JP2006028154A - Method for producing optically active compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain an optically active amide compound or an optically active carboxylic acid compound efficiently in a good yield by widely extending the application range of an epimerizing crystallization method compared with those of conventional methods. <P>SOLUTION: The subject method for producing the optically active compound (Ia) or (Ib) comprises a process (epimerizing crystallization process) of crystallizing the optically active compound (Ia) or (Ib) in a same reaction system while performing an equilibrium epimerization of a carbon atom at the α-position of a carbonyl group of a diastereomeric mixture (I) [wherein, R<SB>1</SB>, R<SB>2</SB>are each an organic group; and R<SB>3</SB>, R<SB>4</SB>are each a group bonded with the carbon atom at the α-position of the carbonyl group by a carbon-carbon bond, and stable in the presence of a base, and provided that each of the R<SP>1</SP>and R<SP>2</SP>or R<SP>3</SP>and R<SP>4</SP>does not mean the same group at the same time] of an amide compound obtained by performing the reaction of a carboxylic acid ester compound with an optically active primary amine, in the presence of a base. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a method for efficiently and efficiently producing an optically active compound such as an optically active amide compound or an optically active carboxylic acid compound. The optically active compound which is the target compound of the present invention is useful as various biologically active compounds such as pharmaceuticals and agricultural chemicals, or as a synthetic intermediate for biologically active compounds.

  Methods for obtaining optically active compounds practically include (1) a method of deriving from readily available optically active raw materials (for example, natural products), (2) an asymmetric synthesis method, (3) an optical resolution method, etc. Is mentioned. Of these, (1) has a limited number of available optically active compounds, and thus often requires a complicated process to lead to the target compound. In addition, asymmetric synthesis methods still have limited industrially applicable reactions. Therefore, at present, the optical resolution method capable of reliably obtaining an optically active compound is most widely used.

  In the optical resolution method, a racemate is treated with an optically active compound to form a mixture of diastereomers, and only the desired diastereomer is obtained by fractional recrystallization or the like, and then decomposed to obtain only the desired optically active substance. The so-called diastereomeric method obtained is generally carried out. In this method, the racemic body contains only half of the desired optically active substance, and since the yield from the raw material can be obtained only up to 50%, the atom economy is low and waste is increased. There's a problem. Therefore, in order to improve the atom economy, it is necessary to isomerize and recover the unnecessary stereoisomers to be recovered.

  In order to reuse unnecessary stereoisomers, further isomerization (racemization, equilibrium epimerization, etc.) and crystallization steps are required, which requires considerable labor and time to implement industrially. In this case, when a step of chemically changing the compound as a compound (for example, hydrolysis or the like) is required, the labor is further increased. Furthermore, even if this recovery operation is carried out for one cycle, the resolution yield can only be theoretically achieved up to a maximum of 150% (yield 75% from the racemate). In order to further improve the atom economy, the recovery operation is performed. Must be repeated.

  In order to solve such a problem, a method of combining equilibrium epimerization and crystallization in the same reaction system (referred to as “epi-crystallization method” in this specification) has been reported (for example, non Patent Documents 1 to 5 and Patent Document 1). This method theoretically attempts to obtain an optically active substance in a yield of 100% from a racemate by crystallizing only the desired diastereomer while allowing the diastereomeric mixture to undergo equilibrium epimerization. In addition, since it is possible to achieve a resolution efficiency of 100% or more (yield from racemic product of 50% or more) in one step, it is a highly practical method.

  Most of the conventional epicrystallization methods use an object that can achieve equilibrium epimerization under moderate conditions as the specificity of the target compound. For example, when equilibrium epimerization is performed using a mixture of diastereomeric salts, the equilibrium epimerization must be performed in a relatively narrow pH range where the salt does not dissociate or under mild reaction conditions. (See Non-Patent Documents 1 to 3 and Patent Document 1).

On the other hand, N- (S)-(1-phenylethyl) -α-chloro-α-phenylacetamide is used as an epicrystallization method using a diastereomer mixture of an amide compound of a carboxylic acid compound and an optically active primary amine. Has been reported (see Non-Patent Document 5), in which an electron-withdrawing phenyl group and a halogen atom are bonded to a carbon atom at the carbonyl group α-position. Since the acidity of the α-position hydrogen atom is very strong, it is considered that equilibrium epimerization is proceeding even with a weak base such as aqueous ammonia.
“Journal of the Chemical Society, Perkin Transactions 1” (UK), 1976, p. 475 “Chemistry Letters”, 1983, p. 661 “Journal of Organic Chemistry”, 2002, Vol. 67, p. 7741-7749 “Chemical Society Reviews”, 1996, Vol. 25, p. 447-456 “Synlett”, 2001, p. 1941-1943 JP 58-52254 A

In N- (S)-(1-phenylethyl) -α-chloro-α-phenylacetamide, the halogen atom bonded to the carbonyl group α-position is very reactive and in the presence of a relatively strong base, Since the reaction occurs, it is considered that the reaction is limited to an embodiment in which equilibrium epimerization is possible under mild conditions such as aqueous ammonia.
In addition, when the acidity of NH of the amide compound is relatively high and the acidity of the hydrogen atom at the carbonyl group α is lower, it is considered that equilibrium epimerization is unlikely to occur, and therefore N— (S) — ( It is assumed that only an embodiment in which the acidity of the hydrogen atom at the carbonyl group α-position was very high, such as 1-phenylethyl) -α-chloro-α-phenylacetamide, was attempted.

  The present invention makes it possible to apply the epicrystallization method to all amide compounds, thereby broadening the scope of application of the epicrystallization method, compared with the conventional method, in an efficient and high yield. It aims at providing the method of obtaining the optically active carboxylic acid compound.

The inventors of the present invention have made extensive studies in order to achieve such an object. As a result, even in the case of an amide compound having a low acidity of the hydrogen atom at the carbonyl group α-position, if the presence of a relatively strong base is present, the primary It has been found that the carbonyl group α-position hydrogen atom of an amide compound of an amine can be equilibrium epimerized, that is, the epicrystallization method can be applied to all amide compounds. Also, in the process of obtaining the epicrystallization method and the raw material diastereomer mixture, the relatively strong base used for the epicrystallization process promotes the amidation reaction between the carboxylic acid ester compound and the optically active primary amine. As a result, it has been found that the amidation reaction and the epicrystallization can be performed in a one-pot reaction, and the present invention has been completed.
That is, the present invention is as follows.
(1) General formula (II):

[Wherein R ⁵ represents a lower alkyl group, R ³ represents a group which is connected to the carbon atom at the α-position of the carbonyl group by a carbon-carbon bond and is stable in the presence of a base, and R ⁴ represents a carbonyl group. a group that is connected to a carbon atom at the α-position by a carbon-carbon bond or a carbon-heteroatom bond (excluding a carbon-halogen atom bond) and is stable in the presence of a base; and R ³ and R ⁴ May be linked to form a ring together with the carbon atoms to which they are bonded (provided that R ³ and R ⁴ do not mean the same group at the same time). ] (Hereinafter also referred to as compound (II)) in the presence of a base, general formula (III):

