JP3479720B2 - Method for producing carbapenems - Google Patents

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a production method advantageous for industrial mass production of synthetic intermediates used for producing 1-methylcarbapenem antibiotics and the like having excellent antibacterial activity.

[0002]

2. Description of the Related Art (1R, 5S, 6S) -p-Nitrobenzyl-2-diphenylphosphoryloxy-6- used for the production of 1-methylcarbapenem which is useful as an antibacterial compound.
[(R) -1-Hydroxyethyl] -1-methyl-carbapenem-3-carboxylate has been previously disclosed in JP-A-57-
Reaction formula described in 123182

[0003]

[Chemical 15]

[Chemical 16]

[Chemical 17]

[Chemical 18]

[0004]

[Chemical 19]

[Chemical 20]

[Chemical 21] [Wherein R ¹ , R ² , R ³ and R ⁴ are hydrogen (R ¹ and R ² are not hydrogen at the same time) or a substituted or unsubstituted group of the following: 1-10 carbon atoms Having alkyl, alkenyl and alkynyl: cycloalkyl having 3-6 carbon atoms in the cycloalkyl ring portion, and having 3-6 carbon atoms in the alkyl portion, cycloalkylalkyl and alkylcycloalkyl: having 3-6 carbon atoms Spirocycloalkyl: phenyl: aryl moieties are phenyl and the alkyl chain has 1-6 carbon atoms aralkyl, alkenyl and alkalkynyl: heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl (to which one or more The substituents on are amino, mono-, di- and trialkylamino, hydroxyl, alcohol Hexyl, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino,
Selected from the group consisting of nitro, chloro, bromo, fluoro, iodo, cyano and carboxy): wherein the heteroatom or heteroatoms of the above heterocycle moiety is 1-4 oxygen;
When selected from the group consisting of nitrogen or sulfur atoms: when the alkyl portion of the above-mentioned substituents has 1-6 carbon atoms: independently selected from the group consisting of: R ^o is a readily removable protecting group. R ⁷ is a pharmaceutically acceptable ester moiety or a protecting group for a carboxyl group which is easily removed, and X is a leaving group], and JP-A-64-25779. Reaction formula

[0005]

[Chemical formula 22] [Wherein R ³ represents a carboxy protecting group, R ⁴ represents a hydrogen atom or a lower alkyl group, R ^a represents an acyl group, and Z represents a t-butyldimethylsilyl group]. It was

[0006]

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

[0007]

[Means for Solving the Problems] Under these circumstances, the inventors of the present invention have made diligent studies and as a result,

[0008]

[Chemical formula 23] [Wherein, R ¹ represents a hydroxyl-protecting group] or a salt thereof is reacted with (i) N, N′-carbonyldiimidazole, or (ii) halogen in the presence of a base. Reacting a carboxylic ester with imidazole,
Expression obtained

[Chemical formula 24] [Wherein the symbols have the same meanings as defined above], an inorganic salt, and the formula R ² OOCCH ₂ COOH (III) [wherein R ² represents a protective group for a carboxyl group]. Formula obtained by reacting with a compound

[Chemical 25] A compound obtained by reacting a compound represented by [the symbols in the formula have the same meanings as described above] and (i) an azide compound.

[0009]

[Chemical formula 26] [Wherein the symbols in the formula have the same meanings as described above], the compound is reacted with an acid, or (ii) the acid is reacted,
Expression obtained

[Chemical 27] A compound obtained by reacting a compound represented by [the symbols in the formula have the same meanings as described above] with an azide compound.

[Chemical 28] A compound obtained by subjecting a compound represented by [the symbols in the formula have the same meanings as defined above] to a ring closure reaction

[0010]

[Chemical 29] When a compound represented by the formula [wherein the symbols have the same meaning 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 target expression

[Chemical 30] The compound represented by [the symbols in the formula have the same meanings as described above], (1) in high yield, (2) in a consistent production process without isolation of the intermediate, (3) production ( Reaction) time is short,
(4) It is a very industrially advantageous production method that is produced while suppressing the production of by-products, and further, in this production method,

(A) Halogen as a solvent in each reaction
(B) Compound (I) from compound (I)
V) is carried out while removing carbon dioxide gas, (C)
The reaction mixture of the compound (IV) and the diazo compound was added with n-hex
Sun, n-pentane, petroleum ether, toluene, xyle
Compound or isopropyl ether was added to add compound (V)
Separate the reaction between (d) compound (V) and acid with dichloro
Methane, chloroform, acetonitrile or acetone
And lower alcohol, tetrahydrofuran or dioxa
Of (e) compound (IV) and an acid in a mixed solvent with
Reaction is dichloromethane, chloroform, acetonitrile
Or acetone and lower alcohol, tetrahydrofuran
Or in a mixed solvent with dioxane, or (and
And (f) As the halogenated hydrocarbon described in (a) above
With dichloromethane, a large amount of compound (VIII)
We found that production could be made even more advantageous, and based on this,
Based on this, the present invention has been completed.

