Process for the production of beta-lactam compounds

Abstract

A method for manufacturing a β-lactam compound includes the following steps: introducing a reaction solution (i), a solution of an acid halide (ii), and a solution (iii) of a β-lactam compound (a) having an amino group into different flow paths, allowing each solution to flow within its respective flow path. The reaction solution (i) is a reaction solution obtained by dissolving a metal salt (y) of formula (2) obtained by introducing a protecting group onto the amino group of the metal salt (x) in a solution of formula (1); generating a mixed acid anhydride by merging the reaction solution (i) and solution (ii); and generating a β-lactam compound (b) having an amide bond by merging the merged liquid (M1) and solution (iii). In the formulas, R represents a cyclic hydrocarbon group, M represents an alkali metal, and X represents a protecting group.

Description

Technical Field

[0001] This invention relates to a method for manufacturing a β-lactam compound. Background Technology

[0002] β-lactam compounds (compounds containing a β-lactam ring) are widely known as antibiotics and are important compounds for maintaining the health of humans and other animals. Examples of known β-lactam antibiotics include ampicillin, epicillin, cephalexin, cefadroxil, and cefaclor.

[0003] As a method for synthesizing these β-lactam compounds, the so-called Dane salt method is known. For example, Patent Document 1 describes a method for synthesizing ampicillin based on the Dane salt method. In this method, 4-methylpyridine as a catalyst is added to a suspension containing a high content of potassium DN-(1-ethoxycarbonylpropen-2-yl)-α-aminophenylacetate as a Dane salt in n-butyl acetate, and the mixture is stirred at room temperature for 15 hours, then cooled to -33°C. Next, neopentanoyl chloride is added, and the mixture is stirred at -20°C for 90 minutes to react with the Dane salt, thereby obtaining a mixture containing mixed carboxylic anhydrides. In addition, triethylamine (TEA) as a base is added to a mixed solvent of isopropanol (IPA) and water to prepare a solution in which 6-aminopenicillanic acid (6-APA) is dissolved. The solution was added dropwise to the above mixture at a temperature of -45 to -30°C for 45 minutes, and the reaction mixture was further stirred at -30 to -35°C for 90 minutes, thereby forming an amide bond between the mixed carboxylic anhydride and 6-APA, and water played a role in removing the 1-ethoxycarbonylpropen-2-yl (also known as: 3-ethoxy-1-methyl-3-oxo-1-propenyl) as a protecting group, thereby generating ampicillin.

[0004] If this reaction is presented as a reaction scheme, it would be as follows.

[0005] [Chemical Formula 1]

[0006] Previous technical documents

[0007] Patent documents

[0008] Patent Document 1: Japanese Patent Application Publication No. 5-97865 Summary of the Invention

[0009] The technical problem to be solved by the invention

[0010] The aforementioned Dane salts have extremely low solvent solubility, resulting in excessively low concentrations if used in solution for the reaction, making industrial application impractical. Therefore, as mentioned above, Dane salts must currently be used in the reaction in suspension form. Consequently, the synthesis of β-lactam compounds based on the Dane salt method is practically limited to batch reactions, and as described above, requires a relatively long reaction time while mixing the suspension.

[0011] In chemical synthesis reactions, unlike batch reactions, there are known flow-type reactions capable of continuous synthesis. In flow-type reactions, two or more feedstock solutions typically flow in separate flow paths and then merge downstream. The target synthesis reaction occurs as the merged liquid flows further downstream. Therefore, as long as the feedstock supply continues, the target product can be obtained continuously. Compared to batch reactions, production efficiency can be improved by combining precise temperature management of the reaction system with increased stirring efficiency based on the merging of liquids. However, flow-type reactions rely on the premise of smooth liquid flow within the flow path. When applying the aforementioned suspension containing a high concentration of Dane salt to a flow-type reaction, smooth liquid flow within the flow path is impossible, and blockages occur during the flow process, making it impractical.

[0012] The objective of this invention is to provide a method for manufacturing β-lactam compounds that uses starting materials with low solvent solubility, such as Dane salts, but can continuously and efficiently obtain the target β-lactam compound through a flow reaction, via the generation of mixed anhydrides and even amidation reactions.

[0013] means for solving technical problems

[0014] The inventors have conducted in-depth research on the aforementioned issues. As a result, they discovered that if glycine compounds with cyclic hydrocarbon groups, such as phenylglycine, are dissolved in an organic solvent containing alkali metal hydroxides to form alkali metal salts, and a protecting group is introduced into the amino group of this metal salt to synthesize Dane salts or similar salts, then although the salts with the introduced protecting group have low solvent solubility in the solid state as described above, these salts are in a state of high concentration dissolution in the synthesis reaction solution, and even if the synthesis reaction solution is concentrated to a certain extent, these salts can still maintain their dissolved state.

[0015] This invention was completed through further and repeated research based on these insights.

[0016] The above-mentioned problems of the present invention are solved by the following solution.

[0017] [1]

[0018] A method for manufacturing a β-lactam compound, comprising the following steps: The reaction solution (i), the solution (ii) formed by dissolving the acid halide, and the solution (iii) formed by dissolving the β-lactam compound (a) having an amino group are introduced into different flow paths, so that each solution flows in the respective flow path. The reaction solution (i) is a reaction solution formed by dissolving the metal salt (y) represented by the following formula (2) in a solution formed by dissolving the metal salt (x) represented by the following formula (1). This metal salt (y) is generated by introducing a protecting group into the amino group of the metal salt (x). By merging the above reaction solution (i) with the above solution (ii), during the downstream flow of the merged liquid (M1), the above metal salt (y) reacts with the above acid halide to generate a mixed acid anhydride; and The above-mentioned combined liquid (M1) is combined with the above-mentioned solution (iii). During the downstream flow of the combined liquid (M2), the above-mentioned mixed acid anhydride reacts with the above-mentioned β-lactam compound (a) having an amino group to generate a β-lactam compound (b) having an amide bond.

[0019] [Chemical Formula 1]

[0020] In the formula, R represents a cyclic hydrocarbon group, M represents an alkali metal, and X represents a protecting group.

[0021] [2]

[0022] According to the method for manufacturing the β-lactam compound described in [1], the above reaction solution (i) and the above solution (ii) are combined at -40 to 0°C.

[0023] [3]

[0024] According to the method for manufacturing the β-lactam compound described in [1] or [2], the above-mentioned combined liquid (M1) and the above-mentioned solution (iii) are combined at -40 to 0°C.

