CN1580058A - Method for preparig 3-chloromethyl-3-cephem derivative crystalline - Google Patents

Abstract

The invention provides a method for producing 3-chloromethyl-3-cephem derivative crystals with high yield and high purity without interrupting the reaction. The production method of the 3-chloromethyl-3-cephem derivative crystal represented by general formula (2) is to make chlorine represented by general formula (1) Piazetidinone derivatives and alkoxides are reacted, (wherein, R ₁ represents substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic residues, R ₂ and R ₃ represent substituted or unsubstituted aromatic hydrocarbons).

Description

Method for producing 3-chloromethyl-3-cephem derivative crystal

technical field

The present invention relates to the manufacture method of 3-chloromethyl-3-cephem derivative crystal, particularly relate to can obtain and can be used as the synthetic intermediate of various antibiotics of 3-chloromethyl-3-cephem, with following general A method for producing crystals of 3-chloromethyl-3-cephem derivatives represented by formula (2).

(wherein, R ₂ and R ₃ represent substituted or unsubstituted aromatic hydrocarbon groups).

Background technique

It is known that the 3-chloromethyl-3-cephem derivative represented by the above-mentioned general formula (2) is a compound that can be used as a synthetic intermediate for the synthesis of cephalosporins (Japanese Patent Laid-Open No. 59-172493 , JP-A-58-72591, JP-60-255796, JP-61-5084, JP-1-156984, JP-1-308287, International Publication No. WO99/10352 Publication No., International Publication No. WO98/58932, etc.).

In the past, the production method of 3-chloromethyl-3-cephem derivatives represented by the above general formula (2), for example, proposed to make the 3-acetoxy group of 3-acetoxymethyl cephalosporin derivatives The method of halogenating the acetoxy group of the methyl group in the presence of Lewis acids such as boron trichloride (Tetradedronlett., 3991p.1974), after the 2-azetidinone derivative prepared by penicillin G is chlorinated by electrolytic reaction, through The method (Tetradedronlett., 23, 2187p, 1982) of the method (Tetradedronlett., 23, 2187p, 1982) of alkali treatment ring-closing to form cephem derivatives, according to the following reaction formula (1),

Reaction formula (1)

In the presence of alkaline earth metal carbonates, the method of reacting 7-substituted amino-3-hydroxymethyl-3-cephem-4-carboxylate (compound (3)) with a chlorination reagent (Japanese Patent Application No. 4 -66584 bulletin); according to the following reaction formula (2),

A method of reacting an azetidinone derivative (compound (1a)) in an organic solvent in the presence of a base (JP-A-58-74689).

Among them, Japanese Unexamined Patent Publication No. 58-74689 is a method for producing oily 3-chloromethyl-3-cephem derivatives. The method is to mix the raw material azetidinone derivative (compound (1a)) with the reaction product 3 -Chloromethyl-3-cephem derivatives are dissolved together in N,N-dimethylformamide used as a reaction solvent, and weakly basic ammonia or ammonia water is used as a base to prevent the reaction product from decomposing A method of carrying out the reaction to obtain an oily 3-chloromethyl-3-cephem derivative.

In addition, in JP-A-58-74689, examples of reaction solvents include alcohols such as methanol, ethanol, and isopropanol, and examples of bases include highly basic metal hydroxides such as sodium hydroxide and potassium hydroxide. , but because the alcohol cannot dissolve the 3-chloromethyl-3-cephem derivative as the reaction product, an oily product cannot be obtained, and because if these alcohols react with the alkali to generate water, the alkali is dissolved in the water, thereby making the reaction When the pH value of the system increases and becomes alkaline, the reaction product 3-chloromethyl-3-cephem derivative will be decomposed, thereby reducing the yield.

And, because there is very reactive chlorine atom in the molecule of 3-chloromethyl-3-cephem derivative, it is unstable in the state of oil, for example, hydrochloric acid will be released to promote self-dissolution when preserved at room temperature. Decomposition, resulting in reduced quality, so people hope to obtain products with longer time stability under mild conditions.

Therefore, a method for crystallizing 3-chloromethyl-3-cephem derivatives from oils has been proposed.

For example, in International Publication No. WO99/10352, it is proposed to make the N, N-dimethylformamide solution of the oil of 3-chloromethyl-3-cephem derivatives in cooled alcohol or alcohol - A method for obtaining crystals of 3-chloromethyl-3-cephem derivatives by crystallization in water.

However, according to WO99/10352, once the oily substance of 3-chloromethyl-3-cephem derivatives is synthesized, it must go through complicated procedures such as crystallization, which is unfavorable for industrial production.

Contents of the invention

Therefore, the object of the present invention is to provide a kind of 3-chloromethyl-3-cephem derivatives that can be used as various antibiotic synthetic intermediates of cephalosporin series with high yield and high purity continuously by reaction Crystallized, industrially beneficial 3-chloromethyl-3-cephem derivative crystals.

In view of the above-mentioned problems, the inventors of the present invention have intensively studied a method for continuously obtaining crystals of 3-chloromethyl-3-cephem derivatives by reaction, and found that the raw materials of azetidinone chloride derivatives and A combination of alcohols, and a combination of an alcohol that does not dissolve the crystals of 3-chloromethyl-3-cephem derivatives and an ether that can dissolve the raw material chlorinated azetidinone derivatives and the impurities of the reaction by-products was found to be used as a reaction solvent . According to this reaction system, if the progress of the reaction is controlled at a pH value in a specific range in an anhydrous state, the product represented by the above general formula (2) can be obtained in high yield and high purity without interruption through the reaction. The object 3-chloromethyl-3-cephem derivative was crystallized, thereby completing the present invention.

That is, the present invention is a method for producing 3-chloromethyl-3-cephem derivative crystals represented by the following general formula (2), characterized in that, in an alcohol-containing solvent at a pH of 8 or less, Make the following general formula (1)

(In the formula, R ₁ represents a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclic residue, and R ₂ and R ₃ represent a substituted or unsubstituted aromatic hydrocarbon group.)

(In the formula, R ₂ and R ₃ represent substituted or unsubstituted aromatic hydrocarbon groups.)

The indicated chloride azetidinone derivatives are reacted with alkoxides.

And, the present invention provides a kind of manufacture method of 3-chloromethyl-3-cephem derivative crystal as shown in following general formula (2), it is characterized in that, in the solvent containing alcohol and ether, pH value is Under the condition of 8 or less, the azetidinone chloride derivative represented by the following general formula (1) and the alkoxide were reacted.

(wherein, R ₁ represents a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclic residue, R ₂ and R ₃ represent a substituted or unsubstituted aromatic hydrocarbon group);

(wherein, R ₂ and R ₃ represent substituted or unsubstituted aromatic hydrocarbon groups).

In the present invention, it is preferable to add the above-mentioned chlorinated azetidinone derivative solution (A) dissolved in an ether-containing solvent and the alkoxide solution (B) dissolved in an alcohol-containing solvent to the alcohol-containing solution (C ) for the reaction.

Preferably, in the above-mentioned alcohol-containing solution (C), an azetidine chloride containing 5 to 30 mol% of reaction equivalent is added as a part of the azetidinone chloride derivative solution (A) dissolved in an ether-containing solvent. After the ketone derivative solution (A), the remaining solution (A) containing the chlorinated azetidinone derivative and the alkoxide solution (B) dissolved in the alcohol-containing solvent are simultaneously added to the above-mentioned alcohol-containing solution (C) react in.

The above-mentioned reaction of the chlorinated azetidinone derivative and the alkoxide is preferably carried out at a ratio of 1 mol of the chlorinated azetidinone derivative to 0.8 to 1.5 mol of the alkoxide.