(Wherein R ¹ and R ² each independently represents an organic group, provided that R ¹ and R ² do not mean the same group at the same time) (hereinafter referred to as compound (III)) And the general formula (I):

(Wherein each symbol is as defined above), a step of obtaining a diastereomeric mixture (hereinafter also referred to as diastereomeric mixture (I)), and the diastereomeric mixture (I). In the presence of a base, the hydrogen atom on the carbon atom at the α-position of the carbonyl group is subjected to equilibrium epimerization while the general formula (Ia):

(Wherein each symbol is as defined above) or an optically active compound (hereinafter also referred to as optically active compound (Ia)) or general formula (Ib):

(Wherein each symbol has the same meaning as described above), which includes a step of crystallizing an optically active compound (hereinafter also referred to as optically active compound (Ib)). A process for producing compound (Ia) or optically active compound (Ib) or a process for separating optically active compound (Ia) or optically active compound (Ib) from diastereomeric mixture (I).
(2) The production method or the separation method according to the above (1), which is carried out by a one-pot reaction.
(3) The optically active compound (Ia) or the optically active compound (Ib) obtained by the production method or separation method described in (1) or (2) above is hydrolyzed under acidic conditions. (IVa):

(Wherein each symbol is as defined above) or an optically active compound (hereinafter also referred to as optically active compound (IVa)) or general formula (IVb):

(In the formula, each symbol has the same meaning as described above.) A process for producing an optically active compound (hereinafter also referred to as optically active compound (IVb)).
(4) Along with the carbon atom to which R ³ and R ⁴ are bonded, general formula (V):

(Wherein, X represents a hydrogen atom, a halogen atom or a lower alkyl group, and R ⁶ represents a lower alkyl group) is formed (hereinafter also referred to as a heterocycle (V)). The production method or separation method according to the above (1) or (2).
(5) The production method or separation method according to the above (4), wherein R ⁵ and R ⁶ are R ⁶ ′ (R ⁶ ′ represents a lower alkyl group).
(6) General formula (VI):

(Wherein X is as defined above) (hereinafter also referred to as compound (VI)) in the presence of an acid, general formula (VII):

(In the formula, R ⁷ represents a hydrogen atom or a lower alkyl group, and R ⁶ ′ has the same meaning as described above), and is reacted with an ortho ester (hereinafter also referred to as ortho ester (VII)). General formula (II '):

(Wherein X and R ⁶ ′ have the same meanings as described above), which includes a step of obtaining a compound represented by the following formula (II ′): ) Manufacturing method.
(7) The production method or separation method according to (5), further including the step according to (6).
(8) The production method or separation method according to any one of (5) to (7), wherein R ⁶ ′ is a methyl group or an ethyl group.
(9) General formula (Ia ′) obtained by the production method or separation method according to any one of (4), (5), (7) and (8) above:

(Wherein each symbol is as defined above) or an optically active compound (hereinafter also referred to as optically active compound (Ia ′)) or general formula (Ib ′):

(Wherein each symbol is as defined above), wherein the optically active compound (hereinafter also referred to as optically active compound (Ib ′)) is deprotected and hydrolyzed under acidic conditions. And general formula (IVa ′):

Wherein X is as defined above (hereinafter also referred to as optically active compound (IVa ′)) or general formula (IVb ′):

(Wherein X is as defined above), a method for producing an optically active compound (hereinafter also referred to as optically active compound (IVb ′)).
(10) The production method according to any one of (4), (5) and (7) to (9), wherein X is a fluorine atom, R ¹ is a phenyl group, and R ² is a methyl group. .
(11) General formula (II ′):

(Wherein X represents a hydrogen atom, a halogen atom or a lower alkyl group, and R ⁶ ′ represents a lower alkyl group).
(12) The compound according to (11) above, wherein X is a fluorine atom, and R ⁶ ′ is a methyl group.
(13) R ⁴ contains 1 to 2 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and may have a substituent, a 5- to 8-membered saturated heterocyclic group or a 5- to 6-membered non-cyclic group. The production method or separation method according to the above (1) or (2), which is a saturated heterocyclic group or a condensed ring group thereof, or the production method according to the above (3).
(14) R ⁴ is represented by the general formula (VIII):

(Wherein Y is independently a hydrogen atom, hydroxyl group, oxo, lower alkoxy group or lower alkyl group, and m and n are each independently an integer of 1 to 3). The production method or separation method according to the above (13), which is a group (hereinafter also referred to as a heterocyclic group (VIII)).
(15) The production method or separation method according to the above (14), wherein R ³ is a lower alkyl group which may have a substituent.
(16) The production method or separation method according to the above (14) or (15), wherein Y is a hydrogen atom, R ³ is an ethyl group, and m is 1.

  According to the present invention, a mixture of diastereomeric amides of a primary amine having a relatively low acidity of the hydrogen atom at the carbonyl group α position, which has been conventionally considered to be difficult to equilibrate, can be subjected to equilibrium epimerization, That is, it has become possible to use all primary amine amide compounds in the epicrystallization process. As a result, the application range of the epicrystallization method can be extended to carboxylic acid compounds that are considered to be difficult to apply by conventional methods, so that there is a great practical merit.

  Furthermore, since the method of the present invention can be carried out in a one-pot reaction from the stage of producing the raw diastereomeric mixture, it is an extremely excellent method in terms of labor (number of steps, time, etc.) required for production, yield and cost. .

Hereinafter, the present invention will be described in detail.
The “halogen atom” represented by X is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom.

The “lower alkyl group” represented by X, Y, R ⁵ , R ⁶ , R ⁶ ′ and R ⁷ is a linear or branched alkyl group having 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms, For example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group and the like can be mentioned, and a methyl group or an ethyl group is preferable.

Examples of the “organic group” represented by R ¹ and R ² include a lower alkyl group which may have a substituent, an aryl group which may have a substituent, and an aralkyl group which may have a substituent. Etc. However, since the carbon atom to which R ¹ and R ² are bonded needs to be an asymmetric carbon, R ¹ and R ² do not mean the same group at the same time.

  Examples of the “lower alkyl group” of the “lower alkyl group optionally having substituent (s)” include the same as the lower alkyl group defined above, and the substituents are the same as those described above for hydroxyl, oxo and the above. And a lower alkoxy group having a lower alkyl group. Examples of the lower alkoxy group include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, and a butoxy group, and a methoxy group or an ethoxy group is preferable. The number of the substituents is not particularly limited and is preferably 1 to 3, and may be the same or different. The same applies to the “lower alkoxy group” represented by Y.

  As the “aryl group” of the “aryl group optionally having substituent (s)”, aryl groups having 6 to 10 carbon atoms such as phenyl, 1- or 2-naphthyl and the like can be mentioned. Atom, the same lower alkyl group as described above, or the same substituent as the above-mentioned “alkyl group optionally having substituent (s)” and the like can be mentioned. The number of the substituents is not particularly limited and is preferably 1 to 3, and may be the same or different.

