Method for producing β-lactam compound

Abstract

Provided is a method for producing a β-lactam compound, the method comprising: introducing a reaction solution (i) obtained by dissolving a metal salt (y) of formula (2) produced by introducing a protective group onto the amino group of a metal salt (x) of formula (1) in a solution of the metal salt (x), a solution (ii) of an acid halide, and a solution (iii) of a β-lactam compound (a) having an amino group, respectively into different flow paths and passing the solutions through the respective flow paths; causing the reaction solution (i) and the solution (ii) to meet each other to thereby yield a mixed acid anhydride; and causing the confluence liquid (M1) and the solution (iii) to meet each other to thereby yield a β-lactam compound (b) having an amide bond.　In the formulae, R represents a cyclic hydrocarbon group, M represents an alkali metal, and X represents a protective group.

Description

Method for producing β-lactam compounds

[0001] The present invention relates to a method for producing a β-lactam compound.

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

[0003] The so-called Dane salt method is known as a method for synthesizing these β-lactam compounds. For example, Patent Document 1 describes a method for synthesizing ampicillin using the Dane salt method. In this method, 4-picoline is added as a catalyst to a suspension containing a high concentration of Dane salt, potassium D-N-(1-ethoxycarbonylpropen-2-yl)-α-aminophenylacetate, in n-butyl acetate, and the mixture is stirred at room temperature for 15 hours and then cooled to −33°C. Pivaloyl chloride is then added and stirred at −20°C for 90 minutes to react with the Dane salt, thereby obtaining a mixture containing a mixed carboxylic acid anhydride. Separately, triethylamine (TEA) is added as a base to a mixed solvent of isopropanol (IPA) and water, and 6-aminopenicillanic acid (6-APA) is dissolved in this solution to prepare a solution. This solution was added dropwise to the above mixture over 45 minutes at a temperature of -45 to -30°C, and the reaction mixture was stirred for an additional 90 minutes at -30 to -35°C, thereby forming an amide bond between the mixed carboxylic acid anhydride and 6-APA, and at the same time, water acted on the carboxylic acid anhydride to eliminate the protecting group, 1-ethoxycarbonylpropen-2-yl group (also known as 3-ethoxy-1-methyl-3-oxo-1-propenyl group), thereby producing ampicillin. This reaction is shown in the following reaction scheme.

[0004]

[0005] Japanese Patent Application Publication No. 5-97865

[0006] The Dehn salt has extremely low solvent solubility, and if it is used in a solution state in a reaction, the concentration becomes too low, making its application to industrial production impractical. Therefore, at present, Dehn salt must be used in a reaction in the form of a suspension, as described above. Therefore, the synthesis of β-lactam compounds using the Dehn salt method is practically limited to a batch reaction, and as described above, a relatively long reaction time is required while mixing the suspension.

[0007] Flow reactions, which differ from batch reactions in that they allow for continuous synthesis, are known as chemical synthesis reactions. In flow reactions, two or more raw material solutions are typically circulated through separate channels, merged downstream, and the target synthesis reaction proceeds as the combined solution flows further downstream. This allows for continuous production of the target product as long as the raw materials are continuously supplied. This, combined with precise temperature control of the reaction system and improved mixing efficiency due to the merging of the liquids, allows for higher production efficiency than batch reactions. However, flow reactions are reaction systems that require the liquid to flow smoothly through the channels. When a suspension containing a high concentration of the above-mentioned Dane salt is used in a flow reaction, the liquid cannot flow smoothly through the channels, and the channels may become clogged during flow, making this impractical.

[0008] An object of the present invention is to provide a method for producing a β-lactam compound, which enables the production of a target β-lactam compound continuously and efficiently through a flow reaction from the production of a mixed acid anhydride to an amidation reaction, even when using a starting material with low solvent solubility, such as a Dane salt.

[0009] The present inventors have conducted extensive research in light of the above-mentioned problems. As a result, they have found that when a glycine compound having a cyclic hydrocarbon group, such as phenylglycine, is dissolved in an organic solvent containing an alkali metal hydroxide to form an alkali metal salt, and a protecting group is then introduced into the amino group of this metal salt to synthesize a Dehn salt or a salt similar thereto, the salt into which the protecting group has been introduced has low solubility in the solvent in the solid state as described above, but the salt is dissolved at a high concentration in the synthesis reaction solution, and the salt can still remain dissolved even when the synthesis reaction solution is concentrated to a certain extent. The present invention was completed based on these findings and through further research.

[0010] The above-mentioned object of the present invention is achieved by the following means: [1] A reaction solution (i) obtained by dissolving a metal salt (x) represented by the following formula (1) in a solution in which a protecting group is introduced into the amino group of the metal salt (x) to produce a metal salt (y) represented by the following formula (2): a solution (ii) in which an acid halide is dissolved, and a solution (iii) in which a β-lactam compound (a) having an amino group is dissolved are introduced into different flow paths, and each solution is allowed to flow through each flow path; by merging the reaction solution (i) and the solution (ii), the metal salt (y) and the acid halide react to produce a mixed acid anhydride while this merged liquid (M1) flows downstream; a combined liquid (M1) and a combined liquid (iii) are combined, and while the combined liquid (M2) is flowing downstream, the mixed acid anhydride reacts with the β-lactam compound (a) having an amino group to produce a β-lactam compound (b) having an amide bond. In the formula, R represents a cyclic hydrocarbon group, M represents an alkali metal, and X represents a protecting group. [2] The method for producing a β-lactam compound according to [1], wherein the reaction solution (i) and the solution (ii) are joined at -40 to 0°C. [3] The method for producing a β-lactam compound according to [1] or [2], wherein the joined liquid (M1) and the solution (iii) are joined at -40 to 0°C. [4] The method for producing a β-lactam compound according to any of [1] to [3], wherein the solution (iii) contains 5 to 50 mass% of water. [5] The method for producing a β-lactam compound according to any of [1] to [4], wherein the solution (iii) contains a base. [6] The method for producing a β-lactam compound according to any one of [1] to [5], wherein the protecting group is a 3-ethoxy-1-methyl-3-oxo-1-propenyl group and / or a 3-methoxy-1-methyl-3-oxo-1-propenyl group. [7] The method for producing a β-lactam compound according to any one of [1] to [6], wherein the acid halide includes an carboxylic acid halide. [8] The method for producing a β-lactam compound according to [7], wherein the reaction of the metal salt (y) with the carboxylic acid halide in the combined liquid (M1) is carried out in the presence of a basic catalyst. [9] The method for producing a β-lactam compound according to [8], wherein the basic catalyst has a pyridine skeleton.

