JPWO2008020597A1 - Method for producing 1-methylcarbapenem intermediate - Google Patents

Abstract

An industrially suitable method for producing 1-methylcarbapenem production intermediate (II) is disclosed that uses inexpensive raw materials and does not involve complicated steps. The production method is a production method in which 1-methylcarbapenems production intermediate (II) is obtained by reacting general formula (I) with imidazole, then reacting with malonic ester, and further optionally diazotizing. is there.
[Chemical 1]

Description

  The present invention relates to a method for producing an azetidinone derivative useful as an intermediate for producing 1-methylcarbapenems having excellent antibacterial activity.

  1-methylcarbapenems having excellent antibacterial activity and high safety are clinically extremely useful substances as antibacterial substances for injection. In addition, recently, it is being developed as an oral administration agent, and is one of the substances that are expected to receive more and more attention in the future.

  However, while antibiotics occupying a group of conventional antibacterial drugs are derived from natural organic compounds, 1-methylcarbapenems have to depend on chemical synthesis, so the production cost associated with chemical synthesis is large. In view of the problem, the antibacterial substances or methods for producing the intermediates for producing them have been actively studied at home and abroad.

（式中、R^１は水素原子または水酸基の保護基を表し、R^６は水素原子またはカルボキシル基の保護基を表し、OR^８は脱離基を表す。）Several key intermediates have been proposed as intermediates for the production of 1-methylcarbapenems. As an example, there is a compound represented by the following general formula (V).

(Wherein R ¹ represents a hydrogen atom or a protecting group for a hydroxyl group, R ⁶ represents a protecting group for a hydrogen atom or a carboxyl group, and OR ⁸ represents a leaving group.)

  Various methods for producing the compound represented by the general formula (V) have been proposed so far, and among them, the azetidinone derivative represented by the general formula (II) is another important intermediate. Classified as a body.

（式中、R^１は水素原子または水酸基の保護基を表し、R^２は水素原子またはアミノ基の保護基を表し、Ｒ^５は水素原子または窒素原子を表し、R^６は水素原子またはカルボキシル基の保護基を表す。）

(In the formula, R ¹ represents a protecting group for a hydrogen atom or a hydroxyl group, R ² represents a protecting group for a hydrogen atom or an amino group, R ⁵ represents a hydrogen atom or a nitrogen atom, and R ⁶ represents a hydrogen atom or a carboxyl group. Represents a protecting group of

（式中、R^１は水素原子または水酸基の保護基を表し、R^２は水素原子またはアミノ基の保護基を表し、R^５は水素原子または窒素原子を表し、R^６は水素原子またはカルボキシル基の保護基を表し、OR^８は脱離基を表し、R^９は補助基を表す。）For example, the compound represented by the general formula (II) is described as an intermediate for the production of the general formula (V) in the method disclosed in JP-A-6-321946. That is, it is represented by the following general formula (III ′) disclosed in Japanese Patent No. 3220985, Japanese Patent No. 3450193 and Tetrahedron 52, 331-357, 1996, etc., and is commercially available 4- A method of obtaining a compound of the following general formula (VI) by subjecting a compound such as an acetoxyazetidinone derivative and a compound of the following formula (A) having an auxiliary group to a stereoselective carbon-carbon bond forming reaction. Has been proposed over a wide range. Furthermore, after removing the auxiliary group part (R ⁹ ) of the compound of the following general formula (VI) by a method such as hydrolysis to obtain a compound of the general formula (VII), the carboxyl group is activated, A method for synthesizing a compound of the general formula (II) by increasing the number of carbon units is shown, and the compound of the general formula (II) is one of the key intermediates for the production of 1-methylcarbapenems. To the compound of general formula (V).

(In the formula, R ¹ represents a protecting group for a hydrogen atom or a hydroxyl group, R ² represents a protecting group for a hydrogen atom or an amino group, R ⁵ represents a hydrogen atom or a nitrogen atom, and R ⁶ represents a hydrogen atom or a carboxyl group. And OR ⁸ represents a leaving group, and R ⁹ represents an auxiliary group.)

  However, several problems arise when trying to produce 1β-methylcarbapenems, which are expected to be more useful among the 1-methylcarbapenems. For example, when synthesizing the compound of the general formula (VI), high stereoselectivity is required, so that it is indispensable to use an expensive auxiliary group, or a reagent for smoothly forming a carbon-carbon bond is expensive. Or Moreover, once the auxiliary group is removed, the carboxyl group is activated, and a complicated process such as re-submission to the carbon increase reaction may be required. As a result, the conventional method leaves room for improvement as an industrially suitable method.

  Specifically, for example, in JP-A-6-256327 and JP-A-7-82248, a titanium reagent or a zirconium reagent used in the present invention is used in the reaction to obtain the general formula (VI). However, a compound having an expensive auxiliary group is used to improve stereoselectivity. Moreover, although it is suggested in the above-mentioned Japanese Patent No. 3220985 etc. to lead to the compound of the formula (VII), the compound of the general formula (I) can be led to the compound of the general formula (V). There is no suggestion.

Further, improved methods that do not include a complicated process of re-addition after the removal of the auxiliary group are disclosed in JP-A-63-284176, JP-A-10-87657, and the like. That is, starting from the compound of the general formula (VI ′), the auxiliary group required for obtaining the high stereoselectivity in the preceding step without passing through the compound of the general formula (VII) is a kind of desorption. A method is described which leads to a compound of general formula (II), considered as a leaving group (see scheme below).

(In the formula, R ¹ represents a protecting group for a hydrogen atom or a hydroxyl group, R ² represents a protecting group for a hydrogen atom or an amino group, R ⁵ represents a hydrogen atom or a nitrogen atom, and R ⁶ represents a hydrogen atom or a carboxyl group. OR ⁸ represents a leaving group, R ⁹ represents an auxiliary group, R ¹⁰ , R ¹¹ , R ¹² , and R ¹³ are the same or different and have hydrogen or a substituent. Represents a lower alkyl group, and X and Y represent an oxygen atom or a sulfur atom)

  However, this method is specialized for an auxiliary group having a specific cyclic structure in which the auxiliary group regarded as a kind of the leaving group has a complicated substituent, and this auxiliary group is used for the versatility of the compound. It is expensive because of its scarcity and complicated manufacturing. As a result, this method also leaves room for improvement as an industrially suitable method. Also, these prior arts do not suggest that the compound of the formula (I) having an inexpensive auxiliary group as in the present invention is led to the compound of the formula (II) or the compound of the formula (V).

  Under the circumstances as described above, development of a more industrially suitable production method of 1-methylcarbapenems production intermediate using inexpensive raw materials without complicated processes is still desired.

  The present inventors have now completed an industrially suitable method for producing an azetidinone derivative represented by the general formula (II), which is one of the useful intermediates for producing 1-methylcarbapenems.

  Therefore, the present invention is a method for producing an azetidinone derivative useful as a production intermediate of 1-methylcarbapenems or 1β-methylcarbapenems having excellent antibacterial activity, through a complicated process using an inexpensive auxiliary group. The object is to provide an industrially superior method without the need to do so.

（式中、
Ｒ^１は、水素原子または水酸基の保護基を表し、
Ｒ^２は、水素原子またはアミノ基の保護基を表し、
Ｒ^５は、水素原子または窒素原子を表し、
Ｒ^６は、水素原子またはカルボキシル基の保護基を表す。）
（ａ）下記式（Ｉ） で表される化合物：

（式中、
Ｒ^３は、置換基を有していてもよいアリール基を表し、
Ｒ^４は、置換基を有していてもよいアリール基、置換基を有していてもよいアラルキル基、または置換基を有していてもよいアルキル基を表す。）
を、イミダゾールと、その後マロン酸エステルと反応させて、Ｒ^５が水素原子である式（II）の化合物を得て、さらに
（ｂ）Ｒ^５が窒素原子である式（II）の化合物が所望の場合には、工程（ａ）で得られた化合物をさらにジアゾ化することを含んでなることを特徴とするものである。And according to one aspect of this invention, the manufacturing method of the compound represented by following formula (II) is provided, The method is:

(Where
R ¹ represents a hydrogen atom or a hydroxyl-protecting group,
R ² represents a hydrogen atom or an amino-protecting group,
R ⁵ represents a hydrogen atom or a nitrogen atom,
R ⁶ represents a hydrogen atom or a protecting group for a carboxyl group. )
(A) Compound represented by the following formula (I):

(Where
R ³ represents an aryl group which may have a substituent,
R ⁴ represents an aryl group which may have a substituent, an aralkyl group which may have a substituent, or an alkyl group which may have a substituent. )
Is reacted with imidazole followed by a malonic ester to obtain a compound of formula (II) in which R ⁵ is a hydrogen atom, and (b) a compound of formula (II) in which R ⁵ is a nitrogen atom is desired. In this case, the compound obtained in step (a) is further diazotized.