In the above formula, R ¹ represents a hydroxyl-protecting group,
As such a protecting group, for example, those used in the field of peptide chemistry, β-lactam compounds and the like can be used, and for example, formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, propionyl, butyryl, 4-toluoyl, 4
-Halogen such as anisoyl, 4-nitrobenzoyl and 2-nitrobenzoyl groups (eg chlorine, bromine, fluorine etc.)
Or C _1-7 optionally substituted with 1 to 3 nitro or the like
Acyl groups such as benzyl, 4-methoxybenzyl, 2
A C _7-19 aralkyl group which may be substituted with 1 to 3 C _1-4 alkoxy (eg, methoxy, ethoxy, etc.) such as -nitrobenzyl, 4-nitrobenzyl, diphenylmethyl, triphenylmethyl group or nitro; , For example, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl,
C _1-4 such as 2-trimethylsilylethoxycarbonyl group
C _1-6 alkyloxy- which may be substituted by 1 to 3 alkoxy (eg methoxy, ethoxy etc.), halogen (eg chlorine, bromine etc.) or tri-C _1-4 alkylsilyl (eg trimethylsilyl etc.) and the like. Carbonyl group,
For example, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl,
A C _7-19 aralkyloxy-carbonyl group, which may be substituted with a C _1-4 alkoxy (eg, methoxy, ethoxy, etc.) such as a _4- nitrobenzyloxycarbonyl group, or a nitro group, such as vinyloxycarbonyl, allyloxy. C _2-6 alkenyloxy-carbonyl group such as carbonyl group, halogen such as methoxymethyl, t-butoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl group (eg chlorine, bromine, fluorine) Etc.), a methyl group having 1 to 3 substituents such as C _1-4 alkoxy (eg, methoxy, ethoxy, etc.) which may be substituted with, for example, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 2, C _1-4 alkoxy (e.g. methoxy, ethoxy, etc.), such as 2,2-trichloroethyl group or a halogen (e.g., Iodine, bromine, fluorine, etc.)
A tri-C _1-4 alkylsilyl group such as trimethylsilyl, triethylsilyl, dimethylisopropylsilyl, t-butyldimethylsilyl, triisopropylsilyl group, etc., such as diphenylmethylsilyl, diphenylethyl. A diphenyl-C _1-4 alkylsilyl group such as silyl group is used, and preferably C _7-19 aralkyloxycarbonyl group (benzyloxycarbonyl group etc.), C _2-6 alkenyloxycarbonyl group (vinyloxycarbonyl group etc.) ), Tri-C _1-4
Alkylsilyl group (trimethylsilyl group etc.)
More preferably, a tri-C _1-4 alkylsilyl group or the like is used, and particularly preferably, a t-butyldimethylsilyl group or the like is used.

R ² represents a protecting group for a carboxyl group, and as such a protecting group, a group that is less likely to be removed than a protecting group for a hydroxyl group is used in the step of removing a protecting group for a hydroxyl group. C _1-8 alkyl groups such as ethyl, n-propyl, isopropyl, n-, iso-, sec-, tert-butyl and n-hexyl groups, halogens such as bromo-t-butyl and trichloroethyl (eg, chlorine, Bromine, fluorine, iodine, etc.) 1 to 3 substituted C _1-6 alkyl group, benzyl, p-nitrobenzyl, o-nitrobenzyl, p-methoxybenzyl group, nitro such as pt-butylbenzyl, C _1-4 alkoxy group (eg methoxy, ethoxy etc.) or C _1-4 alkyl group (eg methyl, ethyl, n- or iso-propyl, n-, iso-, s
ec- or tert-butyl etc.) or the like, which may be mono- or disubstituted with C _7-14 aralkyl group, acetoxymethyl, propionyloxymethyl, n-, iso-, butyryloxymethyl, valeryloxymethyl, pi Valoyloxymethyl, 1- (or 2-) acetoxyethyl, 1
-(Or 2- or 3-) acetoxypropyl, 1-
(Or 2- or 3- or 4-) acetoxybutyl, 1- (or 2-) propionyloxyethyl, 1
-(Or 2- or 3-) propionyloxypropyl, 1- (or 2-) butyryloxyethyl, 1-
(Or 2-) isobutyryloxyethyl, 1- (or 2-) pivaloyloxyethyl, 1- (or 2-)
C _1-4 alkanoyloxy-C such as hexanoyloxyethyl, isobutyryloxymethyl, 2-ethylbutyryloxymethyl, 3,3-dimethylbutyryloxymethyl, 1- (or 2-) pentanoyloxyethyl _1-4
Alkyl group, such as 2 Meshiruechiru C _1-4 alkanesulfonyl -C _1-4 alkyl group such as, for example, methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyl-oxymethyl, tert-butoxycarbonyl-oxy, 1- A C _1-4 alkoxycarbonyloxy-C _1-4 alkyl group such as (or 2-) methoxycarbonyloxyethyl, 1- (or 2-) ethoxycarbonyloxyethyl, 1- (or 2-) isopropoxycarbonyloxyethyl , t- butyl-dimethyl-silyl, tri C _1-4 alkylsilyl group such as trimethylsilyl, allyl, meta-C _2-6 alkenyl groups allyl and the like, methoxymethyl, ethoxymethyl, propoxy methyl, C _1-4, such as isopropoxymethyl Alkoxy-methyl group, (2-methylthio)- A C _1-4 alkylthio C _1-4 alkyl group such as ethyl, a 3-methyl-2-butenyl group, a 5-indanyl group, a 3-phthalidyl group and the like are used, and preferably, for example, nitro and a C _1-4 alkyl group. And the like, a C _7-14 aralkyl group which may be mono- or disubstituted with etc., and more preferably a p-nitrobenzyl group, etc. are used.

