoxyl groups of the above compounds; R ² is tert Butoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group Acetyl group, methoxyacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, compounds of the above is a group selected from the group the group consisting of a formyl group and a benzoyl group; R ² is above a benzyloxycarbonyl group A compound represented by the formula (IIa), which is constituted by the following steps 1 and 2

[0022]

Embedded image Step 1: Formula (II)

[0023]

Embedded image [In the formula, R ¹ represents, as a substituent, at least one group selected from the group consisting of a hydrogen atom, an alkyl group having 1 to 6 carbon atoms (a halogen atom and an alkoxyl group having 1 to 6 carbon atoms). And an aryl group (having, as a substituent, at least one group selected from the group consisting of a halogen atom, a nitro group, an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms). Or an aralkyl group (having a structure in which an aryl group is substituted on an alkyl group having 1 to 6 carbon atoms; the aryl group portion is a halogen atom, a nitro group, an alkyl group having 1 to 6 carbon atoms) And at least one group selected from the group consisting of an alkoxyl group having 1 to 6 carbon atoms as a substituent; the alkyl group portion includes an alkyl group having 1 to 6 carbon atoms and a group having 1 to 6 carbon atoms. 6 of a Represents may.) Which have one or more groups selected from the group of radicals consisting of Kokishiru group as a substituent, R ² represents a hydrogen atom, an alkyl group (a halogen atom and the carbon number of 1 to 6 carbon atoms It may have at least one group selected from the group consisting of 1 to 6 alkoxyl groups as a substituent.), Aryl group (halogen atom, nitro group, alkyl group having 1 to 6 carbon atoms and carbon atom). It may have one or more groups selected from the group consisting of alkoxyl groups of formulas 1 to 6 as a substituent.), Aralkyl group (an aryl group is substituted on an alkyl group having 1 to 6 carbon atoms). The aryl group moiety has at least one group selected from the group consisting of a halogen atom, a nitro group, an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms as a substituent. Doing Good; the alkyl group portion may have as a substituent one or more groups selected from the group consisting of an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms.) A group (which may be aliphatic or aromatic; in the case of an aliphatic group, is selected from the group consisting of an aryl group, a halogen atom, and an alkoxyl group having 1 to 6 carbon atoms; The aryl group as a substituent on the aliphatic chain in the case of an aromatic or aliphatic group may be a halogen atom,
Nitro group, alkyl group having 1 to 6 carbon atoms and 1 carbon atom
1 selected from the group consisting of
It may have the above groups as substituents. ), An alkyloxycarbonyl group having 2 to 7 carbon atoms (this alkyl group may have as a substituent at least one group selected from a group consisting of a halogen atom and an alkoxyl group having 1 to 6 carbon atoms) Aralkyloxycarbonyl group (where the aralkyl group has a structure in which an aryl group is substituted on an alkyl group having 1 to 6 carbon atoms; an aryl group portion includes a halogen atom, a nitro group, And at least one group selected from the group consisting of an alkyl group having 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms; the alkyl group portion may have an alkyl group having 1 to 6 carbon atoms and It may have at least one group selected from the group consisting of alkoxyl groups having 1 to 6 carbon atoms as a substituent.) Or a substituted sulfonyl group (aliphatic or aromatic). It may be either a group; in the case of aliphatic C 1 -C
To 6 and may have, as a substituent, at least one group selected from the group consisting of an aryl group, a halogen atom and an alkoxyl group having 1 to 6 carbon atoms; In the case of aliphatic, the aryl group as a substituent on the aliphatic chain is at least one selected from the group consisting of a halogen atom, a nitro group, an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms. May be present as a substituent. ) Represents a substituent on the pyrrolidine ring

[0024]

Embedded image R ¹ HN— and

[0025]

Embedded image —CH ₂ OH is in a cis configuration. A mixture of the enantiomers of the compound of formula (IIIa)

[0026]

Embedded image Formula (IIIb),

[0027]

Embedded image Formula (IVa),

[0028]

Embedded image Or formula (IVb)

[0029]

Embedded image Wherein R ³ and R ⁴ are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms (halogen) May have, as a substituent, at least one group selected from the group consisting of an atom and an alkoxyl group having 1 to 6 carbon atoms; an aryl group (halogen atom, nitro group, 1 to 6 carbon atoms); It may have at least one group selected from the group consisting of an alkyl group and an alkoxyl group having 1 to 6 carbon atoms as a substituent.), An aralkyl group (1 carbon atom).
A structure in which an aryl group is substituted on an alkyl group having from 1 to 6; the aryl group portion is a group of a group consisting of a halogen atom, a nitro group, an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms The alkyl group moiety may have at least one group selected from the group consisting of an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms. May be present as a substituent. ), An acyl group (which may be aliphatic or aromatic;
To 7 and may have, as a substituent, at least one group selected from the group consisting of an aryl group, a halogen atom and an alkoxyl group having 1 to 6 carbon atoms; In the case of aliphatic, the aryl group as a substituent on the aliphatic chain is at least one selected from the group consisting of a halogen atom, a nitro group, an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms. May be present as a substituent. ) Or a substituted sulfonyl group (which may be aliphatic or aromatic; in the case of aliphatic, a group consisting of an aryl group, a halogen atom, and an alkoxyl group having 1 to 6 carbon atoms. And an aryl group as a substituent on the aliphatic chain in the case of an aromatic or aliphatic group may be a halogen atom, a nitro group, a carbon atom or a nitro group. R ⁵ and R ⁶ may have at least one group selected from the group consisting of an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms. Each independently, an alkyl group having 1 to 6 carbon atoms (which may have, as a substituent, one or more groups selected from the group consisting of a halogen atom and an alkoxyl group having 1 to 6 carbon atoms), and aryl Group (halogen , An aralkyl group, a nitro group, an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms.) (This is a structure in which an aryl group is substituted on an alkyl group having 1 to 6 carbon atoms; the aryl group moiety is a halogen atom, a nitro group, an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms. The alkyl group moiety may have one or more groups selected from the group consisting of a group consisting of an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms. And Step 2: treating the salt formed in Step 1 with a base to obtain a free compound represented by the formula (IIa). Step of obtaining; Step 1 There, the compounds used for the treatment [the compound represented by formula (IIa) wherein for obtaining a compound represented by (II)] having the formula (IIIa)