  The “aralkyl group” of the “aralkyl group optionally having substituent (s)” is formed by substituting the “aryl group” defined above at any position of the “lower alkyl group” defined above. Aralkyl groups such as benzyl, 1- or 2-phenethyl, 1-, 2- or 3-phenylpropyl, 1- or 2-naphthylmethyl, benzohydryl and the like. Examples of the substituent include the same substituent as the above-mentioned “aryl group optionally having substituent (s)” for the aryl moiety, and the above-mentioned “alkyl group optionally having substituent (s)” for the alkyl moiety. The same substituents can be mentioned. The number of the substituents is not particularly limited and is preferably 1 to 3, and may be the same or different.

Examples of the “group connected to the carbon atom at the carbonyl group α-position by the carbon-carbon bond and stable in the presence of a base” represented by R ³ and R ⁴ include “substituents defined above”. A lower alkyl group that may have ", an" aryl group that may have a substituent "as defined above, an" aralkyl group that may have a substituent "as defined above, and a substituent. An cycloalkyl group which may be substituted, a saturated heterocyclic group which may have a substituent, an unsaturated heterocyclic group which may have a substituent, or a substituent substituted with these heterocyclic groups, as defined above And lower alkyl groups.

  The “cycloalkyl group” of the “cycloalkyl group optionally having substituent (s)” is a cycloalkyl group having 3 to 8 carbon atoms, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cyclo A heptyl group or a cyclooctyl group is mentioned. Examples of the substituent include the same lower alkyl group as described above or the same substituent as the above-mentioned “lower alkyl group which may have a substituent”. The number of the substituents is not particularly limited and is preferably 1 to 3, and may be the same or different.

  As the “saturated heterocyclic group” of the “saturated heterocyclic group optionally having substituent (s)”, for example, a hetero atom selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom is 1-2. 5 to 8 membered saturated heterocyclic groups including ones connected by carbon atoms, such as 2- or 3-tetrahydrofuryl group, 2-, 3- or 4-tetrahydropyranyl group, 2- or 3- Tetrahydrothienyl group, 2-, 3- or 4-tetrahydrothiopyranyl group, 1,3-dioxolan-2 or 4-yl group, 1,4-dioxan-2-yl group, 2- or 3-pyrrolidinyl group, Examples include 2-, 3- or 4-piperidinyl group, 2-piperazinyl group, 2- or 3-morpholinyl group, 2- or 4-imidazolidinyl group and the like. Examples of the substituent include the same substituent as the above-mentioned “cycloalkyl group optionally having substituent (s)”. The number of the substituents is not particularly limited and is preferably 1 to 3, and may be the same or different.

  As the “unsaturated heterocyclic group” of the “unsaturated heterocyclic group which may have a substituent”, for example, a hetero atom selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom is 1 5 to 6-membered unsaturated heterocyclic group containing 2 or its condensed ring group connected by a carbon atom, such as 2- or 3-thienyl, 1,2-dihydrothiophene-2, 3, 4 or 5-yl, 1,4-dihydrothiophene-2 or 3-yl, 2- or 3-furyl, 1,2-dihydrofuran-2, 3, 4 or 5-yl, 1,4-dihydrofuran-2 or 3-yl, 2- or 3-pyrrolyl, 2-pyrrolin-2, 3, 4 or 5-yl, 3-pyrrolin-2 or 3-yl, 3,4-dihydro-2H-pyran-2,3,4 , 5 or 6-yl, 3,4-dihydro-2H-thiopyran-2,3 , 5 or 6-yl, 2- or 4-imidazolyl, 2- or 4-imidazolinyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-oxazolinyl, 2-, 4- or 5-thiazolyl 2-, 4- or 5-thiazolinyl, 3-, 4- or 5-pyrazolyl, 3-, 4- or 5-pyrazolinyl, 3-, 4- or 5-isoxazolyl, 3-, 4- or 5-iso Oxazolinyl, 3-, 4- or 5-isothiazolyl, 3-, 4- or 5-isothiazolinyl, 1,2,4-triazol-3 or 5-yl, 1,2,3-triazol-4-yl, 1H-tetrazol-1 or 5-yl, 2H-tetrazol-2 or 5-yl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2-, 3--4 -, 5-, 6- or 7-yne Ryl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 4-, 5-, 6- or 7-benzimidazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- Or 8-isoquinolyl etc. are mentioned. Examples of the substituent include the same substituent as the above-mentioned “aryl group optionally having substituent (s)”. The number of the substituents is not particularly limited and is preferably 1 to 3, and may be the same or different.

Examples of the group represented by R ⁴ "a group connected to a carbon atom at the carbonyl group α-position and a carbon-heteroatom bond and stable in the presence of a base" include heteroatoms such as a nitrogen atom, an oxygen atom and a sulfur atom. One of the connecting hydrogen atoms protected by a commonly used protective group (eg, tert-butoxycarbonyl group, benzyloxycarbonyl group, benzoyl group, alkanoyl group (acetyl group, propionyl group, etc.)), the heteroatom Or a group formed by bonding a “group connected to a carbon atom at the carbonyl group α-position by a carbon-carbon bond and stable in the presence of a base” as defined above, or “defined above” A saturated heterocyclic group or an unsaturated heterocyclic group optionally having substituent (s) connected by a hetero atom (for example, 1-pyrrolidinyl, heterocyclic group (VIII), 1-pi Lysinyl, 1-piperazinyl, 4-morpholinyl, 1-- imidazolidinyl, 4-Chiomoruhoniru), with a Hajime Tamaki (VIII) are preferred. In addition, when the said hetero atom is a halogen atom, since it reacts with the base used in an equilibrium epimerization reaction and a side reaction may occur, a halogen atom is excluded from a hetero atom.

“Stable in the presence of a base” in R ³ and R ⁴ means stable in the presence of a base used for equilibrium epimerization of the diastereomeric mixture (I).

As the “ring” that R ³ and R ⁴ may be connected to form with the carbon atom to which they are bonded, a 5- to 8-membered homocyclic ring (for example, cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc.) Or a 5- to 8-membered non-aromatic heterocyclic ring containing 1 to 2 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom (for example, tetrahydrofuran, tetrahydropyran, tetrahydrothiopyran, tetrahydrothiophene, 1,4- Dioxane, piperidine, etc.) or condensed rings of these rings and benzene rings. The ring may further have a substituent, and the substituent is the same as the above-mentioned “lower alkyl group which may have a substituent”; a hetero atom such as a nitrogen atom, an oxygen atom or a sulfur atom; One of the connecting hydrogen atoms protected by a commonly used protecting group (eg, tert-butoxycarbonyl group, benzyloxycarbonyl group, benzoyl group, alkanoyl group (acetyl group, propionyl group, etc.)) or the hetero atom And a group formed by bonding a “group connected to the carbon atom at the α-position of the carbonyl group and a carbon-carbon bond and stable in the presence of a base” as defined above. The number of the substituents is not particularly limited and is preferably 1 to 3, and may be the same or different.

