KR20210030635A - Method for preparing compound - Google Patents

Abstract

The present invention relates to a method for preparing a compound of chemical formula 3, comprising the steps of: (a) preparing a mixture by introducing a compound of chemical formula 1 and a compound of chemical formula 2 into a continuous reactor; and (b) supplying the mixture formed in the step (a) to a reactor (z) connected in series with the continuous reactor to obtain the compound of the chemical formula 3. In the present invention, the control of heat generation during mixing of raw materials is easy.

Description

Manufacturing method of compound {METHOD FOR PREPARING COMPOUND}

The present invention relates to a method for preparing a compound, and more particularly, to a method for preparing a compound containing a sulfonyloxy group.

Methyl (s)-2-(alkyl sulfonyloxy)propanoate is a synthetic intermediate produced during the production of Metalaxyl-M, which is used as a fungicide among crop protection agents, and it is important to develop a synthetic method to obtain an economical and high-purity product. Do.

Korean Patent Application Publication No. 10-2004-0104639

Conventionally, a method of sulfonylation by dropwise addition of sulfonyl chloride to a hydroxy group through a batch reactor was mainly used. However, when using a batch reactor, heat generation is severe when sulfonyl chloride is added dropwise, and impurities are generated, and since the property is liquid, it is impossible to use the recrystallization method, which is easy for mass processing, so that a product with a purity of less than 97% is not possible. Was formed.

In addition, when a batch reactor is used, there is a problem in that the size of the reactor must be excessively large in order to produce a compound on an industrial scale. In the method of operating a plurality of batch reactors, there is a problem in that it is difficult to set the temperature of each reactor and the facility becomes complicated.

In order to solve the above problems, the present invention provides a step (a) of preparing a mixture by adding a compound of the following formula 1 and a compound of the following formula 2 to a continuous reactor; And supplying the mixture formed in step (a) to a reactor (z) connected in series with the continuous reactor to obtain a compound of formula 3 below. do.

[Formula 1]

[Formula 2]

[Formula 3]

In Formulas 2 and 3, R is an alkyl group; Or an aryl group unsubstituted or substituted with one or more substituents selected from the group consisting of an alkyl group, a halogen group, and a nitro group.

The present invention relates to a method for preparing a compound of Formula 3 using a continuous reactor. The compounds of Formulas 1 and 2 are mixed using a continuous reactor and then added to the reactor (z) to react. It is easy to control heat generation.

Thus, by using the production method of the present invention, a compound of Formula 3 having a purity of 99% or more can be obtained without additional purification.

In addition, according to the manufacturing method of the present invention, there is an advantage that the reactor size can be reduced and the operation is convenient.

1 is a process chart schematically showing a method of preparing a compound of Formula 3 according to an exemplary embodiment of the present invention.

The contents of the present invention will be clearly understood from the following detailed description and the accompanying drawings, and in the case where it is determined that the description of related known technologies may unnecessarily obscure the subject matter of the present invention, The explanation is omitted.

In the present specification, when a certain part is said to be'connected' with another part, this includes not only a case in which it is directly connected but also a case in which it is connected through another component in the middle.

In the present specification, when a certain part'includes' or'includes' a certain element, it does not exclude other elements, but may further include or include other elements unless otherwise stated. Means that.

In the present specification, the'continuous type' of the continuous reactor means that the supply and mixing of raw materials are performed continuously, that is, without interruption of the process. In the present specification, the term'raw material' may refer to all materials introduced into the continuous reactor.

Hereinafter, the present invention will be described in detail with reference to the drawings.

The present invention is characterized in that the raw materials are mixed in a continuous reactor and introduced into the reactor (z). By mixing the raw materials quickly and uniformly in a continuous reactor that allows easy temperature control, it is easy to control heat generation when the raw materials are introduced, so that the compound of Formula 3 can be obtained with high purity.