[0025] [4]

[0026] The method for manufacturing a β-lactam compound according to any one of [1] to [3], wherein the above solution (iii) contains 5 to 50% by mass of water.

[0027] [5]

[0028] The method for manufacturing a β-lactam compound according to any one of [1] to [4], wherein the above solution (iii) contains an alkali.

[0029] [6]

[0030] The method for manufacturing a β-lactam compound according to any one of [1] to [5], wherein the protecting group is 3-ethoxy-1-methyl-3-oxo-1-propenyl and / or 3-methoxy-1-methyl-3-oxo-1-propenyl.

[0031] [7]

[0032] The method for manufacturing a β-lactam compound according to any one of [1] to [6], wherein the acid halide comprises a carboxylic acid halide.

[0033] [8]

[0034] According to the method for manufacturing the β-lactam compound described in [7], the reaction of the metal salt (y) in the above-mentioned combined liquid (M1) with the above-mentioned carboxylic acid halide is carried out in the presence of an alkaline catalyst.

[0035] [9]

[0036] According to the method for manufacturing the β-lactam compound described in [8], the alkaline catalyst described above has a pyridine skeleton.

[0037]

[10]

[0038] According to the method for manufacturing the β-lactam compound described in [8] or [9], the molar amount of the alkaline catalyst is set to 0.001 to 0.1 relative to 1 molar amount of the β-lactam compound (a) having an amino group.

[0039]

[11]

[0040] The method for manufacturing a β-lactam compound according to any one of [7] to

[10] , wherein the carboxylic acid halide comprises a carboxylic acid chloride.

[0041]

[12]

[0042] The method for manufacturing a β-lactam compound according to any one of [1] to

[11] , wherein the hydrocarbon ring of the cyclic hydrocarbon group is a benzene ring or a 1,4-cyclohexadiene ring.

[0043]

[13]

[0044] The method for manufacturing a β-lactam compound according to any one of [1] to

[12] , wherein M is sodium or potassium.

[0045]

[14]

[0046] The method for manufacturing a β-lactam compound according to any one of [1] to

[13] , wherein the above-mentioned β-lactam compound (a) having an amino group is 6-aminopenicillanic acid or 7-aminodeacetoxycephalosporanic acid.

[0047]

[15]

[0048] The method for manufacturing a β-lactam compound according to any one of [1] to

[14] , wherein the β-lactam compound (b) is ampicillin.

[0049] In this specification, the numerical range indicated by “~” refers to the range encompassed by the values ​​recorded before and after “~” as the lower and upper limits.

[0050] In this invention, the term "substituent" refers to a condition in which, in addition to the substituent itself, the substituent is further substituented in a manner that does not impair the effects of the invention. For example, "cyclic hydrocarbon group" refers to both an unsubstituted cyclic hydrocarbon group and a cyclic hydrocarbon group with a substituent. Similarly, "phenyl" refers to both an unsubstituted phenyl group and a phenyl group with a substituent.

[0051] Invention Effects

[0052] According to the method for producing β-lactam compounds of the present invention, even when using starting materials with low solvent solubility such as Dane salts, the target β-lactam compound can be obtained continuously and efficiently through a flow reaction, including the generation of mixed acid anhydrides and even amidation reaction. Attached Figure Description

[0053] Figure 1 This is a schematic diagram illustrating an example of a flow reaction system used in the manufacturing method of the present invention. Detailed Implementation

[0054] [Methods for manufacturing β-lactam compounds]

[0055] In the method for manufacturing the β-lactam compound of the present invention (hereinafter also referred to as "the manufacturing method of the present invention"), a flow-flow reaction is employed. In this flow-flow reaction, the following reaction solutions (i), (ii), and (iii) are flowed in different flow paths and then merged sequentially to carry out the target reaction.

[0056] Reaction solution (i): A reaction solution is prepared by dissolving a metal salt (y) represented by formula (2), which is produced by introducing a protecting group into the amino group of the metal salt (x) represented by formula (1) below, in a solution prepared by dissolving the metal salt (x) represented by formula (1) below.

[0057] [Chemical Formula 2]

[0058] In the formula, R represents a cyclic hydrocarbon group, M represents an alkali metal, and X represents a protecting group.

[0059] Furthermore, the metal salt (x) represented by formula (1) above can be either L-form or D-form. For example, from the viewpoint that the β-lactam compound (b) described later as the final product exhibits higher antibacterial activity, the D-form is preferred. The metal salt (y) represented by formula (2) above is the same.

[0060] Solution (ii): A solution formed by dissolving acid halides.

[0061] Solution (iii): A solution obtained by dissolving an amino-containing β-lactam compound (a).

[0062] In the above-described flow reaction, by merging the reaction solution (i) and solution (ii), during the downstream flow of the merged liquid (M1), the metal salt (y) reacts with the acid halide to generate a mixed acid anhydride. Furthermore, by merging the merged liquid (M1) and solution (iii), during the downstream flow of the merged liquid (M2), the mixed acid anhydride reacts with the amino-containing β-lactam compound (a) to generate a β-lactam compound (b) containing an amide bond. This β-lactam compound (b) containing an amide bond is the target β-lactam compound (final product) manufactured by the manufacturing method of the present invention.

[0063] In this specification, the terms "upstream" and "downstream" are used relative to the direction in which the liquid flows. The side where the liquid enters (the side from which the liquid flows) is upstream, and the side from which the liquid flows out is downstream.

[0064] Preferred forms of the above-mentioned reaction solutions (i), (ii) and (iii) will be described.

[0065] <Reaction Solution (i)>

[0066] As described above, reaction solution (i) is a reaction solution obtained by dissolving the metal salt (y) produced by introducing a protecting group into the amino group of the metal salt (x) (through a protecting group introduction reaction) in a solution obtained by dissolving the metal salt (x). That is, the reaction solution in which the protecting group introduction reaction has occurred, or a concentrate or dilution of the reaction solution, can be used as reaction solution (i). In reaction solution (i), the metal salt (y) does not precipitate and remains in a solution state. From the viewpoint of subsequent reaction efficiency, reaction solution (i) is preferably the above-mentioned concentrate. Reaction solution (i) is preferably able to maintain a solution state at -20°C, more preferably able to maintain a solution state at -30°C, even more preferably able to maintain a solution state at -40°C, and even more preferably able to maintain a solution state at -50°C.