[0030]

Embedded image Or formula (IIIb),

[0031]

Embedded image (In the above formula, the definitions of R ³ and R ⁴ are the same as the above definition.)
Wherein the salt formed in the above is a salt represented by the following formula (Ia):

[0032]

Embedded image (Wherein R ¹ and R ² are the same as defined above, n ¹ and
n ² each independently represents an integer of 1 or more. ); N ¹ and
n ² is the above-described manufacturing method both are 1; R ¹ is, the manufacturing method described above is a hydrogen atom; is R ^2, a tert-butoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyl Selected from the group consisting of oxycarbonyl, paramethoxybenzyloxycarbonyl, paranitrobenzyloxycarbonyl, acetyl, methoxyacetyl, trifluoroacetyl, chloroacetyl, pivaloyl, formyl, and benzoyl groups R ² is a benzyloxycarbonyl group; R ² is a benzyloxycarbonyl group; R ² is a benzyloxycarbonyl group; R ² is a benzyloxycarbonyl group; R ² is an inorganic base; The above-mentioned production method, which is a carbonate or a metal bicarbonate; The above-mentioned production method, wherein the metal is an alkali metal or an alkaline earth metal Metals, the manufacturing method described above is an alkali metal; a above; and a manufacturing method using the base as an aqueous solution; inorganic base sodium hydroxide, or the above-described manufacturing method is potassium hydroxide.

[0033]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention relates to a method for preparing one enantiomer of a 3,4-cis-3-amino-4-hydroxymethylpyrrolidine derivative which is a racemic or enantiomeric mixture with D-, Or
Fractional crystallization as a salt using L-tartaric acid gives one enantiomer salt, which is then treated with a base to obtain a free pure enantiomer compound.

The compound represented by the formula (II) of the present invention will be described. R ¹ of the substituent is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group, or an aralkyl group. When R ¹ is a group other than a hydrogen atom, it is preferable that R ¹ does not decrease the basicity of the amino group in order to form a salt with the tartaric acid derivative. Further, when R ¹ is a group which functions as a protecting group and has a property of being easily removed, for example, a benzyl group, it is useful as a starting compound which can be further converted into various compounds. The alkyl group may be linear, branched, or cyclic. The alkyl group may have, as a substituent, at least one group selected from the group consisting of a halogen atom and an alkoxyl group having 1 to 6 carbon atoms.
These substitution positions are not particularly limited, but those on terminal carbon atoms are preferred. As the halogen atom, a fluorine atom or a chlorine atom is preferable. The number of substitution of the halogen atom may be one or more, but in the case of a fluorine atom, the substitution may be perfluoro. The alkyl portion of the alkoxyl group may be linear, branched or cyclic. Examples of the alkyl group include a methyl group, an ethyl group,
Propyl group, butyl group, further trifluoromethyl group,
A methoxymethyl group and a methoxyethyl group are preferred. Examples of the aryl group include a phenyl group and a naphthyl group. The aryl group may have, as a substituent, at least one group selected from the group consisting of a halogen atom, a nitro group, an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms. Among these, the alkyl part of the alkyl group and the alkoxy group may be any of linear, branched and cyclic. As the aryl group, a phenyl group, a dimethoxyphenyl group, and a p-methoxyphenyl group are preferable. The aralkyl group may have a structure in which an aryl group is substituted on an alkyl group having 1 to 6 carbon atoms. Among them, the aryl group includes a halogen atom, a nitro group,
And at least one group selected from the group consisting of an alkyl group having 1 to 6 and an alkoxyl group having 1 to 6 carbon atoms. Similarly, the alkylene group may have, as a substituent, one or more groups selected from the group consisting of an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms. The alkyl portion of these alkyl groups and alkoxy groups may be any of linear, branched and cyclic. As the aralkyl group, an α-phenylethyl group, a benzyl group, a nitrobenzyl group, a trityl group, and a toluyl group are preferable.