In the case of reacting the compounds of Formulas 1 and 2 using a batch reactor, it is difficult to control heat generation such as greater energy consumption for cooling or longer cooling time as the size of the batch reaction increases. According to the manufacturing method according to an exemplary embodiment of the present invention, since a smaller amount of reaction liquid flows through the tube by using a tube-shaped continuous reactor, the self-heating amount is smaller than when using a batch reactor, so that heat generation is more efficiently controlled. can do.

In an exemplary embodiment, a method of preparing a compound of Formula 3 comprises the steps of: (a) preparing a mixture by adding the compound of Formula 1 and the compound of Formula 2 to a continuous reactor; And a step (b) of supplying the mixture formed in step (a) to a reactor (z) connected in series with the continuous reactor to obtain the compound of formula (3).

Step (a)

In the step (a), the continuous reactor serves to mix the compound of Formula 1 and the compound of Formula 2.

When the compound of Formula 1 and the compound of Formula 2 are mixed using a continuous reactor, heat generation is easily controlled compared to a method of mixing raw materials by stirring in a batch reactor, and side reactions that generate impurities are easily suppressed.

In the step (a), the continuous reactor includes a mixing device capable of micro-mixing the compound of Formula 1 and the compound of Formula 2, and the mixing device is in the group consisting of a static mixer and a micromixer. It may include at least one selected.

The reaction between the compound of Formula 1 and the compound of Formula 2 below proceeds from the moment when the compounds of Formulas 1 and 2 are introduced into a continuous reactor and mixed. At this time, a by-product salt (eg, triethylamine hydrochloride salt) may be generated as the reaction proceeds. When salt is generated as a solid and precipitated inside the continuous reactor, it interferes with the flow of the fluid inside the continuous reactor. In order to facilitate the flow of the fluid, a mixing device is installed inside the continuous reactor to collect droplets and particles of the fluid. It is preferred to crush and mix. In one embodiment, the mixing device is 1 to 10; More preferably, it may be 2 to 10, but is not limited thereto. In the present specification, the fluid may mean a mixture flowing inside a continuous reactor.

In the present specification,'micro-mixing' refers to pulverizing and mixing droplets of the raw material containing the compound of Formula 1 and Formula 2 to a diameter of 1000 μm or less, preferably 100 μm or less, more preferably 50 μm or less. Means process.

The micromixer is a mixer that mixes fluids through separation, recombination, and readjustment of fluids, and is a mixing device using a multilayer plate-like laminar flow.

In one embodiment, the micromixer is a fork-like micromixer, a stack-like micromixer, a Mobius-type micromixer, and a catepillar micromixer. micromixer) may include one or more selected from the group consisting of.

In one embodiment, the micromixer includes a plurality of mixing channels for mixing fluids, and the width of each mixing channel may be 10 µm to 3000 µm, preferably 50 µm to 1600 µm. have.

The static mixer is a mixing device capable of mixing multiple fluids, and is a mixing device capable of continuously and uniformly mixing two or more types of fluids simply by passing through the pipe without a rotating part or special power.

The static mixer is a Kenics type marketed by Kenics of the United States; The Thruzer type sold by Thruzer Corporation; Sakura Seisakusho's Skaya Mixer; High Mixer of Toray Co., Ltd.; Lau Chemical's T.K.-ROSS LPD mixer; Sulzer type mixer from sulzer chemtech; Koch-Glitch (Koch-Glitch LP) SMX (SMX) mixer, etc. may be used, but is not limited thereto.

In the step (a), the compound of Formula 1 and the compound of Formula 2 may be individually introduced into a continuous reactor, or if necessary, dissolved or dispersed in an appropriate solvent and introduced into the continuous reactor. .

In step (a), the compound of Formula 1 may be introduced into the continuous reactor in the form of a first solution including the compound of Formula 1 and a first solvent. In the step (a), the compound of Formula 2 may be introduced into the continuous reactor in the form of a second solution including the compound of Formula 2 and a second solvent.

