JP2002338572A - Method for producing carbapenems - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for industrially advantageously producing carbapenems. SOLUTION: This method for producing the compound (VIII) in the formula comprises reacting a compound (I) (R<1> is a protective group of OH) in the formula with (i) N,N'-carbonyldiimidazole, or (ii) a halogenated carbonic acid ester and an imidazole in the presence of a base, reacting the product with an inorganic salt and R<2> OOCCH2 COOH (R<2> is a protective group of COOH), further reacting the obtained product with an azide compound, reacting the resultant product with an acid, subjecting the obtained product to a ring-closing reaction, and reacting the ring-closed product with R<3> OH (R<3> is an acyl group) or a reactive derivative thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a process which is advantageous for industrial mass production of synthetic intermediates used for producing 1-methylcarbapenem antibiotics having excellent antibacterial activity.

[0002]

2. Description of the Related Art (1R, 5S, 6S) -p-Nitrobenzyl-2-diphenylphosphoryloxy-6 used for producing 1-methylcarbapenem useful as an antibacterial compound.
[(R) -1-hydroxyethyl] -1-methyl-carbapenem-3-carboxylate is disclosed in
Reaction formula described in 123182

[0003]

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[0004]

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Embedded image [Wherein R ¹ , R ² , R ³ and R ⁴ are hydrogen (R ¹ and R ² are not simultaneously hydrogen) or substituted and unsubstituted groups: Alkyl, alkenyl and alkynyl having: cycloalkyl having 3-6 carbon atoms in the cycloalkyl ring portion and cycloalkyl, cycloalkylalkyl and alkylcycloalkyl having 1-6 carbon atoms in the alkyl portion having 3-6 carbon atoms. Spirocycloalkyl: phenyl: aralkyl, alkenyl and alkynyl in which the aryl moiety is phenyl and the alkyl chain has 1-6 carbon atoms: heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl (one or more of which Substituents are amino, mono-, di- and trialkylamino, hydroxyl, alcohol Hexyl, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino,
Nitro, chloro, bromo, fluoro, iodo, cyano and carboxy): one or more heteroatoms of said heterocyclic moiety is 1-4 oxygen,
When selected from the group consisting of nitrogen or sulfur atoms: where the alkyl moiety of the substituents above has 1-6 carbon atoms: independently selected from the group consisting of: wherein ^Ro is a readily removable protecting group Wherein R ⁷ represents a pharmaceutically acceptable ester moiety or a carboxyl group-protecting group which is easily removed, and X represents a leaving group], and the method described in JP-A-64-25779. Reaction formula

[0005]

Embedded image[Wherein, R^ThreeIs a carboxy protecting group, R^FourIs a hydrogen atom or
Represents a lower alkyl group, R ^aRepresents an acyl group, and Z represents t-butyl.
Shows a dimethylsilyl group]
Had been manufactured.

[0006]

However, these conventional production methods are (1) low in yield, (2) it is necessary to separate and purify intermediates at each step, and the production process is complicated. 3) The time required for production (reaction time, etc.) is long,
Since it is extremely insufficient as a method for industrially mass-producing the target product, an improved production method has been demanded.

[0007]

Under these circumstances, the inventors of the present invention have made intensive studies and made efforts to obtain the following equation (1).

[0008]

Embedded image Wherein R ¹ represents a hydroxyl-protecting group or a salt thereof and (i) N, N'-carbonyldiimidazole, or (ii) halogen in the presence of a base. Reacting carbonized carbonate with imidazole,
The resulting expression

Embedded image Wherein the symbols are as defined above, an inorganic salt and a compound represented by the formula R ² OOCCH ₂ COOH (III)
R ² represents a carboxyl-protecting group] and a compound represented by the formula

Embedded image [The symbols in the formula are as defined above] and (i) an azide compound are reacted to obtain a compound represented by the following formula:

[0009]

Embedded image [The symbols in the formula are as defined above] and an acid, or (ii) reacting with an acid;
The resulting expression

Embedded image [The symbols in the formula are as defined above] and an azide compound are reacted with each other to obtain a compound represented by the following formula:

Embedded image [The symbols in the formula are as defined above.]

[0010]

Embedded image When the compound represented by the formula [wherein the symbols are as defined above] is reacted with an acid represented by the formula R ³ OH [wherein R ³ represents an acyl group] or a reactive derivative thereof. , Unexpectedly the desired expression

Embedded image The compound represented by the formula [wherein the symbols have the same meanings as described above] can be obtained by (1) high yield, (2) consistent production process without isolating the intermediate, and (3) production ( Reaction) time is short,
(4) It is a production method which is produced under suppression of by-product formation and is extremely industrially advantageous.

(A) A compound (I) is obtained from the compound (I) by using a halogenated hydrocarbon as a solvent in each reaction.
The reaction to obtain V) is performed while removing carbon dioxide gas.
N-Hexane, n-pentane, petroleum ether, toluene, xylene or isopropyl ether is added to the reaction mixture of compound (IV) and diazo compound to separate compound (V). (D) Compound (V) and acid Is carried out in a mixed solvent of dichloromethane, chloroform, acetonitrile or acetone and a lower alcohol, tetrahydrofuran or dioxane. (E) The reaction of the compound (IV) with an acid is performed with dichloromethane, chloroform, acetonitrile or acetone and a lower alcohol, tetrahydrofuran Alternatively, if the reaction is carried out in a mixed solvent with dioxane, or (and) (f) dichloromethane is used as the halogenated hydrocarbon described in (a), the industrial mass production of the compound (VIII) can be performed more advantageously. And completed the present invention based on this.