[10] The method for producing a β-lactam compound according to [8] or [9], wherein the molar amount of the basic catalyst is 0.001 to 0.1 relative to 1 molar amount of the β-lactam compound (a) having an amino group.

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

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

[12] The method for producing 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.

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

[12] , wherein M is sodium or potassium.

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

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

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

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

[0011] In this specification, a numerical range expressed using "to" means a range that includes the numerical values ​​before and after "to" as the lower and upper limits.

[0012] In the present invention, the term representing a substituent includes not only the substituent itself but also a form in which the substituent has a further substituent, as long as the effect of the present invention is not impaired. For example, the term "cyclic hydrocarbon group" means to include both an unsubstituted cyclic hydrocarbon group and a substituted cyclic hydrocarbon group. Furthermore, for example, the term "phenyl" means to include both an unsubstituted phenyl group and a substituted phenyl group.

[0013] According to the method for producing a β-lactam compound of the present invention, even when a starting material having low solvent solubility such as a Dane salt is used, the target β-lactam compound can be obtained continuously and highly efficiently through a flow reaction from the generation of a mixed acid anhydride to an amidation reaction.

[0014] FIG. 1 is a schematic diagram showing an example of a flow reaction system used in the production method of the present invention.

[0015] [Method for Producing a β-lactam Compound] The method for producing a β-lactam compound of the present invention (hereinafter also referred to as the "production method of the present invention") employs a flow reaction. In this flow reaction, the following reaction solution (i), solution (ii), and solution (iii) are circulated through different flow paths and then merge in sequence to allow the target reaction to proceed.

[0016] Reaction solution (i): A reaction solution obtained by dissolving a metal salt (x) represented by the following formula (1) in a solution, and dissolving a metal salt (y) represented by the following formula (2) produced by introducing a protecting group into the amino group of the metal salt (x).

[0017] In the formula, R represents a cyclic hydrocarbon group, M represents an alkali metal, and X represents a protecting group. The metal salt (x) represented by the above formula (1) may be in the L-form or the D-form, and is preferably in the D-form from the viewpoint of the final product, a β-lactam compound (b) described below, exhibiting higher antibacterial properties. The same applies to the metal salt (y) represented by the above formula (1).

[0018] Solution (ii): A solution obtained by dissolving an acid halide.

[0019] Solution (iii): A solution obtained by dissolving a β-lactam compound (a) having an amino group.

[0020] In the flow reaction, reaction solution (i) and solution (ii) are joined, and while this combined liquid (M1) flows downstream, the metal salt (y) and the acid halide react to produce a mixed acid anhydride. Furthermore, while the combined liquid (M1) and solution (iii) are joined, and while this combined liquid (M2) flows downstream, the mixed acid anhydride reacts with the β-lactam compound (a) having an amino group to produce a β-lactam compound (b) having an amide bond. This β-lactam compound (b) having an amide bond is the target β-lactam compound (final product) produced by the production method of the present invention.

[0021] In this specification, the terms "upstream" and "downstream" are used in relation to the direction of liquid flow, with the side where the liquid is introduced (the side where the liquid flows in) being upstream and the side where the liquid flows out being downstream.

[0022] Preferred forms of the reaction solution (i), solution (ii) and solution (iii) will now be described.

[0023] <Reaction Solution (i)> As described above, the reaction solution (i) is a reaction solution obtained by dissolving the metal salt (x) in a solution in which the metal salt (y) is produced by introducing a protecting group into the amino group of the metal salt (x) (by a protecting group introduction reaction). That is, the reaction solution itself in which the protecting group introduction reaction has occurred, or a concentrated or diluted solution of this reaction solution, can be used as the reaction solution (i). In the reaction solution (i), the metal salt (y) remains in a solution state without precipitating. From the viewpoint of the efficiency of the subsequent reaction, the reaction solution (i) is preferably the concentrated solution. The reaction solution (i) is preferably capable of maintaining a solution state at −20° C., more preferably at −30° C., even more preferably at −40° C., and even more preferably at −50° C. An example of the reaction scheme for the above-mentioned protecting group introduction reaction is shown below, taking as an example a reaction in which D-phenylglycine is used as the starting material and a 3-ethoxy-1-methyl-3-oxo-1-propenyl group is introduced as a protecting group for the amino group (i.e., one form of the synthesis reaction for Dane salts). In the following scheme, Et represents ethyl.