Since the carbon atom to which R ³ and R ⁴ are bonded must be an asymmetric carbon, R ³ and R ⁴ do not mean the same group at the same time.

R ¹ and R ² are preferably a lower alkyl group or an aryl group which may have a substituent, preferably a combination of a lower alkyl group and an aryl group which may have a substituent, and the optical activity of the compound (III) A combination of a methyl group and a phenyl group, or a methyl group and a naphthyl group is more preferable because it is easily available as an amine.

As R ³ and R ⁴ , an embodiment in which a ring is formed together with the carbon atoms to be bonded is preferable. As the ring, tetrahydropyran or a condensed ring with a benzene ring, particularly a heterocyclic ring (V) is disclosed in JP-A-1 This is preferable because it becomes a useful intermediate of a drug having aldose reductase inhibitory activity described in JP-A-93588.

In a further preferred embodiment, R ⁴ and the carbon atom at the α-position of the carbonyl group are connected by a carbon-heteroatom bond, and R ⁴ is defined as the above-mentioned “saturated heterocyclic group which may have a substituent or An embodiment of “saturated heterocyclic group connected by hetero atom” is mentioned, and heterocyclic group (VIII) is particularly preferable. When R ⁴ is a heterocyclic group (VIII), R ³ is preferably a lower alkyl group, more preferably an ethyl group.

  X in the heterocyclic ring (V), compounds (Ia ′), (Ib ′), (II ′), (IVa ′), (IVb ′), and (VI) is preferably a halogen atom, more preferably a fluorine atom. .

R ⁵ and R ⁶ are preferably a lower alkyl group, and more preferably a methyl group or an ethyl group.

  Y in the heterocyclic group (VIII) is preferably a hydrogen atom, and m is preferably 1.

  The method of the present invention is shown in the following reaction scheme.

(In the formula, each symbol and wavy line have the same meaning as described above.)
That is, according to the present invention, the diastereomeric mixture (I), which is a mixture of the optically active compound (Ia) and the optically active compound (Ib), is subjected to equilibrium epimerization of the hydrogen atom on the carbon atom at the α-position of the carbonyl group in the presence of a base. The optically active compound (Ia) or the optically active compound comprising the step of crystallizing the optically active compound (Ia) or the optically active compound (Ib) in the same reaction system (hereinafter also referred to as epicrystallization step). It is a method for producing compound (Ib), or a method for separating optically active compound (Ia) or optically active compound (Ib) from diastereomeric mixture (I). Further, each of the obtained compounds is subjected to a step of hydrolysis under acidic conditions (hereinafter referred to as a hydrolysis step), thereby maintaining the chirality of the carbon atom at the carbonyl group α-position while maintaining the chirality of the optically active carboxylic acid. It can lead to optically active compound (IVa) or optically active compound (IVb) which is an acid compound.

  Furthermore, as a method for producing the diastereomeric mixture (I) as a raw material for the epicrystallization step, a step of reacting compound (II) with compound (III) in the presence of a base (hereinafter referred to as amidation step). ) Can be performed more efficiently because the epicrystallization process and the amidation process can be performed by a one-pot reaction.

  In the epicrystallization step of the present invention, the diastereomer having the carbon atom α-position of the desired configuration in the optically active compound (Ia) or optically active compound (Ib) is crystallized. If set, the direction in which an unnecessary diastereomer epimerizes to a desired diastereomer by relatively fast equilibrium epimerization (in the above scheme, when the desired diastereomer is an optically active compound (Ia)). Since it shifts to the left side, the right side in the case of the optically active compound (Ib), theoretically, all the desired diastereomers can be obtained as crystals as the crystallization progresses. There is a great advantage that a splitting yield can be achieved. Here, the resolution yield means a yield converted to 100% when all the desired stereoisomers are recovered in the optical resolution of the racemate, and is a value obtained by doubling the yield from the racemate. .

In the epicrystallization process, which of the optically active compound (Ia) and the optically active compound (Ib) is crystallized is determined by the difference in crystallinity and solubility of each compound in the reaction system. The compound with higher properties or lower solubility crystallizes. The crystallinity and solubility of optically active compounds (Ia) and (Ib) can be easily controlled by selecting R ¹ and R ² of compound (III) relative to compound (II) in the amidation step. An appropriate compound (III) may be selected so that a diastereomer having a carbonyl group α-position carbon atom having a desired configuration crystallizes. In addition, the compound to be crystallized can be freely controlled by selecting the configuration of compound (III).
Hereafter, each process of this invention is demonstrated.

1. Epimerization Crystallization Step In the epimerization crystallization step, the optically active compound (Ia) or (Ib) is crystallized from the reaction system by reacting the diastereomeric mixture (I) with a base in a solvent or without a solvent, for example. Can be performed. In this case, the addition order of the reagent is not particularly limited, and the diastereomeric mixture (I) and the base may be added sequentially or simultaneously.
By performing such an operation, the optically active compound (Ia) or (Ib) can be crystallized in the same reaction system while the diastereomeric mixture (I) is allowed to undergo equilibrium epimerization.

  Crystallization in the epicrystallization step means that crystals containing either one of the optically active compounds (Ia) or (Ib) are precipitated. There is no particular limitation on the diastereoexcess ratio (de) of the crystal to be crystallized, but in order to perform optical resolution efficiently, 70% d.e. e. Or more, preferably 90% d. e. The above is more preferable.

  As shown in the following scheme, equilibrium epimerization means that an optically active compound (Ia) or (Ib) is converted into each other by isomerizing the asymmetric carbon at the carbonyl group α-position of the diastereomeric mixture (I). This means that an equilibrium state is reached.

(In the formula, each symbol is as defined above.)
By the equilibrium epimerization, an optically active compound (Ia) and an optically active compound (Ib) are usually reached in the mother liquor when the optically active compound (Ia) is crystallized. Since the equilibrium reaction tends to be converted into the optically active compound (Ia) (left side in the above scheme), the optically active compound (Ia) can be produced in a high yield.

  The epicrystallization process is usually performed in a solvent in order to perform smoothly, but depending on the form of the diastereomeric mixture (I), it can also be performed almost without a solvent. The solvent used in the solvent may be appropriately selected from optically active compounds (Ia) or (Ib) that crystallize the desired diastereomers and do not inhibit the equilibrium epimerization reaction. Alcohols (eg, methanol, ethanol, n-propanol, 2-propanol, n-butanol, etc.), ethers (eg, ethylene glycol dimethyl ether, tetrahydrofuran, methyl tert-butyl ether, etc.), hydrocarbon solvents (eg, heptane, An aliphatic hydrocarbon such as octane or decane, or an aromatic hydrocarbon such as toluene or xylene) or a mixed solvent such as lower alcohols, preferably 2-propanol or the like. is there. The solvent used is preferably anhydrous in order not to decompose the base.