In the above formula, R¹Represents a hydroxyl-protecting group,
Such protecting groups include, for example, peptide chemistry, β-la
It is possible to use those used in the field of
For example, formyl, acetyl, chloroacetyl, di
Chloroacetyl, trichloroacetyl, trifluoroa
Cetyl, propionyl, butyryl, 4-toluoyl, 4
-Anisoyl, 4-nitrobenzoyl, 2-nitroben
Halogen such as zoyl group (for example, chlorine, bromine, fluorine, etc.)
Or C 1-3 optionally substituted with nitro or the like_1-7
Acyl groups such as benzyl, 4-methoxybenzyl, 2
-Nitrobenzyl, 4-nitrobenzyl, diphenylmethyl
C such as tyl and triphenylmethyl groups_1-4Alkoxy (example
For example, methoxy, ethoxy, etc.) or nitro, etc.
Optionally substituted C_7-19Aralkyl groups such as meth
Xoxycarbonyl, ethoxycarbonyl, t-butoxyca
Rubonyl, 2,2,2-trichloroethoxycarbonyl,
C such as 2-trimethylsilylethoxycarbonyl group_1-4
Alkoxy (eg, methoxy, ethoxy, etc.), halogen
(Eg, chlorine, bromine, etc.) or tri-C_1-4Alkylsi
1 to 3 substituents such as ril (for example, trimethylsilyl etc.)
C that may be_{1- 6}An alkyloxy-carbonyl group,
For example, benzyloxycarbonyl, 4-methoxybenzyl
Leoxycarbonyl, 3,4-dimethoxybenzyloxy
Cicarbonyl, 2-nitrobenzyloxycarbonyl,
C such as 4-nitrobenzyloxycarbonyl group_1-4Al
Coxy (eg methoxy, ethoxy, etc.) or nitro group
And the like; C_7-19Aralkyloxy
A carbonyl group, for example vinyloxycarbonyl, ant
C such as luoxycarbonyl group_2-6Alkenyloxy-ca
Carbonyl group such as methoxymethyl, t-butoxime
Chill, 2-methoxyethoxymethyl, 2,2,2-tric
Halogen such as loroethoxymethyl group (eg chlorine, odor
C which may be substituted with_1-4Alkoki
1 to 3 positions (e.g., methoxy, ethoxy, etc.)
A substituted methyl group such as 1-ethoxyethyl, 1-methyl
Tyl-1-methoxyethyl, 2,2,2-trichloroethyl
C such as_{1- Four}Alkoxy (eg methoxy, ethoxy)
Etc.) or halogen (eg, chlorine, bromine, fluorine, etc.)
An ethyl group substituted by 1 to 3 such as trimethyl
Silyl, triethylsilyl, dimethylisopropylsilyl
, T-butyldimethylsilyl, triisopropylsilyl
Tri-C such as_1-4Alkylsilyl groups such as diphe
Dimethylsilyl and diphenylethylsilyl groups
Phenyl-C_1-4Alkylsilyl groups are used and are preferred
Kuha C_7-19Aralkyloxycarbonyl group (benzylo
Xycarbonyl group), C_2-6Alkenyloxycarbo
Nyl group (vinyloxycarbonyl group etc.), tri-C_1-4
Alkylsilyl groups (such as trimethylsilyl groups)
More preferably tri-C_1-4Alkylsilyl group etc.
Preferably, a t-butyldimethylsilyl group or the like is used.
You.

R^TwoRepresents a carboxyl-protecting group.
Protecting groups such as in the step of removing hydroxyl protecting groups
Therefore, a group that is harder to leave than a protecting group for a hydroxyl group is used.
For example, methyl, ethyl, n-propyl, isopropyl
Pill, n-, iso-, sec-, tert-butyl, n-hexyl
C such as_1-8Alkyl group, bromo-t-butyl, tri
Halogen such as chloroethyl (eg, chlorine, bromine, fluorine)
Substituted with 1 to 3 carbon atoms_1-6Alkyl
Group, benzyl, p-nitrobenzyl, o-nitrobenzyl
, P-methoxybenzyl group, pt-butylbenzyl
Nitro such as C_{1- Four}Alkoxy groups (eg methoxy, d
Toxi) or C_1-4Alkyl groups (eg, methyl, d
Chill, n- or iso-propyl, n-, iso-, s
ec- or tert-butyl) or the like.
C that may be_7-14Aralkyl group, acetoxymethyl
, Propionyloxymethyl, n-, iso-, butyric
Ruoxymethyl, valeryloxymethyl, pivaloylo
Xymethyl, 1- (or 2-) acetoxyethyl, 1
-(Or 2- or 3-) acetoxypropyl, 1-
(Or 2- or 3- or 4-) acetoxybuty
1,1- (or 2-) propionyloxyethyl, 1
-(Or 2- or 3-) propionyloxypropyl
1,1- (or 2-) butyryloxyethyl, 1-
(Or 2-) isobutyryloxyethyl, 1- (also
Is 2-) pivaloyloxyethyl, 1- (or 2-)
Hexanoyloxyethyl, isobutyryloxymethyl
, 2-ethylbutyryloxymethyl, 3,3-dimethyl
Rubutyryloxymethyl, 1- (or 2-) pentano
C such as iloxyethyl_1-4Alkanoyloxy-C_1-4
An alkyl group such as a 2-mesylethyl group;_1-4Al
Cansulfonyl-C_1-4Alkyl groups such as methoxyca
Rubonyloxymethyl, ethoxycarbonyloxymethyl
, Propoxycarbonyloxymethyl, tertiary butoxy
Cicarbonyloxymethyl, 1- (or 2-) methoxy
Cicarbonyloxyethyl, 1- (or 2-) ethoxy
Cycarbonyloxyethyl, 1- (or 2-) isoprop
C such as ropoxycarbonyloxyethyl_1-4Alkoxy
Carbonyloxy-C_1-4Alkyl group, t-butyldim
Tri-C such as tylsilyl and trimethylsilyl_1-4Alkyl
C such as silyl group, allyl and methallyl_2-6Alkenyl
Group, methoxymethyl, ethoxymethyl, propoxymeth
C such as tyl and isopropoxymethyl_1-4Alkoxy-meth
C such as a tyl group and (2-methylthio) -ethyl_1-4Archi
Lucio C_1-4Alkyl group, 3-methyl-2-butenyl
Group, 5-indanyl group, 3-phthalidyl group and the like are used.
And preferably, for example, nitro, C_1-4With an alkyl group, etc.
C which may be substituted by 1 or 2_7-14Aralkyl group
And more preferably a p-nitrobenzyl group and the like.
Used.

R ³ represents an acyl group, and such an acyl group is a group obtained by removing an OH group from an acid. In a broad sense, it also includes an acyl group derived from an organic sulfonic acid or an organic phosphoric acid, such as (i) a C _1-4 alkanoyl group such as acetyl, propionyl, and butyryl group, (ii) methanesulfonyl, trifluoromethane. 1 with a halogen such as a sulfonyl group (eg, chlorine, fluorine, etc.)
To 3 optionally substituted C _1-4 alkylsulfonyl group, (iii) benzenesulfonyl, p- nitrobenzenesulfonyl, p- bromobenzenesulfonyl, toluenesulfonyl, nitro, such as 2,4,6-triisopropyl benzenesulfonyl group Group, halogen (eg, bromine, chlorine, fluorine, iodine, etc.), C _1-4 alkyl group (eg,
An arylsulfonyl group optionally substituted by 1 to 3 with methyl, ethyl, propyl, isopropyl and the like, (iv) a diphenylphosphoryl group and the like are used, and preferably, for example, a diphenylphosphoryl group and the like are used.