[0024]

[0025] In the above reaction scheme, D-phenylglycine is converted into a potassium salt by potassium hydroxide in a mixed solvent of toluene and methanol. This potassium salt corresponds to the metal salt (x). Next, this potassium salt is reacted with ethyl acetoacetate to introduce a protecting group into the amino group of the potassium salt, thereby obtaining a Dane salt. This Dane salt corresponds to the metal salt (y). In the above reaction scheme, methanol is used as part of the solvent in order to dissolve potassium hydroxide. Because methanol can cause side reactions in subsequent reactions, it is preferable to use reaction solution (i) as a concentrated solution obtained by removing methanol from the reaction solution. Below, we will explain preferred forms of reaction solution (i) in the present invention, without limiting it to the above-exemplified reaction scheme.

[0026] As represented by the above formula (1), the metal salt (x) is a compound in which the carbon atom to which the amino group of glycine is bonded has a cyclic hydrocarbon group as a substituent, and the carboxy group is in the state of an alkali metal salt. The hydrocarbon ring (cyclic hydrocarbon) of this cyclic hydrocarbon group is preferably a six-membered ring, and more preferably a benzene ring or a 1,4-cyclohexadiene ring. Furthermore, this hydrocarbon ring may be unsubstituted or may have a substituent within the scope of not impairing the effects of the present invention. Preferred specific examples of the metal salt (x) include, for example, phenylglycine, 2-(2,5-dihydroxyphenyl)glycine, 4-fluoro-2-phenylglycine, 2-(2-chlorophenyl)glycine, 2-(4-chlorophenyl)glycine, etc., in which the carboxy group is in the state of a salt with an alkali metal. The metal salt (x) is an alkali metal salt, preferably a sodium salt or potassium salt, and more preferably a potassium salt.

[0027] The protecting group introduced in the above protecting group introduction reaction is not particularly limited as long as it is a protecting group for an amino acid, and examples thereof include Ac (acetyl group), Boc (t-butoxycarbonyl group), Cbz (carbobenzoxy group), Fmoc (9-fluorenylmethyloxycarbonyl group), Bz (benzoyl group), Bzl (benzyl group), Troc (2,2,2-trichloroethoxycarbonyl group), Teoc (2-(trimethylsilyl)ethoxycarbonyl group), Alloc (allyloxycarbonyl group), 3-ethoxy-1-methyl-3-oxo-1-propenyl group, and 3-methoxy-1-methyl-3-oxo-1-propenyl group. From the viewpoint of ease of deprotection with water contained in the solution (iii), the protecting group introduced in the protecting group introduction reaction is preferably a 3-ethoxy-1-methyl-3-oxo-1-propenyl group or a 3-methoxy-1-methyl-3-oxo-1-propenyl group, and more preferably a 3-ethoxy-1-methyl-3-oxo-1-propenyl group.

[0028] The solvent for the protecting group introduction reaction is not particularly limited as long as it can dissolve an alkali metal compound (preferably an alkali metal hydroxide) for forming a salt with an alkali metal, the metal salt (x), and the metal salt (y). A preferred solvent is a mixed solvent of an aromatic hydrocarbon solvent and an aliphatic alcohol solvent. It is preferable that the solvents constituting the mixed solvent are mutually compatible (do not undergo phase separation). 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 the aromatic hydrocarbon solvent. Preferred aliphatic alcohol solvents include lower alcohols such as methanol, ethanol, and propanol. One or more aliphatic alcohol solvents can also be used in combination. In the mixed solvent of an aromatic hydrocarbon solvent and an aliphatic alcohol solvent, the mixing ratio of the respective solvents is not particularly limited and can be set appropriately. For example, the proportion of the aliphatic alcohol solvent in the mixed solvent can be 1 to 40 mass %, more preferably 3 to 30 mass %, and even more preferably 5 to 20 mass %. By including the aliphatic alcohol solvent in the above-mentioned preferred amount, it is possible to sufficiently dissolve a base such as an alkali metal hydroxide, and it is possible to produce the metal salt (x) in the mixed solvent with high efficiency and to keep the metal salt (x) in a dissolved state.

[0029] In a flow reaction, the reaction solution (i) flowing through the flow channel is preferably a reaction solution from the protecting group introduction reaction in which the aliphatic alcohol solvent has been removed, from the viewpoint of further suppressing side reactions in the subsequent reaction. That is, the solvent constituting the reaction solution (i) is preferably an aromatic hydrocarbon solvent. The solids concentration (concentration of components other than the 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, from the viewpoint of achieving both improved productivity through high concentration and suppression of precipitation. For example, as described above, the solubility of solid Dehn salt in solvents is very low. However, the reaction solution (i) is a solution in which the metal salt (y) is dissolved at a much higher concentration. The proportion of the metal salt (y) in the solids 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. It is preferable that all of the solid content in the reaction solution (i) is the metal salt (y), but a certain amount of by-products may be generated or raw materials may remain. The proportion of the metal salt (y) in the solid content in the reaction solution (i) is preferably 50 to 100 mass%, also preferably 50 to 98 mass%, also preferably 60 to 97 mass%, also preferably 70 to 96 mass%, and also preferably 80 to 95 mass%.

[0030] In the present invention, when the metal salt (y) obtained by the above-mentioned protecting group introduction reaction is precipitated into a solid state (dry product), and this is dissolved in a mixed solvent of toluene / methanol = 90 / 10 (mass ratio), the solubility at 25°C (the amount of metal salt (y) that dissolves in 100 g of mixed solvent when 100 g of mixed solvent and 10 g of solid metal salt (y) are mixed and allowed to stand at 25°C for 24 hours) is preferably 1.0 g or less. For example, the above-mentioned Dane salt satisfies this solubility requirement.