The substituent R ² is a hydrogen atom, having 1 to 6 carbon atoms.
Alkyl group, aryl group, aralkyl group, acyl group,
It is an alkyloxycarbonyl group having 2 to 7 carbon atoms, an aralkyloxycarbonyl group, or a substituted sulfonyl group. Substituents R ² is different from the substituents R ^1, is not limited to the impact basic. Substituent R ² serves as a protecting group, considering that the pyrrolidine derivative of formula (II) will eventually bind to the quinolone via the nitrogen atom to which substituent R ² is attached Characteristic ones are preferred. The alkyl group, aryl group and aralkyl group having 1 to 6 carbon atoms of the substituent R ² may be considered in the same manner as the substituent R ¹ . Examples of the alkyl group include a methyl group, an ethyl group, a propyl group and a butyl group, and further, a trifluoromethyl group, a methoxymethyl group and a methoxyethyl group; and an aryl group such as a phenyl group, a dimethoxyphenyl group and a p-methoxyphenyl group. Preferred aralkyl groups are α-phenylethyl, benzyl, nitrobenzyl, trityl, toluyl and the like; An acyl group is
It may be either aliphatic or aromatic. In the case of an aliphatic acyl group, it has 1 to 7 carbon atoms and may be linear or branched. Further, the aliphatic chain may have, as a substituent, one or more groups selected from the group consisting of an aryl group, a halogen atom and an alkoxyl group having 1 to 6 carbon atoms. These substitution positions are not particularly limited, but are preferably on terminal carbon atoms. The halogen atom is preferably a chlorine atom or a fluorine atom, and when it is a fluorine atom, it may be substituted with perfluoro. The aryl group as a substituent on the aliphatic chain of the aromatic acyl group or the aliphatic acyl group is a group consisting of a halogen atom, a nitro group, an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms. And may have one or more groups selected from The alkyl portion of these alkyl groups and alkoxy groups may be any of linear, branched and cyclic. As the acyl group, acetyl, methoxyacetyl, trifluoroacetyl, chloroacetyl, pivaloyl, formyl, benzoyl and nitrophenylacetyl are preferred. The alkyloxycarbonyl group may have 2 to 7 carbon atoms. This alkyl group portion may have, as a substituent, one or more groups selected from a group consisting of a halogen atom and an alkoxyl group having 1 to 6 carbon atoms. The halogen atom is preferably a fluorine atom or a chlorine atom, and the alkyl part of the alkoxy group may be any of linear, branched and cyclic. As the alkyloxycarbonyl group, a methyloxycarbonyl group, a tertiary butoxycarbonyl group, and a 2,2,2-trichloroethoxycarbonyl group are preferable. The aralkyloxycarbonyl group may be considered in the same manner as the aralkyl group described above for the aralkyl group. As the aralkyloxycarbonyl group, a benzyloxycarbonyl group, a paramethoxybenzyloxycarbonyl group, and a paranitrobenzyloxycarbonyl group are preferable. The substituted sulfonyl group may be either aliphatic or aromatic. The aliphatic portion and the aromatic portion may be considered in the same manner as in the acyl group. As the substituted sulfonyl group, p-
Preferred are a toluenesulfonyl group, a benzylsulfonyl group and a methanesulfonyl group. Preferred as the substituent R ² is a hydrogen atom, an aralkyl group, an acyl group, an alkyloxycarbonyl group and aralkyloxycarbonyl group. Further preferred are an alkyloxycarbonyl group and an aralkyloxycarbonyl group. Specifically, a methyloxycarbonyl group, a tertiary butoxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, a benzyloxycarbonyl group, a paramethoxybenzyloxycarbonyl group, and a paranitrobenzyloxycarbonyl group are preferred.

The compound represented by the formula (II) can be produced by the method shown as a reference example in the specification of the present application, or can be produced by making a change usually conceivable to those skilled in the art.

Next, a tartaric acid derivative represented by the formula (III):

[0038]

Embedded image Is described. The substituents R ³ and R ⁴ each independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group, an aralkyl group, an acyl group, or a substituted sulfonyl group, or R ³ and R ⁴ are integrated. And the following equation:

[0039]

Embedded image And a compound having the structure represented by Here, the substituents R ⁵ and R ⁶ are an alkyl group having 1 to 6 carbon atoms, an aryl group, and an aralkyl group. The substituents R ³ and R ⁴ may be considered in the same manner as the alkyl, aryl, aralkyl, acyl, and substituted sulfonyl groups having 1 to 6 carbon atoms described for the substituent R ² of the compound (II). . Preferred substituents R ³ and R ⁴ include, as an alkyl group, a methyl group, an ethyl group, a propyl group, a butyl group, further a trifluoromethyl group, a methoxymethyl group, a methoxyethyl group, and the like; Aralkyl groups such as α-phenylethyl group, benzyl group, nitrobenzyl group, trityl group, toluyl group, etc .; acyl groups such as acetyl group, methoxyacetyl group, A trifluoroacetyl group, a chloroacetyl group, a pivaloyl group, a formyl group, a benzoyl group, a nitrophenylacetyl group and the like; as the substituted sulfonyl group, p-toluenesulfonyl group, benzylsulfonyl group, methanesulfonyl group and the like are each preferable is there. Further, the substituents R ⁵ and R ⁶ may be considered in the same manner as the alkyl, aryl, and aralkyl groups having 1 to 6 carbon atoms described for the substituent R ¹ of the compound (II). Examples of the alkyl group include a methyl group, an ethyl group, a propyl group and a butyl group, and further, a trifluoromethyl group, a methoxymethyl group and a methoxyethyl group; and an aryl group such as a phenyl group, a dimethoxyphenyl group and a p-methoxyphenyl group. Preferred aralkyl groups are α-phenylethyl, benzyl, nitrobenzyl, trityl, toluyl and the like; As the tartaric acid derivative, those in which the substituents R ³ and R ⁴ are each a hydrogen atom are preferred.

Formula (IIa)

[0041]

Embedded image Or formula (IIb)

[0042]

Embedded image And a compound represented by the formula (IIIa)

[0043]

Embedded image Or formula (IIIb)

[0044]

Embedded image The composition of the salt formed by n ¹ : n ² = 1: 1 and n ¹ : n ² =
The ratio is usually 1: 2 or n ¹ : n ² = 2: 1, but may be other composition ratio. This is the composition ratio substituent R ² of the compound (II) is affected by whether or not to decrease the basicity of the amine moiety. Examples of the solvent used for forming the compound represented by the formula (Ia) or the formula (Ib) include hydrocarbon solvents such as benzene and toluene; ether solvents such as isopropyl ether and tetrahydrofuran; and chloroform and dichloromethane. Halogenated hydrocarbon solvents; alcohol solvents such as ethanol and methanol; esters such as ethyl acetate; and water may be used in addition thereto. These solvents may be used alone or as a mixture. Among these solvents, hydrous alcohols are preferable, and hydrous ethanol or methanol is more preferable. The amount of these solvents can be used to crystallize the salt using 10 to 20 times the amount of the compound represented by the formula (I), but is preferably about 10 times. Equation (II)
The mixing ratio of the compound represented by the formula and the tartaric acid derivative is represented by the formula (II)
The amount of the tartaric acid derivative may be 0.5 mol or more per 1 mol of the compound represented by the formula, but is preferably about 0.5 to 2 mol, particularly preferably 1 mol.