The aforementioned alcohol is preferably at least one selected from methanol or ethanol.

The aforementioned ether is preferably dioxane.

The aforementioned alkoxide is preferably sodium methoxide or sodium ethoxide.

The above reaction is preferably carried out at below 5°C.

The solution (A) containing the azetidinone chloride derivative is preferably a solution obtained by dissolving the azetidinone derivative in dioxane or alcohol.

The above-mentioned alkoxide-containing solution (B) is preferably a solution obtained by dissolving alkoxide in alcohol.

The aforementioned alcohol-containing solution (C) is preferably a mixed solvent of alcohol and dioxane.

It is preferable to add the above-mentioned solution (A) and solution (B) by dropwise addition to react.

The above reaction is preferably carried out in an anhydrous state.

Detailed ways

The present invention will be described in detail below.

The present invention provides a method for producing crystals of 3-chloromethyl-3-cephem derivatives represented by the following general formula (2), characterized in that, dissolving in ether-containing solvents as represented by the following general formula (1) A chlorinated azetidinone derivative solution (A) (hereinafter referred to as "chlorinated azetidinone derivative-containing solution (A)"); and an alkoxide solution (B) dissolved in an alcohol-containing solvent (hereinafter referred to as "alcoholate-containing solution (B)") was added dropwise to the alcohol-containing solution (C), and reacted at pH 8 or less.

(In the formula, R ₁ represents a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclic residue, and R ₂ and R ₃ represent a substituted or unsubstituted aromatic hydrocarbon group.)

In addition, the dropwise amounts of the solution (A) containing the azetidinone derivative and the solution (B) containing the alkoxide are preferably between the above-mentioned solution (A) containing the azetidinone derivative and the above-mentioned In the solution (B) containing an alkoxide, the molar ratio of an alkoxide is 0.8-1.5 times mol with respect to 1 mol of azetidinone chlorides.

In addition, the amount of dropping is preferably such that the alcohol content in the reaction solvent is 30 to 95% by weight at the end of the dropping.

And, above-mentioned reaction is preferably to be prepared into the solution (A) that contains the chlorinated azetidinone derivative represented by above-mentioned general formula (1), first make the reaction equivalent of chlorinated azetidinone derivative be 5～30mol% A part of the solution (A) containing the above-mentioned chlorinated azetidinone derivatives is added dropwise to the alcohol-containing solvent, and the rest of the solution containing the chlorinated azetidinone derivatives represented by the above general formula (1) (A) and an alkoxide-containing solution (B) are simultaneously dripped and reacted in alcohol-containing solution (C).

Furthermore, the solution (A) containing the azetidinone chloride derivative is preferably a solution obtained by dissolving the azetidinone chloride derivative in a mixed solvent of dioxane and alcohol.

On the other hand, the solution (B) containing an alkoxide is preferably a solution in which an alkoxide is dissolved in alcohol.

Furthermore, the alcohol-containing solution (C) is preferably a mixed solvent of alcohol and dioxane.

The reaction formula of the method for producing crystals of the 3-chloromethyl-3-cephem derivative of the present invention is shown below.

Next, the above-mentioned solutions (A) to (C) used in the production method of the present invention will be described.

<Solution (A) Containing Chlorinated Azetidinone Derivatives>

_R1 of the chlorinated azetidinone derivative (hereinafter also referred to as "chlorinated azetidinone derivative (compound (1))") represented by the above-mentioned general formula (1) as a raw material used in the present invention represents a substituted or unsubstituted aryl group or a substituted or unsubstituted heterocyclic residue. Specific examples of the aryl group include phenyl, p-methylphenyl, p-methoxyphenyl, p-nitrophenyl, p-chlorophenyl, pentachlorophenyl and the like. As substituted or unsubstituted heterocyclic residues, 2-pyridyl, 2-benzothiazolyl, 1,3,4-thiadiazol-5-yl, 2-methyl-1,3 , 4-thiadiazol-5-yl, 1,2,3,4-tetrazol-5-yl, 1-methyl-1,2,3,4-tetrazol-5-yl, 1-phenyl -1,2,3,4-tetrazol-5-yl and the like.

And R ₂ and R ₃ represent substituted or unsubstituted aromatic hydrocarbon groups. Specific examples include benzyl, p-methoxybenzyl, phenyl, p-tolyl, etc. _R2 and _R3 may be the same or different.

Chlorinated azetidinone derivatives represented by the above-mentioned general formula (1), for example, in the general formula (1), R ₂ is benzyl, and R ₃ is a compound of p-methoxybenzyl, which can be thiazoline azetidine Pyridone derivatives are used as raw materials, and are produced by the two-step reaction of the following reaction formula (3) and reaction formula (4) (refer to Japanese Patent Publication No. 5-9425).

Reaction formula (3)

Reaction formula (4)

(In the formula, _R1 has the same meaning as above).

<Solution (A) Containing Chlorinated Azetidinone Derivatives>

The solution (A) containing the azetidinone chloride derivative of the present invention can be adjusted by dissolving the reaction product obtained by the reaction formula (4) in which the azetidinone chloride derivative is dissolved in a solvent.

In addition, as the solution (A) containing the chlorinated azetidinone derivative used in the present invention, the above-mentioned chlorinated azetidinone derivative (compound (1a)) dissolved in a solvent and adjusted to a predetermined concentration can be used. The solution.

The solution (A) containing the chlorinated azetidinone derivative is a solution in which the above-mentioned chlorinated azetidinone derivative (compound (1)) is dissolved in a solvent and adjusted to a predetermined concentration.

As the solvent which can dissolve the chlorinated azetidinone derivatives, for example, esters such as methyl formate, ethyl formate, methyl acetate, ethyl acetate, butyl acetate, ethyl propionate; dichloromethane, Chloroform, carbon tetrachloride, dichloroethane, dibromoethane, chlorobenzene and other halogenated hydrocarbons; diethyl ether, dibutyl ether, dioxane, tetrahydrofuran and other ethers; acetonitrile, butyronitrile and other nitriles; pentane , hexane, cyclohexane and other hydrocarbons, these solvents can use one or more than two (hereinafter referred to as "solvent A"). Among them, dioxane is preferred.

The content of these solvents is 50 to 500 parts by weight, preferably 100 to 500 parts by weight, based on 100 parts by weight of the chlorinated azetidinone derivative (compound (1)).

Such a solution in which the chlorinated azetidinone derivative is dissolved can be used as it is, but since such a solution has a high viscosity, it is preferable to add an alcohol ( Hereinafter referred to as "solvent A2") to reduce the viscosity to facilitate handling during dropwise addition. Usable alcohols include, for example, one or two or more of lower alcohols such as methanol, ethanol, isopropanol, and n-propanol. Wherein as the lower alcohol used, if use methyl alcohol or ethanol to carry out the reaction under the following reaction conditions, because can obtain with the 3-chloromethyl-3-cephalosporin represented by above-mentioned general formula (2) with high yield and high purity Alkene derivatives crystallize and are therefore particularly preferred.

At this time, the proportioning amount of the alcohol (A2 solvent) is preferably 100 to 500 parts by weight, more preferably 200 to 300 parts by weight, relative to 100 parts by weight of the chlorinated azetidinone derivative (compound (1)). In the range.

The solution containing such a chlorinated azetidinone derivative has a content of the chlorinated azetidinone derivative (compound (1)) of 0.05 to 1 mol/L, preferably 0.1 to 0.5 mol/L.

<Alkoxide-containing solution (B)>

The present invention is characterized in that an alkoxide is used in the crystallization reaction.