[0031] The reaction solution (i) preferably contains a basic catalyst. This basic catalyst catalyzes the subsequent amidation reaction with the β-lactam (a) having an amino group. Examples of basic catalysts include 4-dimethylaminopyridine (DMAP), 4-picoline, N-methylimidazole, 2,6-lutidine, N-methylmorpholine, 1,4-diazabicyclo[2.2.2]octane (DABCO), N-benzyldimethylamine, N-methylpiperidine, and dicyclohexylmethylamine. The basic catalyst is preferably a compound having a tertiary amino group, more preferably a compound having a pyridine skeleton or a compound having an imidazole skeleton, and even more preferably a compound having a pyridine skeleton. Among the above specific examples, DMAP, 4-picoline, and / or N-methylimidazole are preferably used, with DMAP being particularly preferred. The molar amount of the basic catalyst is preferably 0.001 to 0.1 per 1 molar amount of the β-lactam (a) having an amino group.

[0032] <Solution (ii)> The acid halide contained in solution (ii) is preferably a carboxylic acid halide, a sulfonic acid halide, or a halogenoformate ester. In the present invention, the term "acid halide" is used in a broader sense than usual. More specifically, when referring to an acid halide in the present invention, it is used to include not only general acid halides but also halogenoformate esters. The halogen atom in the acid halide is preferably a chlorine atom. Among these, the acid halide is preferably a carboxylic acid halide, and more preferably a carboxylic acid chloride. Specific examples of preferred acid halides include pivaloyl chloride (PivCl), methanesulfonyl chloride, ethyl chloroformate, etc., and pivaloyl chloride can be preferably used from the viewpoints of improving reactivity and suppressing by-products.

[0033] The aromatic hydrocarbon solvents described for the reaction solution (i) are suitable as the solvent for the solution (ii). Examples include benzene, toluene, styrene, o-xylene, p-xylene, m-xylene, and mesitylene, and one or more of these can be used. It is preferable that the type of aromatic hydrocarbon solvent used in the solution (ii) is the same as that used in the reaction solution (i).

[0034] The concentration of the acid halide in solution (ii) is not particularly limited and can be appropriately set based on stoichiometry, for example, taking into consideration the amount of metal salt (y) in the mixed solution (combined solution (M1)) combined with reaction solution (i) and the flow rates of reaction solution (i) and solution (ii). For example, the concentration of the acid halide in solution (ii) can be 5 to 25 mass%, and preferably 10 to 20 mass%. In order to more reliably convert metal salt (y) to a mixed acid anhydride, it is preferable to have 1.05 equivalents or more of acid halide present relative to metal salt (y) immediately after reaction solution (i) and solution (ii) are combined (assuming the combined solution is still unreacted). Furthermore, from the viewpoint of suppressing the reaction of the acid halide with the β-lactam compound (a) having an amino group in the solution (iii) to be subsequently reacted, it is preferable to have 1.50 equivalents or less of the acid halide present relative to the metal salt (y) immediately after the reaction solution (i) and the solution (ii) are joined together, and it is more preferable to have 1.05 to 1.30 equivalents (preferably 1.05 to 1.20 equivalents) of the acid halide present relative to the metal salt (y) immediately after the reaction solution (i) and the solution (ii) are joined together.

[0035] <Solution (iii)> The β-lactam compound (a) having an amino group contained in solution (iii) is not particularly limited as long as it is a β-lactam compound having an amino group. When the combined liquid (M1) and solution (iii) are combined, the mixed acid anhydride (activated carboxy group) reacts with the amino group of the β-lactam compound (a) having an amino group while the combined liquid (M2) flows downstream, producing the target β-lactam compound (b) having an amide bond. From the viewpoint of obtaining the β-lactam compound (b) useful as an antibiotic or the like, preferred specific examples of the β-lactam compound (a) having an amino group include 6-aminopenicillanic acid (6-APA), 7-aminodesacetoxycephalosporanic acid (7-ADCA), and 7-amino-3-chlorocephalosporanic acid (7-ACCA) having the following structures:

[0036]

[0037] By using 6-APA as the β-lactam compound (a) having an amino group, it is possible to obtain, for example, ampicillin or epicillin having the following structure as the β-lactam compound (b). Furthermore, by using 7-ADCA as the β-lactam compound (a) having an amino group, it is possible to obtain, for example, cephalexin or cephradine having the following structure as the β-lactam compound (b). Furthermore, by using 7-ACCA as the β-lactam compound (a) having an amino group, it is possible to obtain, for example, cefaclor having the following structure.

[0038]

[0039] The solvent for solution (iii) is preferably, for example, a solvent obtained by mixing an organic solvent and water. Furthermore, solution (iii) preferably contains a base. By including a base, the solubility of the β-lactam compound (a) having an amino group can be further increased. Furthermore, by including water, the protecting group can be deprotected without the need for a special procedure. The organic solvent is not particularly limited, and examples thereof include water-soluble organic solvents that are compatible with water (e.g., alcohol, acetone, acetonitrile, N,N-dimethylacetamide, tetrahydrofuran, etc.). From the viewpoint of further suppressing by-products, the organic solvent is preferably an aliphatic alcohol solvent, more preferably an aliphatic lower alcohol solvent having 1 to 3 carbon atoms, and even more preferably isopropyl alcohol. The content of water in 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, from the viewpoint of further increasing the solubility of the β-lactam compound (a) having an amino group. Examples of the base include aliphatic amines, aromatic amines, and heterocyclic amines. Among these, trialkylamines are preferred, and triethylamine is particularly preferred. By containing a base, the pH of the solution (iii) is preferably controlled to 7.5 to 9.5, and more preferably to 8.0 to 9.0. This can further increase the solubility of the β-lactam compound (a) having an amino group.