[0067] Regarding the above-mentioned protecting group introduction reaction, taking the reaction using D-phenylglycine as the starting material and introducing 3-ethoxy-1-methyl-3-oxo-1-propenyl as the amino protecting group (i.e., one method of Dane salt synthesis) as an example, an example of its reaction scheme is shown below. In the following scheme, Et represents ethyl.

[0068] [Chemical Formula 3]

[0069] In the above reaction scheme, D-phenylglycine is converted into a potassium salt state in a mixed solvent of toluene and methanol by potassium hydroxide. This potassium salt is equivalent to the aforementioned metal salt (x). Next, by reacting this potassium salt with ethyl acetoacetate, a protecting group is introduced into the amino group of the potassium salt to obtain a Dane salt. This Dane salt is equivalent to the aforementioned metal salt (y). In the above reaction scheme, methanol is used in part of the solvent to dissolve the potassium hydroxide. Methanol may produce side reactions in subsequent reactions; therefore, the reaction solution (i) is preferably used as a concentrated solution obtained by removing methanol from the above reaction solution.

[0070] Hereinafter, without being limited to the reaction schemes exemplified above, preferred forms of the reaction solution (i) in this invention will be described.

[0071] Regarding the aforementioned metal salt (x), as represented by formula (1) above, in compounds where the carbon atom bonded to the amino group of glycine has a cyclic hydrocarbon group as a substituent, the carboxyl group is in the state of an alkali metal salt. The hydrocarbon ring (cyclic hydrocarbon) of this cyclic hydrocarbon group is preferably a 6-membered ring, more preferably a benzene ring or a 1,4-cyclohexadiene ring. Furthermore, this hydrocarbon ring may be unsubstituted or may have substituents within a range that does not impair the effects of the present invention. Specific examples of preferred metal salts (x) include compounds in which the carboxyl group is in the salt state via an alkali metal in phenylglycine, 2-(2,5-dihydroxyphenyl)glycine, 4-fluoro-2-phenylglycine, 2-(2-chlorophenyl)glycine, 2-(4-chlorophenyl)glycine, etc.

[0072] The metal salt (x) mentioned above is an alkali metal salt, preferably a sodium salt or a potassium salt, more preferably a potassium salt.

[0073] In the above-mentioned protecting group introduction reaction, there are no particular limitations as long as the protecting group introduced is an amino acid protecting group. For example, Ac group (acetyl), Boc group (tert-butoxycarbonyl), Cbz group (benzyloxycarbonyl), Fmoc group (9-fluorenylmethoxycarbonyl), Bz group (benzoyl), Bzl group (benzyl), Troc group (2,2,2-trichloroethoxycarbonyl), Teoc group (2-(trimethylsilyl)ethoxycarbonyl), Alloc group (allyloxycarbonyl), 3-ethoxy-1-methyl-3-oxo-1-propenyl, 3-methoxy-1-methyl-3-oxo-1-propenyl, etc. From the viewpoint that deprotection can be easily carried out using the water contained in solution (iii), the protecting group introduced in the above-mentioned protecting group introduction reaction is preferably 3-ethoxy-1-methyl-3-oxo-1-propenyl or 3-methoxy-1-methyl-3-oxo-1-propenyl, more preferably 3-ethoxy-1-methyl-3-oxo-1-propenyl.

[0074] The solvent used in the above-mentioned protecting group introduction reaction is not particularly limited as long as it can dissolve the alkali metal compound (preferably an alkali metal hydroxide) used to form the salt formed from the alkali metal, can dissolve the metal salt (x), and can dissolve the metal salt (y). A mixture of aromatic hydrocarbon solvent and aliphatic alcohol solvent is preferred as such a solvent. The solvents constituting the mixture are preferably miscible (not phase-separable).

[0075] Examples of aromatic hydrocarbon solvents include benzene, toluene, styrene, o-xylene, p-xylene, m-xylene, and mesitylene. One or more aromatic hydrocarbon solvents can be used as aromatic hydrocarbon solvents.

[0076] As aliphatic alcohol solvents, lower alcohols such as methanol, ethanol, and propanol are preferred. One aliphatic alcohol solvent or a combination of two or more can also be used.

[0077] In a mixed solvent of aromatic hydrocarbon solvent and aliphatic alcohol solvent, the mixing ratio of each solvent is not particularly limited and can be appropriately set. For example, the proportion of aliphatic alcohol solvent in the mixed solvent can be set to 1 to 40% by mass, more preferably 3 to 30% by mass, and even more preferably 5 to 20% by mass. By using aliphatic alcohol solvent containing the above-mentioned preferred amounts, alkali metal hydroxides and other bases can be sufficiently dissolved, the above-mentioned metal salt (x) can be generated efficiently in the mixed solvent, and the metal salt (x) can exist in a dissolved state.

[0078] From the viewpoint of further suppressing side reactions in the subsequent reaction, the reaction solution (i) flowing in the flow path in the flow-through reaction preferably has the aforementioned aliphatic alcohol solvent removed from the reaction liquid into which the protecting group was introduced. That is, the solvent constituting the reaction solution (i) is preferably an aromatic hydrocarbon solvent. From the viewpoint of balancing improved productivity through high concentration and suppression of precipitation, the concentration of solid components (concentration of components other than solvent) in the reaction solution (i) is preferably 10 to 40% by mass, more preferably 10 to 30% by mass, and even more preferably 20 to 30% by mass. For example, as mentioned above, the solvent solubility of solid Dane salts is very low. However, the reaction solution (i) is a solution in which the metal salt (y) is dissolved at a much higher concentration.

[0079] The proportion of metal salt (y) in the solid component of the reaction solution (i) is preferably 50% by mass or more, more preferably 60% by mass or more, even more preferably 70% by mass or more, and even more preferably 80% by mass or more. The solid component of the reaction solution (i) is preferably entirely metal salt (y), but sometimes a certain amount of byproducts or residual raw materials may also be generated. The proportion of metal salt (y) in the solid component of the reaction solution (i) is preferably 50-100% by mass, more preferably 50-98% by mass, more preferably 60-97% by mass, more preferably 70-96% by mass, and more preferably 80-95% by mass.

[0080] In this invention, when the metal salt (y) obtained through the above-described protecting group introduction reaction is precipitated to form a solid state (dried product), its solubility at 25°C (the amount of metal salt (y) dissolved in 100g of the mixed solvent when 100g of the mixed solvent and 10g of the solid metal salt (y) are mixed and left to stand at 25°C for 24 hours) is preferably 1.0g or less. For example, the above-described Dane salt satisfies this solubility requirement.