Alkoxides useful in the present invention are represented by the general formula _R4 -OM. R ₄ in the formula is a straight-chain or branched lower alkyl group having 1 to 4 carbon atoms, examples of which include alkyl groups such as methyl, ethyl, isopropyl, and n-butyl. M in the formula represents alkali metals such as lithium, sodium, and potassium.

Specific examples of the alkoxide compound include sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium methoxide, lithium ethoxide, and potassium t-butoxide, and one or more of these alkoxides can be used.

Among them, sodium methoxide or sodium ethoxide is preferably used as the alkoxide.

The alkoxide-containing solution (B) is a solution in which the above-mentioned alkoxide is dissolved using a solvent and adjusted to a predetermined concentration.

Alcohol is preferably used as the solvent for dissolving the above-mentioned alkoxide (hereinafter referred to as "solvent B1"), specifically methanol, ethanol, isopropanol, n-butanol, etc., and one or more of them can be used. Among them, methanol or ethanol is preferably used.

<Alcoholic solution (C)>

The alcohol-containing solution uses at least a single solvent of alcohol (hereinafter referred to as "solvent C1"), or a mixed solvent with other solvents (hereinafter referred to as "solvent C2"). Usable alcohols include lower alcohols such as methanol, ethanol, isopropanol, and n-butanol, and one or two or more of these alcohols can be used. Among them, methanol or ethanol is preferably used as the alcohol.

Alcohol can dissolve the raw material chloride azetidinone derivative represented by general formula (1), but in order not to dissolve the reaction product 3-chloromethyl-3-cephem derivative represented by general formula (2), preferably A reaction solvent capable of recovering the reaction product as direct crystallization is used.

And because the other solvent (solvent C2) mixed with alcohol (solvent C1) can dissolve the raw material chlorinated azetidinone derivative (compound (1)), and can dissolve the unreacted raw material azetidine chloride which becomes an impurity at the end of the reaction Impurities such as pyridone derivatives and reaction by-products, so the crystals of 3-chloromethyl-3-cephem derivatives represented by the above general formula (2) can be recovered with high purity from the reaction solution. Examples of such solvents include esters such as methyl formate, ethyl formate, methyl acetate, ethyl acetate, butyl acetate, and ethyl propionate; dichloromethane, chloroform, carbon tetrachloride, dichloromethane Halogenated hydrocarbons such as ethane, dibromoethane, and chlorobenzene; ethers such as diethyl ether, dibutyl ether, dioxane, and tetrahydrofuran; nitriles such as acetonitrile and butyronitrile; hydrocarbons such as benzene, hexane, and cyclohexane , one or two or more of these solvents may be used. Among them, dioxane is preferably used.

If alcohol (solvent C1) and other solvents (solvent C2), with respect to the alcohol (solvent C1) of 100 weight parts, other solvents (solvent C2) are 10～30 weight parts, preferred 10～20 weight parts mixing ratio, Carrying out the reaction under the following conditions can obtain the 3-chloromethyl-3-cephem derivative crystal represented by the above general formula (2) with high yield and high purity, so it is preferred, on the other hand, when other When solvent (solvent C2) is less than 10 parts by weight, along with the progress of reaction, the crystallization of 3-chloromethyl-3-cephem derivatives that generates will agglomerate with impurities such as reaction by-products during crystallization, thereby Can not obtain 3-chloromethyl-3-cephem derivative crystals with high purity and high yield, when exceeding 30 parts by weight, because the 3-chloromethyl-3-cephem derivative crystals of generation dissolve and cause yield rate is reduced and therefore not used.

The amount of the alcohol-containing solution (C) is preferably 300 to 2000 parts by weight, more preferably 500 to 1000 parts by weight, relative to 100 parts by weight of the chlorinated azetidinone derivative represented by the above general formula (1), when When it is less than 500 parts by weight, the reaction is difficult to proceed and unreacted raw materials remain, and when it exceeds 1000 parts by weight, it is industrially unfavorable to use more solvent than necessary.

<reaction conditions>

The method for producing 3-chloromethyl-3-cephem derivative crystals represented by the above general formula (2) of the present invention is characterized in that azetidinone chloride represented by the above general formula (1) is The solution (A) of the derivative and the solution (B) containing the above-mentioned alkoxide are added dropwise to the alcohol-containing solution (C), and the reaction is carried out at a pH of 8 or less.

In the present invention, the reaction is carried out at a pH value below 8, preferably at a pH value of 6-8. The reason why the pH value in the reaction is set in this range is because the reaction product 3-chloromethyl-3-cephem derivative crystal is extremely unstable to alkali, and when the pH value is above 8, it will decompose during the reaction process , but cannot obtain the crystallization of the target 3-chloromethyl-3-cephem derivative with high purity and high yield, so it is not selected.

Because the reaction is carried out very quickly, the measurement of the pH value in the reaction is preferably, for example, taking out the reaction solution from the reaction system and putting it on litmus paper, and then adding water dropwise to measure it, or taking a small amount of the reaction solution, adding twice the amount of water , measured by a pH meter, etc. Since the unreacted alkoxide represents a weakly basic group, the pH in the reaction rises and tends to be more basic.

Therefore, in the reaction in the present invention, the solution (A) containing the chlorinated azetidinone derivative (compound (1)) and the solution (B) containing the alkoxide are preferably added dropwise in the range of the above-mentioned pH value. Alcoholic solution (C).

And, the dripping amount of the solution (A) containing the chloride azetidine derivative represented by the above-mentioned general formula (1) and the solution (B) containing the above-mentioned alkoxide, if expressed with respect to containing azetidine chloride The molar ratio of the alkoxide in the alkoxide-containing solution (B) of the chlorinated azetidinone derivative (compound (1)) in the solution (A) of the ketone derivative is 0.8 to 1.5 times mol, preferably 1.1 to The ratio of 1.2 times mol is added dropwise, because the residual amount of unreacted raw material chloride azetidinone derivative (compound (1)) can be reduced, the 3-chloromethyl- 3-cephem derivatives are crystallized, so it is preferred, and when less than 0.8 times mol, the residual amount of unreacted raw material chloride azetidinone derivatives (compound (1)) is more than the necessary value, and if it exceeds When it is 1.5 times mol, the pH value of the reaction solution will exceed 8 and be alkaline, and the generated 3-chloromethyl-3-cephem derivative crystals will decompose, so they are not selected.

In addition, the dropwise addition amount of the solution (A) containing the above-mentioned azetidinone derivative and the solution (B) containing the above-mentioned alkoxide is preferably such that the solution (A) to the solution (C) at the end of the dropwise addition ) in all reaction solvents (solvent A1+solvent A2+solvent B1+solvent C1+solvent C2) alcohol content (solvent A2+solvent B1+solvent C1) is 30～95% by weight, preferably 60～90% by weight. If the alcohol content in the reaction solvent at the end of the dropwise addition is less than 30% by weight, the alkoxide of the reaction raw material is difficult to dissolve in the reaction solution, and will cause the crystallization of 3-chloromethyl-3-cephem derivatives to dissolve and reduce the yield. On the other hand, if the reaction is carried out at a ratio of more than 95% by weight, impurities such as reaction by-products during crystallization of the 3-chloromethyl-3-cephem derivative crystals generated cannot be dissolved, and these impurities are formed. Agglomerates, so the 3-chloromethyl-3-cephem derivative crystals cannot be obtained with high purity and high yield, so they are not selected.

Especially in the present invention, if for the solution (A) containing the chlorinated azetidinone derivative (compound (1)), dioxane ( A mixed solvent of solvent A1) and methanol and/or ethanol (solvent A2), using methanol and/or ethanol (solvent B1) as the alkoxide-containing solution (B), and using The mixed solvent of methanol and/or ethanol (solvent C1) and dioxane (solvent C2), the content of methanol and/or ethanol in the reaction solvent (solvent A1+solvent A2+solvent B1+solvent C1+solvent C2) at the end of dropwise addition 20 to 60% by weight, preferably 30 to 50% by weight, the 3-chloromethyl-3-cephem derivative crystal represented by the above general formula (2) can be obtained with high yield and high purity. particularly preferred.