R ³ represents an acyl group, and such an acyl group is a group obtained by removing an OH group from an acid and is not limited to the rest of atomic groups obtained by removing OH from a carboxyl group of an organic carboxylic acid. In a broad sense, it also includes an acyl group derived from an organic sulfonic acid or an organic phosphoric acid. For example, (i) a C _1-4 alkanoyl group such as acetyl, propionyl, butyryl group, (ii) methanesulfonyl, trifluoromethane. 1 for halogen such as sulfonyl group (eg chlorine, fluorine, etc.)
To optionally substituted C _1-4 alkylsulfonyl group, (iii) benzenesulfonyl, p-nitrobenzenesulfonyl, p-bromobenzenesulfonyl, toluenesulfonyl, nitro such as 2,4,6-triisopropylbenzenesulfonyl group Group, halogen (eg, bromine, chlorine, fluorine, iodine, etc.), C _1-4 alkyl group (eg,
An arylsulfonyl group which may be substituted 1 to 3 with (methyl, ethyl, propyl, isopropyl, etc.) and the like, (iv) a diphenylphosphoryl group and the like are used, and preferably a diphenylphosphoryl group and the like are used.

In the method of the present invention, first, the compound (I) is used.
Alternatively, compound (II) is obtained by reacting the salt thereof with (i) N, N'-carbonyldiimidazole or (ii) reacting the halogenated carbonate with imidazole in the presence of a base. Examples of the base used in this step 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 (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, and preferably tertiary aliphatic amines substituted with 1 to 3 C _1-4 alkyl groups such as triethylamine and N, N-diisopropylethylamine, pyridine, and 4 are used. −
Good pyridine optionally substituted by di-C _1-4 alkylamino group such as dimethylamino pyridine and, preferably tri C _1-4 alkyl amines such as triethylamine are used. Examples of the halogenated carbonic acid ester include halogenated carbonic acid C _1-4 alkyl ester such as methyl chlorocarbonate, ethyl chlorocarbonate, propyl carbonate, methyl bromocarbonate, ethyl bromocarbonate and propyl bromocarbonate, phenyl chlorocarbonate, phenyl bromocarbonate and the like. The halogenated carbonic acid phenyl ester and the like are used, and ethyl chlorocarbonate is preferably used. As the reaction solvent, for example, benzene,
Hydrocarbon solvents such as toluene, xylene and cyclohexane, ether solvents such as tetrahydrofuran, dioxane and 1,2-dimethoxyethane, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, trichloroethylene and 1,2-dichloroethane. A reaction solvent such as a system solvent and a highly aprotic solvent such as dimethylformamide and acetonitrile is used, and methylene chloride, acetonitrile and tetrahydrofuran are particularly preferable. Further, considering the separation and purification operation after the reaction, methylene chloride, which is industrially insoluble in water, is most preferable.

In the reaction (ii), the compound (I),
The base, the halogen carbonate and the imidazole may be reacted at the same time, but it is preferable that the base and the halogenated carbonate are mixed and then reacted with the compound (I) and then with the imidazole. Examples of the salt of compound (I) include, for example, in the production of cephem antibiotics,
Commonly used salts are used, for example, C _1-4 such as alkali metal (eg lithium, potassium, sodium etc.), alkaline earth metal (eg calcium, magnesium etc.), ammonium (eg triethylammonium, diisopropylethylammonium etc.). A salt with an alkyl group having 1 to 3 substituents such as ammonium),
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 its salt to N, N'-carbonyldiimidazole is 1: 1 to 3, preferably 1: 1 to 1.5. The ratio (weight ratio) of the compound (I) and the solvent is
It is 1:50 to 1000, preferably 1: 100 to 500. The usage ratio (molar ratio) of the compound (I) and the base is
It is 1: 1 to 5, preferably 1: 1 to 2. The use 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
It 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 20 ° C, preferably -40 to 0 ° C. Since this reaction is adversely affected by moisture, it is preferable to carry out this reaction in an inert gas atmosphere such as nitrogen gas or argon gas so as not to absorb moisture in the air. The compound (II) obtained by this reaction can be used for the next reaction after separation and purification according to a conventional method, but it is advantageous to use it as it is for the next reaction. The compound (I) or a salt thereof used as a starting material in this reaction is described in, for example, Journal of Organic Chemistry Vol. 47, page 606, published in 1989 or 49
Volume, p. 104, published in 1991, etc., or a method analogous thereto.