[0040] The content of the β-lactam compound (a) having an amino group in the solution (iii) is not particularly limited and can be appropriately set based on stoichiometry, taking into consideration the amount of mixed acid anhydride in the mixed solution (combined solution (M2)) immediately after merging with the combined solution (M1), and also taking into consideration the flow rates of the combined solution (M1) and solution (iii). For example, the content of the β-lactam compound (a) having an amino group in the solution (iii) can be 5 to 25% by mass, and preferably 10 to 20% by mass. Immediately after merging the combined solution (M1) and solution (iii) (assuming the combined solution is still unreacted), it is preferable that 0.7 to 1.3 equivalents of the β-lactam compound (a) having an amino group be present relative to the mixed acid anhydride, and more preferably 0.8 to 1.0 equivalents of the β-lactam compound (a) having an amino group be present.

[0041] <Flow Reaction System> One embodiment of a flow reaction system used in the present invention will be described with reference to the drawings. Note that each drawing is an explanatory diagram for facilitating understanding of the present invention, and the size or relative size relationship of each component may be changed for the sake of convenience of explanation and does not directly represent the actual relationship. Furthermore, matters other than those specified in the present invention are not limited to the external shapes and forms shown in these drawings. Figure 1 is a schematic diagram showing an example of a flow reaction system used in the production method of the present invention. The flow reaction system (10) shown in FIG. 1 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 junction (J1) where the flow paths (1) and (2) join, a reaction flow path (3) connected to the downstream end of the junction (J1), a flow path (4) having an inlet (Ic) for introducing the solution (iii), a junction (J2) where the reaction flow path (3) and the flow path (4) join, and a reaction flow path (5) connected to the downstream end of the junction (J2).

[0042] A liquid-transfer pump (not shown), such as a syringe pump or a diaphragm pump, is usually connected to each of the inlets (Ia), (Ib), and (Ic), and by operating this pump, each solution can be made to flow through each flow path at a desired flow rate.

[0043] Each component of the embodiment shown in FIG. 1 will now be described in more detail.

[0044] (Flow Channel (1)) The flow channel (1) supplies the reaction solution (i) introduced from the inlet (Ia) to the confluence (J1). The flow channel (1) preferably has an equivalent diameter of 0.2 to 50 mm. By making the equivalent diameter of the flow channel (1) 0.2 mm or more, it is possible to suppress pressure increases during liquid transfer and to suppress blockage of the flow channel even when insoluble matter is generated. Furthermore, by making the equivalent diameter of the flow channel (1) 50 mm or less, it is possible to appropriately control the liquid temperature at the time of introduction into the confluence (J1). The equivalent diameter of the flow channel (1) is more preferably 0.5 to 30 mm, and even more preferably 1 to 20 mm. The above-mentioned "equivalent diameter" is also called the equivalent diameter and is a term used in the field of mechanical engineering. When a circular pipe equivalent to a piping or flow channel having an arbitrary internal cross-sectional shape is imagined, the diameter of the internal cross section of the equivalent circular pipe is called the equivalent diameter. The equivalent diameter (deq) is defined as deq = 4A / p, where A is the inner cross-sectional area of ​​the pipe and p is the wetted edge length (inner circumference) of the pipe. When applied to a circular pipe, this equivalent diameter is equal to the diameter of the inner cross section of the circular pipe. The equivalent diameter is used to estimate the flow or heat transfer characteristics of the pipe based on the data of the equivalent circular pipe, and represents the spatial scale (representative length) of the phenomenon. For a regular square pipe with an inner cross section of side a, the equivalent diameter is deq = 4a ２ / 4a = a, and for an equilateral triangle tube with one side a, deq = a / 3 １／２ In the case of a flow between parallel plates with a flow path height h, deq=2h (see, for example, "Mechanical Engineering Dictionary," edited by the Japan Society of Mechanical Engineers, 1997, Maruzen Co., Ltd.).

[0045] The length of the flow path (1) is not particularly limited, and for example, it can be constituted by a tube having a length of approximately 10 cm to 200 m (preferably 30 cm to 100 m). The material of the tube is also not particularly limited, and examples thereof include perfluoroalkoxyalkane (hereinafter referred to as PFA), polytetrafluoroethylene (hereinafter referred to as PTFE), aromatic polyether ketone resin, stainless steel, copper or copper alloy, nickel or nickel alloy, titanium or titanium alloy, quartz glass, and lime soda glass. From the viewpoints of flexibility and chemical resistance, the material of the tube is preferably PFA, PTFE, stainless steel, nickel alloy, or titanium.

[0046] The flow rate at which the reaction solution (i) is introduced from the inlet (Ia) is not particularly limited, and can be appropriately set depending on the purpose, taking into consideration the equivalent diameter of each flow path, the concentration of each solution, the introduction flow rate, etc. For example, the flow rate is preferably 0.1 to 10,000 mL / min (minute), more preferably 0.5 to 8,000 mL / min, and even more preferably 1 to 6,000 mL / min.

[0047] The temperature of the flow channel (1) can be, for example, -40 to 0°C, preferably -30 to -10°C, and more preferably -25 to -15°C.

[0048] (Flow Channel (2)) The flow channel (2) is a flow channel that supplies the solution (ii) introduced from the inlet (Ib) to the confluence (J1). The flow channel (2) preferably has an equivalent diameter of 0.2 to 50 mm. By making the equivalent diameter of the flow channel (2) 0.2 mm or more, it is possible to suppress pressure increases during solution delivery and to suppress clogging of the flow channel even in the event of the formation of insoluble matter. Furthermore, by making the equivalent diameter of the flow channel (2) 50 mm or less, it is possible to appropriately control the temperature of the solution when it is introduced into the confluence (J1). The equivalent diameter of the flow channel (2) is more preferably 0.5 to 30 mm, and even more preferably 1 to 20 mm.