In the method of the present invention, first, compound (I)
Or a salt thereof and (i) N, N'-carbonyldiimidazo
Or (ii) halogen in the presence of a base
Reaction between imidated carbonate and imidazole
(II) is obtained. As the base used in this step
Is, for example, trimethylamine, triethylamine, N,
N-diisopropylethylamine, tributylamine,
Trioctylamine, triallylamine, dimethylben
Dilamine, tetramethyl-1,3-diaminopropa
, N-methylmorpholine, N-methylpyrrolidine, N
-Methylpiperidine, N, N-dimethylaniline, 1,8
-Diazabicyclo [5,4,0] undec-7-ene (D
BU), 1,5-diazabicyclo [4,3,0] nona-5
Tertiary aliphatic amines such as -ene (DBN), pyridine,
4-dimethyl-aminopyridine, picoline, lutidine,
Aromatic amines such as quinoline and isoquinoline are used.
Preferably, for example, triethylamine, N, N-di
C such as isopropylethylamine_{1 -Four}1 in alkyl group
Cis-substituted tertiary aliphatic amine, pyridine, 4-
Di-C such as dimethylaminopyridine_1-4Alkylamino group
Pyridine and the like which may be substituted with
Tri-C such as ethylamine_1-4Alkylamine etc. are used
It is. Halogenated carbonates include chlorocarbonate
Chill, ethyl chlorocarbonate, propyl chlorocarbonate, bromo
Methyl carbonate, ethyl bromocarbonate, propyl bromocarbonate, etc.
Halogenated carbonic acid C_1-4Alkyl ester, chlorocarbonic acid
Halogenated carbonates such as phenyl and phenyl bromocarbonate
Nyl ester or the like is used, and preferably chlorocarbonate is used.
Is used. As a reaction solvent, for example, benzene,
Hydrocarbon solvents such as toluene, xylene and cyclohexane
Medium, tetrahydrofuran, dioxane, 1,2-dimethoate
Ether solvents such as xyethane, methylene chloride, chloro
Form, carbon tetrachloride, trichloroethylene, 1,2-di
Halogenated hydrocarbon solvents such as chloroethane, dimethyl
Highly aprotic solvents such as formamide and acetonitrile
A reaction solvent such as a solvent is used.
Setonitrile, tetrahydrofuran and the like are preferred. Further
Is industrially soluble in water, considering the separation and purification procedure after the reaction.
Most difficult is methylene chloride.

In the reaction (ii), the compound (I)
The base, the halogenated carbonate and the imidazole may be reacted simultaneously, but it is preferable to mix the base and the halogenated carbonate, react with the compound (I), and then react with the imidazole. As the salt of compound (I), for example, in the production of cephem antibiotics,
Commonly used salts are used, for example, alkali metals (eg, lithium, potassium, sodium, etc.), alkaline earth metals (eg, calcium, magnesium, etc.), and ammoniums (eg, C _1-4 such as triethylammonium, diisopropylethylammonium, etc.). Such as ammonium substituted with 1 to 3 alkyl groups, etc.)
Preferably, a salt with an alkali metal such as potassium or sodium is used.

In this reaction, the ratio (molar ratio) of compound (I) or a salt thereof to N, N'-carbonyldiimidazole is from 1: 1 to 3, preferably from 1: 1 to 1.5. The use ratio (weight ratio) of the compound (I) and the solvent is
It is 1: 50-1000, preferably 1: 100-500. The use ratio (molar ratio) of compound (I) and base is
The ratio is 1: 1 to 5, preferably 1: 1 to 2. The usage ratio (molar ratio) of the compound (I) and the halogenated carbonate is 1: 1 to 5, preferably 1: 1 to 2. The use ratio (molar ratio) of compound (I) and imidazole is
The ratio is 1: 1 to 5, preferably 1: 1 to 2. The reaction time is 0.5 to 20 hours, preferably 1 to 5 hours. The reaction temperature is -70 to 20C, preferably -40 to 0C. Since this reaction is adversely affected by moisture, it is preferably carried out in an atmosphere of an inert gas such as nitrogen gas or argon gas so as not to absorb moisture in the air. The compound (II) obtained in this reaction can be used for the next reaction after separation and purification according to a conventional method, but it is advantageous to use the reaction mixture as it is for the next reaction. Compound (I) or a salt thereof used as a starting material in this reaction can be obtained, for example, in the journal of the Society of Organic Chemistry, Vol. 47, p. 606, published in 1989 or 49.
Volume, p. 104, published in 1991, or the like or a method analogous thereto.

Next, the compound (II) obtained by the above reaction
Is reacted with an inorganic salt and a compound (III) to give a compound (IV)
Get. As the inorganic salt used in this step,
For example, alkali earth metal halides such as magnesium chloride, magnesium bromide, and magnesium iodide are used, and preferably, magnesium chloride and the like are used. Examples of the reaction solvent include hydrocarbon solvents such as benzene, toluene, xylene and cyclohexane, ether solvents such as tetrahydrofuran, dioxane and 1,2-dimethoxyethane, methylene chloride, chloroform, carbon tetrachloride, trichloroethylene and 1,2. Reaction solvents such as halogenated hydrocarbon solvents such as dichloroethane and highly aprotic solvents such as dimethylformamide and acetonitrile are used, and methylene chloride, acetonitrile, tetrahydrofuran and the like are particularly preferable. Further, considering the separation and purification operation after the reaction, methylene chloride which is hardly soluble in water is most preferable industrially.

This reaction is preferably carried out in the presence of a base. Examples of such a base include trimethylamine, triethylamine, N, N-diisopropylethylamine, tributylamine, trioctylamine, triallylamine, dimethylbenzylamine and tetramethylamine. Methyl-1,3-diaminopropane, N-methylmorpholine,
N-methylpyrrolidine, N-methylpiperidine, N, N
-Dimethylaniline, 1,8-diazabicyclo [5,4,
0] undec-7-ene (DBU), 3,5-diazabicyclo [4,3,0] non-5-ene (DBN)
Aromatic amines such as lower aliphatic amines, pyridine, 4-dimethyl-aminopyridine, picoline, lutidine, quinoline, isoquinoline and the like are used, preferably, for example, C _1-4 alkyl such as triethylamine, N, N-diisopropylethylamine and the like. Tertiary aliphatic amines which are substituted with 1 to 3 groups, pyridines which may be substituted with a diC _1-4 alkylamino group such as pyridine and 4-dimethylaminopyridine, etc .; _1-4
An alkylamine or the like is used. The reaction of the compound (II), the inorganic salt and the compound (III) may be carried out simultaneously or in any order, but the inorganic salt is added to the compound (II), and then the compound (III) is added. Preferably, the reaction is carried out. The base is preferably added simultaneously with the inorganic salt or after adding the inorganic salt and before adding the compound (III).
This reaction is preferably carried out in an atmosphere of an inert gas such as nitrogen gas or argon gas. It is more preferable to carry out while removing the gas.