The method of adding dropwise the solution (A) containing the above-mentioned azetidinone derivative (compound (1)) and the solution (B) containing the above-mentioned alkoxide to the alcohol-containing solution (C) includes the following: The dripping method of 1-2 mentioned above.

1. preparation contains the solution (solution A) of the chlorinated azetidinone derivative represented by above-mentioned general formula (1) and the solution (B) containing above-mentioned alkoxide, in dropwise adding the solution (B) containing above-mentioned alkoxide Before, the solution (A) containing the above-mentioned azetidinone chloride derivatives was added dropwise, and the solutions (A) and (B) were continuously or intermittently added dropwise to the alcohol-containing solution (C), so that the reaction system A method in which the pH is within the above range (hereinafter referred to as "dropping method 1.").

2. preparation contains the solution (A) of the chlorinated azetidinone derivative represented by the above-mentioned general formula (1), at first making the reaction equivalent of the chlorinated azetidinone derivative be 5～30mol%, preferably 10～ 20mol% of the above-mentioned solution (A) is added dropwise in the alcohol-containing solution (C), and then the rest of the solution (A) containing the azetidinone chloride derivative represented by the above general formula (1) is mixed with the solution (A) containing The solution (B) of alkoxide is added dropwise in the alcohol-containing solution (C) at the same time, so that the pH value of the reaction system is in the method of the above-mentioned range (hereinafter referred to as "dropping method 2".).

The above-mentioned dropping method 1 is to properly adjust the dropping order of the solution (A) containing the chlorinated azetidinone derivative and the solution (B) containing the alkoxide, so that the pH value in the reaction system is always within the above-mentioned range A method in which the solution (A) containing the above-mentioned azetidinone chloride derivative and the solution (B) containing the alkoxide are added dropwise to the alcohol-containing solution (C). And dropwise method 2 is to add predetermined amount of solution (A) containing azetidinone derivatives dropwise in advance in the alcoholic solution (C), so that the reaction system is in the acidic range (for example, the pH value is 4) , at this time, the rest of the solution (A) containing the chlorinated azetidinone derivative and the solution (B) containing the alkoxide are continuously added dropwise to the alcohol-containing solution (C) almost simultaneously, so that the reaction system A dropwise addition method in which the pH is always within the above range.

In addition, in the method for producing 3-chloromethyl-3-cephem derivative crystals of the present invention, when preparing the alcohol-containing solution (C), the content is 5-30 mol%, preferably 10-30 mol%. The above-mentioned chlorinated azetidinone derivatives are added to the alcoholic solution (C), and then according to the same operation as the dropwise addition method 2, then in the alcoholic solution (C), dropwise add chlorine containing the required amount of reaction. The solution of the azetidinone derivative and the solution containing the alkoxide keep the pH value in the reaction system always within the above-mentioned range.

In the reaction of the present invention, the reaction product 3-chloromethyl-3-cephem derivative crystal is extremely unstable to alkali, and when the pH value is above 8, it will decompose in the reaction, if it will contain The solution (A) of chlorinated azetidinone derivatives and the solution (B) containing alkoxide are added dropwise in the alcohol-containing solution (C) at the same time, because they will move to the alkaline side, so as the above-mentioned drop method 1, As shown in 2, it is preferable to add the azetidinone chloride derivative (compound (1)) continuously first, and make the pH value not exceed 8 which is basic when the reaction is carried out. In addition, the pH value of the solution (A) containing the chloride azetidinone derivative is about 4, and the pH value of the reaction system is raised by adding the solution (B) containing the alkoxide.

In the present invention, among the above-mentioned dropping methods 1 and 2, the dropping method 2 is particularly industrially advantageous in terms of easy pH control.

And, in the present invention, after all the solution (A) containing the raw material chlorinated azetidinone derivatives is added to the alcohol-containing solution (C), the dropwise addition of the solution (B) containing alkoxide is carried out at a pH of 8 or less. During the reaction, as the reaction proceeds, the resulting reaction product 3-chloromethyl-3-cephem derivative crystals may contain impurities, thereby causing a reduction in quality, but since the crystallization can be obtained without interruption, although the subsequent The burden of the purification process, but the reaction can be carried out with simple operation.

In the present invention, the solution of the chlorinated azetidinone derivative obtained by the chlorination reaction of the azetidinone derivative in the process before obtaining the raw material chlorinated azetidinone derivative can be used as a Raw material solution (A) of butyridinone. Examples of such solutions include solutions of azetidinone derivatives produced by chlorination of azetidinone derivatives by the method described in JP-A-5-9425. If such a solution is used, crystals of the 3-chloromethyl-3-cephem derivative which is the object of the present invention can be obtained through continuous steps starting from the azetidinone derivative which is the raw material in the previous manufacturing step.

In the production method of the present invention, the solution (A) containing the raw material chlorinated azetidinone derivative is preferably a dioxane solution in which the chlorinated azetidinone derivative is dissolved in dioxane, because dioxane The melting point of dioxane in the solution is 11°C. For example, when the reaction is carried out at a reaction temperature below 10°C, the viscosity of the solution may increase or even solidify. Alcohols such as methanol or ethanol dilute the butidinone derivatives to reduce the viscosity of the solution, making the dropwise addition easy.

In addition, in the production method of the present invention, it is preferable to carry out the reaction through a reaction system containing dioxane used as a reaction solvent. If the content of dioxane is small, the resulting reaction product 3-chloromethane Impurities such as crystallization of base-3-cephem derivatives and reaction by-products during crystallization will combine into agglomerates, so the content of dioxane in the reaction system maintains The range of 10 to 30 parts by weight is preferable.

And, because in the manufacture method of the present invention, reaction is carried out in reaction solvent, also can not generate water in reaction, is to react under anhydrous state, so just have: do not produce alkali because alkoxide is dissolved in water The role of easy to prevent the decomposition of 3-chloromethyl-3-cephem derivative crystals caused by alkali.

The reason why the production method of the present invention is preferred is because the above-mentioned reaction is carried out at a reaction temperature below 5° C., which suppresses the formation of by-products, so that the target product of the above-mentioned general formula can be obtained in high yield. Crystals of the 3-chloromethyl-3-cephem derivative represented by (2). On the other hand, since raw materials and impurities are precipitated at lower than -20°C, the reaction is carried out at -20 to 5°C, preferably at -10 to 5°C.

In this way, by the crystallization reaction of the 3-chloromethyl-3-cephem derivative represented by the above-mentioned general formula (2) as the object, the crystallization can be judged at any time by the reaction solution becoming white and turbid, and after the reaction is finished, After neutralization, filtration and drying, crystallization was obtained. If necessary, it can also be refined by washing and recrystallization.

As solvents that can be used for washing and recrystallization, for example, alcohols such as methanol, ethanol, isopropanol, and n-butanol; nitriles such as acetonitrile and butyronitrile; ketones such as acetone and methyl ethyl ketone; dimethylformamide , diethylformamide and other amides, or one or more of them.

And, according to the production method of the 3-chloromethyl-3-cephem derivative crystal represented by the above-mentioned general formula (2) of the present invention, for example, azetidinone chloride derivative (compound (1a)) and alcohol Salt (compound (7)) reacts according to following reaction formula (5),

Reaction formula (5)

(wherein, R ₁ represents a substituted or unsubstituted aromatic hydrocarbon group, R ₄ represents an organic group, and M represents an alkali metal).