The crystallization temperature may be about 0 to 30 ° C., but may be heated when mixing the pyrrolidine derivative and the tartaric acid derivative prior to the crystallization step. About 2 to 7 hours are sufficient for the crystallization time.

The precipitated crystals are collected and then further purified by repeating the recrystallization using the above-mentioned solvent, reprecipitating, or stirring in a slurry state to increase the optical purity. be able to. The treatment temperature at this time is preferably about 0 to 30 ° C.

The salt thus obtained may contain the solvent used for the precipitation and purification of the salt as a crystallization solvent or an adhesion solvent. Further, water of crystallization or attached water may be included in some cases.

The compound represented by the formula (Ia) or (Ib) of the present invention can be treated with a base to give the free compound of the formula (II)
a) or a compound of formula (IIb) can be obtained. The base used here is not particularly limited, as long as it has basicity equal to or higher than pyrrolidine, and is not particularly limited, but it is usually preferable to treat with an inorganic base. Examples of such an inorganic base include hydroxides, carbonates and bicarbonates of alkali metals and alkaline earth metals. Specific examples include hydroxides and carbonates of sodium and potassium. These bases may be used in a solution state. After treatment with a base, the free pyrrolidine compound is separated by extraction, and after removing the extraction solvent, it can be further purified by a commonly used method such as chromatography.

[0049]

Next, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.

Example 1 (3S, 4S) -3-Amino-4-hydride
Roxymethyl-1-benzyloxycarbonylpyrrolidine
D-Tartrate D-tartaric acid (1.51 g) is dissolved in 10% aqueous ethanol (12.5 ml), and cis-3-amino-4-hydroxymethyl-N-benzyloxycarbonyl is stirred at an external temperature of 45 ° C. A solution of pyrrolidine (2.52 g) dissolved in ethanol (12.5 ml) was gradually added. Thereafter, when the solution was stirred and allowed to cool at room temperature, crystals were gradually precipitated. After stirring for further 2 hours, the precipitated crystals were collected by filtration, washed with a small amount of ethanol, and dried under reduced pressure to obtain 1.18 g (29%) of crude crystals of the title compound. 10 mg was collected from the crude crystals obtained here, and a diluted alkaline aqueous solution was added thereto (3
After obtaining (S, 4S) -3-amino-4-hydroxymethyl-1-benzyloxycarbonylpyrrolidine as a free form, Boc ₂ O
oc. As a result of measuring the optical purity using HPLC, 96.8
% ee. Melting point: 150.2-150.7 ° C. Specific rotation: -11.29 ° (20 ° C., c = 0.01) Optical purity: 96.8% ee (HPLC) Elemental analysis; As C ₁₇ H ₂₄ N ₂ O ₉ : Calculated: C, 50.99; H, 6.04; N, 6.99 Found: C, 50.92; H, 6.07; N, 6.89 ¹ H-NMR (270 MHz, CD ₃ OD) δ ppm: 2.60-2.78 (1H, m), 3.48-3.9
5 (7H, m), 4.40 (2H, s), 5.13 (2H, s), 7.30-7.39 (5H, m)

Example 2 (3R, 4R) -3-Amino-4-hydride
Roxymethyl-1-benzyloxycarbonylpyrrolidine
L-Tartrate L-tartaric acid (0.93 g) is dissolved in 15% aqueous ethanol (10 ml), and cis-3-amino-4-hydroxymethyl-N-benzyloxycarbonylpyrrolidine is stirred at an external temperature of 45 ° C. A solution of (1.56 g; 45% ee; (3R, 4R) -rich mixture) in 5% aqueous ethanol (30 ml) was slowly added. Thereafter, when the solution was stirred and allowed to cool at room temperature, crystals were gradually precipitated. After further stirring for 2 hours, the precipitated crystals were collected by filtration, washed with a small amount of ethanol, and dried under reduced pressure to obtain 1.18 g (47.4%) of crude crystals of the title compound. 10 mg was collected from the crude crystals obtained here, and a diluted alkaline aqueous solution was added thereto to give (3R, 4R) -3-amino-4
-Hydroxymethyl-1-benzyloxycarbonylpyrrolidine was obtained as a free form, and then Bocated with Boc ₂ O. As a result of measuring the optical purity by using HPLC, it was 88.3% ee. Melting point: 150.2-150.7 ° C. Specific rotation: + 12.41 ° (20 ° C., c = 0.01) Optical purity: 88.3% ee (HPLC) Elemental analysis; As C ₁₇ H ₂₄ N ₂ O ₉ : Calculated: C, 50.99; H, 6.04; N, 6.99 Found: C, 50.80; H, 6.06; N, 6.83 ¹ H-NMR (270 MHz, CD ₃ OD) δ ppm: 2.60-2.78
(1H, m), 3.44-3.97 (7H, m), 4.
40 (2H, s), 5.14 (2H, s), 7.30-
7.39 (5H, m)