The use ratio (molar ratio) of the compound (II) to the inorganic salt in this reaction is 1: 1 to 5, preferably 1: 1 to 5.
2. Use ratio of compound (II) and solvent (weight ratio)
Is 1:50 to 1000, preferably 1: 100 to 500
It is. The use ratio (molar ratio) of compound (II) to compound (III) is 1: 1 to 5, preferably 1: 1 to 3. The use ratio (molar ratio) of compound (II) and base is
The ratio is 1: 1 to 5, preferably 1: 1 to 3. The reaction time is 0.5 to 20 hours, preferably 1 to 5 hours. The reaction temperature is 15 to 100 ° C, preferably 30 to 60 ° C. The compound (IV) obtained in this reaction can be used for the next reaction after separation and purification according to a conventional method, but it is convenient to use the reaction mixture as it is for the next reaction. When the reaction solvent is insoluble in water, an appropriate amount of the reaction mixture (the use ratio of the reaction mixture to water (volume ratio) is 1: 0.1 to 1: 1).
0, preferably 1: 0.5-5), and then separated into an aqueous layer and a solvent layer containing the target compound (IV),
Water-soluble impurities can also be removed.

Conventionally, compound (IV) is compound (II) and (R
² OOCCH ₂ COO) ₂ Mg [wherein R ² represents a carboxyl-protecting group and Mg represents magnesium], and is obtained by reacting with a magnesium malonate compound represented by the following formula: Was not enough. Therefore, the present inventors have studied various methods for obtaining the compound (IV). As a result, the one-pot reaction of reacting the compound (II) with the inorganic salt and the compound (III) in the same system unexpectedly improved the yield. Was found to be effective. That is, compound (II)
In a solution containing, an inorganic salt is added, and then the compound (III)
Is excellent in terms of yield. In this one-pot reaction, the mixing order of the compound (II), the inorganic salt, the base and the compound (III) is not strictly limited, but it is preferable to carry out in the order described above.

The one-pot reaction using this compound (II) is a carbon-enrichment reaction, and the moisture in the air has an adverse effect, so that the conventional method does not absorb moisture under an inert gas such as nitrogen gas or argon gas. It is performed under the atmosphere.
However, under such conditions, the yield of this carbon increase reaction is not constant, and sometimes the yield may extremely decrease. Accordingly, the present inventors have studied various methods for improving the yield of compound (IV) and found that carbon dioxide gas generated by passing an inert gas such as nitrogen gas or argon gas was removed to the outside of the reaction system. Then, it was unexpectedly found that the reaction can be completed more quickly at a lower temperature and a higher yield can be obtained. When the carbon-rich reaction is carried out using a low-boiling solvent such as dichloromethane, the reaction can be completed in a relatively short time.

Next, the compound (IV) obtained by the above reaction
And azide compound to give compound (V). In this step, the reaction solvent used includes hydrocarbon solvents such as benzene, toluene, xylene and cyclohexane, ether solvents such as tetrahydrofuran, dioxane and 1,2-dimethoxyethane, methylene chloride, chloroform and carbon tetrachloride. , Trichlorethylene, 1,2
Reaction solvents such as halogenated hydrocarbon solvents such as dichloroethane and the like and highly aprotic solvents such as dimethylformamide and acetonitrile are used, and methylene chloride, acetonitrile and tetrahydrofuran are particularly preferable.
Further, considering the separation and purification operation after the reaction, methylene chloride which is hardly soluble in water is most preferable industrially. As the azide compound, sulfonyl azides such as toluenesulfonyl azide, dodecylbenzenesulfonyl azide, p-carboxybenzenesulfonyl azide, and methanesulfonyl azide can be used. Less dangerous dodecylbenzenesulfonyl azide and the like are preferred.

This reaction is preferably carried out in the presence of a base, such as triethylamine, diethylamine, C, such as N, N-diisopropylethylamine.
1 _1-4 alkyl group to 3-substituted amine, pyridine, 4-di C _1-4 good pyridine optionally substituted with alkyl amino such as diethylamino pyridine or the like is used,
Preferably, triethylamine, N, N-diisopropylethylamine and the like are used. The base is preferably added after mixing the compound (IV) with the azide compound. The ratio (molar ratio) of the compound (IV) to the azide compound in this reaction is from 1: 1 to 5, preferably from 1: 1 to 2. The use ratio (weight ratio) of the compound (IV) and the solvent is 1:
It is 1 to 100, preferably 1: 2 to 50. The use ratio (molar ratio) of the compound (IV) to the base is 1: 0.1 to
2, preferably 1: 0.2-1. Reaction time is 0.5
２４24 hours, preferably 1-10 hours. The reaction temperature is -20 to 100C, preferably 0 to 50C.
Since this reaction is adversely affected by moisture, it is preferably carried out in an atmosphere of an inert gas such as nitrogen gas or argon gas so as not to absorb moisture in the air. Usually, the diazotization reaction completed solution contains equimolar amounts of the diazo compound (V) and the sulfonamide, and the diazo compound (V)
Although silica gel chromatography and the like have been used to isolate and purify only the product, it is not satisfactory in terms of purity and yield. The present inventors have conducted intensive studies on this point, and as a result, after appropriately concentrating the solvent after completion of the reaction, adding a solvent such as n-hexane, n-pentane, petroleum ether, toluene, xylene, or isopropyl ether, the diazo compound Only (V) was found to be selectively obtained as high purity crystals. In particular, it is most preferable to add n-hexane after the reaction using dichloromethane as a solvent at the time of the reaction as a selective production method of the compound (V).
The step of reacting the compound (IV ') with the diazo compound to obtain the compound (VI) can be carried out in the same manner as in the reaction of the compound (IV) with the diazo compound.