Simultaneously with formation of the target 3-chloromethyl-3-cephem derivative crystal (compound (2a)), a sulfonic acid metal salt (compound (8)) was produced as a by-product. For example, reclaim 3-chloromethyl-3-cephem derivative crystallization, make sulfonic acid metal salt crystallization (compound (8)) by the mother liquor after recovery, then make the sulfonic acid metal salt of this precipitation in solvent and bromine The reaction yields sulfonyl bromide, which can be reused as a raw material for the production of, for example, the thiazolinazetidinone derivative (compound (4)) of the above reaction formula (3).

The 3-chloromethyl-3-cephem derivative crystals represented by the above general formula (2) obtained by the production method of the present invention have excellent long-term stability under mild conditions, for example,

According to the following reaction formula (6),

Reaction formula (6)

It can be derivatized into 7-amino-3-chloromethyl-3-cephem derivatives (compound (9)) which can be used as various cephalosporin antibiotics.

Example

The present invention will be described in detail below based on examples, but the present invention is not limited thereto.

Example 1

68.6g (0.052mol) containing 47.7% by weight of the following compound (10)

A dioxane solution of the indicated azetidinone chloride derivative (compound (10)) was placed in a dropping funnel purged with nitrogen, and diluted with 50 g of anhydrous methanol (Kanto Chemical Co., Ltd.) to obtain liquid A.

Dilute 13.5 g (0.060 mol) of a methanol solution containing 24 wt % sodium methoxide (reagent grade 1) with 67.2 g of anhydrous methanol to prepare a methanol solution containing 4 wt % sodium methoxide as liquid B.

In the reaction flask, add 13g of dioxane, add 160mL of absolute ethanol, and cool to -2~2°C. In the four-neck flask filled with the cooled reaction solvent, add 1/8 of the total amount of the above liquid A (pH value is 4) into the above prepared reaction solvent.

Then, while maintaining the temperature of the reaction system between -2°C and 2°C, the above liquid A and liquid B were simultaneously added dropwise. After about 1/8 of liquid B was added dropwise, the reaction liquid began to appear white turbid and became a slurry containing white crystals. Then, while maintaining the temperature of the reaction system between -2 and 2°C, the above liquid A and liquid B were added dropwise at the same time, and the dropwise addition was completed in about 4 hours (pH value was 7 to 8). After completion of the dropwise addition, the mixture was further stirred at 0° C. for 0.25 hours to perform a reaction.

After the reaction was completed, 0.48 g of acetic acid was added to the reaction solution after the reaction for neutralization. The pH value of the neutralized reaction system is 4-5. After the neutralization treatment, the mixture was further aged with stirring at -2 to 2°C for 0.5 hours.

Then, after the aging is finished, filter with a 3G glass filter, rinse the obtained filter cake with 18g of ice-cooled methanol, then use 36g of 30% methanol solution containing water for the second rinse, and rinse with 18g of ice-cooled methanol. Methanol for the third rinse.

Put the washed filter cake into a desiccator, place it overnight at room temperature, and dry it with a vacuum pump to obtain 22.9 g of 3-chloromethyl-3-cephem derivative crystals (general formula (2a)) (purity 94.1 %, yield 85.1%).

(authentication data)

¹ H-NMR (δ, CDCl ₃ )

3.41 (1H, d, j = 18.5), 3.59 (1H, d, j = 18.5), 4.92 (1H, d, j = 4.9), 5.82 (1H, d, d, j = 4.9, 9.3), 6.12 ( 1H, d, j = 9.3), 3.58 (1H, d, j = 16.1), 3.67 (1H, d, j = 16.1), 7.40 ~ 7.28 (5H, m), 4.39 (1H, d, j = 11.9) , 4.50 (1H, d, j = 11.9), 5.20 (2H, s), 7.32 (2H, d, j = 8.6), 6.88 (2H, d, j = 8.6), 3.80 (3H, s)

FT-IR (cm ^-1 , KBr)

3499cm ^-1 , 3271cm ^-1 , 1778cm ^-1 , 1703cm ^-1 , 1645cm ^-1 , 1251cm ^-1

FAB-MS

M+1: 487m/z

Then, using the X-ray diffraction apparatus RINT2400 manufactured by Rigaku Co., Ltd., the crystallization of the 3-chloromethyl-3-cephem derivative obtained in Example 1 was carried out using a copper ray of λ=1.5418 Å passing through a monochromatic filter. X-ray diffraction analysis. Its X-ray diffraction pattern is shown in Table 1.

Table 1 d I/I ₀ 12.91 0.81 11.67 0.64 6.45 0.39 6.32 0.29 5.80 0.48 4.94 0.31 4.72 0.65 4.65 0.89 4.50 0.71 4.44 0.33 4.28 0.58 4.16 1.00 d I/I ₀ 4.04 0.13 3.97 0.15 3.85 0.71 3.77 0.50 3.70 0.11 3.45 0.46 3.37 0.20 3.20 0.13 3.16 0.18 3.09 0.12 2.90 0.13 -

(Note) d in Table 1 is the spacing between lattice planes; I/I ₀ is the relative intensity of the diffraction peak relative to d=4.17

Example 2

68.6 g (0.052 mol) of a dioxane solution containing 47.7% by weight of azetidinone derivatives (compound (10)) was added to a dropping funnel replaced with nitrogen, and 50 g of anhydrous methanol (Kanto Chemical Co., Ltd. Reagent) was diluted as solution A.

4.46 g (0.063 mol) of sodium ethoxide was dissolved in 103 g of methanol to prepare a methanol solution containing 4% by weight of sodium ethoxide as liquid B.

Add 13 g of dioxane to the reaction flask, add 160 mL of absolute ethanol, and cool to -2 to 2°C. In the four-neck flask added with the cooled reaction solvent, add 1/8 of the total amount of the above liquid A into the above prepared reaction solvent (pH value is 4).

Then, while maintaining the temperature of the reaction system between -2°C and 2°C, the above-mentioned liquid A and liquid B were added dropwise at the same time. When about 1/5 of the liquid B was added dropwise, the reaction liquid began to appear white turbid, and became a slurry containing white crystals. Then, while maintaining the temperature of the reaction system between -2 and 2°C, the above liquid A and liquid B were added dropwise at the same time, and the dropwise addition was completed in about 4 hours (pH value was 7 to 8). After completion of the dropwise addition, the mixture was further stirred at 0° C. for 0.25 hours to perform a reaction.

After the reaction was completed, 0.44 g of acetic acid was added to the reaction solution after the reaction for neutralization. In addition, the pH value of the reaction system after neutralization is 4-5. After the neutralization treatment, it was aged at -2 to 2° C. for 0.5 hour with stirring.

Then, after the aging is finished, filter with a 3G glass filter, rinse the obtained filter cake with 18g of ice-cooled methanol, then use 36g of 30% methanol solution containing water for the second rinse, and rinse with 18g of ice-cooled methanol. Methanol for the third rinse.

Put the washed filter cake into a desiccator, place it overnight at room temperature, and dry it with a vacuum pump to obtain 21.8 g of 3-chloromethyl-3-cephem derivative crystals (general formula (2a)) (purity 94.3 %, yield 81.2%).