Example 3 (3S, 4S) -3-Amy
No-4-hydroxymethyl-1-benzyloxycarbonylpi
Loridine L-Ditoluoyltartrate L-Ditoluoyltartaric acid (386 mg) was added to ethanol (3 ml), and the mixture was stirred and dissolved at an external temperature of 45 ° C.
A solution of hydroxymethyl-N-benzyloxycarbonylpyrrolidine (250 mg) dissolved in ethanol (2 ml) was gradually added. Thereafter, when the solution was stirred and allowed to cool at room temperature, crystals were gradually precipitated. After further stirring for 24 hours, the precipitated crystals were collected by filtration, washed with a small amount of ethanol, and dried under reduced pressure to obtain 453 mg (67%) of crude crystals of the title compound. 10 mg was collected from the crude crystals obtained here, and a diluted alkaline aqueous solution was added thereto (3
After obtaining (S, 4S) -3-amino-4-hydroxymethyl-1-benzyloxycarbonylpyrrolidine as a free form, Boc ₂ O
oc. As a result of measuring the optical purity using HPLC, 15% e
e. Melting point: 159.7−160.0 ° C. Specific rotation: −89.61 ° (20 ° C., c = 0.01) Optical purity: 15% ee (HPLC) Elemental analysis: C ₃₃ H ₃₆ N ₂ O ₁₁ .C ₂ H ₅ OH: Calculated Value: C, 61.76; H, 5.92; N, 4.11 Found: C, 61.57; H, 5.65; N, 4.26 ¹ H-NMR (270 MHz, CD ₃ OD) δ ppm: 2.40 (6H, s), 2.63-2.68 (1H,
m), 3.42-3.94 (7H, m), 5.13 (2H, s), 5.87 (2H, s), 7.27-7.36
(9H, m), 7.99-8.03 (4H, m)

[Reference Example 1] 1-benzyloxycarboni
Ethyl acrylate (65.01 ml, 600.0 mmol) was added to a toluene (1200 ml) solution of ethyl 4-ethoxycarbonyl-3-oxopyrrolidine N-benzyloxycarbonylglycine ethyl ester (156.3 g, 600.0 mmol), and then cooled on ice. Below, sodium hydride (60% oil; 26.40 g, 660.0 mmo
l) was added. After stirring at the same temperature for 10 minutes, the ice bath was removed, and the mixture was stirred at room temperature for 20 minutes and then at 50 ° C. for 3 hours. After completion of the reaction, a 10% aqueous citric acid solution was added to the reaction solution under ice-cooling to adjust the pH to about 3, and ethyl acetate was added thereto, followed by shaking and separation. The organic layer was separated and washed with saturated saline, and the aqueous layer was further extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solvent was distilled off under reduced pressure to give the title compound 196.
7 g (600.0 mmol, quantitative) were obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.22-1.32 (3H, m), 3.93-4.05
(1H, m), 4.05-4.31 (5H, m), 5.13-5.23 (2H, m), 7.28-7.40 (5
H, m).

[Reference Example 2] 1-benzyloxycarboni
4-ethoxycarbonyl-3-methoxyiminopyrrolidine 1-benzyloxycarbonyl-4-ethoxycarbonyl-3-
Oxopyrrolidine (196.7 g, 600.0 mmol) was added to pyridine (7
O-methylhydroxylamine hydrochloride (76.55 g, 916.5 mmol) was added under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes and then at room temperature for 5 hours. Pyridine was distilled off under reduced pressure, 1N hydrochloric acid and ethyl acetate were added to the residue, and the mixture was shaken and separated. The organic layer was washed with saturated saline, and the aqueous layer was further extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to give the title compound (187.5 g, 589.1 mmol, 589.1 mmol). 98.2%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.15-1.32 (3H, m), 3.55-4.05 (5
H, m), 4.05-4.25 (4H, m), 5.09-5.20 (2H, m), 7.28-7.40 (5H,
m).

Reference Example 3 3,4-cis-1-benzyloxy
Cicarbonyl-3-tert-butoxycarbonylamino-4-hi
Droxymethylpyrrolidine 1-benzyloxycarbonyl-4-ethoxycarbonyl-3-
Methoxyiminopyrrolidine (248.8 g, 550.0 mmol) was dissolved in anhydrous tetrahydrofuran (1000 ml), and a 1 M borane-tetrahydrofuran complex in tetrahydrofuran solution (2.75 l, 2.75 mol) was added dropwise at −78 ° C. with stirring, and the mixture was heated to the same temperature. hand
The mixture was stirred for 1 hour and 30 minutes, under ice cooling for 2 hours, and then at room temperature for 12 hours. Under ice cooling, water was added to the reaction solution until no gas was generated, and then potassium carbonate (60.8 g) was added, followed by stirring at room temperature for 1 hour. Next, di-tert-butyl dicarbonate (144.0 g, 660.0 mmol) was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 16 hours. Water and ethyl acetate were added to the reaction solution,
After shaking, the organic layer was separated. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue crystallized. A part of the precipitated crystals was subjected to silica gel column chromatography.
(N-hexane: ethyl acetate = 2: 1), and combined with unpurified crystals, 121.99 g (348.1 mmol, 68.1 mmol) of the title compound
3.3%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46 (9 H, s), 2.52-2.56 (1 H, m),
2.88-2.96 (1H, m), 3.44-3.92 (6H, m), 4.28 (1H, br), 4.76-
4.81 (1H, m), 5.10 (1H, d, J = 13.0Hz), 5.14 (1H, d, J = 13.0H
z), 7.29-7.37 (5H, m).