In one embodiment, the first solvent and the second solvent may be the same as or different from each other, and may each independently be an organic solvent, an aqueous solvent, an aqueous based solvent, water, or a mixture thereof.

In one embodiment, the first solvent and the second solvent are the same as or different from each other, and each independently aliphatic, alicyclic, and aromatic hydrocarbons; Halogenated hydrocarbons; Heteroaromatic compounds; ether; Ketones; Nitrile; amides; Tertiary amine; Sulfone; Alcohol; And it may include one or more selected from the group consisting of water.

In an exemplary embodiment, the first solvent and the second solvent may be the same as or different from each other, and may each independently be an aromatic hydrocarbon such as toluene, xylene, chlorobenzene, or the like.

In the step (a), in addition to the compound of Formula 1 and the compound of Formula 2, other compounds necessary for the synthesis of the compound of Formula 3 may be added to the continuous reactor.

In the step (a), a base may be further added to the continuous reactor. In this case, it may be a step (a) of preparing a mixture by introducing the compound of Formula 1, the compound of Formula 2, and a base into a continuous reactor.

In one embodiment, the first solution may further contain a base.

In consideration of the ease of introduction of raw materials into the continuous reactor and prevention of clogging of the tube, the use of an inorganic base is not possible, and thus the base is preferably an organic base.

In one embodiment, the base is an amine; Or it may be a nitrogen-containing heterocycle. The nitrogen-containing heterocycle may be a heterocycle containing one or more nitrogens in the ring.

In one embodiment, specific examples of the base include triethylamine, trimethylamine, diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, tri-n-hexylamine, tricyclohexylamine , N-methylcyclohexylamine, N-methylpyrrolidine, N-methylpiperidine, N-ethylpiperidine, N,N-dimethylaniline, N-methylmorpholine, pyridine, 2-, 3-, 4-picoline, 2-methyl-5-ethylpyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, quinoline, quinaldine, N,N,N,N-tetra -Methyl-ethyl-diamine, N,N-dimethyl-1,4-diazacyclohexane, N,N-diethyl-1,4-diazacyclohexane, 1,8-bis(di-methylamino)naphthalene , Diazabicyclooctane (DABCO), diazabicyclononane (DBN), diazabicycloundecane (DBU), methylimidazole and butylimidazole, and the like, but are not limited thereto.

In an exemplary embodiment, the equivalent of the base is 1 to 1.5 times the equivalent of the compound of Formula 1; Preferably it may be 1 to 1.3 times. The equivalent of the base may be the equivalent of the base added to the continuous reactor for 1 second compared to the equivalent of the compound of Formula 1 added to the continuous reactor for 1 second.

In one embodiment, the equivalent of the compound of Formula 2 is 1 to 1.5 times the equivalent of the compound of Formula 1; Preferably it may be 1 to 1.3 times. The equivalent of the compound of Formula 2 may be the equivalent of the compound of Formula 2 added to the continuous reactor for 1 second compared to the equivalent of the compound of Formula 1 injected into the continuous reactor for 1 second.

In the step (a), the temperature of the compound of Formula 1 introduced into the continuous reactor may be -5°C to 0°C.

In the step (a), the temperature of the compound of Formula 2 introduced into the continuous reactor may be in the range of -5°C to 0°C.

In the step (a), the temperature of the continuous reactor is preferably -5 ℃ to 0 ℃. In one embodiment, the temperature of the continuous reactor may mean the'temperature of the fluid' inside the continuous reactor, and the temperature of the continuous reactor is a compound of Formula 1 or a counter ion thereof and a compound of Formula 2 When meeting and generating heat, the heat may affect the quality of the compound of Formula 3, so it is preferable to adjust the temperature within the above range.