(authentication data)

¹ H-NMR (δ, CDCl ₃ )

3.41 (1H, d, j = 18.5), 3.59 (1H, d, j = 18.5), 4.92 (1H, d, j = 4.9), 5.82 (1H, d, d, j = 4.9, 9.3), 6.12 ( 1H, d, j = 9.3), 3.58 (1H, d, j = 16.1), 3.67 (1H, d, j = 16.1), 7.40 ~ 7.28 (5H, m), 4.39 (1H, d, j = 11.9) , 4.50 (1H, d, j = 11.9), 5.20 (2H, s), 7.32 (2H, d, j = 8.6), 6.88 (2H, d, j = 8.6), 3.80 (3H, s)

FT-IR (cm ^-1 , KBr)

3449cm ^-1 , 3271cm ^-1 , 1778cm ^-1 , 1251cm ^-1

FAB-MS

M+1: 487m/z

Then, X-ray diffraction analysis was performed on the 3-chloromethyl-3-cephem derivative crystal obtained in Example 2 in the same manner as in Example 1, and the same X-ray diffraction pattern as in Example 1 was shown.

Example 3

69.75 g (0.052 mol) of a dioxane solution containing 46.9% by weight of azetidinone derivatives (compound (10)) was added to a dropping funnel replaced with nitrogen, and 50 g of anhydrous methanol (Kanto Chemical Co., Ltd. Reagent) was diluted as solution A.

4.46 g (0.063 mol) of sodium ethoxide was dissolved in 103 g of absolute ethanol to prepare an ethanol solution containing 4% by weight of sodium ethoxide as liquid B.

Add 13g of dioxane to the reaction flask, add 160mL of absolute ethanol, and cool to -2~2°C. In the four-neck flask added with the cooled reaction solvent, add 1/8 of the total amount of the above liquid A into the above prepared reaction solvent (pH value 4).

Then, while maintaining the temperature of the reaction system between -2°C and 2°C, the above-mentioned liquid A and liquid B were added dropwise at the same time. When about 1/4 of the liquid B was added dropwise, the reaction liquid began to appear white turbid, and became a slurry containing white crystals. Then, while maintaining the temperature of the reaction system at -2-2°C, the above liquid A and liquid B were added dropwise at the same time, and the dropwise addition was completed in about 4 hours (pH value was 7-8). After completion of the dropwise addition, the mixture was further stirred at 0° C. for 0.25 hours to perform a reaction.

After the reaction was completed, 0.43 g of acetic acid was added to the reaction solution after the reaction for neutralization. The pH value of the reaction system after neutralization is 4-5. After the neutralization treatment, the mixture was further aged with stirring at -2 to 2°C for 0.5 hours.

Then, after the aging is finished, filter with a 3G glass filter, rinse the obtained filter cake with 18g of ice-cooled methanol, then use 36g of 30% methanol solution containing water for the second rinse, and rinse with 18g of ice-cooled methanol. Methanol for the third rinse.

Put the washed filter cake into a desiccator, place it overnight at room temperature, and dry it with a vacuum pump to obtain 23.28 g of 3-chloromethyl-3-cephem derivative crystals (general formula (2a)) (purity 91.6 %, yield 84.2%).

(authentication data)

¹ H-NMR (δ, CDCl ₃ )

3.41 (1H, d, j = 18.5), 3.59 (1H, d, j = 18.5), 4.92 (1H, d, j = 4.9), 5.82 (1H, d, d, j = 4.9, 9.3), 6.12 ( 1H, d, j = 9.3), 3.58 (1H, d, j = 16.1), 3.67 (1H, d, j = 16.1), 7.40 ~ 7.28 (5H, m), 4.39 (1H, d, j = 11.9) , 4.50 (1H, d, j = 11.9), 5.20 (2H, s), 7.32 (2H, d, j = 8.6), 6.88 (2H, d, j = 8.6), 3.80 (3H, s)

FT-IR (cm ^-1 , KBr)

3449cm ^-1 , 3271cm ^-1 , 1778cm ^-1 , 1251cm ^-1

FAB-MS

M+1: 487m/z

Furthermore, X-ray diffraction analysis was performed on the 3-chloromethyl-3-cephem derivative crystal obtained in Example 3 in the same manner as in Example 1, and the same X-ray diffraction pattern as in Example 1 was shown.

Example 4

64.55 g (0.052 mol) of a dioxane solution containing 50.6% by weight of azetidinone derivatives (compound (10)) was added to a dropping funnel replaced with nitrogen, and 50 g of anhydrous methanol (Kanto Chemical Co., Ltd. Reagent) was diluted as solution A.

Dilute 13.5 g of a methanol solution containing 24% by weight of sodium methoxide (reagent grade 1) with 67.2 g of anhydrous methanol to prepare a methanol solution containing 4% by weight of sodium methoxide (0.060 mol) as liquid B.

Add 13g of dioxane to the reaction flask, add 160mL of absolute ethanol, and cool to -2~2°C. In the four-neck flask added with the cooled reaction solvent, add 1/8 of the total amount of the above liquid A into the above prepared reaction solvent (pH value 4).

Then, while maintaining the temperature of the reaction system between -2°C and 2°C, the above-mentioned liquid A and liquid B were added dropwise at the same time. When about 1/4 of the liquid B was added dropwise, the reaction liquid began to appear white turbid, and became a slurry containing white crystals. Then, while maintaining the temperature of the reaction system between -2 and 2°C, the above-mentioned liquid A and liquid B were added dropwise at the same time, and the dropwise addition was completed in about 2 hours (pH value was 7-8). After completion of the dropwise addition, the mixture was further stirred at 0° C. for 0.25 hours to perform a reaction.

After the reaction was completed, 0.48 g of acetic acid was added to the reaction solution after the reaction for neutralization. In addition, the pH value of the reaction system after neutralization is 4-5. After the neutralization treatment, the mixture was further aged with stirring at -2 to 2°C for 0.5 hours.

Then, after the aging is finished, filter with a 3G glass filter, rinse the obtained filter cake with 18g of ice-cooled methanol, then use 36g of 30% methanol solution containing water for the second rinse, and rinse with 18g of ice-cooled methanol. Methanol for the third rinse.

The washed filter cake is put into a desiccator, placed overnight at room temperature, and dried with a vacuum pump to obtain 22.58 g of 3-chloromethyl-3-cephem derivative crystals (general formula (2a)) (purity 94.4 %, yield 84.2%).

(authentication data)

¹ H-NMR (δ, CDCl ₃ )

3.41 (1H, d, j = 18.5), 3.59 (1H, d, j = 18.5), 4.92 (1H, d, j = 4.9), 5.82 (1H, d, d, j = 4.9, 9.3), 6.12 ( 1H, d, j = 9.3), 3.58 (1H, d, j = 16.1), 3.67 (1H, d, j = 16.1), 7.40 ~ 7.28 (5H, m), 4.39 (1H, d, j = 11.9) , 4.50 (1H, d, j = 11.9), 5.20 (2H, s), 7.32 (2H, d, j = 8.6), 6.88 (2H, d, j = 8.6), 3.80 (3H, s)

FT-IR (cm ^-1 , KBr)

3449cm ^-1 , 3271cm ^-1 , 1778cm ^-1 , 1251cm ^-1

FAB-MS

M+1: 487m/z

In addition, X-ray diffraction analysis was performed on the 3-chloromethyl-3-cephem derivative crystal obtained in Example 4 in the same manner as in Example 1, and the same X-ray diffraction pattern as in Example 1 was shown.

Example 5

57.4 g (0.052 mol) of a dioxane solution containing 57.6% by weight of azetidinone derivatives (compound (10)) was added to a dropping funnel replaced with nitrogen, and 50 g of anhydrous methanol (Kanto Chemical Co., Ltd. Reagent) was diluted as solution A.

Dilute 13.5 g of a methanol solution containing 24% by weight of sodium methoxide (reagent grade 1) with 67.0 g of anhydrous methanol to prepare a methanol solution containing 4% by weight of sodium methoxide (0.060 mol) as liquid B.