Next, the compound (II) obtained by the above reaction
To react compound (IV) with an inorganic salt and compound (III)
To get As the inorganic salt used in this step,
For example, halides of alkaline earth metals such as magnesium chloride, magnesium bromide and magnesium iodide are used, and magnesium chloride is preferably 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. A reaction solvent such as a halogenated hydrocarbon solvent such as dichloroethane or a highly aprotic solvent such as dimethylformamide or acetonitrile is used, and methylene chloride, acetonitrile or tetrahydrofuran is particularly preferable. Further, considering the separation and purification operation after the reaction, methylene chloride, which is industrially insoluble in water, is most preferable.

This reaction is preferably carried out in the presence of a base, and examples of such a base include trimethylamine, triethylamine, N, N-diisopropylethylamine, tributylamine, trioctylamine, triallylamine, dimethylbenzylamine and tetra. Methyl-1,3-diaminopropane, N-methylmorpholine,
N-methylpyrrolidine, N-methylpiperidine, N, N
-Dimethylaniline, 1,8-diazabicyclo [5,4,
Third] such as [0] undec-7-ene (DBU) and 1,5-diazabicyclo [4,3,0] non-5-ene (DBN)
Aromatic amines such as higher aliphatic amines, pyridine, 4-dimethyl-aminopyridine, picoline, lutidine, quinoline and isoquinoline are used, and preferably C _1-4 alkyl such as triethylamine and N, N-diisopropylethylamine. A tertiary aliphatic amine substituted with 1 to 3 groups, pyridine, pyridine optionally substituted with a di C _1-4 alkylamino group such as 4-dimethylaminopyridine, etc., preferably tri-C such as triethylamine. _1-4
An alkylamine or the like is used. The reaction of the compound (II) with the inorganic salt and the compound (III) may be carried out simultaneously or in any order. However, the inorganic salt is added to the compound (II), and then the compound (III) is added. It is preferable to react with each other. The base is preferably added at the same time as the inorganic salt or after the inorganic salt is added and before the compound (III) is added.
This reaction is preferably carried out in an atmosphere of an inert gas such as nitrogen gas or argon gas, and the carbon dioxide generated in this reaction can be generated by aeration of these inert gases rather than simply reacting in an atmosphere. It is more preferable to carry out while removing the gas.

In the reaction, the compound (II) and the inorganic salt are used in a ratio (molar ratio) of 1: 1 to 5, preferably 1: 1.
It is 2. Use ratio of compound (II) and solvent (weight ratio)
Is 1:50 to 1000, preferably 1: 100 to 500
Is. The use ratio (molar ratio) of the compound (II) and the compound (III) is 1: 1 to 5, preferably 1: 1 to 3. The ratio (molar ratio) of the compound (II) and the base is
It is 1: 1 to 5, preferably 1: 1 to 3. The reaction time is 0.5 to 20 hours, preferably 1 to 5 hours. reaction
The 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 it as it is for the next reaction. When the reaction solvent is insoluble in water, an appropriate amount of the reaction mixture (the ratio of the reaction mixture and water (volume ratio) is 1: 0.1 to 1) is used.
0, preferably 1: 0.5 to 5) in water, and then separated into a water layer and a solvent layer containing the target compound (IV),
It is also possible to remove water-soluble impurities.

Conventionally, the compound (IV) is the compound (II) and (R
² OOCCH ₂ COO) ₂ Mg [wherein R ² is a protecting group for a carboxyl group, and Mg is magnesium], and was obtained by reacting with a magnesium malonate compound. It wasn't enough. Therefore, as a result of various studies on the method for obtaining the compound (IV), the present inventors unexpectedly improved the yield in the one-pot reaction in which the compound (II), the inorganic salt and the compound (III) were reacted in the same system. Found to be effective. That is, compound (II)
Inorganic salt is added to the solution containing
The method of adding and reacting 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 preferably carried out in the above order.

The one-pot reaction using this compound (II) is a carbon-increasing reaction, and under the condition that moisture is not adversely affected by the conventional method, for example, an inert gas such as nitrogen gas or argon gas, is adversely affected. It is done in an atmosphere.
However, under such a condition, the yield of this carbon-boosting reaction is not constant, and sometimes the yield is extremely lowered. Therefore, as a result of various studies on the method for improving the yield of the compound (IV), the present inventors removed carbon dioxide gas generated by aeration of an inert gas such as nitrogen gas or argon gas to the outside of the reaction system. Then, unexpectedly, it was found that the reaction can be completed more rapidly at a lower temperature and a high yield can be obtained. It is also possible to complete the reaction in a relatively short time by carrying out this carbon-boosting reaction using a low boiling point solvent such as dichloromethane.