（式中、
Ｒ^１はおよびＲ^２は前記と同義であり、
Ｒ^７は、アルキルカルボニルオキシ基を表す。）
で表される化合物を、をジルコニウム試薬の存在下、下記式（ＩＶ）：

（式中、Ｒ^３およびＲ^４は前記と同義である）
で表される化合物と反応させることを含んでなる。According to another aspect of the present invention, there is provided a process for producing a compound represented by the above general formula (I), which comprises the following formula (III):

(Where
R ¹ and R ² are as defined above,
R ⁷ represents an alkylcarbonyloxy group. )
In the presence of a zirconium reagent, the compound represented by the following formula (IV):

(Wherein R ³ and R ⁴ are as defined above)
And reacting with a compound represented by:

The auxiliary group (—N (R ³ ) SO ₂ R ⁴ ) employed in the present invention can be easily produced at low cost, unlike the auxiliary group having a specific cyclic structure and the like required in the conventional method. It is industrially suitable and further effectively acts as a leaving group. That is, the auxiliary group (—N (R ³ ) SO ₂ R ⁴ ) employed in the present invention can be easily produced from versatile substances such as anilines and sulfonic acid derivatives, and sulfonanilide compounds (HN (R ³ ) SO ₂ R ⁴ ) itself is highly versatile, including some that are used as industrial raw materials, and can be easily manufactured at low cost. Furthermore, the method according to the present invention does not require a complicated process of activating the carboxyl group after once removing the auxiliary group, and is industrially excellent.

In addition, as far as the present inventors know, regarding the method for producing the compound of the general formula (I) constituting another aspect of the present invention, in the case of targeting 1β-methylcarbapenems, the general formula (I) In the production of the compound, a known method described in Japanese Patent No. 3220985, Japanese Patent No. 3450193, and Tetrahedron 52, 331-357, 1996, etc. is used as an auxiliary group (—N (R ³ ) When applied to SO ₂ R ⁴ ), sufficient stereoselectivity may not always be obtained. However, the above method according to the present invention has the advantageous effect that always high stereoselectivity can be obtained, especially when carried out in the presence of a zirconium reagent.

DETAILED DESCRIPTION OF THE INVENTION

Definitions In the present specification, a lower alkyl group as a group or a part of the group represents a chain, branched, or cyclic alkyl group having preferably 1 to 6 carbon atoms. Specific examples thereof include a methyl group. , Ethyl group, n-propyl group, i-propyl group, cyclopropyl, n-butyl group, i-butyl group, sec-butyl group, t-butyl group, cyclobutyl group, n-pentyl group, cyclopentyl group, n- A hexyl group, a cyclohexyl group, etc. are mentioned.
The aryl group is an aromatic cyclic compound, and examples thereof include a phenyl group, a naphthyl group, and a pyridyl group.
An aralkyl group represents an arylalkyl group, wherein the alkyl group portion preferably represents the lower alkyl group, and the aryl group portion represents the aryl group. Therefore, specific examples thereof include benzyl group, phenethyl group, 3-phenylpropyl group, naphthylmethyl group, pyridylmethyl group and the like.
Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

Production of compounds of formula (II)
Step (a)
In the method according to the present invention, first, a compound of the general formula (I) is reacted with imidazole to give an imidazolide compound, and then reacted with a malonic ester to give a compound of formula (II) in which R ⁵ is a hydrogen atom. obtain.

In the formulas (I) and (II), R ¹ represents a hydrogen atom or hydroxyl protecting group, R ² represents a hydrogen atom or amino group protecting group, and R ⁶ represents a hydrogen atom or a carboxyl protecting group. As the protecting groups for the hydroxyl group, amino group, and carboxyl group, respectively, commonly used protecting groups described in PROTECTVE GROUPS in ORGANIC SYNTHESIS THIRD EDITION (WILEY) can be used. Specific examples include hydroxyl group protecting groups such as trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group and other silyl protecting groups, and amino group protecting groups include trimethylsilyl group, triethylsilyl group, t -Silyl protecting groups such as butyldimethylsilyl group, benzyl protecting groups such as benzyl group, paramethoxybenzyl group, paranitrobenzyl group, benzhydryl group, etc. Benzyl protecting groups such as benzyl group, paranitrobenzyl group, benzhydryl group, pivaloyloxymethyl group, 1- (cyclohexyloxycarbonyloxy) ethyl group, acetoxymethyl group, 1- (isopropyloxycarbonyloxy) ethyl group, 1- (ethoxycarbonyloxy) ethyl group Examples include cyclohexyloxycarbonyloxymethyl group, 1- (cyclohexyloxycarbonyloxy) -2-methylpropan-1-yl group, isopropyloxycarbonyloxymethyl group, phthalidyl group, and other ester groups that can be hydrolyzed in vivo. It is done.

In formula (I) and formula (II), preferred R ¹ includes a hydrogen atom, a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, and the like, and more preferably a t-butyldimethylsilyl group. Can be mentioned.

In formula (I) and formula (II), preferred R ² is a hydrogen atom, trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group, benzyl group, paramethoxybenzyl group, paranitrobenzyl group, benzhydryl. A hydrogen atom, a paranitrobenzyl group, and the like are more preferable.

In the formula (II), preferable R ⁶ includes benzyl group, paramethoxybenzyl group, paranitrobenzyl group, benzhydryl group, pivaloyloxymethyl group, 1- (cyclohexyloxycarbonyloxy) ethyl group, acetoxymethyl group, Examples include 1- (isopropyloxycarbonyloxy) ethyl group, cyclohexyloxycarbonyloxymethyl group, ester group that can be hydrolyzed in the body, and more preferable examples include paranitrobenzyl group and paramethoxybenzyl group.

R ³ is an aryl group which may have a substituent, and preferred examples of the aryl group include aromatic cyclic compounds such as a phenyl group, a naphthyl group, and a pyridyl group. In addition, examples of the substituent include halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom, methyl group, trifluoromethyl group, trichloromethyl group, ethyl group, n-propyl group, i-propyl group, n- Lower alkyloxy group such as butyl group, i-butyl group, sec-butyl group, t-butyl group and the like, which may be substituted with halogen atom, lower alkyloxy group such as methoxy group, ethoxy group, amino group, monoalkyl An amino group (for example, monomethylamino group, monoethylamino group, etc.), an amino group such as a dialkylamino group (for example, dimethylamino group, diethylamino group, etc.), a cyano group, a nitro group, and the like can be mentioned. There may be one or a plurality of substituents, and when there are a plurality of substituents, they may be the same or different. When there is a single substituent, the substitution position is selected from the 2-position, 3-position or 4-position of the bonding position. In the case of disubstitution, the substitution position selected from the 2,3 position, 2,4 position, 2,5 position, 2,6 position, 3,4 position or 3,5 position of the bond position When there is a group, a position selected from any conceivable position may be substituted. When the substituent is adjacent disubstitution, the ends of both substituents may be united, in which case, an aliphatic ring to which propylene, butylene, etc. are bonded, methylenedioxy, ethylenedioxy, etc. In which a cyclic ether compound in which is bonded is formed.

According to a preferred embodiment of the present invention, preferred R ³ includes phenyl group, bromophenyl group, fluorophenyl group, chlorophenyl group, methylphenyl group, dimethylphenyl group, ethylphenyl group, i-propylphenyl group, t-butyl. Phenyl group, methyl-methoxyphenyl group, chloro-methylphenyl group, trifluoromethylphenyl group, methoxyphenyl group, cyanophenyl group, nitrophenyl group, methoxycarbonylphenyl group, methylenedioxyphenyl group, ethylenedioxyphenyl group, etc. And the position of the substituent on the phenyl group is as described above.

R ⁴ is an aryl group, aralkyl group, or alkyl group which may have a substituent, and examples of the substituent include the same substituents as those described above for R ³ . An alkyl group is a lower alkyl group which may be substituted with a halogen atom, for example, a methyl group, a trifluoromethyl group, a trichloromethyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group. Group, i-butyl group, sec-butyl group, t-butyl group and the like. The aryl group which may have a substituent has the same meaning as described above, and examples thereof include a phenyl group, a methylphenyl group, a naphthyl group, and a pyridyl group. The aralkyl group has the same meaning as described above, and examples thereof include a benzyl group, a phenethyl group, a 3-phenylpropyl group, a naphthylmethyl group, and a pyridylmethyl group. Preferred examples of R ⁴ include a phenyl group, a methylphenyl group, a benzyl group, and a methyl group.
R ⁵ is a hydrogen atom or a nitrogen atom.

The malonic acid ester to be reacted after reacting the compound of formula (I) with imidazole is preferably a malonic acid monoester, and the ester part of the malonic acid monoester corresponds to R ⁶ . Accordingly, this ester moiety is preferably selected from those listed for R ⁶ , and specific examples of malonic acid monoesters include malonic acid monobenzyl ester, malonic acid mono-p-nitrobenzyl ester, malonic acid monopivalo. Iloxymethyl ester and the like can be mentioned, and malonic acid mono-p-nitrobenzyl ester and the like are preferable.

In the step (a), that is, the reaction for obtaining a compound in which R ⁵ is a hydrogen atom among the compounds represented by the general formula (II), the organic solvent is used in an inert gas atmosphere such as nitrogen or argon as the first step. Among them, imidazole is allowed to act in the presence or absence of a base catalyst.

  As the organic solvent, any inert solvent that does not participate in the reaction can be used. For example, hydrocarbon solvents such as n-pentane, n-hexane, cyclohexane, n-heptane or a mixture of isomers thereof, methylene chloride Chlorinated solvents such as 1,2-dichloroethane and chloroform, aromatic hydrocarbon solvents such as benzene, chlorobenzene, toluene and xylene, diethyl ether, diisopropyl ether, dimethoxyethane, tetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether An organic solvent such as an ether solvent such as ethyl acetate and butyl acetate or an aprotic polar solvent such as acetonitrile can be used singly or in appropriate combination, and preferably methylene chloride , Ethyl acetate, acetonitrile Etc., and the like.