The amount of the solvent used may be appropriately determined within a range that can be crystallized with high purity and high yield, depending on the solubility of the desired diastereomer in the solvent to be used. For example, when 2-propanol is used for the diastereomeric mixture (I) in which R ³ and R ^4, which are preferred embodiments of the present invention, form a heterocyclic ring (V), 1 part by weight of the diastereomeric mixture (I) On the other hand, the range of 1 to 5 parts by weight is preferable, and the range of 2 to 4 parts by weight is more preferable. The amount of 2-propanol can be used outside this range, but if it exceeds this range, the recovery rate tends to be low, and if it is less, stirring after crystallization becomes difficult or the purity decreases. There is.

The base used in the epicrystallization step is a relatively strong base that can perform equilibrium epimerization of the diastereomeric mixture (I), for example, the pKa of the conjugate acid is in the range of 16 to 35. Certain bases are preferred. Examples of such bases include alkali metal salts and strongly basic organic amines of compounds having a pKa in the above range, such as alkali metal hydrides (eg, sodium hydride, potassium hydride, etc.), alkali metal alkoxides (eg, Sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium propoxide, potassium propoxide, sodium 2-propoxide, potassium 2-propoxide, etc.), strongly basic organic amines (eg, 1,8 -Diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) and the like), sodium hydride, sodium, etc. Methoxide, sodium 2-propoxide and the like are preferable.
In addition, when alkali metal hydrides are used in a lower alcohol solvent, the alkali metal alkoxide produced by the reaction of them acts as a base.
Further, when the alkali metal alkoxide is used in a lower alcohol solvent, when the alkali metal alkoxide having an alkoxy group different from the solvent used is used, the produced different alcohol can be removed by distillation or the like.

  The amount of the base used is, for example, preferably in the range of 0.1 to 2 equivalents and more preferably in the range of 0.5 to 1 equivalents with respect to the diastereomeric mixture (I). The amount of the base used can be outside this range, but if it is less than this range, the equilibrium epimerization tends to be slow, and there is a tendency that epicrystallization does not occur smoothly. This may cause operational problems and is economically disadvantageous.

  The reaction temperature in the epicrystallization step is usually 20 ° C to 150 ° C, but preferably 30 ° C to 80 ° C. The reaction temperature can be carried out outside this range, but if it is lower than this range, the equilibrium epimerization tends to be slow, and if it is high, side reaction may proceed. Although the reaction time is not particularly limited, it may be carried out until the crystallization of the optically active compound (Ia) or (Ib) proceeds sufficiently, and is usually in the range of 3 to 24 hours.

  After completion of the epicrystallization step, the reaction solution is poured into cold water (0 ° C. to room temperature) to stop the reaction, and then extracted, washed and concentrated, and then the concentrate is crystallized from a solvent suitable for crystallization. The crystals of the optically active compound (Ia) or (Ib) can be isolated.

  As another embodiment of the isolation and purification of the optically active compound (Ia) or (Ib), after the completion of the epicrystallization crystallization reaction, 10 to 10 in order to sufficiently crystallize the desired diastereomer remaining in the mother liquor. Cool to 20 ° C and filter the crystals. At this time, the optically active compound (Ia) or (Ib) is gradually cooled with stirring (for example, at a rate of 2 to 15 ° C./hour) in order to cause crystallization with high purity and high yield. Further, aging is preferably performed at 25 to 40 ° C. for 2 to 24 hours. The sufficiently crystallized compound can be isolated by washing with a used solvent (preferably cooled) after filtration.

  The mother liquor recovered by the isolation and purification operation described above contains the optically active compound (Ia) or (Ib), and is used as a diastereomeric mixture (I) that is a raw material for the epicrystallization process as necessary. The crystal can be obtained repeatedly. At that time, if necessary, the amount of solvent may be adjusted by distillation or a base may be added.

2. Amidation process (one-pot reaction with epicrystallization process)
The diastereomeric mixture (I) as the raw material for the epicrystallization process is produced, for example, by reacting the compound (II) with the compound (III) in the presence of a base, that is, the amidation process of the present invention. can do. In the amidation step, the diastereomeric mixture (I) may be once isolated as a diastereomeric crystal and used for the epicrystallization step, but the relatively strong base used in the epicrystallization step is an amidation step. In order to efficiently promote the reaction, it is preferable that the amidation step and the epimerization crystallization step be performed in a one-pot reaction by using the same solvent and base used in the amidation step as those in the epimerization crystallization step. it can. In the present specification, the one-pot reaction means a reaction in which two or more successive steps are carried out continuously or simultaneously in the same reaction vessel without isolating the intermediate. The amidation step will be described below, but for convenience, an embodiment performed in the one-pot reaction will be described.
When a weak base such as aqueous ammonia is used for equilibrium epimerization, such a weak base does not promote the amidation process very efficiently, and furthermore, in the prior art using aqueous ammonia, Since the raw material ester reacts with ammonia to produce an amide, amidation and epicrystallization cannot be performed in a one-pot reaction.

In the one-pot reaction, for example, in a solvent, compound (II) is reacted with compound (III) in the presence of a base, and the resulting diastereomeric mixture (I) is reacted with the optically active compound (Ia) or This can be done by crystallizing (Ib). In this case, the addition order of the reagent is not particularly limited, and the compound (II), the compound (III) and the base may be added sequentially or simultaneously.
By performing such an operation, the diastereomer mixture (I) can be produced from the compound (II) and the compound (III), and the epicrystallization process can be carried out as it is in the same reaction system.

  As the compound (III) to be used, an optically active 1-phenyl can be used since any optically active primary amine that can be used can be used without particular limitation, is easily available, is inexpensive, and is available in both R and S forms. Ethylamine, optically active 1- (1-naphthyl) ethylamine, optically active 2-amino-1-butanol, norephedrine and the like are preferable, and optically active 1-phenylethylamine and optically active 1- (1-naphthyl) ethylamine are more preferable.

  In the one-pot reaction, the amount of compound (III) used is preferably in the range of 0.9 to 2 equivalents, more preferably in the range of 1 to 1.5 equivalents, relative to compound (II). The amount of compound (III) can be used outside this range, but if it is less than this range, compound (II) may not be sufficiently converted to diastereomeric mixture (I), and the amount used is more than this range. Even if there is no effect commensurate with the amount used, it is disadvantageous in terms of cost.

The solvent and base used for the one-pot reaction may be the same as those used in the epicrystallization step. Alternatively, in the amidation step, an excess amount of compound (III) may be used as compared with compound (II), and the excess amount of compound (III) may be allowed to act as a base. Moreover, what is necessary is just to make the usage-amount into the usage-amount by converting the usage-amount in an epicrystallization process into the quantity of the diastereomeric mixture (I) manufactured by an amidation process. Specifically, the amount of the base used is preferably in the range of 0.1 to 2 equivalents, more preferably in the range of 0.5 to 1 equivalents, relative to compound (II).
When lower alcohols are used as solvents, if the alcohol represented by R ⁵ OH released from the alkyl ester of compound (II) is different from the solvent used, the generated alcohol should be removed by distillation or the like. Can do.