[0081] The reaction solution (i) preferably contains a basic catalyst. This basic catalyst catalyzes the subsequent amidation reaction of the amino-containing β-lactam (a). Examples of such basic catalysts include 4-dimethylaminopyridine (DMAP), 4-methylpyridine, N-methylimidazolium, 2,6-dimethylpyridine, N-methylmorpholine, 1,4-diazabicyclo[2.2.2]octane (DABCO), N-benzyldimethylamine, N-methylpiperidine, dicyclohexylmethylamine, etc.

[0082] The aforementioned basic catalyst is preferably a compound having a tertiary amine, more preferably a compound having a pyridine skeleton or an imidazole skeleton, and even more preferably a compound having a pyridine skeleton. In the specific examples above, DMAP, 4-methylpyridine, and / or N-methylimidazole are preferred, with DMAP being particularly preferred.

[0083] The molar amount of the above-mentioned alkaline catalyst is preferably used in such a way that it is 0.001 to 0.1 relative to 1 molar amount of β-lactam (a) having an amino group.

[0084] <Solution (ii)>

[0085] The acid halide contained in solution (ii) is preferably a carboxylic acid halide, a sulfonic acid halide, or a halocarbamate. Furthermore, in this invention, the term "acid halide" is used in a broader sense than is usually understood. More specifically, in this invention, the term "acid halide" is used to mean that, in addition to the usual acid halide, it also includes halocarbamates.

[0086] The halogen atom in the acid halide is preferably a chlorine atom. The acid halide is preferably a carboxylic acid halide, and more preferably a carboxylic acid chloride. Specific examples of preferred acid halides include pivyl chloride, methanesulfonyl chloride, and ethyl chloroformate; pivyl chloride is preferred from the viewpoint of improving reactivity and suppressing byproducts.

[0087] As the solvent for solution (ii), an aromatic hydrocarbon solvent described in reaction solution (i) is preferred. Examples include benzene, toluene, styrene, o-xylene, p-xylene, m-xylene, mesitylene, etc., and one or more of these can be used. The aromatic hydrocarbon solvent used in solution (ii) is preferably the same type as the aromatic hydrocarbon solvent used in reaction solution (i).

[0088] The concentration of the acid halide in solution (ii) is not particularly limited. For example, the amount of metal salt (y) in the reaction solution (i) and the combined solution (M1) can be taken into consideration, as well as the flow rates of the reaction solution (i) and solution (ii), and can be appropriately set according to stoichiometry. For example, the concentration of the acid halide in solution (ii) can be set to 5 to 25% by mass, and preferably 10 to 20% by mass. In order to more reliably convert the metal salt (y) into the mixed anhydride, it is preferable that the acid halide is present at 1.05 equivalents or more relative to the metal salt (y) immediately after the reaction solution (i) and solution (ii) are combined (assuming it is an unreacted combined solution). Furthermore, from the viewpoint of suppressing the reaction between the β-lactam compound (a) having the above-mentioned amino group and the acid halide in the reaction solution (iii) thereafter, it is preferable that the acid halide is present at 1.50 equivalents or less relative to the metal salt (y) immediately after the reaction solution (i) and solution (ii) are combined. More preferably, immediately after the reaction solution (i) and solution (ii) have merged, the acid halide is present in an amount of 1.05 to 1.30 equivalents (preferably 1.05 to 1.20 equivalents) relative to the metal salt (y).

[0089] <Solution (iii)>

[0090] There are no particular restrictions on the amino-containing β-lactam compound (a) contained in solution (iii). If the combined liquid (M1) is combined with solution (iii), the above-mentioned mixed anhydride (activated carboxyl group) reacts with the amino group of the above-mentioned amino-containing β-lactam compound (a) during the downstream flow of the combined liquid (M2) to generate the amide-containing β-lactam compound (b) as the target.

[0091] From the viewpoint of obtaining β-lactam compounds (b) that are useful as antibiotics, preferred specific examples of β-lactam compounds (a) having an amino group include 6-aminopenicillanic acid (6-APA), 7-aminodeacetoxycephalosporanic acid (7-ADCA) or 7-amino-3-chlorocephalosporanic acid (7-ACCA) with the following structures.

[0092] [Chemical Formula 4]

[0093] By using 6-APA as an amino-containing β-lactam compound (a), ampicillin or epilicipall with the following structure can be obtained as β-lactam compounds (b). Furthermore, by using 7-ADCA as an amino-containing β-lactam compound (a), cefalexin or cefadroxil with the following structure can be obtained as β-lactam compounds (b). Additionally, by using 7-ACCA as an amino-containing β-lactam compound (a), cefaclor with the following structure can be obtained.

[0094] [Chemical Formula 5]

[0095] The solvent for solution (iii) is preferably a solvent formed by mixing an organic solvent and water. Furthermore, solution (iii) preferably contains a base. By containing a base, the solubility of the β-lactam compound (a) having an amino group can be further improved. Also, by containing water, the protecting group can be deprotected without special operation.

[0096] There are no particular limitations on the organic solvent; examples include water-soluble organic solvents that are compatible with water (e.g., alcohols, acetone, acetonitrile, N,N-dimethylacetamide, tetrahydrofuran, etc.). From the viewpoint of further suppressing byproducts, the organic solvents mentioned above are preferably aliphatic alcohol solvents, more preferably aliphatic lower alcohol solvents with 1 to 3 carbon atoms, and even more preferably isopropanol.

[0097] From the viewpoint of further improving the solubility of the amino-containing β-lactam compound (a), the water content in the solution (iii) is preferably 5 to 50% by mass, more preferably 8 to 40% by mass, and even more preferably 10 to 30% by mass.

[0098] Examples of bases include aliphatic amines, aromatic amines, and heterocyclic amines, with trialkylamines being preferred, and triethylamine being particularly preferred. By containing a base, solution (iii) is preferably controlled at pH 7.5 to 9.5, more preferably at pH 8.0 to 9.0. This further improves the solubility of the β-lactam compound (a) having an amino group.

[0099] The content of the amino-containing β-lactam compound (a) in solution (iii) is not particularly limited. Taking into account the amount of mixed anhydride in the mixed solution (mixed liquid (M2)) immediately after merging with the mixed liquid (M1), as well as the flow rates of the mixed liquid (M1) and solution (iii), it can be appropriately set according to stoichiometry. For example, the content of the amino-containing β-lactam compound (a) in solution (iii) can be set to 5 to 25% by mass, and preferably 10 to 20% by mass.