Next, the compound (V) obtained by diazotizing the compound (IV) is reacted with an acid to remove R ¹ which is a protecting group for a hydroxyl group, to obtain a compound (VI). In the hydrolysis reaction, examples of the acid used include inorganic acids such as hydrohalic acid (hydrochloric acid, hydrofluoric acid and the like), sulfuric acid, phosphoric acid and the like, and organic acids such as acetic acid and the like. Hydrohalic acid such as hydrochloric acid is used.

This hydrolysis reaction is usually carried out using water or a mixed solvent of water and a lower alcohol solvent such as methanol or ethanol, or a mixed solvent of ether solvents such as tetrahydrofuran or dioxane, and preferably methanol-water- This is performed using a mixed solvent of hydrochloric acid or the like. The use ratio (molar ratio) of the compound (V) and the acid in this reaction is as follows:
1: 0.5 to 10, preferably 1: 1 to 5. The use ratio (volume ratio) of the acid and the solvent is 1: 0.5 to 1000,
Preferably it is 1: 5-100. For example, in the above-mentioned three-component system of methanol-water-hydrochloric acid, the ratio (volume ratio) of hydrochloric acid and the mixed solvent is 1: 1 to 100, preferably 1: 5 to 50. The ratio (volume ratio) of methanol to water is 1: 0.01 to 100, preferably 1: 0.0.
05 to 1: 1. The concentration of hydrochloric acid used is 35% (w /
w). The reaction time is 0.5 to 20 hours, preferably 1 to 10 hours. The reaction temperature is 0-100 ° C, preferably 0-40 ° C. In addition, compound (V) is
0% (w / v) (25 ° C.), preferably 30 to 50%
It is preferable to add a solvent that dissolves (w / v) (25 ° C.) or more. Examples of suitable solvents to be added here include halogenated hydrocarbon solvents such as methylene chloride and chloroform, lower ketone solvents such as acetone and methyl ethyl ketone, and highly aprotic solvents such as dimethylformamide and acetonitrile. And a halogenated hydrocarbon solvent such as methylene chloride is preferably used. The ratio (weight ratio) of the compound (V) to the solvent in which the compound (V) is dissolved is 1: 0.1 to 30, preferably 1:
1 to 10. The ratio (by volume) of the acid or a mixed solvent thereof to the solvent dissolving the compound (V) is 1: 0.01.
-10, preferably 1: 0.1-1. Specifically, for example, in a four-component system of methylene chloride-methanol-water-hydrochloric acid, the mixing ratio (volume ratio) of the compound (V) that does not dissolve and separate into two layers is 1: 0.01 to 0: 1. 0.8, more preferably 1: 0.05 to 0.5. In general, this reaction requires a long time for the reaction because the compound (V) is hardly dissolved in an acid or a solvent, and generates a decomposition product that inhibits the reaction in a later step. These decomposition products increase the amount of expensive noble metal catalyst used particularly in the ring closure reaction step. Therefore, the present inventors have studied various methods for producing compound (VI) which suppresses generation of unnecessary decomposed products. Was found to proceed.

The resulting (VI) can be isolated according to a conventional method, but it is advantageous to use the reaction mixture as a raw material in the next step. In particular, in the case of a reaction using methylene chloride, if water is added to the reaction-terminated liquid, there is an advantage that the liquid is separated into two layers and the compound (VI) is selectively extracted into the methylene chloride layer. According to this method, the methylene chloride solution can be subjected to the next ring closing reaction without a complicated operation such as concentration and drying, and silica gel chromatography. If necessary, high-purity (VI) crystals can also be obtained by adding a solvent such as n-hexane or isopropyl ether after appropriately concentrating and evaporating methylene chloride after the reaction. The step of reacting the compound (IV) with an acid to obtain the compound (IV ') can be carried out in the same manner as in the reaction of the compound (V) with the acid.

Next, compound (VII) can be obtained by subjecting compound (VI) obtained by the above reaction to a ring closure reaction. This reaction is, for example, benzene, toluene, hydrocarbon solvents such as cyclohexane, ester solvents such as ethyl acetate, methylene chloride, chloroform,
Leave it in a halogenated hydrocarbon solvent such as 1,2-dichloroethane, an ether solvent such as tetrahydrofuran or dioxane, preferably a hydrocarbon solvent such as toluene, or a halogenated hydrocarbon solvent such as methylene chloride. However, in order to promote the reaction, usually, rhodium acetate, rhodium octanoate, palladium acetate, bis (acetylacetonate) Cu (II), Cu
It is carried out in the presence of a metal catalyst such as SO ₄ , Cu or the like, preferably rhodium acetate, rhodium octanoate, palladium acetate or the like. The use ratio (molar ratio) of the compound (VI) to the catalyst is 0.05 to 5 mol%, preferably 0.1 to 3 mol%.
It is. The reaction time is generally 0.5 to 20 hours, preferably 1 to 5 hours. The reaction temperature is usually 20 to 10
0 ° C, preferably 30 to 80 ° C. Since this reaction is adversely affected by moisture, it is preferably carried out in an atmosphere of an inert gas such as nitrogen gas or argon gas so as not to absorb moisture in the air. (VII) obtained by this reaction can be subjected to the next acylation reaction as it is in the reaction mixture. However, if necessary, the reaction solvent can be appropriately concentrated and distilled off to obtain a solid.

The compound (VI) obtained by the above reaction
I) is reacted with an acid represented by the formula R ³ OH, wherein the symbols have the same meanings as described above, or a reactive derivative thereof to obtain the desired compound (VIII). In this step, the formula R ³ O
Examples of the acid represented by H or a reactive derivative thereof include acetyl chloride, propionyl chloride, toluenesulfonyl chloride, p-bromobenzenesulfonyl chloride, diphenylchlorophosphate, acetic anhydride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, p-Toluenesulfonic anhydride, p-nitrobenzenesulfonic anhydride, 2,4,6-triisopropylbenzenesulfonic anhydride and the like are used, and diphenylphosphoric acid chloride is particularly preferred.