Next, the compound (IV) obtained by the above reaction
And azide compound are reacted to obtain compound (V). In this step, reaction solvents used include 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
A reaction solvent such as a halogenated hydrocarbon solvent such as dichloroethane or a highly aprotic solvent such as dimethylformamide or acetonitrile is used, and methylene chloride, acetonitrile or tetrahydrofuran is particularly preferable.
Further, considering the separation and purification operation after the reaction, methylene chloride, which is industrially insoluble in water, is most preferable. As the azide compound, sulfonyl azides such as toluene sulfonyl azide, dodecylbenzene sulfonyl azide, p-carboxybenzene sulfonyl azide, methane sulfonyl azide can be used. Dodecylbenzenesulfonyl azide and the like, which are less dangerous, are preferable.

This reaction is preferably carried out in the presence of a base, and examples of such a base include C such as triethylamine, diethylamine and N, N-diisopropylethylamine.
Amine which is 1 to 3 substituted with _1-4 alkyl group, pyridine, pyridine which may be substituted with di C _1-4 alkylamino such as 4-diethylaminopyridine and the like are used,
Preferably, triethylamine, N, N-diisopropylethylamine and the like are used. The base is preferably added after mixing the compound (IV) and the azide compound. The ratio (molar ratio) of the compound (IV) to the azide compound used in this reaction is 1: 1 to 5, preferably 1: 1 to 2. The ratio (weight ratio) of the compound (IV) and the solvent used is 1:
It is 1 to 100, preferably 1: 2 to 50. The use ratio (molar ratio) of the compound (IV) and the base is 1: 0.1 to
2, preferably 1: 0.2-1. Reaction time is 0.5
-24 hours, preferably 1-10 hours. The reaction temperature is -20 to 100 ° C, preferably 0 to 50 ° C.
Since this reaction is adversely affected by moisture, it is preferable to carry out this reaction in an inert gas atmosphere such as nitrogen gas or argon gas so as not to absorb moisture in the air. Usually, this diazotization reaction completed liquid contains equimolar amounts of diazo compound (V) and sulfonamide.
Silica gel chromatography and the like have been used to isolate and purify only that, but it is not satisfactory in terms of purity and yield. As a result of earnest studies on this point, the inventors of the present invention have found that the solvent is appropriately concentrated after completion of the reaction, and then a solvent such as n-hexane, n-pentane, petroleum ether, toluene, xylene, or isopropyl ether is added to the diazo compound. It was found that only (V) was selectively obtained as a high-purity crystal. In particular, it is most preferable as a selective production method of the compound (V) to use dichloromethane as a solvent during the reaction and add n-hexane after the reaction.
Further, the step of reacting the compound (IV ′) with a diazo compound to obtain the compound (VI) can also be carried out in the same manner as the reaction between the compound (IV) and the diazo compound.

Next, the compound (V) obtained by the diazotization of the compound (IV) is reacted with an acid to eliminate R ¹ which is a hydroxyl-protecting group to obtain a compound (VI). Examples of the acid used in this hydrolysis reaction include hydrohalic acid (hydrochloric acid, hydrofluoric acid, etc.), inorganic acids such as sulfuric acid and phosphoric acid, organic acids such as acetic acid, etc. 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 an ether solvent such as tetrahydrofuran or dioxane, and preferably methanol-water- It is carried out using a mixed solvent of hydrochloric acid or the like. The ratio (molar ratio) of the compound (V) and the acid used in this reaction is
It is 1: 0.5-10, preferably 1: 1-5. The use ratio (volume ratio) of the acid and the solvent is 1: 0.5 to 1000,
It is preferably 1: 5 to 100. For example, in the above-mentioned three-component system of methanol-water-hydrochloric acid, the ratio (volume ratio) of hydrochloric acid to the mixed solvent is 1: 1 to 100, preferably 1: 5 to 50. The ratio of methanol to water (volume ratio) is 1: 0.01 to 100, preferably 1: 0.
It is 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 to 100 ° C, preferably 0 to 40 ° C. Furthermore, compound (V) is added to 5 to 7
0% (w / v) (25 ° C), preferably 30-50%
It is preferable to add a solvent that dissolves at least (w / v) (25 ° C.). 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, or highly aprotic solvents such as dimethylformamide and acetonitrile. Is used, but 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 (volume ratio) of the acid or the mixed solvent thereof and the solvent in which the compound (V) is dissolved 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) in which the compound (V) is dissolved and the liquid is not separated into two layers is 1: 0.01 to 0. 0.8 is preferable, and more preferably 1: 0.05 to 0.5. Usually, in this reaction, since the compound (V) is difficult to dissolve in an acid or a solvent, the reaction requires a long time, and a decomposition product that inhibits the reaction is produced in a subsequent step. These decomposition products increase the amount of expensive noble metal catalyst used especially in the ring closure reaction step. Therefore, the present inventors have conducted various studies on the production method of the compound (VI) which suppresses the generation of unnecessary decomposition products, and as a result, if a solvent dissolving the compound (VI) is added to the reaction system, a homogeneous system under mild conditions is obtained. I found that the reaction proceeded in.