[0100] Immediately after the combined liquid (M1) and solution (iii) have merged (assuming the combined liquid is unreacted), it is preferable to have 0.7 to 1.3 equivalents of an amino-containing β-lactam compound (a) relative to the mixed anhydride, more preferably 0.8 to 1.0 equivalents of an amino-containing β-lactam compound (a).

[0101] <Flow-type reaction system>

[0102] An embodiment of the flow reaction system (flow reaction system) used in the present invention will be described using the accompanying drawings. Please note that the drawings are for illustrative purposes to facilitate understanding of the invention; for ease of explanation, the dimensions and relative sizes of the components may have been altered, and the actual relationships are not necessarily shown verbatim. Furthermore, the shapes and forms shown in these drawings are not limited to those specified in the present invention.

[0103] Figure 1 This is a schematic diagram illustrating an example of a flow reaction system used in the manufacturing method of the present invention. Figure 1The flow reaction system (10) shown includes: a flow path (1) having an inlet (Ia) for introducing the reaction solution (i); a flow path (2) having an inlet (Ib) for introducing the solution (ii); a confluence section (J1) where the flow path (1) and the flow path (2) merge; a reaction flow path (3) connected to the downstream end of the confluence section (J1); a flow path (4) having an inlet (Ic) for introducing the solution (iii); a confluence section (J2) where the reaction flow path (3) and the flow path (4) merge; and a reaction flow path (5) connected to the downstream end of the confluence section (J2).

[0104] The inlet ports (Ia), (Ib) and (Ic) are typically connected to a liquid delivery pump such as a syringe pump or a diaphragm pump (not shown), which can be configured to allow each solution to flow at a desired flow rate in each flow path by operating the pump.

[0105] right Figure 1 The structures of the embodiments shown will be described in more detail.

[0106] (Flow path (1))

[0107] The flow path (1) is a flow path that supplies the reaction solution (i) introduced from the inlet (Ia) to the confluence section (J1). The flow path (1) preferably has an equivalent diameter of 0.2 to 50 mm. By setting the equivalent diameter of the flow path (1) to 0.2 mm or more, pressure rise during liquid delivery can be suppressed, and even in the event of insoluble matter formation, flow path blockage can be prevented. Furthermore, by setting the equivalent diameter of the flow path (1) to 50 mm or less, the liquid temperature at the confluence section (J1) can be appropriately suppressed. The equivalent diameter of the flow path (1) is more preferably 0.5 to 30 mm, and even more preferably 1 to 20 mm.

[0108] The aforementioned "equivalent diameter," also known as the equivalent (straight) diameter, is a term used in mechanical engineering. When considering a circular pipe equivalent to any piping or flow path with an arbitrary internal cross-sectional shape, the diameter of the internal cross-section of this equivalent circular pipe is called the equivalent diameter. The equivalent diameter (deq) is defined as deq = 4A / p, using A: the internal cross-sectional area of ​​the piping and p: the wetted perimeter (inner circumference) of the piping. When applied to a circular pipe, the equivalent diameter is the same as the diameter of the internal cross-section of the circular pipe. Based on the data of the equivalent circular pipe, the equivalent diameter is used to estimate the flow or heat transfer characteristics of the piping, representing the spatial scale (representative length) of the phenomenon. In a regular quadrilateral pipe with an internal cross-section of side 'a', the equivalent diameter is deq = 4a. 2 / 4a=a, which becomes deq=a / 3 in an equilateral triangle tube with side a. 1 / 2In the flow between parallel plates at a flow path height h, deq becomes 2h (e.g., see: The Japan Society of Mechanical Engineers, ed., “Dictionary of Mechanical Engineering”, 1997, MARUZEN Co., Ltd.).

[0109] The length of the flow path (1) is not particularly limited. For example, it can be made of a flexible tube with a length of about 10cm to 200m (preferably 30cm to 100m).

[0110] There are no particular restrictions on the material of the hose. Examples include perfluoroalkoxyalkane (hereinafter referred to as PFA), polytetrafluoroethylene (hereinafter referred to as PTFE), aromatic polyetherketone resins, stainless steel, copper or copper alloys, nickel or nickel alloys, titanium or titanium alloys, quartz glass, and soda ash glass. From the viewpoint of flexibility and chemical resistance, the preferred materials for the hose are PFA, PTFE, stainless steel, nickel alloys, or titanium.

[0111] There is no particular limitation on the flow rate of the reaction solution (i) introduced through the aforementioned inlet (Ia). It can be appropriately set according to the purpose, taking into account the equivalent diameter of each flow path, the concentration of each liquid, and the introduction flow rate. For example, it is preferably 0.1 to 10000 mL / min, more preferably 0.5 to 8000 mL / min, and even more preferably 1 to 6000 mL / min.

[0112] The temperature of the flow path (1) can be set to -40 to 0°C, preferably -30 to -10°C, and more preferably -25 to -15°C.

[0113] (Flow path (2))

[0114] The flow path (2) is a flow path that supplies the solution (ii) introduced from the inlet (Ib) to the confluence section (J1). The flow path (2) preferably has an equivalent diameter of 0.2 to 50 mm. By setting the equivalent diameter of the flow path (2) to 0.2 mm or more, pressure rise during liquid delivery can be suppressed, and even in the event of insoluble matter formation, blockage of the flow path can be suppressed. Furthermore, by setting the equivalent diameter of the flow path (2) to 50 mm or less, the liquid temperature when introduced into the confluence section (J1) can be appropriately suppressed. The equivalent diameter of the flow path (2) is more preferably 0.5 to 30 mm, and even more preferably 1 to 20 mm.

[0115] The length of the flow path (2) is not particularly limited, for example, it can be made of a flexible tube with a length of about 10cm to 200m (preferably 30cm to 100m).

[0116] There are no particular restrictions on the material of the hose, and hoses of the materials exemplified in the above flow path (1) can be used.

[0117] There are no particular limitations on the flow rate of the solution (ii) introduced through the aforementioned inlet (Ib). The flow rate can be appropriately set according to the purpose, taking into account the equivalent diameter of each flow path, the concentration of each liquid, and the introduction flow rate. For example, it is preferably 0.1 to 10000 mL / min, more preferably 0.5 to 8000 mL / min, and even more preferably 1 to 6000 mL / min.