Reference Example 4 3,4-cis-3-amino-4-hydride
Roxymethyl-N-benzyloxycarbonylpyrrolidine 3- (N-tert-butoxycarbonyl) amino-4-hydroxymethyl-N-benzyloxycarbonylpyrrolidine (10.0 g,
28.54 mmol) in 1N-hydrochloric acid / ethanol (150 ml),
The mixture was stirred at 45 ° C for 15 hours. The reaction solution was evaporated under reduced pressure, dichloromethane and 1N-sodium hydroxide were added to the residue, and the mixture was shaken and separated. After extracting the organic layer, the extract was concentrated to dryness to obtain 7.13 g (28.49 mmol, quantitative) of the title compound. ¹ H-NMR (270 MHz, CDCl ₃ ) δ (ppm): 2.29-2.41 (1H, m, H4), 3.2
5-3.69 (5H, m, H2a, H2b, H3, H5a, H5b), 3.80 (2H, d, 4-C H 2 0
H), 5.l3 (2H, s, l-NC0 ₂ C H ₂ Ph), 7.30-7.37 (5H, m, l-NC0 ₂ CH ₂
Ph ) MASS: m / e = 25l (FABMS)

Claims (23)

[Claims] 1. A compound represented by the following formula (IIa): Or formula (IIb): And a compound represented by the formula (IIIa): Or the formula (IIIb): Or a compound represented by the formula (IVa): Or the formula (IVb) Or a hydrate thereof, wherein R ¹ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms (a halogen atom and an alkoxyl group having 1 to 6 carbon atoms) May have one or more groups selected from the group consisting of the following as a substituent.), An aryl group (a halogen atom, a nitro group, an alkyl group having 1 to 6 carbon atoms and an alkoxyl having 1 to 6 carbon atoms) May have one or more groups selected from the group consisting of groups as substituents), or an aralkyl group (having a structure in which an aryl group is substituted on an alkyl group having 1 to 6 carbon atoms; The aryl group moiety is
The alkyl group moiety may have at least one group selected from the group consisting of a halogen atom, a nitro group, an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms; And at least one group selected from the group consisting of an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms. And R ² has, as a substituent, at least one group selected from the group consisting of a hydrogen atom, an alkyl group having 1 to 6 carbon atoms (a halogen atom and an alkoxyl group having 1 to 6 carbon atoms). And an aryl group (having, as a substituent, at least one group selected from the group consisting of a halogen atom, a nitro group, an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms). Aralkyl group (having a structure in which an aryl group is substituted on an alkyl group having 1 to 6 carbon atoms; the aryl group portion includes a halogen atom, a nitro group, an alkyl group having 1 to 6 carbon atoms and It may have one or more substituents selected from the group consisting of alkoxyl groups having 1 to 6 carbon atoms as substituents; the alkyl group portion is an alkyl group having 1 to 6 carbon atoms and 1 to 6 carbon atoms. Arco One or more groups selected from the group the group consisting of isoleucyl group which may have a substituent.),
An acyl group (which may be aliphatic or aromatic; in the case of an aliphatic group, is selected from the group consisting of an aryl group, a halogen atom and an alkoxyl group having 1 to 6 carbon atoms; The aryl group as a substituent on the aliphatic chain in the case of an aromatic or aliphatic group may be a halogen atom, a nitro group, a C1 to C6 group. May have one or more groups selected from the group consisting of an alkyl group and an alkoxyl group having 1 to 6 carbon atoms as substituents).
An alkyloxycarbonyl group having 2 to 7 carbon atoms (this alkyl group may have, as a substituent, at least one group selected from a group consisting of a halogen atom and an alkoxyl group having 1 to 6 carbon atoms); ), An aralkyloxycarbonyl group (where the aralkyl group has a structure in which an aryl group is substituted on an alkyl group having 1 to 6 carbon atoms; an aryl group portion includes a halogen atom, a nitro group, The alkyl group may have one or more groups selected from the group consisting of an alkyl group and an alkoxyl group having 1 to 6 carbon atoms as a substituent; the alkyl group portion includes an alkyl group having 1 to 6 carbon atoms and a carbon atom having 1 to 6 carbon atoms. It may have, as a substituent, one or more groups selected from the group consisting of 1 to 6 alkoxyl groups) or a substituted sulfonyl group (aliphatic or aromatic) Any one of aliphatic groups having 1 to 6 carbon atoms and having at least one group selected from the group consisting of an aryl group, a halogen atom and an alkoxyl group having 1 to 6 carbon atoms as a substituent; An aryl group as a substituent on the aliphatic chain in the case of an aromatic or aliphatic group may be a halogen atom, a nitro group,
It may have as a substituent one or more groups selected from the group consisting of an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms. ), R ³ and R ⁴
Each independently represents, as a substituent, one or more groups selected from the group consisting of a hydrogen atom, an alkyl group having 1 to 6 carbon atoms (a halogen atom and an alkoxyl group having 1 to 6 carbon atoms) Good), an aryl group (halogen atom,
Nitro group, alkyl group having 1 to 6 carbon atoms and 1 carbon atom
1 selected from the group consisting of
It may have the above groups as substituents. ), An aralkyl group (having a structure in which an aryl group is substituted on an alkyl group having 1 to 6 carbon atoms; an aryl group portion includes a halogen atom, a nitro group, an alkyl group having 1 to 6 carbon atoms, and an alkyl group having 1 to 6 carbon atoms). May have, as a substituent, one or more groups selected from the group consisting of alkoxyl groups of the formula: wherein the alkyl group moiety comprises an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms. The substituent may have one or more groups selected from the group consisting of groups), an acyl group (which may be aliphatic or aromatic; in the case of aliphatic, it has from 1 to 7 carbon atoms). May have, as a substituent, at least one group selected from the group consisting of an aryl group, a halogen atom and an alkoxyl group having 1 to 6 carbon atoms; On the fatty chain Aryl group as a substituent, a halogen atom,
Nitro group, alkyl group having 1 to 6 carbon atoms and 1 carbon atom
1 selected from the group consisting of