12.9 g of dioxane and 160 mL of absolute ethanol were added to a reaction flask replaced with nitrogen, and cooled to -2 to 2°C. In the four-neck flask added with the cooled reaction solvent, all the above liquid A was added to the reaction solvent (pH value 4).

Then, liquid B was added dropwise over about 2 hours while maintaining the temperature of the reaction system between -2°C and 2°C. When about 1/3 of the liquid B was added dropwise, the reaction liquid began to appear white turbid, and became a slurry containing white crystals. At the end of the addition, the pH was 8. After completion of the dropwise addition, the mixture was further stirred at 0° C. for 0.25 hours to perform a reaction.

After the reaction was completed, 0.40 g of acetic acid was added to the reaction solution after the reaction for neutralization. The pH value of the reaction system after neutralization is 4-5. After the neutralization treatment, the mixture was further aged with stirring at -2 to 2°C for 0.5 hours.

Then, after the aging is finished, filter with a 3G glass filter, rinse the obtained filter cake with 18g of ice-cooled methanol, then use 36g of 30% methanol solution containing water for the second rinse, and rinse with 18g of ice-cooled methanol. Methanol for the third rinse.

Put the washed filter cake into a desiccator, place it overnight at room temperature, and dry it with a vacuum pump to obtain 20.50 g of 3-chloromethyl-3-cephem derivative crystals (general formula (2a)) (purity 92.0 %, yield 74.5%).

(authentication data)

¹ H-NMR (δ, CDCl ₃ )

3.41 (1H, d, j = 18.5), 3.59 (1H, d, j = 18.5), 4.92 (1H, d, j = 4.9), 5.82 (1H, d, d, j = 4.9, 9.3), 6.12 ( 1H, d, j = 9.3), 3.58 (1H, d, j = 16.1), 3.67 (1H, d, j = 16.1), 7.40 ~ 7.28 (5H, m), 4.39 (1H, d, j = 11.9) , 4.50 (1H, d, j = 11.9), 5.20 (2H, s), 7.32 (2H, d, j = 8.6), 6.88 (2H, d, j = 8.6), 3.80 (3H, s)

FT-IR (cm ^-1 , KBr)

3449cm ^-1 , 3271cm ^-1 , 1778cm ^-1 , 1251cm ^-1

FAB-MS

M+1: 487m/z

Comparative example 1

65.8 g (0.052 mol) of a dioxane solution containing 49.7% by weight of azetidinone derivatives (compound (10)) was added to a dropping funnel replaced with nitrogen, and 50 g of anhydrous methanol (Kanto Chemical Co., Ltd. Reagent) was diluted as solution A.

Dilute 17.0 g of a methanol solution containing 24% by weight sodium methoxide (reagent grade 1) with 85.0 g of anhydrous methanol to prepare a methanol solution containing 4% by weight of sodium methoxide (0.076 mol) as liquid B.

Add 13 g of dioxane to the reaction flask, add 160 mL of absolute ethanol, and cool to -2 to 2°C. Add 1/8 of the total amount of the above liquid A into the prepared reaction solvent (pH 4) in the four-necked flask with cooled reaction solvent.

Then, liquid A and liquid B were simultaneously added dropwise while maintaining the temperature of the reaction system between -2°C and 2°C. When about 1/5 of the liquid B was added dropwise, the reaction liquid began to appear white turbid, and became a slurry containing white crystals. Then add liquid A and liquid B dropwise at the same time, and continue to add dropwise for about 4 hours until the dropwise addition of liquid A is completed (pH value is 7-8). At this time, the amount of liquid B added dropwise was 80.4 g, and the pH value was 7-8. It takes 30 minutes to add the remaining 20 g of liquid B dropwise. The reaction liquid at this time was reddish brown. The pH at the end of the dropwise addition was 10. The reaction was further stirred at 0°C for 0.25 hours.

After the reaction was completed, 0.64 g of acetic acid was added to the reaction solution after the reaction for neutralization. The pH value of the reaction system after neutralization is 4-5. After the neutralization treatment, the mixture was further aged with stirring at -2 to 2°C for 0.5 hours.

Then, after the aging is finished, filter with a 3G glass filter, rinse the obtained filter cake with 18g of ice-cooled methanol, then use 36g of 30% methanol solution containing water for the second rinse, and rinse with 18g of ice-cooled methanol. Methanol for the third rinse.

The washed filter cake is put into a desiccator, placed overnight at room temperature, and dried with a vacuum pump to obtain 18.07g of 3-chloromethyl-3-cephem derivative crystals (general formula (2a)) (purity 85.9 %, yield 61.3%).

Comparative example 2

Under a nitrogen atmosphere, 71.48 g (0.104 mol) of the azetidinone chloride derivative (compound (10)) was dissolved in 640 mL of anhydrous DMF, and cooled to -30°C. Then, 28% 17.76 g of ammonia water (0.292 mol, equivalent to 2.8 times mol) was added dropwise in small amounts at a time at -30 to -20°C. After dropping, mature at -30～-20°C for 1 hour.

After the reaction, 5% hydrochloric acid was added to the reaction solution to adjust the pH value to 4-5, and then 1.92L acetic acid was added, and the organic layer was separated at 0°C. Then, the separated organic layer was washed twice with saturated brine, and anhydrous sodium sulfate was added to the organic layer for dehydration.

Then, the dehydrated organic layer was concentrated under reduced pressure to obtain 38.0 g (purity 93.3%, yield 70.0%) of an oily 3-chloromethyl-3-cephem derivative (general formula (2a)).

(authentication data)

¹ H-NMR (δ, CDCl ₃ )

3.41 (1H, d, j = 18.5), 3.59 (1H, d, j = 18.5), 4.92 (1H, d, j = 4.9), 5.82 (1H, d, d, j = 4.9, 9.3), 6.12 ( 1H, d, j = 9.3), 3.58 (1H, d, j = 16.1), 3.67 (1H, d, j = 16.1), 7.40 ~ 7.28 (5H, m), 4.39 (1H, d, j = 11.9) , 4.50 (1H, d, j = 11.9), 5.20 (2H, s), 7.32 (2H, d, j = 8.6), 6.88 (2H, d, j = 8.6), 3.80 (3H, s)

FT-IR (cm ^-1 , KBr)

3449cm ^-1 , 3271cm ^-1 , 1778cm ^-1 , 1251cm ^-1

FAB-MS

M+1: 487m/z

Comparative example 3

10.0 g of the 3-chloromethyl-3-cephem derivative (general formula (2a)) obtained in Comparative Example 2 was dissolved in 28 mL of anhydrous DMF.

In addition, 400 mL of cooled methanol was prepared at 3°C, and the DMF solution in which the oily 3-chloromethyl-3-cephem derivative was dissolved was slowly added dropwise at a temperature of 3 to 5°C to precipitate 3-Chloromethyl-3-cephem derivative crystallization.

After solid-liquid separation, the crystallization of 3-chloromethyl-3-cephem derivatives reclaimed by methanol rinse, then dry under reduced pressure, obtain 8.62g (purity 94.0%, yield 86.2%, obtain by comparative example 2 The yield obtained was 60.3%) of 3-chloromethyl-3-cephem derivative crystals.

(authentication data)

¹ H-NMR (δ, CDCl ₃ )

3.41 (1H, d, j = 18.5), 3.59 (1H, d, j = 18.5), 4.92 (1H, d, j = 4.9), 5.82 (1H, d, d, j = 4.9, 9.3), 6.12 ( 1H, d, j = 9.3), 3.58 (1H, d, j = 16.1), 3.67 (1H, d, j = 16.1), 7.40 ~ 7.28 (5H, m), 4.39 (1H, d, j = 11.9) , 4.50 (1H, d, j = 11.9), 5.20 (2H, s), 7.32 (2H, d, j = 8.6), 6.88 (2H, d, j = 8.6), 3.80 (3H, s)

FT-IR (cm ^-1 , KBr)

3449cm ^-1 , 3271cm ^-1 , 1778cm ^-1 , 1251cm ^-1

FAB-MS

M+1: 487m/z

Then, X-ray diffraction analysis was performed on the 3-chloromethyl-3-cephem derivative crystal obtained in Comparative Example 3 in the same manner as in Example 1, and its X-ray diffraction pattern is shown in Table 2.