  According to the preferable aspect of this invention, reaction can be advanced smoothly by addition of a base catalyst. Base catalysts include pyridine, 4-dimethylaminopyridine, 2-picoline, 3-picoline, 4-picoline, aniline, N-methylaniline, N, N-dimethylaniline, 2,3-lutidine, 2,4-lutidine 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,4,6-collidine, 1,4-diazabicyclo [2.2.2] octane, 1,5-diazabicyclo Examples include organic bases such as [4.3.0] -non-5-ene and 1,8-diazabicyclo [5.4.0] -undec-7-ene, preferably 4-dimethylaminopyridine.

  The use ratio (weight / volume ratio) of the general formula (I) and the solvent is usually 1: 5 to 100, preferably 1:10 to 50. The use ratio (molar ratio) of the general formula (I) to the base catalyst is usually from 1: 0.0 to 0.5, preferably from 1: 0.05 to 0.2. As for the use ratio (molar ratio) of general formula (I) and imidazole, 1: 1-10 are normal, Preferably it is 1: 1-5. The reaction temperature is usually from -30 to 100 ° C, preferably from 30 to 60 ° C. The reaction usually proceeds in 0.5 to 48 hours, preferably 2 to 24 hours, and 3 to 6 hours is preferable.

  The imidazolide compound obtained by this reaction can be isolated by a general separation and purification method, but since the compound is unstable, it is usually convenient to directly apply to the next step. The reaction mixture containing the imidazolide compound thus obtained is usually subsequently subjected to the next step, but can be appropriately cooled and stored. The cooling temperature for storage is -80 to 0 ° C, preferably -30 to -10 ° C. The storage period is from several hours to two days, preferably within 24 hours.

In the step (a), that is, the reaction for obtaining a compound in which R ⁵ is a hydrogen atom among the compounds represented by the general formula (II), imidazole is allowed to act on the compound of the formula (I) as the second step. Add malonic acid ester.

  According to a preferred embodiment of the invention, the reaction is carried out in the presence of a magnesium compound, examples of which are magnesium chloride, magnesium bromide, magnesium bromide-ether complexes, magnesium iodide, magnesium methoxide, magnesium ethoxy. And the like, preferably magnesium chloride.

  According to a preferred embodiment of the present invention, the reaction is carried out in the presence of a base, examples of which include trimethylamine, triethylamine, tributylamine, trioctylamine, diisopropylethylamine, N-methylpyrrolidine, N-methylpiperidine, N -Methylmorpholine, pyridine, 4-dimethylaminopyridine, 2-picoline, 3-picoline, 4-picoline, aniline, N-methylaniline, N, N-dimethylaniline, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,4,6-collidine, 1,4-diazabicyclo [2.2.2] octane, 1,5-diazabicyclo [ 4.3.0] -non-5-ene, 1,8-diazabicyclo [5.4.0] -undec-7-ene and the like are preferable, and triethylamine and the like are preferable.

  In the reaction, there is no particular limitation on the order of adding reagents, and a reaction mixture containing an imidazolide compound obtained separately may be added to a mixture obtained by reacting a magnesium compound, a base and a malonic ester in an organic solvent. Usually, the magnesium compound, base and malonic acid monoester are generally added to the reaction mixture containing the imidazolide compound obtained above. At this time, the use ratio (molar ratio) of the general formula (I) and the magnesium compound is usually 1: 0.5 to 3, preferably 1: 0.7 to 1.5. The use ratio (molar ratio) of the general formula (I) to the base is usually 1: 1 to 6, preferably 1: 1.5 to 3. The use ratio (molar ratio) of the general formula (I) to the malonic acid monoester is usually from 1: 1 to 3, and preferably from 1: 1 to 2. The temperature for adding the magnesium compound, base and malonic acid monoester is usually from -80 to 0 ° C, preferably from -30 to -10 ° C. The reaction temperature after adding all necessary reagents is usually from -30 to 100 ° C, and preferably from 30 to 60 ° C. The reaction usually proceeds in 0.5 to 20 hours, preferably 1 to 5 hours.

The obtained reaction mixture is worked up according to a conventional method, and is isolated by a general separation and purification method, whereby general formula (II) (wherein R ⁵ is a hydrogen atom) can be obtained.

Step (b)
If a compound of formula (II) in which R ⁵ is a nitrogen atom is desired, the compound obtained in step (a) is further diazotized.
Usually, the general formula (II) (wherein R ⁵ is a hydrogen atom) obtained in the step (a) is diazotized as it is without isolating the general formula (II) ( In the formula, R ⁵ can be a nitrogen atom). The organic solvent used at this time can be an inert solvent that does not participate in the above-mentioned reaction, but is preferably a hydrocarbon-based solvent, a chlorinated solvent, an aromatic hydrocarbon that is convenient for use in the post-treatment of the reaction. A system solvent and an acetate ester solvent are used, and n-heptane, methylene chloride, toluene, ethyl acetate and the like are preferably used.

An azide compound and a base are used for diazotization. As the azide compound, sulfonyl azides such as methanesulfonyl azide, toluenesulfonyl azide, p-carboxybenzenesulfonyl azide, and dodecylbenzenesulfonyl azide are used, preferably dodecylbenzenesulfonyl azide.
Bases include trimethylamine, triethylamine, tributylamine, trioctylamine, diisopropylethylamine, N-methylpyrrolidine, N-methylpiperidine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, 2-picoline, 3-picoline, 4 -Picoline, aniline, N-methylaniline, N, N-dimethylaniline, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5 -Lutidine, 2,4,6-collidine, 1,4-diazabicyclo [2.2.2] octane, 1,5-diazabicyclo [4.3.0] -non-5-ene, 1,8-diazabicyclo [5.4.0] -Undec-7-ene etc. are used, Preferably triethylamine etc. are mentioned.

  The use ratio (molar ratio) of the general formula (I) to the azide compound is usually from 1: 0.7 to 2, preferably from 1: 1 to 1.5. The use ratio (molar ratio) of the general formula (I) to the base is usually from 1: 0.1 to 1, preferably from 1: 0.2 to 0.5. The reaction usually proceeds at -20 to 50 ° C, preferably 0 to 50 ° C. The reaction time is usually 0.5 to 48 hours, preferably 1 to 24 hours, and 3 to 15 hours is preferable.

The obtained reaction mixture is subjected to work-up according to a general method commonly used by those skilled in the art, and is further isolated by a general separation and purification method, whereby general formula (II) (wherein R ⁵ is a nitrogen atom) Can be obtained. In this post-treatment, in addition to ordinary water washing, washing with a dilute alkaline aqueous solution in particular facilitates separation and purification of general formula (II) (wherein R ⁵ is a nitrogen atom). As the dilute alkaline aqueous solution at this time, a sodium hydrogen carbonate aqueous solution, a potassium hydrogen carbonate aqueous solution, a sodium carbonate aqueous solution, a potassium carbonate aqueous solution, a sodium hydroxide aqueous solution, a potassium carbonate aqueous solution, an aqueous ammonia, or the like is used, preferably a sodium hydroxide aqueous solution. . In this case, the concentration of the diluted alkaline aqueous solution is usually 0.1 to 3 mol / L, preferably 0.5 to 1 mol / L. Separation and purification can be performed by a general method, but is preferably a method of forming a precipitate, and can be performed by appropriately concentrating the post-treatment solution. As another method, an organic solvent such as n-heptane is appropriately added and further ripened, and the resulting precipitate is collected by filtration to give a general formula (II) useful as an intermediate for producing 1-methylcarbapenems. ) (Wherein R ⁵ is a nitrogen atom).

If there is a protecting group in R ¹ of the general formula (II) obtained, it can be deprotected by a commonly used deprotection method described in PROTECTVE GROUPS in ORGANIC SYNTHESIS THIRD EDITION (WILEY), etc. It can be an azetidinone derivative represented by the general formula (II) (wherein R ¹ is a hydrogen atom and R ⁵ is a hydrogen atom or a nitrogen atom).

As an object of deprotection, isolated and purified general formula (II) (wherein R ¹ is a hydroxyl-protecting group) can be used, but a post-treatment solution for the reaction containing general formula (II) is used. It can also be used as it is. Preferably, the organic solvent used is a solvent that does not participate in the reaction, for example, a hydrocarbon solvent such as n-pentane, n-hexane, cyclohexane, n-heptane or a mixture of isomers thereof, methylene chloride. Chlorinated solvents such as 1,2-dichloroethane, chloroform, aromatic hydrocarbon solvents such as benzene, chlorobenzene, toluene, xylene, diethyl ether, diisopropyl ether, dimethoxyethane, tetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether Ether solvents such as ethyl acetate, acetate solvents such as ethyl acetate, butyl acetate, aprotic polar solvents such as acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, or methanol, ethanol, 1-propanol, 2-propanol, 1 -Bu Organic solvents such as alcohol solvents such as butanol, 2-butanol, isobutyl alcohol, and tertiary butyl alcohol can be used singly or as a mixture of plural kinds, preferably methylene chloride, acetonitrile, tetrahydrofuran, methanol, etc. More preferable examples include methylene chloride and methanol appropriately mixed. The methylene chloride and methanol mixing ratio (volume ratio) at this time is usually 1: 0 to 0: 1, preferably 1: 1 to 4. When the protecting group is a silyl group, the desilylating agent includes organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, hydrochloric acid , Mineral acids such as hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, boron trifluoride, boron trifluoride diethyl ether complex, titanium tetrachloride, zirconium tetrachloride, aluminum chloride, ferric chloride, cupric nitrate Lewis acids such as cerium (III) nitrate, alkali hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, hydrogen fluoride, ammonium fluoride, triethylamine complex with hydrogen fluoride, hydrogen fluoride Pyridine complex, tetrabutylammonium fluoride, lithium fluoride, sodium fluoride, potassium fluoride, fluorine Fluoride such as cesium fluoride, ammonium fluoride, borofluoric acid, and hydrofluoric acid is used singly or as a mixture of a plurality of types, preferably hydrochloric acid.