It may have the above groups as substituents. ) Or a substituted sulfonyl group (which may be aliphatic or aromatic; in the case of aliphatic, a group consisting of an aryl group, a halogen atom, and an alkoxyl group having 1 to 6 carbon atoms. And an aryl group as a substituent on the aliphatic chain in the case of an aromatic or aliphatic group may be a halogen atom, a nitro group, a carbon atom or a nitro group. R ⁵ and R ⁶ may have at least one group selected from the group consisting of an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms. Each of them is independently an alkyl group having 1 to 6 carbon atoms (a halogen atom and 1 to 6 carbon atoms).
May have one or more groups selected from the group consisting of alkoxyl groups as a substituent. ), An aryl group (which may have at least one group selected from the group consisting of a halogen atom, a nitro group, an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms). ) Or an aralkyl group (having a structure in which an aryl group is substituted on an alkyl group having 1 to 6 carbon atoms; the aryl group portion includes a halogen atom, a nitro group,
May have, as a substituent, at least one group selected from the group consisting of an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms; It may have one or more groups selected from the group consisting of the alkoxyl groups of the formulas 1 to 6 as substituents. ). ] 2. A compound represented by the following formula (IIa): Or formula (IIb): And a compound represented by the formula (IIIa): Or formula (IIIb): Or a hydrate thereof, wherein R ¹ , R ² , R ³ and R ⁴ are the same as defined above. 3. The following formula (Ia): Or the formula (Ib): And hydrates thereof, wherein R ¹ and R ²
Is the same as defined above, and n ¹ and n ² each independently represent an integer of 1 or more. ) 4. A compound represented by the following formula (Ia), or a hydrate thereof: (Wherein, the definitions of R ¹ , R ² , n ¹ and n ² are the same as the previous definitions.) 5. The compound according to claim 3, wherein n ¹ and n ² are both 1. 6. The compound according to claim ¹ , wherein R ¹ is a hydrogen atom. 7. R ² is an acyl group (which may be either aliphatic or aromatic; in the case of aliphatic, it has 1 to 7 carbon atoms, an aryl group, a halogen atom and 1 to 6 carbon atoms. The substituent may have one or more groups selected from the group consisting of alkoxyl groups; the aryl group as a substituent on the aliphatic chain in the case of aromatic and aliphatic groups is a halogen atom , Nitro group, 1 to 6 carbon atoms
And at least one group selected from the group consisting of an alkyl group and an alkoxyl group having 1 to 6 carbon atoms. ), An alkyloxycarbonyl group having 2 to 7 carbon atoms (this alkyl group may have as a substituent at least one group selected from a group consisting of a halogen atom and an alkoxyl group having 1 to 6 carbon atoms) Good.)
And an aralkyloxycarbonyl group (where the aralkyl group has a structure in which an aryl group is substituted on an alkyl group having 1 to 6 carbon atoms; the aryl group portion is a halogen atom, a nitro group, an alkyl group having 1 to 6 carbon atoms. And at least one group selected from the group consisting of an alkoxyl group having 1 to 6 carbon atoms as a substituent; the alkyl group portion includes an alkyl group having 1 to 6 carbon atoms and an alkyl group having 1 to 6 carbon atoms. Which may have at least one group selected from the group consisting of an alkoxyl group of from 1 to 6 as a substituent.) The group of any one of claims 1 to 6 Compounds described in 8. R ² is an alkyloxycarbonyl group having 2 to 7 carbon atoms (this alkyl group is substituted with one or more groups selected from the group consisting of a halogen atom and an alkoxyl group having 1 to 6 carbon atoms). May be present as a group.)
And an aralkyloxycarbonyl group (where the aralkyl group has a structure in which an aryl group is substituted on an alkyl group having 1 to 6 carbon atoms; the aryl group portion is a halogen atom, a nitro group, an alkyl group having 1 to 6 carbon atoms. And at least one group selected from the group consisting of an alkoxyl group having 1 to 6 carbon atoms as a substituent; the alkyl group portion includes an alkyl group having 1 to 6 carbon atoms and an alkyl group having 1 to 6 carbon atoms. Which may have at least one group selected from the group consisting of an alkoxyl group of from 1 to 6 as a substituent.) The group of any one of claims 1 to 6 Compounds described in 9. R ² is tert-butoxycarbonyl group, 2,
2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, acetyl group, methoxyacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, formyl group and 2. A group selected from the group consisting of a benzoyl group.
7. The compound according to any one of to 6 10. The compound according to claim 1, wherein R ² is a benzyloxycarbonyl group. 11. A compound represented by the formula (IIa), which is constituted by the following steps 1 and 2. Step 1: Formula (II) [In the formula, R ¹ represents, as a substituent, at least one group selected from the group consisting of a hydrogen atom, an alkyl group having 1 to 6 carbon atoms (a halogen atom and an alkoxyl group having 1 to 6 carbon atoms). And an aryl group (having, as a substituent, at least one group selected from the group consisting of a halogen atom, a nitro group, an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms). Or an aralkyl group (having a structure in which an aryl group is substituted on an alkyl group having 1 to 6 carbon atoms; the aryl group portion is a halogen atom, a nitro group, an alkyl group having 1 to 6 carbon atoms) And at least one group selected from the group consisting of an alkoxyl group having 1 to 6 carbon atoms as a substituent; the alkyl group portion includes an alkyl group having 1 to 6 carbon atoms and a group having 1 to 6 carbon atoms. 6 of a Represents may.) Which have one or more groups selected from the group of radicals consisting of Kokishiru group as a substituent, R ² represents a hydrogen atom, an alkyl group (a halogen atom and the carbon number of 1 to 6 carbon atoms It may have at least one group selected from the group consisting of 1 to 6 alkoxyl groups as a substituent.), Aryl group (halogen atom, nitro group, alkyl group having 1 to 6 carbon atoms and carbon atom). It may have one or more groups selected from the group consisting of alkoxyl groups of formulas 1 to 6 as a substituent.), Aralkyl group (an aryl group is substituted on an alkyl group having 1 to 6 carbon atoms). The aryl group moiety has at least one group selected from the group consisting of a halogen atom, a nitro group, an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms as a substituent. Doing Good; the alkyl group portion may have as a substituent one or more groups selected from the group consisting of an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms.) A group (which may be aliphatic or aromatic; in the case of an aliphatic group, is selected from the group consisting of an aryl group, a halogen atom, and an alkoxyl group having 1 to 6 carbon atoms; The aryl group as a substituent on the aliphatic chain in the case of an aromatic or aliphatic group may be a halogen atom,