[0049] The length of the flow path (2) is not particularly limited, and for example, it can be configured by a tube having a length of about 10 cm to 200 m (preferably 30 cm to 100 m). The material of the tube is not particularly limited, and tubes made of the materials exemplified for the flow path (1) can be used.

[0050] The flow rate at which solution (ii) is introduced through the inlet (Ib) is not particularly limited and can be set appropriately depending on the purpose, taking into account the equivalent diameter of each flow path, the concentration of each liquid, the introduction flow rate, etc. For example, 0.1 to 10,000 mL / min (min) is preferred, 0.5 to 8,000 mL / min is more preferred, and 1 to 6,000 mL / min is even more preferred. Furthermore, the relationship between the flow rate rB at which solution (ii) is introduced through the inlet (Ib) and the flow rate rA at which liquid (i) is introduced through the inlet (Ia) is not particularly limited and can be set appropriately, taking into account the concentration of each solution, etc. For example, [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. Note that the unit of flow rate in this specification is mL / min.

[0051] The temperature of the flow channel (2) can be, for example, -40 to 0°C, preferably -30 to -10°C, and more preferably -25 to -15°C.

[0052] <Confluence (J1)> The reaction solution (i) introduced into the flow path (1) is joined with the solution (ii) flowing through the flow path (2) at the confluence (J1). The confluence (J1) functions as a mixer and is not particularly limited as long as it can join the flow paths (1) and (2) into a single flow path and send the joined liquid to the reaction flow path (3) connected to the downstream end of the confluence (J1). In the embodiment of FIG. 1, a T-shaped connector having three connection ports is used as the confluence (J1). The equivalent diameter of the flow path in the confluence (J1) is preferably 0.2 to 30 mm from the viewpoint of improving mixing performance.

[0053] The material of the confluence (J1) is not particularly limited, and may be, for example, PFA, PTFE, aromatic polyether ketone resin, stainless steel, copper or copper alloy, nickel or nickel alloy, titanium or titanium alloy, quartz glass, or lime soda glass. A wide variety of commercially available T-connectors can be used, including a cross connector manufactured by Upchurch, a union cross manufactured by Swagelok, a four-way joint manufactured by EYELA, and a SUS cross mixer manufactured by IDEX. In the present invention, the confluence (J1) is not limited to a T-connector, and may be, for example, a Y-connector. Alternatively, a connector having four or more connection ports may be used to introduce the reaction solution (i) and / or solution (ii) through multiple inlets.

[0054] (Reaction flow path (3)) After the reaction solution (i) and the solution (ii) are joined and mixed at the joining point (J1), this joined liquid (M1) flows into the reaction flow path (3). While flowing downstream 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 produce a mixed acid anhydride. The produced mixed acid anhydride is present dissolved in the joined liquid (M1). In other words, the reaction flow path (3) is a flow path that produces a mixed acid anhydride solution and supplies this solution to the joining point (J2).

[0055] The form of the reaction flow channel (3) is not particularly limited, and a tube is usually used. The preferred materials for the reaction flow channel (3) are the same as those for the flow channel (1) described above. Furthermore, the flow time of the combined liquid merged at the confluence (J1) through the flow channel (3) can be adjusted by adjusting the equivalent diameter and length of the reaction flow channel (3) and the flow rate setting of the liquid feed pump. The equivalent diameter of the reaction flow channel (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. The length of the reaction flow channel (3) is preferably 0.5 to 50 m, more preferably 1 to 30 m. A static mixer may be disposed midway through the reaction flow channel (3) to more uniformly mix the reaction solution (i) and the solution (ii) in the reaction flow channel (3) and more reliably obtain a mixed acid anhydride solution. The flow time of the combined liquid flowing through the reaction channel (3) is preferably 0.1 to 20 minutes, more preferably 0.2 to 15 minutes, and even more preferably 0.4 to 10 minutes.

[0056] The temperature of the confluence (J1) and the reaction channel (3) can be, for example, -40 to 0°C, preferably -30 to -10°C, and more preferably -25 to -15°C.

[0057] <Flow path (4)> The flow path (4) supplies the solution (iii) introduced from the inlet (Ic) to the confluence (J2). The equivalent diameter of the flow path (4) is preferably 0.2 to 50 mm. By setting the equivalent diameter of the flow path (4) to 0.2 mm or more, it is possible to suppress pressure increases during liquid delivery and to prevent blockage of the flow path even in the event of the formation of insoluble matter. Furthermore, by setting the equivalent diameter of the flow path (4) to 50 mm or less, it is possible to appropriately control the liquid temperature upon introduction into the confluence (J2). The equivalent diameter of the flow path (4) is more preferably 0.5 to 30 mm, and even more preferably 1 to 20 mm.

[0058] The length of the flow path (4) is not particularly limited, and for example, it can be configured by a tube having a length of about 10 cm to 200 m (preferably 30 cm to 100 m). The material of the tube is not particularly limited, and tubes made of the materials exemplified for the flow path (1) can be used.

[0059] The flow rate at which solution (iii) is introduced through the inlet (Ic) is not particularly limited and can be set appropriately depending on the purpose, taking into account the equivalent diameter of each flow path, the concentration of each liquid, the introduction flow rate, etc. For example, it is preferably 0.1 to 30,000 mL / min (minute), more preferably 0.5 to 20,000 mL / min, and even more preferably 1 to 15,000 mL / min. Furthermore, the relationship between the flow rate rD at which the combined liquid (M1) is introduced from the reaction flow path (3) to the confluence (J2) and the flow rate rC at which solution (iii) is introduced through the inlet (Ic) is not particularly limited and can be set appropriately, taking into account the concentration of each solution, etc. For example, [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.