When the temperature of the continuous reactor is within the above range, the compound of Formula 3 can be obtained as a colorless and transparent liquid having a purity of 99% or more. On the other hand, when the temperature of the continuous reactor exceeds 0°C, the compound of Formula 3 is obtained in the form of a pale yellow or yellow transparent liquid having a purity of 97% or less.

In one embodiment, as a method of controlling the temperature of the continuous reactor, the pipeline of the continuous reactor is provided to be immersed in a refrigerant or cooling water of an external chiller, and the temperature of the refrigerant or cooling water of the external chiller is adjusted. A method of controlling or controlling the temperature of the internal refrigerant by using a continuous reactor in which the pipeline itself has a double-walled structure like a jacketed reactor is used, but is not limited thereto, and the temperature of the reactor is usually controlled. You can use how to do it.

In the step (a), the continuous reactor may be a tubular reactor. The tubular reactor means that the reactor has a tubular shape. In one embodiment, the tubular shape may be a cylindrical shape.

In an exemplary embodiment, step (a) may include the following steps more specifically.

In an exemplary embodiment, the step (a) includes preparing a first solution containing the compound of Formula 1 (a1); Preparing a second solution containing the compound of Formula 2 (a2); And a step (a3) of preparing a mixture by introducing the first solution and the second solution prepared in steps (a1) and (a2) into a continuous reactor.

In an exemplary embodiment, step (a1) may be a step of preparing a first solution at -5°C to 0°C containing the compound of Formula 1.

In an exemplary embodiment, step (a2) may be a step of preparing a second solution at -5°C to 0°C containing the compound of Formula 2.

In an exemplary embodiment, the step (a1) includes preparing a first solution containing the compound of Formula 1 (a1-1); And adjusting the temperature of the first solution prepared in step (a1-1) to -5°C to 0°C (a1-2).

In an exemplary embodiment, step (a1-1) may be a step of preparing a first solution including the compound of Formula 1 and a first solvent. In an exemplary embodiment, step (a1-1) may be a step of preparing a first solution containing the compound of Formula 1 and a base. In an exemplary embodiment, step (a1-1) may be a step of preparing a first solution including the compound of Formula 1, a base, and a first solvent.

In an exemplary embodiment, the step (a2) includes preparing a second solution containing the compound of Formula 2 (a2-1); And adjusting the temperature of the second solution prepared in step (a2-1) to -5°C to 0°C (a2-2).

In an exemplary embodiment, step (a2-1) may be a step of preparing a second solution including the compound of Formula 2 and a second solvent.

As a method of controlling the temperature of the first solution and the second solution, a cooling means is provided in a container for preparing the first solution and the second solution, or a cooler is provided at the inlet where the raw material is injected into the first solution and the second solution. An installation method or the like may be used, but is not limited thereto.

In an exemplary embodiment, the step (a) of preparing the mixture may be a step of preparing a mixture of -5°C to 0°C.

In an exemplary embodiment, the step (a3) of preparing the mixture may be a step of preparing a mixture of -5°C to 0°C.

In the step (a3), the input rate of the first solution to be introduced into the continuous reactor is preferably 1 g/min to 20 g/min, more preferably 1 g/min to 15 g/min. .

In the step (a3), the input rate of the second solution to be introduced into the continuous reactor is preferably 1 g/min to 20 g/min, more preferably 1 g/min to 15 g/min. .

Referring to FIG. 1, an apparatus for producing a compound of Formula 3 according to an exemplary embodiment of the present invention may include raw material containers 101a and 101b each containing a compound of Formula 1 and a compound of Formula 2. Each raw material container may be connected to a raw material injection port (not shown). A cooling device (not shown) such as a cooler for controlling the temperature of the raw material injected into the raw material container may be installed in the raw material injection port. The pressure of the raw material container may be appropriately adjusted (a pressure regulating device not shown).

The compounds of Formulas 1 and 2 are supplied from the raw material container to the continuous reactor, and in one embodiment, the raw material may be supplied through the raw material supply lines 103a and 103b. The size or shape of the raw material supply line can be appropriately selected.