Examples of the reaction solvent include hydrocarbon solvents such as benzene, toluene, xylene, chlorobenzene and cyclohexane, tetrahydrofuran, dioxane, and the like.
Uses ether solvents such as 1,2-dimethoxyethane, halogenated hydrocarbon solvents such as methylene chloride, chloroform, carbon tetrachloride, trichloroethylene and 1,2-dichloroethane, and highly aprotic solvents such as dimethylformamide and acetonitrile. Preferably, for example, tetrahydrofuran, methylene chloride, acetonitrile and the like are used. This reaction is preferably performed in the presence of a base. Examples of such a base include trimethylamine, triethylamine, N, N-diisopropylethylamine,
Tributylamine, trioctylamine, triallylamine, dimethylbenzylamine, tetramethyl-1,3
-Diaminopropane, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, N, N-dimethylaniline, 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU), 1.5 Tertiary aliphatic amines such as -diazabicyclo [4,3,0] non-5-ene (DBN), pyridine, 4-dimethyl-aminopyridine,
Aromatic amines such as picoline, lutidine, quinoline and isoquinoline are used, and preferably, for example, N, N-
A C _1-4 alkyl group such as diisopropylethylamine
_Examples thereof include tertiary aliphatic amines substituted with 3 to 3, pyridines substituted with a di C _1-4 alkylamino group such as 4-dimethylaminopyridine, and the like. The use ratio (molar ratio) of the compound (VII) to the acid or its reactive derivative is 1: 1 to 1
5, preferably 1 to 1 to 3. The usage ratio (weight ratio) of the compound (VII) to the solvent is 1: 5 to 300, preferably 1:10 to 100. The use ratio (molar ratio) of the compound (VII) to the base is 1: 0.5 to 5, preferably 1: 5.
1 to 3. The reaction time is 10 minutes to 10 hours, preferably 0.5 to 3 hours. The reaction temperature is -70 to 40
° C, preferably -40 to 10 ° C. Since this reaction is adversely affected by moisture, it is preferably carried out in an atmosphere of an inert gas such as nitrogen gas or argon gas so as not to absorb moisture in the air. The compound (VII) thus obtained can be isolated according to a conventional method, for example, by concentration, chromatography and the like. In particular, when dichloromethane is used as the reaction solvent, water is added after the reaction is completed, and if liquid separation is performed, the product (VIII) is extracted into the dichloromethane layer, and the organic layer is appropriately concentrated and n-
By adding a solvent such as hexane, a crystal of the desired product (VIII) can be obtained. According to this method, crystals of the compound (VIII) having good purity can be obtained without going through complicated operations such as concentration and drying, and silica gel chromatography.

Thus, the desired compound (VI
II) is obtained. The compound (VIII) is suitably used, for example, as a synthetic intermediate for producing 1-methylcarbapenem antibiotics. For example, JP-A-64-25779 discloses a compound (VIII) which is a useful antibacterial agent.

Embedded image Or anionic charge]] (1R, 5S,
A method for obtaining a 6S) -2-substituted thio-6-[(1R) -1-hydroxyethyl] -1-methyl-carbapenem-3-carboxylic acid derivative or a pharmaceutically acceptable salt thereof is described. . The obtained carbapenem compounds and pharmacologically acceptable salts thereof are extremely useful as antibacterial agents for treating, preventing, etc. bacterial infections caused by various pathogens. It can be safely administered to mammals, including humans, in the form of a pharmaceutical composition containing an antibacterial effective amount. The dosage may vary over a wide range depending on the age, weight, and condition of the patient to be treated, the form of administration of the drug, the diagnosis of a physician, etc., but generally ranges from about 200 to about A dose in the range of 3,000 mg is standard and can usually be administered orally, parenterally or topically once or several times a day. Further, for example, JP-A-60-104088 or JP-A-60-2
Carbapenem compounds which are useful antibacterial agents described in 33076 etc. are also compounds (VIII) obtained by the production method of the present invention.
Can be suitably used by using as a synthetic intermediate. 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.

[0032]

BEST MODE FOR CARRYING OUT THE INVENTION The NMR spectra of the following examples were measured with a Gemini 200 (200 MHz) type spectrometer using tetramethylsilane as an internal standard, and all δ values are shown in ppm. The symbols in the examples have the following meanings. s: singlet d: doublet t: triplet ABq: AB-type quartet dd: double daflet m: multiplet br .: wide J: coupling constant sh: shoulder +> si: t-butyldimethylsilyl group -PNB benzyl -PNB benzyl Group%: Indicates weight% unless otherwise specified

[0033]

EXAMPLES Example 1 (1) (3S, 4S) -3-[(R) -1- (t-butyldimethylsilyloxy) ethyl] -4-[(R)-
Preparation of 1-imidazolyl-ethyl] -azetidin-2-one

Embedded image Under an atmosphere of N ₂ , 28.65 g (0.264 mol) of ethyl chlorocarbonate was added to 1182 ml of anhydrous methylene chloride at -20 ° C.
And cooled. 26.71 g of triethylamine at -20 ° C
(0.264 mol) was added dropwise over 10 minutes.
Stirred for 0 minutes. (3S, 4S) -3-[(R) -1-
(T-butyldimethylsilyloxy) ethyl] -4-
[(R) -1-carboxyethyl] -azetidine-2-
After adding 72.35 g (0.240 mol) of ON and reacting at -20 ° C for 30 minutes, 22.87 g of imidazole (0.20 mol) was added.
336 mol) and reacted at -20 ° C for 30 minutes to obtain a reaction solution containing the title compound.

(2) (3S, 4R) -3-[(R)-
1- (t-butyldimethylsilyloxy) ethyl] -4
-[(R) -1-methyl-3-p-nitrobenzyloxycarbonyl-2-oxo-propyl] -azetidine-
Production of 2-one

Embedded image 22.85 g (0.240 mol) of anhydrous magnesium chloride was added to the reaction solution obtained in the above (1), and
After stirring for 48 minutes, 48.57 g of triethylamine (0.4
(80 mol) was added dropwise over 10 minutes and stirred at -20 ° C for 10 minutes. Mono-p-nitrobenzylmalonate 97.5
9 g (0.408 mol) was added, and the mixture was heated under reflux to remove N ₂ to 0.6.
The reaction was carried out for 2 hours with aeration at 1 / min. The methylene chloride was concentrated and distilled off under reduced pressure, and 762 ml of 1N HCl was added to wash and separate. The organic layer was washed with 318 ml of water, 3% NaHCO ₃
The mixture was washed and separated sequentially with 720 ml of water and 300 ml of 5% NaCl water. The methylene chloride was concentrated and distilled off under reduced pressure to obtain a methylene chloride solution containing 110.31 g of the title compound. (Yield: 96.0%) The title compound was obtained by concentrating the above solution to dryness and subjecting it to silica gel column chromatography (CHCl ₃ : acetone = 7:
It was separated and purified according to 1) to obtain white crystals. NMR (δ, CDCl ₃ ): 0.06 (6H, s), 0.87 (9H, s), 1.1
6 (3H, d), 1.20 (3H, d), 3.63 (2H, s), 5.27 (2H, s), 5.92 (1
H, bs), 7.56,8.24 (4H, aromatic protons)