  The one-pot reaction may be performed at the same temperature as the epicrystallization step, and the amidation step proceeds sufficiently within the temperature range. Since the reaction time needs to complete the amidation step, when the amidation step is included in the epicrystallization step, it is necessary to set the reaction time longer than apparent, and the time required for the amidation step is usually 0. .5 hours to 5 hours.

  The treatment after the end of the one-pot reaction is the same as in the epicrystallization step. In this case, the recovered mother liquor can be reused as a raw material for the epicrystallization step, but compound (II) and compound (III) can be added to the mother liquor and the one-pot reaction can be repeated. In that case, if necessary, the amount of the solvent may be adjusted by distillation or a base may be added.

  As the compound (II) which is a raw material of the amidation step (including a one-pot reaction), a racemic carboxylic acid ester compound can be used without any particular limitation, but when it is a compound (II ′) which is a preferred embodiment, As shown in the following scheme, compound (II ′) can be produced by reacting compound (VI) with orthoester (VII) in the presence of an acid.

(In the formula, each symbol is as defined above.)
Compound (II ′) is a novel compound, suitable as a raw material for the one-pot reaction in the amidation step and epicrystallization step, and can be efficiently led to the optically active compound (IVa ′) described later. It is extremely useful as an intermediate of a pharmaceutical having aldose reductase inhibitory activity described in Kaihei 1-93588. In the compound (II ′), an embodiment in which X is a fluorine atom and R ⁶ ′ is a methyl group is more preferable as a synthetic intermediate of a pharmaceutical product.
In addition, since the production method of the compound (II ′) can protect and esterify the carbonyl group of the compound (VI) in one step, it is useful as an efficient production method of the compound (II ′). high.

In addition, since the aspect which does not protect a carbonyl group in compound (II ') is unstable in presence of a base and cannot use for an epicrystallization process, protection of a carbonyl group is essential.
Hereinafter, the production method of compound (II ′) will be described in detail.

2-1. Method for Producing Compound (II ′) Compound (II ′) can be produced, for example, by reacting compound (VI) with orthoester (VII) in the presence of an acid in a solvent or without a solvent. In this case, the addition order of the reagent is not particularly limited, and compound (VI), orthoester (VII) and acid may be added sequentially or simultaneously.

  The acid used is not particularly limited, and examples thereof include organic acids such as organic sulfonic acids (eg, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, etc.) or mineral acids (eg, hydrochloric acid, sulfuric acid, etc.). P-toluenesulfonic acid is preferred. The amount of the acid used is preferably in the range of 0.01 to 0.1 equivalent, more preferably in the range of 0.01 to 0.05 equivalent, relative to compound (VI).

  The amount of orthoester (VII) used is preferably in the range of 1 to 15 equivalents, more preferably in the range of 1.5 to 10 equivalents, relative to compound (VI). The orthoester (VII) can be used outside this range, but if the amount is less than this range, the yield tends to be low. It is easy to become.

Although the manufacturing method of compound (II ') can also be performed in a solvent, when many orthoesters (VII) are used, it can also be performed without a solvent. When a solvent is used, the solvent is not particularly limited as long as it does not inhibit the reaction. For example, lower alcohols (eg, methanol, ethanol, n-propanol, 2-propanol etc.), toluene alone or a mixed solvent However, it is preferable to use a lower alcohol having the same residue as R ⁶ ′. The amount of the solvent used is preferably in the range of 1 to 10 parts by weight and more preferably in the range of 2 to 5 parts by weight with respect to 1 part by weight of the compound (VI).

  The reaction temperature is usually from room temperature to the boiling point of the solvent. The reaction time is usually 0.5 hours to 10 hours.

  The resulting compound (II ′) can be isolated and purified by a conventional method. For example, after completion of the reaction, the reaction solution is cooled, and a base (eg, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, etc.) is added, or poured into an aqueous solution containing the base, so that the pH is in the range of 7.5 to 12. Adjust to. Then, if necessary, the fixed part can be removed by filtration, and the filtrate can be concentrated or extracted, and the extract can be concentrated to isolate compound (II ′), which is then subjected to recrystallization and the like. And can be purified.

3. Hydrolysis step The optically active compound (Ia) or (Ib) produced by the above method is mixed with an acid (eg, hydrochloric acid, etc.) in a solvent (eg, a mixed solvent of acetic acid and water), for example. The mixture is hydrolyzed in the reflux temperature range for 5 to 20 hours, and is isolated and purified by a conventional method, whereby the respective steric configurations can be maintained to lead to the optically active compound (IVa) or (IVb). At this time, compound (III) by-produced by hydrolysis can be recovered from the reaction mixture, and can be reused as a raw material for the amidation step (including the one-pot reaction).
When the optically active compound (Ia ′) or (Ib ′), which is a preferred embodiment, is hydrolyzed, deprotection of the carbonyl proceeds simultaneously under the acidic conditions, and the optically active compound (IVa ′) or (IVb ′) ) Respectively.

  The optically active compound (IVa) or (IVb) thus obtained is useful as various biologically active compounds such as pharmaceuticals and agricultural chemicals, or as a synthetic intermediate of biologically active compounds. For example, the optically active compound (IVa ') can be led to a drug having aldose reductase inhibitory activity by the method described in JP-A-1-93588. In addition, (2S) -2- (2-oxopyrrolidin-1-yl) butanoic acid is led to a central nervous system drug by a method described in, for example, European Patent No. 0165919 or US Pat. No. 4,943,639. Can do.

  Hereinafter, the present invention will be described more specifically with reference to examples. The present invention is not limited by these.

Example 1: Methyl (RS) -4,4-dimethoxy-6-fluorochroman-2-carboxylic acid Crude (RS) -6-fluoro-4-oxochroman-2-carboxylic acid (50.0 g) in a round bottom flask. , 237.9 mmol), trimethyl orthoformate (250 ml, about 2.28 mol), methanol (150 ml) and p-toluenesulfonic acid monohydrate (1.5 g, 7.9 mmol), and the mixture was heated to 60 ° C. under a nitrogen stream. And stirred for 1 hour. After cooling the internal temperature to 25 ° C., potassium carbonate (1.5 g, 10 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. After filtering the solid content, the filtrate was distilled off under reduced pressure (40 ° C.) and concentrated to dryness. Methanol (150 ml) was added to the concentrated residue, heated to reflux for 10 minutes, and then cooled to 5 ° C. or lower. After stirring at 3-5 ° C. for 1 hour, the crystallized crystals were filtered and washed with cold methanol (50 ml). The crystals were dried at 50 ° C. under reduced pressure to obtain the title compound (49.3 g, 182.4 mmol) (the crude carboxylic acid had a purity of 100% and the yield was 76.7%).