In the deprotection, the use ratio (weight / volume ratio) of the general formula (II) (wherein R ¹ is a hydroxyl-protecting group) and the solvent is usually 1: 2-50, preferably 1: 5-20. It is. The amount of the desilylating agent used is in the range of stoichiometric amount to a large excess amount. The reaction temperature is usually from -20 to 60 ° C, preferably from 0 to 40 ° C. The reaction time is usually 0.5 to 24 hours, preferably 1 to 17 hours.

The reaction mixture thus obtained is worked up by those skilled in the art according to a general method, and is isolated by a general separation and purification method, whereby the deprotected general formula (II) (wherein R ¹ is hydrogen). Atoms, and R ⁵ is a hydrogen atom or a nitrogen atom).

（式中、R^１は水素原子または水酸基の保護基を表し、R^２は水素原子またはアミノ基の保護基を表し、R^３は置換基を有していてもよいアリール基を表し、Ｒ^４は置換基を有していてもよいアリール基、アラルキル基、またはアルキル基を表し、R^７はアルキルカルボニルオキシ基を表す。） Preparation of the compound of the formula (I) The compound of the formula (I) used in the preparation of the compound of the formula (II) according to the present invention is known, for example, the above-mentioned Japanese Patent No. 3220985 and Japanese Patent No. 3450193. And Tetrahedron 52, 331-357, 1996, and the like. However, according to a preferred embodiment of the present invention, the compounds of formula (I) are preferably prepared according to the following scheme, and this process constitutes another aspect of the present invention.

Wherein R ¹ represents a hydrogen atom or a protecting group for a hydroxyl group, R ² represents a protecting group for a hydrogen atom or an amino group, R ³ represents an aryl group which may have a substituent, and R ⁴ Represents an aryl group, an aralkyl group, or an alkyl group which may have a substituent, and R ⁷ represents an alkylcarbonyloxy group.

In the present invention, an industrially useful auxiliary group (—N (R ³ ) SO ₂ R ⁴ ) that is inexpensive and functions as a leaving group is employed. As described above, in the above-described known methods, when this auxiliary group is used to produce a compound of formula (I), particularly a production intermediate of 1β-methylcarbapenem, sufficient stereoselectivity may not be obtained. there were. The process for producing the compound of formula (I) according to the present invention solves this problem. This problem is solved by reacting general formula (III) and general formula (IV) in the presence of a zirconium reagent, preferably general formula (III) and general formula (IV) treated with a zirconium reagent, It was solved by obtaining the general formula (I). The treatment with the zirconium reagent of the general formula (IV) preferably means that the general formula (IV) is carried out by allowing a zirconium compound and a base to act in an organic solvent.

The compound represented by the general formula (IV) can be performed by a known method. For example, an aniline (R ³ NH ₂ ) and a sulfonic acid derivative (R ⁴ SO ₂ X) are reacted to form a sulfonanilide compound (HN (R ³ ) SO ₂ R ⁴ ), which includes propionyl chloride and propionic anhydride. It can be obtained by acting.

In the production method according to the present invention, R ¹ and R ² are a hydrogen atom or a protecting group for a hydroxyl group and an amino group, respectively. The protecting group for a hydroxyl group and an amino group is generally described in the above-mentioned books and the like. For example, the protecting group for hydroxyl group and amino group has the same meaning as described above, and preferred R ¹ includes a hydrogen atom or a trimethylsilyl group, a triethylsilyl group, t-butyldimethylsilyl group. Group, etc. are mentioned, More preferably, t-butyldimethylsilyl group etc. are mentioned.

Preferred R ² includes a hydrogen atom, a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, a benzyl group, a paramethoxybenzyl group, a paranitrobenzyl group, a benzhydryl group, and more preferably a hydrogen atom, Examples thereof include a paranitrobenzyl group.

R ³ has the same meaning as described above, and R ³ is an aryl group which may have a substituent. Examples of the aryl group include aromatic cyclic compounds such as a phenyl group, a naphthyl group, and a pyridyl group. As halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom, methyl group, trifluoromethyl group, trichloromethyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i A lower alkyl group optionally substituted with a halogen atom such as a -butyl group, sec-butyl group or t-butyl group, a lower alkyloxy group such as a methoxy group or an ethoxy group, an amino group, or a monoalkylamino group (for example, Monomethylamino group, monoethylamino group, etc.), dialkylamino groups (for example, dimethylamino group, diethylamino group, etc.). Amino group, and a cyano group and a nitro group. There may be one or a plurality of substituents, and when there are a plurality of substituents, they may be the same or different. When there is a single substituent, the substitution position is selected from the 2-position, 3-position or 4-position of the bonding position. Position, in the case of disubstitution, a position selected from the 2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position, or 3,5-position of the bonding position, or more substituents If there is, a place selected from any possible position may be replaced. When the substituent is adjacent disubstitution, the ends of both substituents may be united, in which case, an aliphatic ring to which propylene, butylene, etc. are bonded, methylenedioxy, ethylenedioxy, etc. In which a cyclic ether compound in which is bonded is formed.

Preferred examples of R ³ include phenyl group, bromophenyl group, fluorophenyl group, chlorophenyl group, methylphenyl group, dimethylphenyl group, ethylphenyl group, i-propylphenyl group, t-butylphenyl group, methyl-methoxyphenyl group, Examples include chloro-methylphenyl group, trifluoromethylphenyl group, methoxyphenyl group, cyanophenyl group, nitrophenyl group, methoxycarbonylphenyl group, methylenedioxyphenyl group, ethylenedioxyphenyl group, etc. The position of the substituent is as described above.

R ⁴ is an aryl group, an aralkyl group or an alkyl group which may have a substituent, and the substituent has the same meaning as the substituent described above for R ³ . An alkyl group is a lower alkyl group which may be substituted with a halogen atom, for example, a methyl group, a trifluoromethyl group, a trichloromethyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group. Group, i-butyl group, sec-butyl group, t-butyl group and the like. The aryl group which may have a substituent has the same meaning as described above, and examples thereof include a phenyl group, a methylphenyl group, a naphthyl group, and a pyridyl group. The aralkyl group has the same meaning as described above, and examples thereof include a benzyl group, a phenethyl group, a 3-phenylpropyl group, a naphthylmethyl group, and a pyridylmethyl group. Preferred examples of R ⁴ include a phenyl group, a methylphenyl group, a benzyl group, and a methyl group.

R ⁷ represents an alkylcarbonyloxy group, preferably an acetyloxy group.

  The reaction is desirably performed in an organic solvent under an inert gas atmosphere such as nitrogen or argon. As the organic solvent, any inert solvent that does not participate in the reaction can be used. For example, hydrocarbon solvents such as n-pentane, n-hexane, cyclohexane, n-heptane or a mixture of isomers thereof, methylene chloride Chlorinated solvents such as 1,2-dichloroethane and chloroform, aromatic hydrocarbon solvents such as benzene, chlorobenzene, toluene and xylene, diethyl ether, diisopropyl ether, dimethoxyethane, tetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether An organic solvent such as an ether solvent can be used singly or as a mixture of plural kinds, and methylene chloride is preferable.

  Examples of the zirconium compound include zirconium tetrafluoride, zirconium tetrachloride, zirconium tetrabromide, zirconium tetraiodide, zirconium tetra-i-propoxide, and preferably zirconium tetrachloride.

  Bases include dimethylamine, trimethylamine, diethylamine, triethylamine, dibutylamine, tributylamine, trioctylamine, diisopropylethylamine, bistrimethylsilylamine, pyrrolidine, N-methylpyrrolidine, piperidine, N-methylpiperidine, morpholine, N-methylmorpholine , Tetramethylethylenediamine, pyridine, 4-dimethylaminopyridine, 2-picoline, 3-picoline, 4-picoline, aniline, N-methylaniline, N, N-dimethylaniline, 2,3-lutidine, 2,4-lutidine 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,4,6-collidine, 1,4-diazabicyclo [2.2.2] octane, 1,5-diazabicyclo [4.3.0] -non-5-ene, 1,8-diazabicyclo [5.4.0] -undec-7-ene, etc. Preferably, triethylamine, tributylamine, diisopropylethylamine and the like can be mentioned.