[0118] Furthermore, there are no particular restrictions on the relationship between the flow rate rB of the solution (ii) introduced from the inlet (Ib) and the flow rate rA of the liquid (i) introduced from the inlet (Ia), and it can be appropriately set considering the concentration of each solution. For example, it can be set to [flow rate rA] / [flow rate rB] = 10 / 1 to 1 / 10, preferably [flow rate rA] / [flow rate rB] = 5 / 1 to 1 / 5, and more preferably [flow rate rA] / [flow rate rB] = 3 / 1 to 1 / 3. In addition, in this specification, the unit of flow rate is mL / min.

[0119] The temperature of the flow path (2) can be set to -40 to 0°C, preferably -30 to -10°C, and even more preferably -25 to -15°C.

[0120] <Confluence part (J1)>

[0121] The reaction solution (i) introduced into the flow path (1) merges with the solution (ii) flowing in the flow path (2) at the confluence (J1). The confluence (J1) functions as a mixer, and there are no particular limitations as long as it can merge the flow path (1) and the flow path (2) into one flow path and deliver the liquid that has merged to the reaction flow path (3) connected to the downstream end of the confluence (J1).

[0122] exist Figure 1 In this embodiment, a T-shaped connector with three connection ports is used as the confluence section (J1). From the viewpoint of improving mixing performance, the equivalent diameter of the flow path within the confluence section (J1) is preferably 0.2 to 30 mm.

[0123] There are no particular restrictions on the material of the confluence section (J1). For example, materials such as PFA, PTFE, aromatic polyetherketone resin, stainless steel, copper or copper alloy, nickel or nickel alloy, titanium or titanium alloy, quartz glass, and soda lime glass can be used.

[0124] As for the aforementioned T-shaped connector, a wide range of commercially available products can be used, such as the cross connector manufactured by Upchurch, the Union Cross connector manufactured by Swagelok, the square connector manufactured by EYELA, and the SUS cross mixer manufactured by IDEX. Furthermore, in this invention, the confluence section (J1) is not limited to a T-shaped connector; for example, a Y-shaped connector can also be used. Moreover, it is also possible to use a connector with four or more connection ports to introduce the reaction solution (i) and / or solution (ii) from multiple inlet ports.

[0125] (Reaction flow path (3))

[0126] After the reaction solutions (i) and (ii) are combined and mixed in the confluence section (J1), the combined liquid (M1) flows into the reaction flow path (3). During the downstream flow in the reaction flow path (3), the metal salt (y) dissolved in the reaction solution (i) reacts with the acid halide dissolved in the solution (ii) to generate a mixed acid anhydride. The generated mixed acid anhydride is dissolved in the combined liquid (M1). That is, the reaction flow path (3) is the flow path for preparing the solution of the mixed acid anhydride and supplying the solution to the aforementioned confluence section (J2).

[0127] The shape of the reaction flow path (3) is not particularly limited, and a flexible tube is usually used. The preferred material of the reaction flow path (3) is the same as that of the flow path (1) described above. Furthermore, the flow time of the confluenced liquid in the confluence section (J1) within the flow path (3) can be adjusted by the equivalent diameter and length of the reaction flow path (3), the flow rate setting of the infusion pump, etc. The equivalent diameter of the reaction flow path (3) is preferably 0.2 to 50 mm, more preferably 0.3 to 30 mm, even more preferably 0.5 to 20 mm, even more preferably 0.7 to 15 mm, and even more preferably 1 to 12 mm. Furthermore, the length of the reaction flow path (3) is preferably 0.5 to 50 m, more preferably 1 to 30 m. In order to obtain a solution of mixed anhydride more reliably by more homogenizing the mixing of the reaction solution (i) and the solution (ii) in the reaction flow path (3), a static mixer can be installed in the middle of the reaction flow path (3).

[0128] The flow time of the combined liquid flowing in the reaction flow path (3) is preferably 0.1 to 20 minutes, more preferably 0.2 to 15 minutes, and even more preferably 0.4 to 10 minutes.

[0129] The temperature of the confluence section (J1) and the reaction flow path (3) can be set to -40 to 0°C, preferably -30 to -10°C, and even more preferably -25 to -15°C.

[0130] <Flow path (4)>

[0131] The flow path (4) is a flow path that supplies the solution (iii) introduced from the inlet (Ic) to the confluence (J2). The flow path (4) preferably has an equivalent diameter of 0.2 to 50 mm. By setting the equivalent diameter of the flow path (4) to 0.2 mm or more, pressure rise during liquid delivery can be suppressed, and even in the event of insoluble matter formation, blockage of the flow path can be suppressed. Furthermore, by setting the equivalent diameter of the flow path (4) to 50 mm or less, the liquid temperature when introduced into the confluence (J2) can be appropriately suppressed. The equivalent diameter of the flow path (4) is more preferably 0.5 to 30 mm, and even more preferably 1 to 20 mm.

[0132] The length of the flow path (4) is not particularly limited, for example, it can be made of a flexible tube with a length of about 10cm to 200m (preferably 30cm to 100m).

[0133] There are no particular restrictions on the material of the hose, and hoses of the materials exemplified in the above flow path (1) can be used.

[0134] There are no particular limitations on the flow rate of the solution (iii) introduced through the aforementioned inlet (Ic). The flow rate can be appropriately set according to the purpose, taking into account the equivalent diameter of each flow path, the concentration of each solution, and the introduction flow rate. For example, it is preferably 0.1 to 30,000 mL / min, more preferably 0.5 to 20,000 mL / min, and even more preferably 1 to 15,000 mL / min.

[0135] Furthermore, there are no particular restrictions on the relationship between the flow rate rD of the combined liquid (M1) introduced from the reaction flow path (3) to the confluence section (J2) and the flow rate rC of the solution (iii) introduced from the inlet (Ic), and it can be appropriately set considering the concentration of each solution. For example, it can be set to [flow rate rC] / [flow rate rD] = 10 / 1 to 1 / 10, preferably [flow rate rC] / [flow rate rD] = 5 / 1 to 1 / 5, and more preferably [flow rate rC] / [flow rate rD] = 3 / 1 to 1 / 3.

[0136] The temperature of the flow path (4) can be set to -40 to 0°C, preferably -30 to -10°C, and even more preferably -25 to -15°C.

[0137] <Confluence part (J2)>

[0138] The confluence liquid (M1) flowing in the reaction flow path (3) and the solution (iii) flowing in the flow path (4) merge at the confluence section (J2). The confluence section (J2) functions as a mixer, and there are no particular limitations as long as it can deliver the liquid that merges the reaction flow path (3) and the flow path (4) into one flow path and merges into the reaction flow path (5) connected to the downstream end of the confluence section (J2).