Table 2 d I/I ₀ 12.95 0.61 11.68 0.51 9.91 0.10 6.47 0.63 6.33 0.24 5.81 0.62 4.96 0.47 4.73 0.70 4.66 0.72 4.51 0.67 4.44 0.31 4.29 0.56 4.17 1.00 4.05 0.25 3.98 0.17 3.86 0.74 3.78 0.47 d I/I ₀ 3.70 0.14 3.56 0.07 3.54 0.06 3.45 0.54 3.37 0.20 3.29 0.14 3.22 0.20 3.20 0.15 3.16 0.20 3.09 0.18 2.90 0.22 2.85 0.10 2.68 0.14 2.60 0.16 2.58 0.11 2.50 0.10 2.49 0.13

(Note) d in Table 2 is the spacing between lattice planes; I/I ₀ is the relative intensity of the diffraction peak with respect to d=4.17.

Comparative example 4

35.74 g (0.052 mol) of the chlorinated azetidinone derivative (compound (10)) was diluted in 135 g of methanol under nitrogen atmosphere and cooled to -5°C. Then, at -5 to -2°C, add dropwise a solution of 35.0 g (0.078 mol, 1.5 times mol) of 20% aqueous ethanol containing 12.5% caustic potash in 30 minutes. After the dropwise addition, it was matured at -2 to 0°C for 1 hour. The pH value after ripening is 9. After aging is completed, acetic acid is added to adjust the pH value to 4-5, and then aged at -2-2°C for 0.5 hours with stirring. Then, after the aging is completed, filter with a 3G glass funnel, rinse the obtained filter cake with 18 g of ice-cooled methanol, then use 36 g of 30% water-containing methanol for the second rinse, and use ice-cooled methanol for the third time. Rinse. Put the washed filter cake into a desiccator, place it overnight at room temperature, and dry it with a vacuum pump to obtain 15.15 g (purity 51.3%, yield 30.7%) of tan 3-chloromethyl-3-cephem The derivative (general formula (2a)) crystallizes.

<Stability Test>

5 g each of the 3-chloromethyl-3 cephem derivatives obtained in Examples 1 to 5 and Comparative Examples 1 to 4 were put into a closed beaker, and placed in a thermostatic chamber set at 25° C. for 30 days.

The purity of each 3-chloromethyl-3-cephem derivative was measured after standing for 30 days, and the results are shown in Table 3.

table 3 Purity before placement (%) Purity after storage (%) Example 1 94.1 94.1 Example 2 94.3 94.3 Example 3 91.6 91.6 Example 4 94.4 94.4 Example 5 92.0 92.0 Comparative example 1 85.9 85.9 Comparative example 2 93.3 89.9 Comparative example 3 94.0 94.0 Comparative example 4 51.3 46.5

The effect of the invention

From the above results, it can be seen that according to the production method of the present invention, synthetic intermediates usable as various antibiotics of the cephalosporin series can be produced continuously with high yield and high purity by an industrially advantageous method Crystallization of 3-chloromethyl-3-cephem derivatives. Furthermore, the 3-chloromethyl-3-cephem derivative crystal obtained by the production method of the present invention has excellent long-term stability under mild conditions.

Claims (14)

1. the 3-chloromethyl shown in the general formula (2)-3-Cephem Derivative crystalline manufacture method is characterized in that, in containing alcoholic solvent, the pH value is under the condition below 8, chlorination azetidinone derivative and the alkoxide shown in the general formula (1) to be reacted:

(in the formula, R ₁Expression replaces or unsubstituted aryl or replacement or unsubstituted heterocycle residue, R ₂And R ₃Expression replaces or unsubstituted aromatic hydrocarbyl);

(in the formula, R ₂And R ₃Expression replaces or unsubstituted aromatic hydrocarbyl).

2. the 3-chloromethyl shown in the general formula (2)-3-Cephem Derivative crystalline manufacture method is characterized in that, in containing the solvent of pure and mild ether, the pH value is under the condition below 8, chlorination azetidinone derivative and the alkoxide shown in the general formula (1) to be reacted:

(in the formula, R ₁Expression replaces or unsubstituted aryl or replacement or unsubstituted heterocycle residue, R ₂And R ₃Expression replaces or unsubstituted aromatic hydrocarbyl)

(in the formula, R ₂And R ₃Expression replaces or unsubstituted aromatic hydrocarbyl).

3. the 3-chloromethyl described in claim 1 or 2-3-Cephem Derivative crystalline manufacture method, it is characterized in that, contain the described chlorination azetidinone derivative solution (A) in the ether solvents with being dissolved in and be dissolved in the alkoxide solution (B) that contains in the alcoholic solvent and join in the alcoholic solution (C) and react.

4. as each described 3-chloromethyl of claim 1～3-3-Cephem Derivative crystalline manufacture method, it is characterized in that, in described alcoholic solution (C), add as a part that is dissolved in the chlorination azetidinone derivative solution (A) that contains in the ether solvents, contain the equivalent that responds be 5～30mol% chlorination azetidinone derivative solution (A) afterwards, with remaining solution (A) that contains chlorination azetidinone derivative be dissolved in the alkoxide solution (B) that contains in the alcoholic solvent and join simultaneously in the described alcoholic solution (C) and react.

5. as each described 3-chloromethyl-3-Cephem Derivative crystalline manufacture method in the claim 1～4, it is characterized in that, described chlorination azetidinone derivative and alkoxide react the ratio of 0.8～1.5mol alkoxide with 1mol chlorination azetidinone derivative.

6. as each described 3-chloromethyl-3-Cephem Derivative crystalline manufacture method in the claim 1～4, it is characterized in that described alcohol is selected from least a in methyl alcohol or the ethanol.

7. as each described 3-chloromethyl-3-Cephem Derivative crystalline manufacture method in the claim 1～4, it is characterized in that described ether is diox.

8. as each described 3-chloromethyl-3-Cephem Derivative crystalline manufacture method in the claim 1～4, it is characterized in that described alkoxide is sodium methylate or sodium ethylate.

9. as each described 3-chloromethyl-3-Cephem Derivative crystalline manufacture method in the claim 1～8, it is characterized in that described being reflected at below 5 ℃ carried out.

10. want 3 or 4 described 3-chloromethyls-3-Cephem Derivative crystalline manufacture method as right, it is characterized in that, described solution (A) is that the chlorination azetidinone is dissolved in the solution that forms in the mixed solvent of diox and alcohol.

11., it is characterized in that described solution (B) is that alkoxide is dissolved in the solution that forms in the alcohol as claim 3 or 4 described 3-chloromethyls-3-Cephem Derivative crystalline manufacture method.

12., it is characterized in that described solution (C) is the mixed solvent of pure and mild diox as claim 3 or 4 described 3-chloromethyls-3-Cephem Derivative crystalline manufacture method.

13. as each described 3-chloromethyl-3-Cephem Derivative crystalline manufacture method in the claim 1～12, it is characterized in that, by dripping described solution (A) and solution (B) reacts.

14., it is characterized in that described being reflected under the anhydrous state carried out as each described 3-chloromethyl-3-Cephem Derivative crystalline manufacture method in the claim 1～13.