  The order in which the reagents are added is not particularly limited, but is preferably added in the order of the zirconium compound, the base and then the general formula (III) to the solution of the organic solvent of the general formula (IV). The use ratio (weight / volume ratio) of the general formula (III) to the solvent is usually from 1:10 to 100, preferably from 1:10 to 30. The use ratio (molar ratio) of the general formula (III) to the general formula (IV) is usually 1: 1 to 3, preferably 1: 1.2 to 2. The use ratio (molar ratio) of the zirconium compound is usually 1: 1 to 3, preferably 1: 1.2 to 2. The use ratio (molar ratio) of the base catalyst is usually 1: 1 to 3, and preferably 1: 1.2 to 2. In addition, it is recommended that an aprotic polar solvent such as acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, etc. be added as appropriate, whereby the reaction yield and / or stereoselectivity can be improved. According to another aspect, the yield can be further improved by adding a trace amount of a protic solvent such as water and methanol. The reaction temperature is usually from -30 to 50 ° C, preferably from -15 to 30 ° C. The reaction time is usually 0.5 to 24 hours, preferably 1 to 5 hours.

  The resulting reaction mixture is worked up according to a conventional method, and is isolated by a general separation and purification method, for example, purification by silica gel column chromatography or formation of a precipitate, to obtain a compound of the general formula (I) be able to.

Hereinafter, the present invention will be described in more detail with reference to specific examples, but the present invention is not limited to these specific examples. The following abbreviations may be used.
Ts: p-toluenesulfonyl group
TEA: Triethylamine
DMAP: 4-dimethylaminopyridine
Ac: Acetyl group
TBS: t-butyldimethylsilyl group
DIPEA: Diisopropylethylamine

For the measurement of ¹ H nuclear magnetic resonance spectrum ( ¹ H NMR) relating to the description of the physical properties in each of the following exemplified examples, a JNM-AL400 type nuclear magnetic resonance apparatus manufactured by JEOL Ltd. was used, and the value of chemical shift was The value when tetramethylsilane (TMS) is set to δ0.00 ppm is shown, the spin coupling constant is represented by J value in Hz, the split mode of spin coupling is s = single line, d = double line, t = Each represents a triple line, dd = double double line, td = triple double line, and m = multiple line, and those with br. Represent broad peaks, and the number of hydrogen atoms is 1H, 2H It expresses like this. Some compounds have been observed as a mixture of two rotamers that may be due to steric hindrance. In this case, only the chemical shift value, the spin bond splitting mode, and the number of hydrogen atoms are shown.

Production Example 1
Production of N-propionyl-N- (2-trifluoromethylphenyl) -p-toluenesulfonamide (Compound 3)

A solution of 32.23 g (0.20 mol) of 2-aminobenzotrifluoride in pyridine (85 mL) was cooled in an ice bath, 38.52 g (0.20 mol) of p-toluenesulfonyl chloride was added, and the mixture was reacted at the same temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with dilute hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was crystallized from ethyl acetate-hexane to obtain 55.79 g (yield 96.5%) of N- (2-trifluoromethylphenyl) -p-toluenesulfonamide (Compound 2) as a yellowish white powder. .
¹ H NMR (400 MHz, CDCl ₃ ): δppm 2.37 (s, 3H), 6.84 (br. S, 1H), 7.16-7.23 (m, 3H), 7.47-7.53 (m, 2H), 7.66 (d, J = 8.3 Hz, 2H), 7.82 (d, J = 8.3 Hz, 1H).

Compound 2 To a solution of 61.49 g (0.20 mol) in methylene chloride (350 mL) was added 31.25 mL (0.24 mol) propionic anhydride, 40.77 mL (0.29 mol) TEA and 1.19 g (0.0097 mol) DMAP in order, Reacted for hours. Water was added to the reaction solution, and the mixture was vigorously stirred, allowed to stand, and separated. The organic layer was concentrated under reduced pressure, and hexane was added to the concentrate. The title compound (compound 3) 67.41 g (yield 93.1%) As obtained.
¹ H NMR (400 MHz, CDCl ₃ ): δppm 0.97 (t, J = 7.3 Hz, 3H), 1.91−2.06 (m, 2H), 2.46 (s, 3H), 7.35−7.38 (m, 3H), 7.65 -7.70 (m, 2H), 7.86 (dd, J = 7.6, 1.7 Hz, 1H), 8.02 (d, J = 8.3 Hz, 2H).

  Other N-propionyl-N-phenyl-p-toluenesulfonamide derivatives can be produced in the same manner as in Production Example 1.

Example 1
N-[(2R) -2-{(3S, 4R) -3-[(1R) -1- (tert-butyldimethylsilyloxy) ethyl] -2-oxoazetidin-4-yl} propionyl] -N- ( Preparation of 2-trifluoromethylphenyl) -p-toluenesulfonamide (compound 4)

In a nitrogen gas atmosphere, a solution of N-propionyl-N- (2-trifluoromethylphenyl) -p-toluenesulfonamide (Compound 3) 22.29 g (60.0 mmol) in methylene chloride (345 mL) was cooled in an ice bath. Zirconium chloride (20.98 g, 90.0 mmol) was added, and the mixture was stirred at the same temperature for 30 minutes. Next, 16.5 mL (94.7 mmol) of DIPEA was added, and after stirring at the same temperature for 30 minutes, (3R, 4R) -4-acetoxy-3-[(R) -1- (tert-butyldimethylsilyloxy) ethyl] -2 -After adding 17.25 g (60.0 mmol) of azetidinone, it was made to react for 1 hour, removing an ice bath and heating up to room temperature. The reaction yield (HPLC) at this time was 58.4%, and the diastereomer production ratio (HPLC) was β / α = 93.5 / 6.5. Water was added to the reaction mixture, and the mixture was vigorously stirred, allowed to stand and separated. The organic layer was washed successively with water and 10% brine, and the organic layer was concentrated under reduced pressure. The resulting concentrated solution was concentrated and replaced with toluene, and hexane was added to obtain 19.28 g (yield 53.7%) of the title compound (Compound 4) as a white powder.
¹ H NMR (400 MHz, CDCl ₃ ): δppm -0.01, -0.01, 0.01, 0.05 (s, 6H), 0.77-1.04 (m, 15H), 2.33-2.46 (m, 4H), 2.62, 2.70 (dd , 1H), 3.74, 3.86 (dd, 1H), 4.08 (m, 1H), 5.49, 5.86 (br.s, 1H), 7.24−7.43 (m, 3H), 7.63−7.72 (m, 2H), 7.85 (m, 1H), 7.95 (m, 2H), the data are observed as rotamers in a ratio of about 1: 1.

Example 2
N-[(2R) -2-{(3S, 4R) -3-[(1R) -1- (tert-butyldimethylsilyloxy) ethyl] -2-oxoazetidin-4-yl} propionyl] -N- ( Preparation of 2-trifluoromethylphenyl) -p-toluenesulfonamide (Compound 4) In a nitrogen gas atmosphere, N-propionyl-N- (2-trifluoromethylphenyl) -p-toluenesulfonamide (Compound 3) 26.75 A solution of g (72.0 mmol) in methylene chloride (345 mL) was cooled in an ice bath, 21.67 g (93.0 mmol) of zirconium chloride was added, and the mixture was stirred at the same temperature for 30 min. Next, 16.2 mL (93.0 mmol) of DIPEA was added and stirred at the same temperature for 30 minutes, then 17.3 mL of DMF was added and stirred at the same temperature for 30 minutes, and (3R, 4R) -4-acetoxy-3-[(R)- After adding 1- (tert-butyldimethylsilyloxy) ethyl] -2-azetidinone 17.25 g (60.0 mmol), the ice bath was removed and the reaction was allowed to proceed to room temperature for 30 minutes. The reaction yield (HPLC) at this time was 63.0%, and the diastereomer production ratio (HPLC) was β / α = 97.4 / 2.6. Water was added to the reaction mixture, and the mixture was vigorously stirred, allowed to stand and separated. The organic layer was washed successively with water and 10% brine, and the organic layer was concentrated under reduced pressure. The resulting concentrated solution was concentrated and replaced with toluene to form a precipitate, whereby 19.71 g (yield 54.9%) of the title compound (Compound 4) was obtained as a white powder.
¹ H NMR of the obtained compound was the same as that of Example 1.

Example 3
N-[(2R) -2-{(3S, 4R) -3-[(1R) -1- (tert-butyldimethylsilyloxy) ethyl] -2-oxoazetidin-4-yl} propionyl] -N- ( 2-Bromophenyl) -p-toluenesulfonamide
The reaction was carried out in the same manner as in Example 2 using 27.53 g (72.02 mmol) of N-propionyl-N- (2-bromophenyl) -p-toluenesulfonamide, and 23.38 g (yield 63.9%) of the title compound was obtained. Obtained as a white powder. The reaction yield (HPLC) in this reaction was 72.5%, and the diastereomer production ratio (HPLC) was β / α = 95.4 / 4.6.
¹ H NMR (400 MHz, CDCl ₃ ): δppm -0.01, -0.01, 0.01, 0.02 (s, 6H), 0.81, 0.83 (s, 9H), 0.83, 0.96, 1.05, 1.12 (d, 6H), 2.25 , 2.44 (m, 1H), 2.44 (s, 3H), 2.68, 2.80 (dd, 1H), 3.77, 3.93 (dd, 1H), 4.09 (m, 1H), 5.65, 5.85 (br. S, 1H) , 7.31-7.47 (m, 5H), 7.72 (m, 1H), 7.96 (d, 2H), the data are observed as rotamers in a ratio of about 1: 1.9.