[0139] exist Figure 1 In this embodiment, a T-shaped connector with three connection ports is used as the confluence section (J2). From the viewpoint of improving mixing performance, the equivalent diameter of the flow path within the confluence section (J2) is preferably 0.2 to 30 mm.

[0140] The material, shape, number of connection ports, etc. of the merging section (J2) can be directly applied to the description of the merging section (J1).

[0141] <Reaction Flow Path (5)>

[0142] The combined liquid that merges and mixes in the above-mentioned confluence section (J2) flows into the reaction flow path (5). During the downstream flow in the reaction flow path (5), the above-mentioned β-lactam compound (a) reacts with the mixed acid anhydride to form an amide bond, generating the target β-lactam compound (b).

[0143] The shape of the reaction flow path (5) is not particularly limited; for example, a flexible tube can be used. The preferred material of the reaction flow path (5) is the same as that of the flow path (1) described above. Furthermore, the reaction time can be adjusted by the equivalent diameter and length of the reaction flow path (5), the flow rate setting of the delivery pump, etc. Generally, the equivalent diameter of the reaction flow path (5) is preferably 0.2 to 50 mm, more preferably 0.3 to 30 mm, even more preferably 0.5 to 20 mm, even more preferably 0.7 to 15 mm, and even more preferably 1 to 12 mm. Furthermore, the length of the reaction flow path (5) is preferably 0.5 to 50 m, more preferably 1 to 30 m. In order to make the mixing of the confluence liquid (M1) and the solution (iii) in the reaction flow path (5) more uniform, a static mixer can be installed in the middle of the reaction flow path (5).

[0144] The flow time of the confluence liquid flowing in the reaction flow path (5) is preferably 0.1 to 10 minutes, more preferably 0.2 to 8 minutes, and even more preferably 0.3 to 5 minutes.

[0145] The temperature (i.e., reaction temperature) of the confluence section (J2) and the reaction flow path (5) can be set to -40 to 0°C, preferably to -30 to -10°C, and even more preferably to -25 to -15°C.

[0146] If the reaction solution containing the target β-lactam compound (b) is removed during the flow in the reaction flow path (5), the target β-lactam compound (b) can be obtained from the removed reaction solution. Furthermore, the β-lactam compound (b) obtained in the reaction solution can be removed as a solid by performing conventional crystallization, filtration, etc. For example, by adding hydrochloric acid to the removed reaction solution to make it acidic and extracting the β-lactam compound (b) into the aqueous phase, and then adding an alkali such as ammonia to make the pH close to neutral, the β-lactam compound (b) can be precipitated in the aqueous phase. By filtering and collecting the precipitate, a solid β-lactam compound (b) can be obtained. Furthermore, by adding, for example, an aqueous solution of sodium bicarbonate to dissolve the filtered and collected β-lactam compound (b), and washing the aqueous phase with ethyl acetate, impurities in the aqueous phase can be removed. Then, by filtering and collecting the solid precipitated after adjusting the pH, a β-lactam compound (b) with higher purity can be obtained.

[0147] The present invention will be further described in detail with reference to the embodiments, but the present invention is not limited to these embodiments except as provided herein.

[0148] Example

[0149] [Example]

[0150] <Preparation of reaction solution (i)>

[0151] According to the following reaction scheme, Dane salt (y) is synthesized by using the potassium salt of D-phenylglycine as the metal salt (x), thereby obtaining the reaction solution (i).

[0152] [Chemical Formula 6]

[0153] Toluene (450 mL), methanol (50 mL), D-phenylglycine (50 g), and KOH (20.2 g) were added to a 1 L three-necked flask, and the mixture was heated to 80–90 °C to dissolve the compounds and form a solution. Then, ethyl acetoacetate (46.1 g) was added, and the mixture was stirred at 80–90 °C for 2 hours using a Dean-Stark mixer. After cooling to room temperature and filtering to remove insoluble matter, the resulting solution was concentrated by distillation to remove the solvent. When the solids concentration reached approximately 30% by mass (approximately 30% by mass as a Dane salt), toluene (200 mL) was added, and the mixture was concentrated again to obtain a toluene solution of Dane salt (approximately 25% by mass of solids, approximately 25% by mass as a Dane salt). Furthermore, methanol was completely removed through the above concentration process.

[0154] DMAP (0.0073 g) was added to a toluene solution (80.8 g) of the above Dane salt to obtain reaction solution (i).

[0155] <Preparation of solution (ii)>

[0156] Solution (ii) was obtained by dissolving PivCl (14.0 g) in toluene (70.0 g).

[0157] <Preparation of solution (iii)>

[0158] Solution (iii) was obtained by dissolving 6-APA (12.0 g) in a mixed solution of isopropanol (IPA, 56.1 g), water (12.0 g), and triethylamine (TEA, 7.1 g).

[0159] <Flow-based reaction>

[0160] The manufacturing method of the present invention was carried out via a flow reaction as follows.

[0161] Will Figure 1 The flow reaction system shown is set up in a constant temperature bath at -20°C to carry out the flow reaction. Therefore, in this flow reaction system, the liquid flowing in the flow path and the confluence is at -20°C.

[0162] The fluid was delivered using a syringe pump.

[0163] Perfluoroalkoxyalkane (PFA) tubing with an outer diameter of 1 / 8 inch and an inner diameter of 1.58 mm was used for flow paths (1), (2), reaction flow path (3), flow path (4) and reaction flow path (5).

[0164] As for the merging sections (J1) and (J2), a swigelok-manufactured tee (SS-200-3) was used.

[0165] The reaction solution (i) is introduced into the flow path (1) through the inlet (Ia) at a flow rate of 2.4 mL / min. Meanwhile, the solution (ii) is introduced into the flow path (2) through the inlet (Ib) at a flow rate of 1.6 mL / min. Thus, the two solutions are combined in the confluence (J1), and the combined liquid (M1) flows downstream in the reaction flow path (3), where mixed acid anhydrides are generated. In the confluence immediately after merging in the confluence (J1) (assuming it is an unreacted, homogeneous confluence), approximately 1.09 equivalents of acid halide are present relative to the metal salt (y).

[0166] Solution (iii) was introduced from the inlet (Ic) at a flow rate of 3.0 mL / min, causing solution (iii) to merge with the confluence liquid (M1) in the confluence section (J2). The confluence liquid (M2) then flowed in the downstream reaction flow path (5), where the amidation reaction and water-based deprotection were carried out. In the confluence liquid immediately after merging in the confluence section (J2) (assuming it to be an unreacted homogeneous confluence liquid), there was approximately 0.9 equivalents of an amino-containing β-lactam compound (a) relative to the mixed anhydride.