In an exemplary embodiment, the raw material supply line may include pumps 102a and 102b for adjusting a flow rate and a flow rate at the time of supplying the raw material. The pumps 102a and 102b may be installed at the discharge portion of the raw material container, or may be installed outside and connected to the raw material supply line by connecting means such as pipes.

In an exemplary embodiment, the raw material supply line may further include coolers 110a and 110b for controlling the temperature of the supplied raw material. The coolers 110a and 110b may be in the form of enclosing the raw material supply line, and may be disposed on some or all of the raw material supply line.

In one embodiment, the raw material supply line may further include a mass flow meter (not shown) for measuring the mass flow rate of the fluid, and may further include a device for adjusting supply conditions of other raw materials.

In FIG. 1, a position where a raw material is injected into the continuous reactor 100 is illustrated as an end portion of the continuous reactor, but the injection position of the raw material is not limited thereto. The shape of the injection portion of the raw material may also be a Y-shape, a T-shape, a cross-shape, or an elbow shape, but is not limited thereto.

As shown in FIG. 1, the continuous reactor may include a mixing device 105, and the raw materials supplied from the raw material containers 101a and 101b to the continuous reactor 100 are mixed while passing through the mixing device 105. Can be.

The continuous reactor 100 may include a jacket 104a for controlling the temperature of the continuous reactor. In FIG. 1, a jacket is installed on all of the continuous reactor, but it may be installed in a part if temperature control is easy. In FIG. 1, a jacket-type cooling means is shown as the cooling means, but other cooling means may be provided.

The raw material mixed while passing through the continuous reactor is transferred to the reactor (z). This? The mixed raw material may be transferred through the mixture transfer line 111. The mixture transfer line 111 may be tubular, for example, and its size or shape is not limited. The mixture transfer line may further include cooling means (not shown) for controlling the temperature of the mixture.

The reactor z may also be provided with a jacket 104b for controlling the temperature of the reactor z. In FIG. 1, the jacket is installed on all of the reactor z, but it may be installed on a part of the reactor. In FIG. 1, a jacket is shown as a cooling means, but other cooling means may be provided.

step (b)

The step (b) is a step of supplying the mixture obtained in step (a) to a reactor (z) connected in series with the continuous reactor to obtain a compound represented by the following formula (3).

In one embodiment, the reactor (z) is a batch reactor.

In an exemplary embodiment, the step (b) includes the step (b1) of supplying the mixture obtained in step (a) to a reactor (z) at -5°C to 0°C connected in series with the continuous reactor (b1); A step (b2) of working-up the mixture obtained in step (b1); And extracting the compound of Formula 3 from the mixture obtained in step (b2) (b3).

In an exemplary embodiment, the step (b) further includes a step (b1') of maintaining the mixture supplied to the reactor (z) at -5°C to 0°C between the steps (b1) and (b2). can do. Here, maintaining the mixture at -5°C to 0°C means leaving the mixture at -5°C to 0°C.

The step (b1') may involve stirring the mixture.

In the step (b1'), the holding time of the mixture may be appropriately selected as long as it is an appropriate time to terminate the reaction. In step (b1'), the mixture may be maintained at -5°C to 0°C until the amount of the compound of Formula 1 in the mixture is 0.1 mol% or less compared to the amount of the compound of Formula 1 initially introduced.

The step (b2) is a step in which a series of processes for terminating the reaction occurs, and may include a step for terminating the reaction of the compounds of Formulas 1 and 2.

In an exemplary embodiment, the step (b2) comprises: mixing an aqueous solution having a pH of less than 7 with the mixture of step (b1) (b2-1); And removing the aqueous solution from the mixture obtained in step (b2-1) (b2-2).