The obtained (VI) can be isolated according to a conventional method, but it is advantageous to use it as a reaction mixture as a raw material in the next step. In particular, in the case of a reaction using methylene chloride, there is an advantage that if water is added to the reaction completed liquid, 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 as it is can be subjected to the next ring-closing reaction without undergoing complicated operations such as concentration to dryness and silica gel chromatography. Further, if necessary, after the reaction, methylene chloride is appropriately concentrated and distilled off, and then a solvent such as n-hexane or isopropyl ether is added to obtain a highly pure (VI) crystal. Further, the step of reacting the compound (IV) with an acid to obtain the compound (IV ′) can also be carried out in the same manner as the reaction between the compound (V) and the acid.

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

Then, the compound (VI
I) is reacted with an acid represented by the formula R ³ OH [where the symbols have the same meanings as defined above] or a reactive derivative thereof to obtain the target 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 chloride is particularly preferable.

Examples of the reaction solvent include hydrocarbon solvents such as benzene, toluene, xylene, chlorobenzene and cyclohexane, tetrahydrofuran, dioxane,
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 non-polar protic solvents such as dimethylformamide and acetonitrile. Preferably, for example, tetrahydrofuran, methylene chloride, acetonitrile, etc. are used. This reaction is preferably carried out in the presence of a base, and 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-
1 with a C _1-4 alkyl group such as diisopropylethylamine
To tri-substituted tertiary aliphatic amine, pyridine substituted with a di-C _1-4 alkylamino group such as 4-dimethylaminopyridine, and the like are used. The ratio (molar ratio) of the compound (VII) to the acid or its reactive derivative is 1: 1 to
5, preferably 1: 1-3. The use ratio (weight ratio) of the compound (VII) and the solvent is 1: 5 to 300, preferably 1:10 to 100. The ratio (molar ratio) of the compound (VII) and the base used is 1: 0.5 to 5, preferably 1 :.
1-3. 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 preferable to carry out this reaction in an inert gas atmosphere 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 a reaction solvent, after the reaction is completed, water is added to carry out liquid separation to extract the product (VIII) in the dichloromethane layer, and the organic layer is appropriately concentrated and n-
Crystals of the desired product (VIII) can be obtained by adding a solvent such as hexane. According to this method, crystals of compound (VIII) with good purity can be obtained without complicated operations such as concentration to dryness and silica gel chromatography.

Thus, the target compound (VI
II) is obtained. The compound (VIII) is suitably used, for example, as a synthetic intermediate in the production of 1-methylcarbapenem antibiotics. For example, in JP-A-64-25779, a compound (VIII) is used to formulate a useful antibacterial agent.

[Chemical 31] Or represents an 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 compound and a pharmacologically acceptable salt thereof are extremely useful as an antibacterial agent for the treatment, prevention, etc. of bacterial infections caused by various pathogenic bacteria, and when using it as an antibacterial agent, It can be safely administered to mammals including humans in the form of a pharmaceutical composition containing an antibacterial effective amount. The dose can be varied over a wide range depending on the age, weight, symptoms of the patient to be treated, dosage form of the drug, diagnosis by a doctor, etc. A dose in the range of 3,000 mg is standard, and usually it can be administered orally, parenterally or topically in one or several divided doses per day. Further, for example, JP-A-60-104088 or JP-A-60-2
The carbapenem compound, which is a useful antibacterial agent described in 33076, is also the compound (VIII) obtained by the production method of the present invention.
Can be suitably produced 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]

EXAMPLES The NMR spectra of the following examples are Gemini using tetramethylsilane as an internal standard.
Measured with a 200 (200MHz) type spectrometer,
All δ values are given in ppm. The symbols in the examples have the following meanings. s: singlet d: doublet t: triplet ABq: AB type quartet dd: double doublet m: multiplet br .: wide J: coupling constant sh: shoulder +> si: t-butyldimethylsilyl group PNB: p-nitrobenzyl Base%: Indicates weight% unless otherwise specified

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

[Chemical 32] Under N ₂ atmosphere, 28.65 g (0.264 mol) of ethyl chlorocarbonate was added to 1182 ml of anhydrous methylene chloride at -20 ° C.
Cooled to. 26.71 g of triethylamine at -20 ° C
(0.264 mol) was added dropwise over 10 minutes, and then 1
Stir for 0 minutes. (3S, 4S) -3-[(R) -1-
(T-Butyldimethylsilyloxy) ethyl] -4-
[(R) -1-Carboxyethyl] -azetidine-2-
After 72.35 g (0.240 mol) of ON was added and reacted at -20 ° C for 30 minutes, 22.87 g of imidazole (0.20 mol) was added.
(336 mol) was added, and the mixture was 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-
2-on manufacturing