[0060] The temperature of the flow path (4) can be, for example, -40 to 0°C, preferably -30 to -10°C, and more preferably -25 to -15°C.

[0061] <Confluence (J2)> The confluence liquid (M1) flowing through the reaction channel (3) and the solution (iii) flowing through the channel (4) are joined at the confluence (J2). The confluence (J2) functions as a mixer and is not particularly limited as long as it can join the reaction channel (3) and the channel (4) into a single channel and send the joined liquid to the reaction channel (5) connected to the downstream end of the confluence (J2). In the embodiment of FIG. 1, a T-shaped connector having three connection ports is used as the confluence (J2). The equivalent diameter of the channel in the confluence (J2) is preferably 0.2 to 30 mm from the viewpoint of improving mixing performance. The same description as for the confluence (J1) can be applied to the material, shape, number of connection ports, etc. of the confluence (J2).

[0062] <Reaction flow path (5)> The combined liquid that has been combined and mixed at the confluence (J2) flows into the reaction flow path (5), and while flowing downstream within the reaction flow path (5), the β-lactam compound (a) reacts with the mixed acid anhydride to form an amide bond, thereby producing the target β-lactam compound (b).

[0063] The form of the reaction flow channel (5) is not particularly limited, and for example, a tube may be used. The preferred materials for the reaction flow channel (5) are the same as those for the flow channel (1) described above. Furthermore, the reaction time can be adjusted by adjusting the equivalent diameter and length of the reaction flow channel (5), the flow rate setting of the liquid transfer pump, and the like. Typically, the equivalent diameter of the reaction flow channel (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 channel (5) is preferably 0.5 to 50 m, more preferably 1 to 30 m. To achieve more uniform mixing of the confluent liquid (M1) and the solution (iii) in the reaction flow channel (5), a static mixer may be disposed midway through the reaction flow channel (5). The flow time of the combined liquid flowing through the reaction channel (5) is preferably 0.1 to 10 minutes, more preferably 0.2 to 8 minutes, and even more preferably 0.3 to 5 minutes.

[0064] The temperature of the confluence (J2) and the reaction channel (5) (i.e., the reaction temperature) can be, for example, −40 to 0°C, preferably −30 to −10°C, and more preferably −25 to −15°C.

[0065] By withdrawing the reaction solution in which the target β-lactam compound (b) is produced while flowing through the reaction flow path (5), the target β-lactam compound (b) is obtained in the withdrawn reaction solution. The β-lactam compound (b) obtained in the reaction solution can be extracted as a solid by common crystallization, filtration, or the like. For example, the withdrawn reaction solution can be acidified by adding hydrochloric acid to extract the β-lactam compound (b) into an aqueous phase, and then a base such as aqueous ammonia can be added to bring the pH closer to neutral, thereby precipitating the β-lactam compound (b) in the aqueous phase. The precipitate can be collected by filtration to obtain a solid β-lactam compound (b). Furthermore, impurities in the aqueous phase can be removed by dissolving the filtered β-lactam compound (b) with, for example, sodium bicarbonate water, and washing the aqueous phase with ethyl acetate or the like. Subsequently, the pH can be adjusted and the precipitated solid collected by filtration to obtain a β-lactam compound (b) of higher purity.

[0066] The present invention will be described in more detail based on examples, but the present invention should not be construed as being limited to these examples except as defined in the present invention.

[0067] [Example] <Preparation of reaction solution (i)> According to the following reaction scheme, a Dane salt as a metal salt (y) was synthesized via a potassium salt of D-phenylglycine as a metal salt (x), thereby obtaining a reaction solution (i).

[0068]

[0069] Toluene (450 mL), methanol (50 mL), D-phenylglycine (50 g), and KOH (20.2 g) were added to a 1 L three-neck flask, and the mixture was heated to 80-90°C to dissolve the components. Ethyl acetoacetate (46.1 g) was then added, and a Dean-Stark was attached. The mixture was stirred for 2 hours while maintaining the temperature at 80-90°C. After cooling to room temperature and removing insoluble matter by filtration, the resulting solution was attached to an evaporator and concentrated by distilling off the solvent. When the solids concentration reached approximately 30% by mass (approximately 30% by mass as Dean salt concentration), toluene (200 mL) was added and the mixture was concentrated again to obtain a toluene solution of Dean salt (solids concentration approximately 25% by mass, approximately 25% by mass as Dean salt concentration). Note that methanol was completely removed by the above concentration procedure. DMAP (0.0073 g) was added to the toluene solution of Dean salt (80.8 g) to obtain reaction solution (i).

[0070] <Preparation of Solution (ii)> PivCl (14.0 g) was dissolved in toluene (70.0 g) to obtain solution (ii).

[0071] <Preparation of Solution (iii)> 6-APA (12.0 g) was dissolved in a mixed solution of isopropyl alcohol (IPA, 56.1 g), water (12.0 g) and triethylamine (TEA, 7.1 g) to obtain a solution (iii).

[0072] <Flow Reaction> The production method of the present invention was carried out using a flow reaction as follows. The flow reaction system shown in FIG. 1 was placed in a thermostatic bath at −20°C, and a flow reaction was carried out. Therefore, in this flow reaction system, the liquids flowing through the channels and the confluence were all at −20°C. A syringe pump was used to transport the liquid. Perfluoroalkoxyalkane (PFA) tubes with an outer diameter of 1 / 8 inch and an inner diameter of 1.58 mm were used for channels (1), (2), reaction channel (3), channel (4), and reaction channel (5). Union tees (SS-200-3) manufactured by Swagelok were used for confluences (J1) and (J2).