(3) (3S, 4R) -3-[(R)-
1- (t-butyldimethylsilyloxy) ethyl] -4
-[(R) -1-methyl-3-diazo-3-p-nitrobenzyloxycarbonyl-2-oxo-propyl]-
Production of azetidin-2-one

Embedded image 105.33 g of dodecylbenzenesulfonyl azide (0.1
300 mol) in 200 ml of anhydrous methylene chloride
(3S, 4R) -3- obtained in the above (2) under ₂ atmospheres
[(R) -1- (t-butyldimethylsilyloxy) ethyl] -4-[(R) -1-methyl-3-p-nitrobenzyloxycarbonyl-2-oxo-propyl] -azetidin-2-one (0.231 mol) in 620 ml of a methylene chloride solution. At 25 ° C., 6.97 g (0.069 mol) of triethylamine was added dropwise over 10 minutes and reacted for 2 hours. The methylene chloride is concentrated and distilled off under reduced pressure.
1740 ml of hexane was added dropwise to cause crystallization. The crystallized solution was concentrated under reduced pressure, collected by filtration and dried to give the title compound 101.
102.50 g of 99.2% pure white crystals containing 68 g were obtained. (Yield 87.4%)

(4) (3S, 4R) -3-[(R)-
1-hydroxyethyl] -4-[(R) -1-methyl-
Preparation of 3-diazo-3-p-nitrobenzyloxycarbonyl-2-oxo-propyl] -azetidin-2-one

Embedded image (3S, 4R) -3-[(R) -1- obtained in the above (3).
(T-butyldimethylsilyloxy) ethyl] -4-
75.69 g (0.150 mol) of [(R) -1-methyl-3-diazo-3-p-nitrobenzyloxycarbonyl-2-oxo-propyl] -azetidin-2-one was dissolved in 227 ml of methylene chloride. , 454 ml of methanol and 76 ml of water. At 25 ° C, 45.57 g of concentrated hydrochloric acid was added to 10
Minutes, and reacted for 3 hours. 6.5% NaHCO
₃ solution 757ml were added dropwise over 10 minutes, methylene chloride 5
30 ml was added, and the mixture was extracted and separated. Organic layer 15% NaC
The mixture was washed and separated sequentially with 530 ml of an aqueous solution and 265 ml of water. The methylene chloride was concentrated and distilled off under reduced pressure to give the title compound 5
A methylene chloride solution containing 7.38 g was obtained. (Yield 98.
0%) IR (cm ^-1 , CHCl ₃ ): 2150, 1750, 1720, 1650 NMR (δ, CDCl ₃ ): 1.23 (3H, d);
30 (3H, d), 2.92 (1H, m), 3.5
0 to 4.30 (3H, m), 5.38 (2H, s),
6.40 (1H, bs), 7.57 and 8.30 (4
H, aromaticprotons)

(5) (1R, 3R, 5R, 6S) -6
-[(R) -1-hydroxyethyl] -2-oxo-1
-Methyl-3-p-nitrobenzyloxycarbonyl-
Production of carbapenem

Embedded image (3S, 4R) -3- obtained in the above (4) under N ₂ atmosphere
[(R) -1-hydroxyethyl] -4-[(R) -1
-Methyl-3-diazo-3-p-nitrobenzyloxycarbonyl-2-oxo-propyl] -azetidine-2
610 ml of a methylene chloride solution of -one (0.147 mol)
, Add 757 ml of anhydrous methylene chloride and heat to 40 ° C.
Refluxed. Rhodium octanoate 340 mg (0.00
(3 mol) was suspended in 57 ml of anhydrous methylene chloride, added dropwise at 40 ° C. under reflux, and reacted for 4 hours. The reaction solution was -15
Cooled to 14 ° C. and 1430 ml of a methylene chloride solution of the title compound.
I got IR (cm ^-1 , CHCl ₃ ): 2950, 2925, 1760, 1730 NMR (δ, CDCl ₃ ): 1.22 (3H, d, J =
8.0Hz), 1.37 (3H, d, J = 6.0H)
z), 2.40 (1H, bs), 2.83 (1H,
q, J = 8.0 Hz), 3.28 (1H, dd),
4.00 to 4.50 (2H, m), 4.75 (1H,
s), 5.28 and 5.39 (2H, ABq, J = 12 Hz), 7.58 and 8.24 (4H, aromatic protons)

(6) (1R, 5R, 6S) -p-nitrobenzyl-2-diphenylphosphoryloxy-6-
Production of [(R) -1-hydroxyethyl] -1-methyl-carbapenem-3-carboxylate

Embedded image In 1430 ml of the solution obtained in the above (5), diphenylchlorophosphate 43.44 was added at −15 ° C. under N ₂ atmosphere.
g (0.162 mol) was added. 25.08 g (0.194 mol) of diisopropylethylamine and 360 mg (0.003 mol) of 4-dimethylaminopyridine were dissolved in 287 ml of anhydrous methylene chloride, and the mixture was added dropwise at -15 ° C for 30 minutes and reacted for 30 minutes. 0.3NH while keeping the temperature below 10 ° C
The mixture was washed and separated successively with 574 ml of Cl and 574 ml of a 5% aqueous NaHCO ₃ solution. The methylene chloride was concentrated and distilled off under reduced pressure, and 402 ml of n-hexane was dropped to crystallize. The crystals were collected by filtration and dried to give 75.16 g of the title compound. (86.0% yield) NMR (δ, CDCl ₃ ): 1.24 (3H, d), 1.
34 (3H, d), 3.30 (1H, q), 3.5
2 (1H, m), 4.10 to 4.40 (2H, m),
5.20 and 5.35 (2H, q), 7.29 (10H, m), 7.58 and
8.18 (4H, d)

Example 2 (3S, 4R) -3-[(R) -1-hydroxyethyl] -4-[(R) -1-methyl-3-diazo-3-p
Preparation of -nitrobenzyloxycarbonyl-2-oxo-propyl] -azetidin-2-one 600 ml of the solution obtained in the same manner as in Example 1, (4),
After concentration under reduced pressure, 1135 ml of n-hexane was added dropwise to crystallize. The crystallization solution was concentrated under reduced pressure, filtered and dried to obtain 53.68 g of 96.0% pure white crystals containing 51.53 g of the title compound. (88.0% yield)

Example 3 Preparation of (1R, 3R, 5R, 6S) -6-[(R) -1-hydroxyethyl] -2-oxo-1-methyl-3-p-nitrobenzylcarbonyl-carbapenem 1450 ml of a methylene chloride solution of the title compound obtained in the same manner as in 1 (5) was concentrated under reduced pressure to a purity of 93.0.
80.34 g of the title compound are obtained. (Yield 85.5%)

Reference Example 1 (3S, 4R) -3-[(R) -1- (t-butyldimethylsilyloxy) ethyl] -4-[(R) -1-methyl-3-p-nitrobenzyloxy Preparation of carbonyl-2-oxo-propyl] -azetidin-2-one Anhydrous magnesium chloride, triethylamine and mono-
Instead of adding p-nitrobenzyl malonate, magnesium [mono-p-nitrobenzyl malonate] (0.4
(08 mol) in the same manner as in Example 1, (2) except that the title compound was obtained in a yield of 80%.