Example 4
N-[(2R) -2-{(3S, 4R) -3-[(1R) -1- (tert-butyldimethylsilyloxy) ethyl] -2-oxoazetidin-4-yl} propionyl] -N-phenyl -P-Toluenesulfonamide production
The reaction was conducted in the same manner as in Example 1 using 3.03 g (10.0 mmol) of N-propionyl-N-phenyl-p-toluenesulfonamide to obtain 2.66 g (yield 50.1%) of the title compound as a white powder. . The reaction yield (HPLC) in this reaction was 60.5%, and the diastereomer production ratio (HPLC) was β / α = 85.6 / 14.4.
¹ H NMR (400 MHz, CDCl ₃ ): δppm -0.01 (s, 3H), 0.01 (s, 3H), 0.81 (s, 9H), 0.94 (d, J = 6.3 Hz, 3H), 1.00 (d, J = 7.1 Hz, 3H), 2.44−2.47 (m, 4H), 2.61 (dd, J = 4.0, 2.2 Hz, 1H), 3.77 (dd, J = 4.5, 2.2 Hz, 1H), 4.05 (td, J = 6.3, 4.5 Hz, 1H), 5.77, (br.s, 1H), 7.21−7.24 (m, 2H), 7.32 (d, J = 8.1 Hz, 2H), 7.46−7.50 (m, 3H), 7.86 (d, J = 8.1 Hz, 2H).

Example 5
N-[(2R) -2-{(3S, 4R) -3-[(1R) -1- (tert-butyldimethylsilyloxy) ethyl] -2-oxoazetidin-4-yl} propionyl] -N- ( Preparation of 2-ethylphenyl) -p-toluenesulfonamide
The reaction was conducted in the same manner as in Example 1 using 3.32 g (10.0 mmol) of N-propionyl-N- (2-ethylphenyl) -p-toluenesulfonamide to give 2.81 g (yield 52.8%) of the title compound. Obtained as a white powder. The reaction yield (HPLC) was 57.0%, and the diastereomer formation ratio (HPLC) was β / α = 89.1 / 10.9.
¹ H NMR (400 MHz, CDCl ₃ ): δppm -0.04, -0.00, 0.01, 0.03 (s, 6H), 0.79, 0.82 (s, 9H), 0.76, 0.90, 0.97, 1.02 (d, 6H), 1.30 , 1.32 (t, 3H), 2.26, 2.42 (m, 1H), 2.44, 2.45 (s, 3H), 2.61 (m, 1H), 2.62, 2.84 (m, 2H), 3.68, 3.88 (dd, 1H) , 4.02, 4.12 (m, 1H), 5.59, 5.82 (br.s, 1H), 6.97, 7.06 (d, 1H), 7.23-7.35 (m, 3H), 7.39 (m, 2H), 7.91 (d, 2H), the data are observed as rotamers in a ratio of about 1.5: 1.

Example 6
N-[(2R) -2-{(3S, 4R) -3-[(1R) -1- (tert-butyldimethylsilyloxy) ethyl] -2-oxoazetidin-4-yl} propionyl] -N- ( Preparation of 3-methylphenyl) -p-toluenesulfonamide
The reaction was carried out in the same manner as in Example 2 using 5.67 g (18.0 mmol) of N-propionyl-N- (3-methylphenyl) -p-toluenesulfonamide to give 5.26 g (yield 64.2%) of the title compound. Obtained as a white powder. The reaction yield (HPLC) was 73.0%, and the diastereomer production ratio (HPLC) was β / α = 94.4 / 5.6.
¹ H NMR (400 MHz, CDCl ₃ ): δppm -0.01 (s, 3H), 0.01 (s, 3H), 0.82 (s, 9H), 0.93 (d, J = 6.3 Hz, 3H), 1.00 (d, J = 6.8 Hz, 3H), 2.39 (s, 3H), 2.44−2.47 (m, 4H), 2.61 (dd, J = 4.6, 2.4 Hz, 1H), 3.77 (dd, J = 4.6, 2.2 Hz, 1H ), 4.05 (td, J = 6.3, 2.2 Hz, 1H), 5.77 (br.s, 1H), 6.99 (d, J = 7.6 Hz, 1H, 7.07 (s, 1H), 7.28-7.36 (m, 4H ), 7.87 (d, J = 8.5 Hz, 2H).

Example 7
N-[(2R) -2-{(3S, 4R) -3-[(1R) -1- (tert-butyldimethylsilyloxy) ethyl] -2-oxoazetidin-4-yl} propionyl] -N- ( 2-Ethoxyphenyl) -p-toluenesulfonamide
Using N-propionyl-N- (2-ethoxyphenyl) -p-toluenesulfonamide (3.48 g, 10.0 mmol), the reaction was carried out in the same manner as in Example 1 to obtain 2.89 g (yield: 48.8%) of the title compound. Obtained as a white powder. The reaction yield (HPLC) was 51.5%, and the diastereomer formation ratio (HPLC) was β / α = 80.0 / 20.0.
¹ H NMR (400 MHz, CDCl ₃ ): δppm -0.01, -0.00, 0.00, 0.02 (s, 6H), 0.79, 0.82 (s, 9H), 0.84, 0.94, 0.97, 1.02 (d, 6H), 1.18 , 1.19 (t, 3H), 2.29, 2.46 (m, 1H), 2.42 (s, 3H), 2.66 (m, 1H), 3.78−4.10 (m, 4H), 5.72, 5.80 (br. S, 1H) , 6.95-7.07 (m, 2H), 7.27-7.45 (m, 4H), 7.91 (d, 2H), the data are observed as rotamers in a ratio of about 1: 1.6.

Example 8
N-[(2R) -2-{(3S, 4R) -3-[(1R) -1- (tert-butyldimethylsilyloxy) ethyl] -2-oxoazetidin-4-yl} propionyl] -N- ( Preparation of 4-methoxyphenyl) -p-toluenesulfonamide
The reaction was carried out in the same manner as in Example 2 using 16.01 g (48.0 mmol) of N-propionyl-N- (4-methoxyphenyl) -p-toluenesulfonamide to give 11.56 g (yield 51.5%) of the title compound. Obtained as a white powder. The reaction yield (HPLC) was 69.6%, and the diastereomer formation ratio (HPLC) was β / α = 93.5 / 6.5.
¹ H NMR (400 MHz, CDCl ₃ ): δppm -0.01 (s, 3H), 0.01 (s, 3H), 0.81 (s, 9H), 0.96 (d, J = 6.3 Hz, 3H), 1.00 (d, J = 6.8 Hz, 3H), 2.44 (s, 3H), 2.49 (m, 1H), 2.61 (m, 1H), 3.76 (dd, J = 4.6, 2.2 Hz, 1H), 3.84 (s, 3H), 4.05 (m, 1H), 5.78 (br.s, 1H), 6.95 (d, J = 8.5 Hz, 2H), 7.12 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.3 Hz, 2H ), 7.85 (d, J = 8.3 Hz).

Example 9
N-[(2R) -2-{(3S, 4R) -3-[(1R) -1- (tert-butyldimethylsilyloxy) ethyl] -2-oxoazetidin-4-yl} propionyl] -N- ( Preparation of 2,6-diethylphenyl) -p-toluenesulfonamide
Using N-propionyl-N- (2,6-diethylphenyl) -p-toluenesulfonamide 3.60 g (10.0 mmol), the reaction was carried out in the same manner as in Example 1 to obtain the title compound 2.66 g (yield 45.4% ) Was obtained as a white powder. The reaction yield (HPLC) was 56.4%, and the diastereomer formation ratio (HPLC) was β / α = 87.1 / 12.9.
¹ H NMR (400 MHz, CDCl ₃ ): δppm 0.01 (s, 3H), 0.01 (s, 3H), 0.81 (d, J = 7.8 Hz, 3H), .84 (s, 9H), 0.92 (d, J = 6.8 Hz, 3H), 1.28 (t, J = 7.3 Hz, 6H), 2.29 (m, 1H), 2.45 (s, 3H), 2.46−2.69 (m, 5H), 3.79 (dd, J = 2.9 , 2.7 Hz, 1H), 4.08 (m, 1H), 5.78 (br.s, 1H), 7.23−7.26 (m, 2H), 7.32−7.40 (m, 3H), 8.00 (d, J = 8.3 Hz, 2H).

Example 10
N-[(2R) -2-{(3S, 4R) -3-[(1R) -1- (tert-butyldimethylsilyloxy) ethyl] -2-oxoazetidin-4-yl} propionyl] -N- ( Preparation of 2,6-diisopropylphenyl) -p-toluenesulfonamide
Using N-propionyl-N- (2,6-diisopropylphenyl) -p-toluenesulfonamide (3.48 g, 10.0 mmol), the reaction was carried out in the same manner as in Example 1 to obtain the title compound (4.18 g, yield 50.0%). ) Was obtained as a white powder. The reaction yield (HPLC) was 60.6%, and the diastereomer formation ratio (HPLC) was β / α = 91.6 / 8.4.
¹ H NMR (400 MHz, CDCl ₃ ): δppm 0.00 (s, 6H), 0.81 (s, 9H), 0.94−0.98 (m, 3H), 1.12−1.34 (m, 15H), 2.45 (s, 3H) , 2.75 (br.m, 1H), 3.01−3.05 (m, 3H), 3.82 (br.m, 1H), 4.10 (m, 1H), 5.85 (br.s, 1H), 7.25−7.45 (m, 5H), 7.97 (br. D, J = 7.6 Hz, 2H).