¹ HNMR (ppm, CDCl ₃ ): δ 2.31 (dd, 1H, J = 9.0Hz, 12.9Hz, C ₃ -H), 2.49 (dd, 1H, J = 3.9Hz, 13.2Hz, C ₃ -H), 3.25 (d, 6H, J = 6.8Hz, -OCH ₃ x2), 3.80 (s, 3H, -COOCH ₃ ), 4.95 (dd, 1H,
_{J = 3.9Hz, 9.3Hz, C 2} -H), 6.91-7.24 (m, 3H).

Example 2: (2S) -N-[(S) -α-methyl (benzyl)]-4,4-dimethoxy-6-fluorochroman-2-carboxamide In a small reaction vessel, (RS) -4,4- Dimethyl-6-fluorochroman-2-carboxylate methyl (2.7 g, 10.0 mmol), isopropyl alcohol (10 ml) and S-(−)-phenylethylamine (1.7 g, 14.0 mmol) were charged, and a nitrogen stream Under the caution, sodium hydride (content 60%, 400 mg, 10.0 mmol) was carefully added. The internal temperature was raised to 60 ° C., and the mixture was stirred at 60 to 70 ° C. for 3 hours. Since crystals precipitated after 3 hours, the mixture was cooled to 40 ° C. over 2 hours and stirred while keeping at 40 ° C. for 3 hours. The mixture was further stirred at 35 ° C. for 16 hours under a nitrogen atmosphere, cooled to 5 ° C. and filtered. Washing with chilled isopropyl alcohol (2 ml) gave 2.55 g (7.1 mmol) of the title compound. Yield 71.0% (division yield 142%). When analyzed by HPLC, the diastereomeric excess was 98.4% d. e. Met.

HPLC analysis conditions:
Column; Develosil ODS-7 (NOMURA CHEMICAL),
Mobile phase: acetonitrile: water = 50: 50,
Flow rate: 1.0 ml / min, wavelength: 246 nm, retention time: around 14 minutes.

¹ HNMR (ppm, CDCl ₃ ): δ1.53 (d, 3H, J = 6.8Hz, -C-CH ₃ ), 2.04 (d, 1H, J = 11.2Hz, 13.2Hz, C ₃ -H), 2.78 (dd, 2H, J = 3.4Hz, 13.2Hz, C ₃ -H), 3.17 (s, 3H, -OCH ₃ ), 3.34 (s, 3H, -OCH ₃ ), 4.80 (dd, 1H, J = 3.2 Hz, 11.0Hz, C ₂ -H), 5.22 (m, 1H, (NH) CH), 6.78-6.84 (br, 1H, NH), 6.84-7.00 (m, 2H), 7.24-7.42 (m, 6H ).

Example 3: (2S) -N-[(S) -α-methyl (benzyl)]-4,4-dimethoxy-6-fluorochroman-2-carboxamide (scale up)
In a round bottom flask was added (RS) -4,4-dimethoxy-6-fluorochroman-2-carboxylate methyl (20.0 g, 74.0 mmol), isopropyl alcohol (74 ml) and S-(-)-phenylethylamine (12 .6 g, 104.0 mmol) was charged, and sodium hydride (content 60%, 3.0 g, 75 mmol) was carefully added under a nitrogen stream. The internal temperature was raised to 60 ° C., and the mixture was stirred at 60 to 70 ° C. for 3 hours. Since crystals precipitated after 3 hours, the mixture was then cooled to 40 ° C. over 2 hours and stirred at 40 ° C. for 2 hours. After cooling to about 20 ° C. and stirring, the mixture was further cooled to 5 ° C. and filtered. After filtration, the crystals were washed with chilled isopropyl alcohol (20 ml) and dried under reduced pressure to obtain 19.1 g (53 mmol) of the title compound. Yield 72% (division yield 144%). When analyzed under the same HPLC conditions as described above, the diastereomer excess was 94.4% d. e. Met. This was repulped with water, collected by filtration, and further subjected to recrystallization with isopropyl alcohol to obtain a 90% recovery rate and a 91.9% d. e. Crystal was obtained.

Example 4: (2S) -N-[(S)-(1-naphthyl) ethyl] -2- (2-oxopyrrolidin-1-yl) butanamide 2- (2-oxopyrrolidine-1- under nitrogen atmosphere Yl) methyl butanoate (2.05 g, 11.1 mmol), (S) -1- (1-naphthyl) ethylamine (2.28 g, 13.3 mmol) was placed in an oil bath at 160 to 165 ° C. and heated for 7 hours. . The reaction mixture was cooled to room temperature, toluene (20 ml) was added once, and the organic layer obtained by washing with 10% hydrochloric acid (10 ml × 2) was washed with 10% aqueous sodium hydroxide (8 ml), 10% brine (10 ml), Washed in order of water (10 ml). When the organic layer was concentrated under reduced pressure, a solid began to precipitate. Diisopropyl ether (30 ml) was added to promote crystallization at room temperature, and then filtered to obtain 1.30 g (36.2%, (SS) of crude crystals. : (R-S) = 89.2: 10.8). This was once dissolved in methanol (10 ml), the solvent was distilled off under reduced pressure, diisopropyl ether (20 ml) was added to crystallize, and then filtered to obtain 1.09 g (30.4%, (S- S) :( RS) = 99.0: 1.0).

The two filtrates obtained by the above operation were concentrated under reduced pressure, and anhydrous isopropanol (3 ml) was added. (The ratio of each crystal component at this time was (SS) :( RS) = 15.6: 84.4.) Under a nitrogen atmosphere, sodium hydride (content 60%, 51 .6 mg, 1.29 mmol) was added, heated at 70 ° C. for 1 hour with stirring, cooled to 60 ° C. to 30 ° C. over 4 hours, and finally held at 25 ° C. for 3 hours. 10% hydrochloric acid (5 ml) and diisopropyl ether (20 ml) were added to the reaction mixture, and the precipitated crystals were filtered, and 1.54 g (42.9%, (SS): (RS) = 97 of crude crystals. .5: 2.5). This was once dissolved in methanol (10 ml), filtered with decolorizing charcoal (0.5 g). Then, the solvent was distilled off under reduced pressure, diisopropyl ether (10 ml) was added to crystallize, and then filtered to obtain 1.45 g (40.4%, (SS) :( RS) = 99. 2: 0.8).
1.45 g of the crude crystals and 1.09 g of the crude crystals obtained in the first operation were combined, dissolved in isopropanol (10 ml), filtered after recrystallization. After drying under reduced pressure, 2.19 g (yield 61.0%, (SS) only) of the title compound was obtained.

HPLC analysis conditions:
Column: Develosil ODS-7 (4.6mm × 30cm, NOMURA CHEMICAL),
Mobile phase: A solution 10 mM KH ₂ PO ₄ , B solution methanol,
Elution condition: Constant at 60% by volume of B solution up to 20 minutes, and gradually increase B solution to 90% by volume by 35 minutes.
Flow rate: 1.0 ml / min, wavelength: 246 nm, retention time: (SS) body around 20.5 minutes, (RS) body around 18.5 minutes.