[Chemical 33] 22.85 g (0.240 mol) of anhydrous magnesium chloride was added to the reaction solution obtained in (1) above, and the mixture was stirred at -20 ° C for 10 minutes.
After stirring for a minute, 48.57 g of triethylamine (0.4
(80 mol) was added dropwise over 10 minutes, and the mixture was stirred at -20 ° C for 10 minutes. Mono-p-nitrobenzyl malonate 97.5
9 g (0.408 mol) was added, the mixture was heated to reflux and N ₂ was added to 0.6
The reaction was carried out for 2 hours while aerating at 1 / min. Methylene chloride was concentrated and distilled off under reduced pressure, and 762 ml of 1N HCl was added for washing and liquid separation. The organic layer is 318 ml of water, 3% NaHC
The mixture was washed successively with 720 ml of O ₃ water and 300 ml of 5% NaCl water and separated. 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 and drying the above solution, followed by silica gel column chromatography (CHCl ₃ : acetone = 7:
It was separated and purified by 1) to obtain white crystals. NMR (δ, CDCl ₃ ): 0.06 (6H, s), 0.87 (9H, s), 1.
16 (3H, d), 1.20 (3H, d), 3.63 (2H, s), 5.27 (2H, s), 5.92
(1H, 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

[Chemical 34] Dodecylbenzenesulfonyl azide 105.33 g (0.3
300 mol) was dissolved in 200 ml of anhydrous methylene chloride, and N was added.
(3S, 4R) -3-obtained in (2) above under ₂ atmospheres
[(R) -1- (t-Butyldimethylsilyloxy) ethyl] -4-[(R) -1-methyl-3-p-nitrobenzyloxycarbonyl-2-oxo-propyl] -azetidin-2-one (0.231 mol) was added to 620 ml of methylene chloride solution. At 25 ° C., 6.97 g (0.069 mol) of triethylamine was added dropwise over 10 minutes, and the mixture was reacted for 2 hours. The methylene chloride was concentrated and distilled off under reduced pressure.
-1740 ml of hexane was added dropwise to crystallize. The crystallized solution was concentrated under reduced pressure, filtered and dried to give the title compound 101.
102.50 g of 99.2% pure white crystals containing 68 g was 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

[Chemical 35] (3S, 4R) -3-[(R) -1- obtained in (3) above.
(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 were added. Concentrated hydrochloric acid 45.57g 10 at 25 ℃
The mixture was added dropwise for 1 minute and reacted for 3 hours. 6.5% NaHC
757 ml of an O ₃ aqueous solution was added dropwise over 10 minutes, 530 ml of methylene chloride was added, and the mixture was extracted and separated. 15% N organic layer
The mixture was washed and separated with 530 ml of aCl aqueous solution and 265 ml of water successively. Methylene chloride was 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), 1.30 (3H, d), 2.
92 (1H, m), 3.50 ~ 4.30 (3H, m), 5.38 (2H, s), 6.40 (1H, b
s), 7.57 and 8.30 (4H, aromatic protons)

(5) (1R, 3R, 5R, 6S) -6
-[(R) -1-hydroxyethyl] -2-oxo-1
-Methyl-3-p-nitrobenzyloxycarbonyl-
Carbapenem manufacturing

[Chemical 36] (3S, 4R) -3-obtained in (4) above under N ₂ atmosphere.
[(R) -1-Hydroxyethyl] -4-[(R) -1
-Methyl-3-diazo-3-p-nitrobenzyloxycarbonyl-2-oxo-propyl] -azetidine-2
610 ml of methylene chloride solution of -one (0.147 mol)
To this, 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 under reflux at 40 ° C., and then reacted for 4 hours. The reaction solution is -15
Cool to ℃, 1430 ml of methylene chloride solution of the title compound
Got IR (cm ^-1 , CHCl ₃ ): 2950, 2925, 1760, 1730 NMR (δ, CDCl ₃ ): 1.22 (3H, d, J = 8.0Hz), 1.37 (3
H, d, J = 6.0Hz), 2.40 (1H, bs), 2.83 (1H, q, J = 8.0Hz), 3.2
8 (1H, dd), 4.00 ~ 4.50 (2H, m), 4.75 (1H, s), 5.28 and 5.
39 (2H, ABq, J = 12Hz), 7.58 and 8.24 (4H, ar
(omatic protons)

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

[Chemical 37] To 1430 ml of the solution obtained in (5) above was added diphenylchlorophosphate 43.44 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. 0.3N while keeping below 10 ℃
The mixture was washed and separated with 574 ml of HCl and 574 ml of 5% NaHCO ₃ aqueous solution. Methylene chloride was concentrated and distilled off under reduced pressure, and 402 ml of n-hexane was added dropwise for crystallization. The crystals were collected by filtration and dried to obtain 75.16 g of the title compound. (Yield 86.0%) NMR (δ, CDCl ₃ ): 1.24 (3H, d), 1.34 (3H, d), 3.
30 (1H, q), 3.52 (1H, m), 4.10 ~ 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 a solution obtained in the same manner as in Example 1 (4)
After concentrating under reduced pressure, 1135 ml of n-hexane was added dropwise to crystallize. The crystallized solution was concentrated under reduced pressure, collected by filtration and dried to give 53.68 g of white crystals with a purity of 96.0% containing 51.53 g of the title compound. (Yield 88.0%)