Reference Example 2 (3S, 4R) -3-[(R) -1- (t-butyldimethylsilyloxy) ethyl] -4-[(R) -1-methyl-3-p-nitrobenzyloxy Production of carbonyl-2-oxo-propyl] -azetidin-2-one The reaction was carried out under N ₂ atmosphere in the same manner as in (2) of Example 1 except that N ₂ gas was not passed, and the yield was 83%. Afforded the title compound.

[0043]

Industrial Applicability The production method of the present invention provides a method for industrially usefully producing an intermediate which can be suitably used for producing a carbapenem compound useful as a therapeutic agent for bacterial infection.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Shuichi Nishimura 27-7 Murozumi-Omachi, Hikari-shi, Yamaguchi (72) Inventor Toshimitsu Hatano 2-12-19, Tomiokacho, Hakodate-shi, Hokkaido (72) Inventor Toshio Kumagai Saitama 3-15-37, Kosenba-cho, Kawagoe-shi (72) Inventor, Hisashi Shimizu 5-17-2, Nobeki, Niiza-shi, Saitama 407, Fukui Term No. 407 F-term (Reference) 4C050 KA08 KB05 KB13 KB16 KC03 4H039 CA60 CA62 CD30 CE20 4H050 AA02 BA51 BB11 BB12 BB21 BB25 BB61 BC10 BC19 BC31 BC35 WA15 WA23

Claims (12)

[Claims] (1) Formula (1) [Wherein R ¹ represents a hydroxyl-protecting group], an inorganic salt, and a compound represented by the formula R ² OOCCH ₂ COOH (III) wherein R ² represents a carboxyl-protecting group. To give a compound of the formula [The symbols in the formula are as defined above] and an azide compound are reacted with each other to obtain a compound represented by the following formula: [The symbols in the formula are as defined above] and an acid are reacted with the compound represented by the following formula: [The symbols in the formula are as defined above], and the compound represented by the formula is obtained by subjecting the compound to a ring closure reaction. Reacting a compound represented by the formula [wherein the symbols are as defined above] with an acid represented by the formula R ³ OH [wherein R ³ represents an acyl group] or a reactive derivative thereof. A formula characterized by the following: [The symbols in the formula are as defined above]. 2. A compound represented by the formula: [Wherein R ¹ represents a hydroxyl-protecting group], an inorganic salt, and a compound represented by the formula R ² OOCCH ₂ COOH (III) wherein R ² represents a carboxyl-protecting group. And reacting the compound with a compound represented by the following formula: [The symbols in the formula are as defined above] and an acid are reacted with the compound represented by the formula: [The symbols in the formula are as defined above] and an azide compound are reacted to obtain a compound represented by the following formula: [The symbols in the formula are as defined above], and the compound represented by the formula is obtained by subjecting the compound to a ring closure reaction. Reacting a compound represented by the formula [wherein the symbols are as defined above] with an acid represented by the formula R ³ OH [wherein R ³ represents an acyl group] or a reactive derivative thereof. A formula characterized by the following: [The symbols in the formula are as defined above]. 3. A compound of the formula Wherein R ¹ represents a hydroxyl-protecting group or a salt thereof and (i) N, N'-carbonyldiimidazole, or (ii) a halogen in the presence of a base. Reaction of imidated carbonate with imidazole gives the formula [The symbols in the formula are as defined above], an inorganic salt, and a compound represented by the formula: R ² OOCCH ₂ COOH (III) [wherein, R ² represents a carboxyl-protecting group] A compound of the formula [The symbols in the formula are as defined above] and an azide compound are reacted with each other to obtain a compound represented by the following formula: [The symbols in the formula are as defined above] and an acid are reacted with the compound represented by the formula: Wherein the compound represented by the formula is subjected to a ring closure reaction. [The symbols in the formula are as defined above]. 4. A compound of the formula Wherein R ¹ represents a hydroxyl-protecting group or a salt thereof and (i) N, N'-carbonyldiimidazole, or (ii) a halogen in the presence of a base. Reaction of imidated carbonate with imidazole gives the formula [The symbols in the formula are as defined above], an inorganic salt, and a compound represented by the formula: R ² OOCCH ₂ COOH (III) [wherein, R ² represents a carboxyl-protecting group] Reacting with a compound to obtain a compound of the formula [The symbols in the formula are as defined above] and an acid are reacted with the compound represented by the following formula: [The symbols in the formula are as defined above] and an azide compound are reacted with each other to obtain a compound represented by the following formula: Wherein the compound represented by the formula is subjected to a ring closure reaction. [The symbols in the formula are as defined above]. 5. The process according to claim 1, wherein a halogenated hydrocarbon is used as a solvent in each reaction. 6. The method according to claim 1, wherein each reaction for obtaining the compound (IV) from the compound (I) or the reaction for obtaining the compound (IV) from the compound (II) is carried out while removing carbon dioxide gas. Manufacturing method. 7. The compound (V) is separated by adding n-hexane, n-pentane, petroleum ether, toluene, xylene or isopropyl ether to a reaction mixture of the compound (IV) and the diazo compound. The method according to claim 1. 8. The method according to claim 1, wherein the reaction between the compound (V) and the acid is carried out in a mixed solvent of dichloromethane, chloroform, acetonitrile or acetone and a lower alcohol, tetrahydrofuran or dioxane.
The manufacturing method described. 9. The method according to claim 2, wherein the reaction between the compound (IV) and the acid is carried out in a mixed solvent of dichloromethane, chloroform, acetonitrile or acetone and a lower alcohol, tetrahydrofuran or dioxane.
The manufacturing method described. 10. The method according to claim 5, wherein the halogenated hydrocarbon is dichloromethane. 11. The method according to claim 1, wherein the inorganic salt is an alkaline earth metal halide. 12. The method according to claim 11, wherein the alkaline earth metal halide is a magnesium halide.