[0073] Reaction solution (i) was introduced into flow channel (1) from inlet (Ia) at a flow rate of 2.4 mL / min. Solution (ii) was introduced into flow channel (2) from inlet (Ib) at a flow rate of 1.6 mL / min. The two solutions were then combined at the confluence (J1), and the combined solution (M1) was passed through the downstream reaction flow channel (3), producing a mixed acid anhydride in the combined solution (M1). In the combined solution immediately after merging at the confluence (J1) (assuming an unreacted homogeneous combined solution), approximately 1.09 equivalents of acid halide were present relative to the metal salt (y). Solution (iii) was introduced from inlet (Ic) at a flow rate of 3.0 mL / min, and solution (iii) and the combined liquid (M1) were merged at confluence (J2). The combined liquid (M2) was then passed through the downstream reaction flow path (5), whereby the amidation reaction and deprotection by the action of water were carried out. The combined liquid (assumed to be an unreacted homogeneous combined liquid) immediately after merging at confluence (J2) contained approximately 0.9 equivalents of β-lactam compound (a) having an amino group relative to the mixed acid anhydride. The flow time of the combined liquid (M1) through reaction flow path (3) was 7 minutes, and the flow time of the combined liquid (M2) through reaction flow path (5) was 1 minute.

[0074] The reaction solution was sampled from the outlet of the reaction flow channel (5) over a period of 20 minutes. 1.5N hydrochloric acid (62 mL) was added to the sampled reaction solution, and the target β-lactam compound (b), ampicillin, was dissolved in the aqueous phase. 28% by mass ammonia water was added to this aqueous phase to adjust the pH to 4.5-5.0, and the precipitated solid was collected by filtration to obtain crude ampicillin (HPLC purity 96%). 5% by mass sodium bicarbonate water (150 g) was added to dissolve the obtained crude ampicillin. Next, ethyl acetate (100 mL) was added to wash the aqueous phase twice, and then 1N hydrochloric acid was added to the aqueous layer to adjust the pH to 4.5-5.0, and the precipitated solid was collected by filtration to obtain purified ampicillin (yield 9.7 g, yield 80%, HPLC purity 98%). During this flow reaction, no flow problems, such as blockages, occurred within each flow channel or at the confluence. The "HPLC purity" is calculated using the following formula after preparing a calibration curve using a standard ampicillin product using the following high performance liquid chromatography (HPLC) apparatus under the following operating conditions. Apparatus: Prominence Series (Shimadzu Corporation) Detector: UV / VIS absorption detector SPD-20A, 220 nm Column: Waters Atrantis T3 3 μm 4.6 mmφ×250 mm Column oven: 30 ° C. Mobile phase A: water, 0.1% phosphoric acid Mobile phase B: acetonitrile, 0.1% phosphoric acid Mobile phase concentration gradient: 0.01 min (B 10%), 10.00 min (B 80%), 15.00 min (B 80%), 15.01 min (B 10%), 17.00 min (B 10%) HPLC purity (%) = 100 × [yield of ampicillin based on the calibration curve] / [theoretical yield of ampicillin calculated based on the amount charged]

[0075] In the above flow reaction, for example, by using a compound in which the benzene ring of phenylglycine is replaced with a 4-cyclohexadiene ring instead of phenylglycine, or by using 7-ADCA or a compound in which the methyl group in 7-ADCA is replaced with a chlorine atom instead of 6-APA, various useful β-lactam compounds having antibacterial activity, such as epicillin, cephalexin, cephradine, and cefaclor, can be continuously and efficiently synthesized by a flow reaction, similar to the above-mentioned ampicillin.

[0076] While the present invention has been described in connection with embodiments thereof, we do not intend to limit our invention to any of the details of the description unless otherwise specified, and believe that the claims should be construed broadly without departing from the spirit and scope of the invention as set forth in the appended claims.

[0077] This application claims priority based on Japanese Patent Application No. 2023-211441, filed on December 14, 2023, the contents of which are incorporated herein by reference as part of the present specification.

Claims

1. A reaction solution (i) obtained by dissolving a metal salt (x) represented by the following formula (1) in a solution in which a protecting group is introduced into the amino group of the metal salt (x) to produce a metal salt (y) represented by the following formula (2): a solution (ii) in which an acid halide is dissolved, and a solution (iii) in which a β-lactam compound (a) having an amino group is dissolved are introduced into different flow paths, and each solution is caused to flow through each flow path; by merging the reaction solution (i) and the solution (ii), the metal salt (y) reacts with the acid halide to produce a mixed acid anhydride while the merged liquid (M1) flows downstream; a combined liquid (M1) and the solution (iii) are combined, and while the combined liquid (M2) is flowing downstream, the mixed acid anhydride and the β-lactam compound (a) having an amino group react to produce a β-lactam compound (b) having an amide bond. In the formula, R represents a cyclic hydrocarbon group, M represents an alkali metal, and X represents a protecting group.

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

3. The method for producing a β-lactam compound according to claim 2, wherein the combined liquid (M1) and the solution (iii) are combined at a temperature of -40 to 0°C.

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

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

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

7. The method for producing a β-lactam compound according to claim 6, wherein the acid halide comprises a carboxylic acid halide.

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

9. The method for producing a β-lactam compound according to claim 8, wherein the basic catalyst has a pyridine skeleton.

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

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

12. The method for producing a 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 producing a β-lactam compound according to claim 12, wherein M is sodium or potassium.

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

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

Images