Example 3 Preparation Example of (1R, 3R, 5R, 6S) -6-[(R) -1-hydroxyethyl] -2-oxo-1-methyl-3-p-nitrobenzylcarbonyl-carbapenem 1
1450 ml of a methylene chloride solution of the title compound obtained in the same manner as in (5) above was concentrated under reduced pressure to obtain 80.34 g of the title compound having a purity of 93.0%. (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
(8 mol) was used and the synthesis was conducted in the same manner as in (2) of Example 1 to obtain the title compound 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 conducted under N ₂ atmosphere in the same manner as in (2) of Example 1 except that N ₂ gas was not bubbled through, and the yield was 83%. To give the title compound.

[0043]

INDUSTRIAL APPLICABILITY The production method of the present invention provides a method for industrially producing an intermediate which can be suitably used for producing a carbapenem compound useful as a therapeutic agent for bacterial infections.

(72) Inventor Tomohiro Akiyama 4-5-1 Mitsui, Hikari-shi, Yamaguchi Takeda Yakuhin Seiun Dormitory (72) Inventor Shuichi Nishimura 4-5-1, Mitsui Hikari-shi, Yamaguchi Takeda Yakuhin Seiun Dormitory (72) Inventor Toshimitsu Hatano 1-6-6 Kashiwa-cho, Shiki City, Saitama Prefecture (72) Inventor Toshio Kumagai 3-153-37, Kosenba Town, Kawagoe City, Saitama Prefecture (72) Inventor, Toshi Shimizu Niiza, Saitama Prefecture 1-33-33, Niiza, Ichigo Co., Ltd. 202, Kopo-Kiri (56) References JP-A 1-203367 (JP, A) JP-A 1-25779 (JP, A) J. Am. Chem. So c. , 1980, 102, p. 6161-6163 (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 477/00-477/26

Claims (9)

(57) [Claims] 1. The formula: [Wherein R ¹ represents a hydroxyl-protecting group] or a salt thereof and a halogenated carbonic acid ester and imidazole are reacted in the presence of a base to obtain a compound of the formula: [Wherein the symbols have the same meanings as defined above], an alkaline earth metal halide, and the formula R ² OOCCH ₂ COOH (III) [wherein R ² represents a protective group for a carboxyl group] A compound represented by the following formula: A compound represented by the formula [wherein the symbols have the same meanings as defined above] is reacted with an azide compound to give a compound of the formula: [Wherein the symbols in the formula have the same meanings as defined above] The compound represented by the formula: A compound represented by the formula [wherein the symbols have the same meanings as defined above] is subjected to a ring closure reaction to obtain a compound of the formula: Reacting a compound represented by the formula [wherein the symbols have the same meanings 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. Which is characterized by the formula: The manufacturing method of the compound represented by [the symbol in a formula shows the same meaning as the above]. 2. The formula: [Wherein R ¹ represents a hydroxyl-protecting group] or a salt thereof is reacted with a halogenated carbonic acid ester and imidazole in the presence of a base to obtain a compound of the formula: [Wherein the symbols have the same meanings as defined above], an alkaline earth metal halide, and the formula R ² OOCCH ₂ COOH (III) [wherein R ² represents a protective group for a carboxyl group] A compound represented by the following formula: [Wherein the symbols in the formula have the same meanings as defined above] The compound represented by the formula: A compound represented by the formula [wherein the symbols have the same meanings as defined above] is reacted with an azide compound to obtain a compound represented by the formula: A compound represented by the formula [wherein the symbols have the same meanings as defined above] is subjected to a ring closure reaction to obtain a compound of the formula: Reacting a compound represented by the formula [wherein the symbols have the same meanings 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. Characterized by the formula: The manufacturing method of the compound represented by [the symbol in a formula shows the same meaning as the above]. 3. The method according to claim 1, wherein a halogenated hydrocarbon is used as a solvent in each reaction. 4. The method according to claim 1 or 2, wherein each reaction for obtaining compound (IV) from compound (I) is carried out while removing carbon dioxide gas. 5. A 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 a diazo compound. The manufacturing method according to claim 1. 6. The method according to claim 1, wherein the reaction of the compound (V) with an acid is carried out in a mixed solvent of dichloromethane, chloroform, acetonitrile or acetone and a lower alcohol, tetrahydrofuran or dioxane. 7. The process according to claim 2, wherein the reaction of the compound (IV) with an acid is carried out in a mixed solvent of dichloromethane, chloroform, acetonitrile or acetone and a lower alcohol, tetrahydrofuran or dioxane. 8. The method according to claim 3, wherein the halogenated hydrocarbon is dichloromethane. 9. An alkaline earth metal halide is magnesi.
The production according to claim 1 or 2, which is a umhalide.
Law.