In the step (b2-1), the method of mixing an aqueous solution having a pH of less than 7 to the mixture is (1) a method of adding water after adding an acid to the mixture of step (b1), (2) the (b1) A method of adding an acid after adding water to the mixture in step) or (3) adding an aqueous solution containing an acid to the mixture in step (b1), but is not limited thereto.

The acid may be used without limitation as long as it is a material having a pH of less than 7. The acid may be hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, etc., but is not limited thereto. In an exemplary embodiment, the aqueous solution having a pH of less than 7 may be 1N HCl aqueous solution.

In an exemplary embodiment, step (b2-1) may be performed at 15°C to 20°C.

In an exemplary embodiment, the step (b2-2) may be a step of allowing the mixture obtained in the step (b2-1) to stand still to separate the aqueous solution and the organic layer, and to separate and remove the aqueous solution from the mixture.

In an exemplary embodiment, step (b2) may be performed at 15°C to 20°C.

In an exemplary embodiment, the step (b3) includes mixing water or an aqueous solution with the mixture obtained in step (b2), and removing the water or aqueous solution (b3-1); And removing the solvent from the mixture obtained in step (b3-1) (b3-2).

Step (b3-1) is a step of removing water-soluble impurities contained in the mixture obtained in step (b2).

In one embodiment, the aqueous solution is a solution containing water and a solute (p). The solute (p) may be ammonium chloride, sodium hydrogen carbonate, or the like, but is not limited thereto.

In an exemplary embodiment, the step (b3-1) may be performed at least once; more than 2 times; Preferably, it may be performed three or more times.

In an exemplary embodiment, the step (b3-1) is preferably repeated until the pH of the water or aqueous solution after mixing into the mixture becomes 7 or more.

In an exemplary embodiment, step (b3-1) may be performed at 15°C to 20°C.

In step (b3-2), the solvent may include a first solvent and a second solvent.

In the step (b3-2), a method of removing the solvent may be appropriately selected in consideration of the first solvent and the second solvent. In an exemplary embodiment, step (b3-2) may be a step of sensitizing concentration of the mixture obtained in step (b3-1). At this time, the conditions for concentration under reduced pressure may be appropriately adjusted according to the first solvent and the second solvent.

In the present specification, all materials used in the present invention, such as the compound of Formula 1, the compound of Formula 2, a solvent, and a catalyst, may be used as long as they are commonly used. Other configurations and manufacturing methods are well known in the art, and thus, detailed descriptions thereof will be omitted.

According to an exemplary embodiment of the present invention, the yield of the compound of Formula 3 is 85 mol% or more and 100 mol% or less. In the present specification, the yield of the compound of formula 3 refers to the formula obtained through actual synthesis compared to the number of moles of the compound of formula 3 that can be theoretically generated when considering the amount of the compound of formula 1 and the compound of formula 2 added to the continuous reactor. It means the number of moles of the compound of 3.

In the final product formed using the method for preparing the compound of Formula 3 according to an exemplary embodiment of the present invention, the GC area% of the compound of Formula 3 is 99% or more and 100% or less. Here, the GC area% of the compound of Formula 3 refers to the ratio of the area of the peak of the compound of Formula 3 to the total area of the peak obtained as a result of GC analysis of the final product. In an exemplary embodiment, the GC area% may mean mol%.

In step (b), the pressure of the reactor (z) may be appropriately selected. The reaction pressure may be appropriately selected in consideration of the solvent and the reaction temperature. In one embodiment, the reaction pressure is 1×10 ³ Pa to 1×10 ⁶ Pa, preferably 5×10 ⁴ Pa to 5×10 ⁵ Pa, more preferably 8×10 ⁴ Pa to 2×10 ^It can be 5 Pa.

In the present invention, a method of controlling the temperature of the reactant may be performed by an appropriate cooling means. The cooling means may include, but is not limited to, a jacket-type cooler surrounding the outside of the reactor, a cooler surrounding a part of the supply line of the reactant, and a double-tube cooler through which the refrigerant passes through the outer wall of the reactor.