Example 11
N-[(2R) -2-{(3S, 4R) -3-[(1R) -1- (tert-butyldimethylsilyloxy) ethyl] -2-oxoazetidin-4-yl} propionyl] -N- ( Production of 3,5-dimethylphenyl) -p-toluenesulfonamide
N-propionyl-N- (3,5-dimethylphenyl) -p-toluenesulfonamide 15.92 g (48.0 mmol) was used in the same manner as in Example 2 to obtain the title compound 14.40 g (yield 64.4% ) Was obtained as a white powder. The reaction yield (HPLC) was 70.6%, and the diastereomer formation ratio (HPLC) was β / α = 94.6 / 5.4.
¹ H NMR (400 MHz, CDCl ₃ ): δppm 0.01 (s, 3H), 0.01 (s, 3H), 0.82 (s, 9H), 0.93 (d, J = 6.3 Hz, 1H), 0.99 (d, J = 6.8 Hz, 3H), 2.34 (s, 6H), 2.44 (s, 3H), 2.47 (td, J = 6.8, 2.2 Hz, 1H, 2.60 (m, 1H), 3.77 (dd, J = 4.6, 2.4 Hz, 1H), 4.06 (td, J = 6.3, 4.6 Hz, 1H), 5.77 (s, 1H), 6.84 (s, 2H), 7.11 (s, 1H), 7.32 (d, J = 8.1 Hz, 2H ), 7.88 (d, J = 8.1 Hz, 2H).

Example 12
N-[(2R) -2-{(3S, 4R) -3-[(1R) -1- (tert-butyldimethylsilyloxy) ethyl] -2-oxoazetidin-4-yl} propionyl] -N-phenyl Production of methanesulfonamide
The reaction was performed in the same manner as in Example 2 using 5.45 g (24.0 mmol) of N-propionyl-N-phenylmethanesulfonamide to obtain 3.74 g (yield: 41.1%) of the title compound as a white powder. The reaction yield (HPLC) was 52.1%, and the diastereomer formation ratio (HPLC) was β / α = 92.3 / 7.7.
¹ H NMR (400 MHz, CDCl ₃ ): δppm 0.03 (s, 3H), 0.04 (s, 3H), 0.84 (s, 9H), 1.09 (d, J = 6.3 Hz, 3H), 1.12 (d, J = 7.1 Hz, 3H), 2.54 (td, J = 7.1, 4.4 Hz, 1H), 2.75 (dd, J = 4.4, 2.2 Hz, 1H), 3.42 (s, 3H), 3.87 (dd, 4.6, 2.2 Hz , 1H), 4.12 (td, J = 6.3, 4.6 Hz, 1H), 5.94 (br. S, 1H), 7.25-7.28 (m, 2H), 7.47-7.50 (m, 3H).

Example 13
N-[(2R) -2-{(3S, 4R) -3-[(1R) -1- (tert-butyldimethylsilyloxy) ethyl] -2-oxoazetidin-4-yl} propionyl] -N- ( 2-Ethylphenyl) methanesulfonamide production
The reaction was conducted in the same manner as in Example 2 using 1.35 g (5.29 mmol) of N-propionyl-N- (2-ethylphenyl) methanesulfonamide, and 0.45 g (yield 21.2%) of the title compound was obtained as a white powder. Obtained. The reaction yield (HPLC) was 60.3%, and the diastereomer formation ratio (HPLC) was β / α = 94.8 / 5.2.
¹ H NMR (400 MHz, CDCl ₃ ): δppm 0.03, 0.03, 0.04, 0.04 (s, 6H), 0.84, 0.85 (s, 9H), 1.02, 1.03, 1.06, 1.08 (d, 6H), 1.29, 1.30 (t, 3H), 2.28, 2.50 (m, 1H), 2.56−2.82 (m, 3H), 3.46, 3.47 (s, 3H), 3.84, 3.93 (dd, 1H), 4.14 (m, 1H), 5.86 ,
5.94 (br.s, 1H), 7.10, 7.17 (d, 1H), 7.24-7.29 (m, 1H), 7.41-7.46 (m, 2H),
The data is observed as a rotamer at a ratio of about 1: 1.

  Reaction was carried out in the same manner as in Example 1 or Example 2 using the donor described in the following table as the compound of formula (IV). The reaction yield (HPLC) and diastereomer formation ratio (HPLC) of these reactions were as shown in Table 1.

Comparative Example 1 (when using TiCl ₄ using the same donor as in Example 4)
Under a nitrogen gas atmosphere, a solution of 303 mg (1.00 mmol) of N-propionyl-N-phenyl-p-toluenesulfonamide in methylene chloride (6 mL) was cooled to −5 ° C., 164 μL (1.50 mmol) of titanium tetrachloride, DIPEA 274 μL (1.58 mmol) and (3R, 4R) -4-acetoxy-3-[(R) -1- (tert-butyldimethylsilyloxy) ethyl] -2-azetidinone 287 mg (1.00 mmol) for 10 minutes Sequentially added at intervals and reacted at the same temperature. The diastereomer formation ratio (HPLC) after 2 hours in this reaction was β / α = 48.9 / 51.1.

Example 13
(4R) -4-{(3R, 4R) -3-[(1R) -1- (tert-butyldimethylsilyloxy) ethyl] -2-oxoazitidin-4-yl} -3-oxopentanoic acid 4-nitro Production of benzyl ester (compound 5)

N-[(2R) -2-{(3S, 4R) -3-[(1R) -1- (tert-butyldimethylsilyloxy) ethyl] -2-oxoazetidin-4-yl} under nitrogen gas atmosphere Propionyl] -N- (2-trifluoromethylphenyl) -p-toluenesulfonamide (Compound 4) 600 mg (1.00 mmol) in acetonitrile (9 mL) in imidazole 200 mg (3.00 mmol) and DMAP 12.5 mg (0.102 mmol) was added and reacted at 60 ° C. for 16 hours. The reaction mixture was cooled in an ice bath, magnesium chloride 95.5 mg (1.00 mmol), TEA 280 μL (2.01 mmol) and malonic acid mono-p-nitrobenzyl ester 407 mg (1.70 mmol) were sequentially added, and the temperature was raised to 50 ° C. And allowed to react for 2 hours. The reaction mixture was concentrated under reduced pressure, the concentrated solution was diluted with toluene, washed successively with 1M hydrochloric acid, 5% aqueous sodium hydrogen carbonate and 10% brine, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/1) to give the title compound (Compound 5) 453 mg (yield 94.6%) as a white solid.
The title compound (Compound 5) was a known substance, and the existing product and the HPLC retention time and ¹ H NMR spectrum were identical.

Example 14
(4R) -4-{(3R, 4R) -3-[(1R) -1- (tert-butyldimethylsilyloxy) ethyl] -2-oxoazitidin-4-yl} -2-diazo-3-oxopentane Production of acid = 4-nitrobenzyl ester (compound 6)

  N-[(2R) -2-{(3S, 4R) -3-[(1R) -1- (tert-butyldimethylsilyloxy) ethyl] -2-oxoazetidin-4-yl} under nitrogen gas atmosphere Propionyl] -N- (2-trifluoromethylphenyl) -p-toluenesulfonamide (Compound 4) To a solution of 3.0 g (5.00 mmol) in acetonitrile (9 mL) was added 1.0 g (15.0 mmol) of imidazole and 60 mg of DMAP (0.491 mmol) was added and reacted at 60 ° C. for 19 hours. The reaction mixture was cooled in an ice bath, magnesium chloride 0.48 g (5.01 mmol), TEA 1.4 mL (10.0 mmol) and malonic acid mono-p-nitrobenzyl ester 2.04 g (8.53 mmol) were sequentially added, and the temperature was raised to 50 ° C. And allowed to react for 2 hours. The reaction mixture was concentrated under reduced pressure, and the concentrated solution was diluted with methylene chloride (48 mL), and washed successively with 1M hydrochloric acid, water, 5% aqueous sodium bicarbonate, and 10% brine. To the resulting solution containing compound 5, dodecylbenzenesulfonyl azide 2.29 g (6.51 mmol) and TEA 210 μL (1.51 mmol) were added and reacted at room temperature for 17 hours. The reaction mixture was then cooled with 1M hydroxide under ice cooling. After washing sequentially with aqueous sodium solution, water, 0.5M hydrochloric acid and 10% brine, the organic layer was concentrated under reduced pressure. N-Heptane was added to the resulting concentrated solution to cause precipitation, followed by filtration, washing and drying to obtain 1.23 g (yield 48.3%) of the title compound (Compound 6) as a white powder.

The title compound (Compound 6) was a known substance, and the existing product and the HPLC retention time and ¹ H NMR spectrum were identical.