Nitro group, alkyl group having 1 to 6 carbon atoms and 1 carbon atom
1 selected from the group consisting of
It may have the above groups as substituents. ), An alkyloxycarbonyl group having 2 to 7 carbon atoms (this alkyl group may have as a substituent at least one group selected from a group consisting of a halogen atom and an alkoxyl group having 1 to 6 carbon atoms) Aralkyloxycarbonyl group (where the aralkyl group has a structure in which an aryl group is substituted on an alkyl group having 1 to 6 carbon atoms; an aryl group portion includes a halogen atom, a nitro group, And at least one group selected from the group consisting of an alkyl group having 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms; the alkyl group portion may have an alkyl group having 1 to 6 carbon atoms and It may have at least one group selected from the group consisting of alkoxyl groups having 1 to 6 carbon atoms as a substituent.) Or a substituted sulfonyl group (aliphatic or aromatic). It may be either a group; in the case of aliphatic C 1 -C
To 6 and may have, as a substituent, at least one group selected from the group consisting of an aryl group, a halogen atom and an alkoxyl group having 1 to 6 carbon atoms; In the case of aliphatic, the aryl group as a substituent on the aliphatic chain is at least one selected from the group consisting of a halogen atom, a nitro group, an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms. May be present as a substituent. ) Wherein the substituents on the pyrrolidine ring, R ¹ HN- and -CH ₂ OH, are in the cis configuration. A mixture of the enantiomers of the compound of formula (IIIa) Formula (IIIb): Formula (IVa): Or formula (IVb): Wherein R ³ and R ⁴ are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms (halogen) May have, as a substituent, at least one group selected from the group consisting of an atom and an alkoxyl group having 1 to 6 carbon atoms; an aryl group (halogen atom, nitro group, 1 to 6 carbon atoms); It may have at least one group selected from the group consisting of an alkyl group and an alkoxyl group having 1 to 6 carbon atoms as a substituent.), An aralkyl group (1 carbon atom).
A structure in which an aryl group is substituted on an alkyl group having from 1 to 6; and the aryl group is a group of a group consisting of a halogen atom, a nitro group, an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms. The alkyl group moiety may have at least one group selected from the group consisting of an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms. May be present as a substituent. ), An acyl group (which may be aliphatic or aromatic;
To 7 and may have, as a substituent, at least one group selected from the group consisting of an aryl group, a halogen atom and an alkoxyl group having 1 to 6 carbon atoms; In the case of aliphatic, the aryl group as a substituent on the aliphatic chain is at least one selected from the group consisting of a halogen atom, a nitro group, an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms. May be present as a substituent. ) Or a substituted sulfonyl group (which may be aliphatic or aromatic; in the case of aliphatic, a group consisting of an aryl group, a halogen atom, and an alkoxyl group having 1 to 6 carbon atoms. And an aryl group as a substituent on the aliphatic chain in the case of an aromatic or aliphatic group may be a halogen atom, a nitro group, a carbon atom or a nitro group. R ⁵ and R ⁶ may have at least one group selected from the group consisting of an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms. Each independently, an alkyl group having 1 to 6 carbon atoms (which may have, as a substituent, one or more groups selected from the group consisting of a halogen atom and an alkoxyl group having 1 to 6 carbon atoms), and aryl Group (halogen , An aralkyl group, a nitro group, an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms.) (This is a structure in which an aryl group is substituted on an alkyl group having 1 to 6 carbon atoms; the aryl group moiety is a halogen atom, a nitro group, an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms. The alkyl group moiety may have one or more groups selected from the group consisting of a group consisting of an alkyl group having 1 to 6 carbon atoms and an alkoxyl group having 1 to 6 carbon atoms. And Step 2: treating the salt formed in Step 1 with a base to obtain a free compound represented by the formula (IIa). The process of obtaining 12. In step 1, the compound used for the treatment is of the formula (IIIa) Or formula (IIIb): (In the above formula, the definitions of R ³ and R ⁴ are the same as the above definition.) The production method according to claim 11, which is a compound represented by the following formula: 13. The production method according to claim 12, wherein the salt formed in step 1 is a salt represented by the following formula (Ia). (Wherein, R ¹ and R ² are the same as defined above, and n ¹ and n ² each independently represent an integer of 1 or more.) 14. The method according to claim 13, wherein n ¹ and n ² are both 1. 15. The production method according to claim 11, wherein R ¹ is a hydrogen atom. 16. R ² is a tertiary butoxycarbonyl group,
2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, acetyl group, methoxyacetyl group, trifluoroacetyl group,
The method according to any one of claims 11 to 15, which is a group selected from the group consisting of a chloroacetyl group, a pivaloyl group, a formyl group, and a benzoyl group. 17. The production method according to claim 11, wherein R ² is a benzyloxycarbonyl group. 18. The production method according to claim 11, wherein the base used in step 2 is an inorganic base. 19. The method according to claim 18, wherein the inorganic base is a metal hydroxide, a metal carbonate or a metal bicarbonate. 20. The method according to claim 19, wherein the metal is an alkali metal or an alkaline earth metal. 21. The metal according to claim 2, wherein the metal is an alkali metal.
Manufacturing method according to 0 22. The method according to claim 21, wherein the inorganic base is sodium hydroxide or potassium hydroxide. 23. The method according to claim 1, wherein the base is used as an aqueous solution.
The manufacturing method according to any one of 8 to 22,