[0167] The flow time of the combined liquid (M1) in the reaction flow path (3) is 7 minutes, and the flow time of the combined liquid (M2) in the reaction flow path (5) is 1 minute.

[0168] The reaction solution was sampled from the outlet of reaction flow path (5) after 20 minutes. 1.5N hydrochloric acid (62 mL) was added to the sampled reaction solution to dissolve ampicillin (b), the target β-lactam compound, in the aqueous phase. 28% ammonia was added to the aqueous phase, the pH was adjusted to 4.5–5.0, and the precipitated solid was filtered off, thus obtaining crude ampicillin (HPLC purity 96%). 5% sodium bicarbonate aqueous solution (150 g) was added to the obtained crude ampicillin and dissolved. Then, after repeatedly washing the aqueous phase with ethyl acetate (100 mL) twice, 1N hydrochloric acid was added to the aqueous layer, the pH was adjusted to 4.5–5.0, and the precipitated solid was filtered off, thus obtaining purified ampicillin (yield 9.7 g, 80% yield, HPLC purity 98%). No flow obstruction or blockage occurred in any of the flow paths or at the confluence points during this flow-through reaction.

[0169] In addition, "HPLC purity" refers to the value calculated using the following formula, obtained by using a high-speed liquid chromatography (HPLC) apparatus under the following operating conditions, preparing a calibration curve with ampicillin standards.

[0170] Device: Prominence series (manufactured by Shimadzu Corporation)

[0171] Detector: UV / VIS absorbance detector SPD-20A, 220nm

[0172] Tubing string: Waters Atlantis T3 3um 4.6mmΦ×250mm

[0173] Column oven: 30℃

[0174] Mobile phase A: water, 0.1% phosphoric acid

[0175] Mobile phase B: Acetonitrile, 0.1% phosphoric acid

[0176] Mobile phase concentration gradient: 0.01 min (B10%), 10.00 min (B80%), 15.00 min (B80%), 15.01 min (B10%), 17.00 min (B10%)

[0177] HPLC purity (%) = 100 × [Ampicillin yield based on calibration curve] / [Theoretical ampicillin yield calculated based on fill volume]

[0178] In the above-mentioned flow reaction, for example, a compound that replaces the benzene ring of phenylglycine with a 1,4-cyclohexadiene ring can be used instead of phenylglycine, or a compound that replaces the methyl group of 7-ADCA or its chlorine atom can be used instead of 6-APA. Thus, in the same manner as ampicillin, various useful β-lactam compounds with antibacterial activities such as epicillin, cephalexin, cefadroxil, and cefaclor can be synthesized continuously and efficiently by flow reaction.

[0179] The invention has been described together with its embodiments; however, unless otherwise specified, no detail in the description is intended to limit the invention, and it should be interpreted broadly without departing from the spirit and scope of the invention as shown in the claims.

[0180] This application claims priority based on Japanese Patent Application 2023-211441, filed in Japan on December 14, 2023, the contents of which are incorporated herein by reference and are part of the description herein.

Claims

1. A method for manufacturing a β-lactam compound, comprising the following steps: The reaction solution (i), the solution (ii) formed by dissolving the acid halide, and the solution (iii) formed by dissolving the β-lactam compound (a) having an amino group are introduced into different flow paths, so that each solution flows in the respective flow path. The reaction solution (i) is a reaction solution formed by dissolving the metal salt (y) represented by the following formula (2) in a solution formed by dissolving the metal salt (x) represented by the following formula (1). This metal salt (y) is generated by introducing a protecting group into the amino group of the metal salt (x). By merging the reaction solution (i) with the solution (ii), during the downstream flow of the merged liquid (M1), the metal salt (y) reacts with the acid halide to generate a mixed acid anhydride; and The combined liquid (M1) is combined with the solution (iii). As the combined liquid (M2) flows downstream, the mixed anhydride reacts with the β-lactam compound (a) having an amino group to generate a β-lactam compound (b) having an amide bond. [Chemical Formula 1] In the formula, R represents a cyclic hydrocarbon group, M represents an alkali metal, and X represents a protecting group.

2. The method for manufacturing the β-lactam compound according to claim 1, wherein, The reaction solution (i) and the solution (ii) are combined at -40 to 0°C.

3. The method for manufacturing the β-lactam compound according to claim 2, wherein, The merging of the combined liquid (M1) and the solution (iii) is carried out at -40 to 0°C.

4. The method for manufacturing the β-lactam compound according to claim 3, wherein, The solution (iii) contains 5 to 50% by mass of water.

5. The method for manufacturing the β-lactam compound according to claim 4, wherein, The solution (iii) contains alkali.

6. The method for manufacturing the β-lactam compound according to claim 5, wherein, The protecting group is 3-ethoxy-1-methyl-3-oxo-1-propenyl and / or 3-methoxy-1-methyl-3-oxo-1-propenyl.

7. The method for manufacturing the β-lactam compound according to claim 6, wherein, The acid halides include carboxylic acid halides.

8. The method for manufacturing the β-lactam compound according to claim 7, wherein, The reaction of the metal salt (y) in the combined liquid (M1) with the carboxylic acid halide is carried out in the presence of an alkaline catalyst.

9. The method for manufacturing the β-lactam compound according to claim 8, wherein, The alkaline catalyst has a pyridine framework.

10. The method for manufacturing the β-lactam compound according to claim 9, wherein, The molar amount of the basic catalyst is set to 0.001 to 0.1 relative to 1 molar amount of the β-lactam compound (a) having an amino group.

11. The method for manufacturing the β-lactam compound according to claim 10, wherein, The carboxylic acid halide includes carboxylic acid chloride.

12. The method for producing the β-lactam compound according to any one of claims 1 to 11, wherein, The hydrocarbon ring of the cyclic hydrocarbon group is a benzene ring or a 1,4-cyclohexadiene ring.

13. The method for manufacturing the β-lactam compound according to claim 12, wherein, M is sodium or potassium.

14. The method for manufacturing the β-lactam compound according to claim 12, wherein, The β-lactam compound (a) having an amino group is 6-aminopenicillanic acid or 7-aminodeacetoxycephalosporanic acid.

15. The method for manufacturing the β-lactam compound according to claim 14, wherein, The β-lactam compound (b) is ampicillin.

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