Example 15
(4R) -4-{(3R, 4R) -3-[(1R) -1- (tert-butyldimethylsilyloxy) ethyl] -2-oxoazitidin-4-yl} -2-diazo-3-oxopentane Production of acid = 4-nitrobenzyl ester (compound 6)
N-[(2R) -2-{(3S, 4R) -3-[(1R) -1- (tert-butyldimethylsilyloxy) ethyl] -2-oxoazetidin-4-yl} propionyl] -N- ( The title compound (Compound 6) 1.67 g (yield 65.9%) was obtained as a white powder by the same method as in Example 14 using 2-bromophenyl) -p-toluenesulfonamide 3.05 g (5.00 mmol). . The mother liquor when the precipitate was filtered contained 0.39 g of the title compound (Compound 6), and the total yield was 81.4%.

Example 16
(4R) -4-{(3R, 4R) -3-[(1R) -1- (tert-butyldimethylsilyloxy) ethyl] -2-oxoazitidin-4-yl} -2-diazo-3-oxopentane Production of acid = 4-nitrobenzyl ester (compound 6)
N-[(2R) -2-{(3S, 4R) -3-[(1R) -1- (tert-butyldimethylsilyloxy) ethyl] -2-oxoazetidin-4-yl} propionyl] -N-phenyl The title compound (Compound 6) (3.70 g, yield 73.4%) was obtained as a white powder in the same manner as in Example 14 using -p-toluenesulfonamide (5.32 g, 10.0 mmol).

Example 17
(4R) -4-{(3R, 4R) -3-[(1R) -1- (tert-butyldimethylsilyloxy) ethyl] -2-oxoazitidin-4-yl} -2-diazo-3-oxopentane Production of acid = 4-nitrobenzyl ester (compound 6)
N-[(2R) -2-{(3S, 4R) -3-[(1R) -1- (tert-butyldimethylsilyloxy) ethyl] -2-oxoazetidin-4-yl} propionyl] -N- ( The title compound (Compound 6) 1.77 g (yield 70.0%) was obtained as a white powder by the same method as in Example 14 using 3-methylphenyl) -p-toluenesulfonamide 2.73 g (5.01 mmol). .

Example 18
(4R) -4-{(3R, 4R) -3-[(1R) -1- (tert-butyldimethylsilyloxy) ethyl] -2-oxoazitidin-4-yl} -2-diazo-3-oxopentane Production of acid = 4-nitrobenzyl ester (compound 6)
N-[(2R) -2-{(3S, 4R) -3-[(1R) -1- (tert-butyldimethylsilyloxy) ethyl] -2-oxoazetidin-4-yl} propionyl] -N- ( 1.75 g (yield 69.5%) of the title compound (Compound 6) was obtained as a white powder by the same method as Example 14 using 2.80 g (5.00 mmol) of 4-methoxyphenyl) -p-toluenesulfonamide. . The mother liquor when the precipitate was filtered contained 0.24 g of the title compound (Compound 6), and the total yield was 79.1%.

Example 19
(4R) -4-{(3R, 4R) -3-[(1R) -1- (tert-butyldimethylsilyloxy) ethyl] -2-oxoazitidin-4-yl} -2-diazo-3-oxopentane Preparation of acid 4-nitrobenzyl ester (compound 6)
N-[(2R) -2-{(3S, 4R) -3-[(1R) -1- (tert-butyldimethylsilyloxy) ethyl] -2-oxoazetidin-4-yl} propionyl] -N-phenyl Using 2.28 g (5.01 mmol) of methanesulfonamide, 1.74 g (yield 68.8%) of the title compound (Compound 6) was obtained as a white powder in the same manner as in Example 14. The mother liquor when the precipitate was filtered contained 0.14 g of the title compound (Compound 6), and the total yield was 74.5%.

Example 20
(4R) -4-{(3R, 4R) -3-[(1R) -1-hydroxyethyl] -2-oxoazitidin-4-yl} -2-diazo-3-oxopentanoic acid 4-nitrobenzyl ester ( Production of compound 8)

N-[(2R) -2-{(3S, 4R) -3-[(1R) -1- (tert-butyldimethylsilyloxy) ethyl] -2-oxoazetidin-4-yl} under nitrogen gas atmosphere To a solution of propionyl] -N-phenyl-p-toluenesulfonamide (Compound 7) 5.32 g (10.0 mmol) in acetonitrile (80 mL) were added 2.05 g (30.1 mmol) of imidazole and 0.12 g (1.00 mmol) of DMAP, and 60 ° C. For 6 hours. The reaction mixture was cooled to −15 ° C., 0.95 g (10.0 mmol) of magnesium chloride, 2.8 mL (20.1 mmol) of TEA and 4.07 g (17.0 mmol) of malonic acid mono-p-nitrobenzyl ester were successively added, and the mixture was heated to 50 ° C. Warmed and allowed to react for 3 hours. The reaction mixture was concentrated under reduced pressure, and the concentrated solution was diluted with methylene chloride (96 mL), and washed successively with 1M hydrochloric acid, water, 5% aqueous sodium hydrogen carbonate and 10% brine. To the resulting solution containing Compound 5, 4.58 g (13.0 mmol) of dodecylbenzenesulfonyl azide and 420 μL (3.01 mmol) of TEA were added and reacted at room temperature for 19 hours. The reaction mixture was ice-cooled, and 1M water was added. After washing successively with aqueous sodium oxide solution, water, 0.5M hydrochloric acid and 10% brine, the organic layer was concentrated under reduced pressure. Methanol (32 mL), water (5.3 mL) and concentrated hydrochloric acid (2.7 mL) were added to the concentrated solution containing the obtained compound 6, and the mixture was reacted at room temperature for 4 hours. The reaction mixture was made weakly alkaline by adding 6.5% aqueous sodium hydrogen carbonate with stirring, and extracted with methylene chloride. The extract was washed with 10% brine, and the organic layer was concentrated under reduced pressure, followed by replacement with ethyl acetate. did. N-Heptane was added to the resulting concentrated solution to cause precipitation, followed by filtration, washing and drying to obtain 3.12 g (yield 82.1%) of the title compound (Compound 8) as a white powder.
The title compound (Compound 8) was a known substance, and the existing product and the HPLC retention time and ¹ H NMR spectrum were identical.

Production Example 1
(4R, 5R, 6S) -3-[(Diphenoxyphosphoryl) oxy] -6-[(1R) -1-hydroxyethyl] -4-methyl-7-oxo-1-diazabicyclo [3.2.0] hept- Preparation of 2-ene-2-carboxylic acid 4-nitrobenzyl ester (compound 10)

(4R) -4-{(3R, 4R) -3-[(1R) -1-hydroxyethyl] -2-oxoazitidin-4-yl} -2-diazo-3-oxopentanoic acid under nitrogen gas atmosphere To a solution of 4-nitrobenzyl ester (Compound 8) 5.00 g (12.8 mmol) in methylene chloride (50 mL) was added 29.9 mg (0.038 mmol) of rhodium caprylate and refluxed for 4 hours. The solution containing this compound 9 was cooled to −15 ° C., and a mixed solution of diphenylchlorophosphate 3.2 mL (15.4 mmol), DIPEA 3.0 mL (16.9 mmol) and DMAP 31.3 mg (0.256 mmol) in methylene chloride (10 mL) was added dropwise. And reacted at the same temperature for 50 minutes. The reaction mixture was washed successively with 0.3 M hydrochloric acid, 5% aqueous sodium hydrogen carbonate and 10% brine, and the organic layer was concentrated under reduced pressure. N-Heptane was added to the concentrated solution to form a precipitate, which was filtered, washed and dried to obtain 6.91 g (yield 98.1%) of the title compound (Compound 10) as a fine yellowish white powder.
The title compound (Compound 10) was a known substance, and the existing product and HPLC retention time and ¹ H NMR spectrum were identical.

Claims (6)

A method for producing a compound represented by the following formula (II):

(Where
R ¹ represents a hydrogen atom or a hydroxyl-protecting group,
R ² represents a hydrogen atom or an amino-protecting group,
R ⁵ represents a hydrogen atom or a nitrogen atom,
R ⁶ represents a hydrogen atom or a protecting group for a carboxyl group. )
(A) Compound represented by the following formula (I):

(Where
R ³ represents an aryl group which may have a substituent,
R ⁴ represents an aryl group which may have a substituent, an aralkyl group which may have a substituent, or an alkyl group which may have a substituent. )
Is reacted with imidazole followed by a malonic ester to obtain a compound of formula (II) in which R ⁵ is a hydrogen atom, and (b) a compound of formula (II) in which R ⁵ is a nitrogen atom is desired. In this case, the method further comprises diazotization of the compound obtained in step (a).   The method according to claim 1, wherein step (a) is performed in the presence of a magnesium compound and / or a base.   The method of claim 1, wherein the malonic acid ester is a malonic acid monoester.   The method of claim 1, further comprising washing the reactant obtained in step (b) with dilute aqueous alkali solution. The compound represented by the formula (I) is represented by the following formula (III):

(Where
R ¹ and R ² are as defined above,
R ⁷ represents an alkylcarbonyloxy group. )
In the presence of a zirconium reagent, the compound represented by the following formula (IV):

(Wherein R ³ and R ⁴ are as defined above)
The method of Claim 1 obtained by making it react with the compound represented by these.   6. The production method according to claim 5, wherein the general formula (IV) is reacted with a compound represented by the formula (III) after acting a zirconium compound and a base.