Physical property data of title compound ((SS) form)
mp 204-206 ° C., TLC Rf value = 0.15 (heptane: ethyl acetate = 1: 2).
¹ H-NMR (ppm, CDCl ₃ ): δ 0.83 (t, 3H, J = 7.5Hz, CH ₃ ), 1.61 (d, 3H, J = 6.8Hz, CH ₃ ), 1.60-2.10 (m, 4H, CH ₂ -CH ₂ ), 2.30-2.50 (m, 2H, CH ₂ ), 3.30-3.65 (m, 2H, CH ₂ -CO), 4.35 (t, 1H, J = 7.5Hz, CHCO), 5.87 (q , 1H, J = 7.3Hz, CHNaphthyl), 6.59 (brs, 1H, NH), 7.35-8.10 (m, 7H, aromatic protons).

(RS) Body property data
mp 124-126 ° C., TLC Rf value = 0.23 (heptane: ethyl acetate = 1: 2).
¹ H-NMR (ppm, CDCl ₃ ): δ 0.90 (t, 3H, J = 7.3Hz, CH ₃ ), 1.63 (d, 3H, J = 6.8Hz, CH ₃ ), 1.60-2.30 (m, 6H, CH ₂ -CH ₂ and CH ₂ ), 3.05-3.40 (m, 2H, CH ₂ -CO), 4.41 (t, 1H, J = 7.3Hz, CHCO), 5.87 (q, 1H, J = 6.8Hz, CHNaphthyl ), 6.57 (brs, 1H, NH), 7.35-8.10 (m, 7H, aromatic protons).

Claims (16)

General formula (II):

[Wherein R ⁵ represents a lower alkyl group, R ³ represents a group which is connected to the carbon atom at the α-position of the carbonyl group by a carbon-carbon bond and is stable in the presence of a base, and R ⁴ represents a carbonyl group. a group that is connected to a carbon atom at the α-position by a carbon-carbon bond or a carbon-heteroatom bond (excluding a carbon-halogen atom bond) and is stable in the presence of a base; and R ³ and R ⁴ May be linked to form a ring together with the carbon atoms to which they are bonded (provided that R ³ and R ⁴ do not mean the same group at the same time). In the presence of a base, the compound represented by the general formula (III):

(Wherein R ¹ and R ² each independently represents an organic group, provided that R ¹ and R ² do not mean the same group at the same time) (I):

(Wherein each symbol has the same meaning as described above), and a step of obtaining a diastereomeric mixture represented by:
In the same reaction system, the diastereomeric mixture was subjected to equilibrium epimerization of the hydrogen atom on the carbon atom at the carbonyl group α-position in the presence of a base.

(Wherein each symbol has the same meaning as described above) or the general formula (Ib):

(Wherein each symbol has the same meaning as described above), and a step of crystallizing the optically active compound represented by the general formula (Ia) or The manufacturing method of the optically active compound represented by the said general formula (Ib).   The production method according to claim 1, wherein the production is performed by a one-pot reaction. General formula (Ia) obtained by the production method according to claim 1 or 2:

[Wherein, R ¹ and R ² each independently represent an organic group (provided that R ¹ and R ² do not mean the same group at the same time), and R ³ represents a carbon atom at the α-position of the carbonyl group; A group which is connected by a carbon-carbon bond and is stable in the presence of a base, and R ⁴ represents a carbon atom at the carbonyl group α-position and a carbon-carbon bond or a carbon-heteroatom bond (however, a carbon-halogen atom bond) And R ³ and R ⁴ may form a ring together with the carbon atoms to which R ³ and R ⁴ are bonded (provided that R ³ and R ⁴ are bonded together). ⁴ does not mean the same group at the same time.) Or an optically active compound represented by the general formula (Ib):

(Wherein each symbol has the same meaning as described above), wherein the optically active compound represented by the general formula (IVa):

(Wherein each symbol is as defined above) or an optically active compound represented by the general formula (IVb):

(Wherein each symbol has the same meaning as described above). Along with the carbon atom to which R ³ and R ⁴ are attached, the general formula (V):

(Wherein, X represents a hydrogen atom, a halogen atom or a lower alkyl group, R ⁶ is. Showing a lower alkyl group) to form a heterocyclic ring represented by claim 1 or 2 A process according. The production method according to claim 4, wherein R ⁵ and R ⁶ are R ⁶ '(R ⁶ ' represents a lower alkyl group). General formula (VI):

(Wherein X represents a hydrogen atom, a halogen atom or a lower alkyl group) in the presence of an acid, the compound represented by the general formula (VII):

(Wherein R ⁷ represents a hydrogen atom or a lower alkyl group, and R ⁶ ′ represents a lower alkyl group), and is reacted with an orthoester represented by the general formula (II ′):

(In the formula, X and R ⁶ ′ have the same meanings as described above.), Which includes a step of obtaining a compound represented by the general formula (II ′).   The manufacturing method according to claim 5, further comprising the step according to claim 6. The manufacturing method as described in any one of Claims 5-7 whose R < ⁶ '> is a methyl group or an ethyl group. General formula (Ia ′) obtained by the production method according to any one of claims 4, 5, 7 and 8:

[Wherein, X represents a hydrogen atom, a halogen atom or a lower alkyl group, and R ¹ and R ² each independently represent an organic group (provided that R ¹ and R ² do not represent the same group simultaneously) ), R ⁶ represents a lower alkyl group. Or an optically active compound represented by the general formula (Ib ′):

(Wherein each symbol has the same meaning as described above), wherein the optically active compound represented by the general formula (IVa ′):

(Wherein X is as defined above) or an optically active compound represented by the general formula (IVb ′):

(Wherein X is as defined above), a method for producing an optically active compound. The production method according to any one of claims 4, 5, and 7 to 9, wherein X is a fluorine atom, R ¹ is a phenyl group, and R ² is a methyl group. General formula (II '):

(Wherein X represents a hydrogen atom, a halogen atom or a lower alkyl group, and R ⁶ ′ represents a lower alkyl group). The compound according to claim 11, wherein X is a fluorine atom, and R ⁶ 'is a methyl group. R ⁴ contains 1 to 2 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and may have a substituent, a 5- to 8-membered saturated heterocyclic group or a 5- to 6-membered unsaturated heterocyclic ring The manufacturing method as described in any one of Claims 1-3 which is group or its condensed ring group. R ⁴ represents the general formula (VIII):

(Wherein Y is independently a hydrogen atom, hydroxyl group, oxo, lower alkoxy group or lower alkyl group, and m and n are each independently an integer of 1 to 3). The production method according to claim 13, which is a group. The production method according to claim 14, wherein R ³ is a lower alkyl group which may have a substituent. The production method according to claim 14 or 15, wherein Y is a hydrogen atom, R ³ is an ethyl group, and m is 1.