Hereinafter, in Formulas 2 and 3, the term of the substituent will be described.

In the present specification, the alkyl group means a linear or branched saturated hydrocarbon group.

In the present specification, an aryl group means an aromatic hydrocarbon ring group in which the element constituting the ring is only carbon.

In the present specification, the halogen group may be a fluoro group, a chloro group, a bromo group, or an iodo group.

In one embodiment, R is a C _1-10 alkyl group; Or _{a C 6-30} aryl group unsubstituted or substituted with one or more substituents selected from the group consisting of a _{C 1-10 alkyl group, a halogen group, and a nitro group.}

In one embodiment, R is a C _1-10 alkyl group; Or _{a C 6-25} aryl group unsubstituted or substituted with one or more substituents selected from the group consisting of a _{C 1-10 alkyl group, a halogen group, and a nitro group.}

In one embodiment, R is a C _1-6 alkyl group; Or _{a C 6-20} aryl group unsubstituted or substituted with one or more substituents selected from the group consisting of a _{C 1-6 alkyl group, a halogen group, and a nitro group.}

In one embodiment, R is a C _1-6 alkyl group; Or a phenyl group unsubstituted or substituted with one or more substituents selected from the group consisting of a _{C 1-6 alkyl group, a halogen group, and a nitro group.}

In an exemplary embodiment, R is a methyl group; Or a phenyl group unsubstituted or substituted with one or more substituents selected from the group consisting of a methyl group, a chloro group, and a nitro group.

In an exemplary embodiment, R is a methyl group; Methylphenyl group; Chlorophenyl group; Or a nitrophenyl group.

In an exemplary embodiment, R is a methyl group; 4-methylphenyl group; 4-chlorophenyl group; Or 4-nitrophenyl group.

Hereinafter, the present invention will be described in more detail based on examples, but the embodiments of the present invention disclosed below are examples only, and the scope of the present invention is not limited to these embodiments. The scope of the present invention is indicated in the claims, and furthermore, it contains the meanings equivalent to the claims recorded and all modifications within the scope.

<Example 1>

Two vacuum-dried 1L stainless steel pressure vessels were prepared. Toluene (250 mL, 217.5 g), (S)-methyl 2-hydroxypropanoate (104.11 g) and triethylamine (131.55 g) were added to the first pressure vessel to prepare a first reaction solution, and then -5°C Cooled to 0°C. Toluene (250 mL, 217.5 g) and methanesulfonyl chloride (118 g) were added to the second pressure vessel to prepare a second reaction solution and cooled to -5°C to 0°C. At this time, the molar ratio of (S)-methyl 2-hydroxypropanoate, triethylamine, and methanesulfonyl chloride was 1:1.3:1.03.

In a state where the pressure of each pressure vessel was maintained at 5 bar, the first reaction solution was transferred to the first continuous channel in the continuous reactor at a rate of 13.5 g/min and the second reaction solution was transferred to the second continuous channel using a mass flow meter. The reaction solution was simultaneously injected at a rate of 10 g/min. At this time, the temperature of the continuous reactor was maintained at -5°C to 0°C, and the internal pressure was maintained at 1 bar using a backpressure regulator. The residence time of the mixture in the continuous reactor was set to be 1 minute, and the mixed reactant produced for 33.4 minutes after stabilization of the continuous (tubular) reactor was transferred and introduced into a batch reactor at a jacket temperature of -5°C to 0°C. While maintaining the internal temperature -5 ℃ to 0 ℃ was stirred for 1 hour.

When the reaction is complete, 1N HCl aqueous solution (300 mL) is injected into the reaction solution, and the mixture is stirred at an internal temperature of 20° C. for 30 minutes to check pH 2 and then settled to separate layers, and the aqueous layer (about 400 mL) is discarded. _{H 2} O (100 mL) was injected into the separated organic layer, stirred at an internal temperature of 20° C. for 30 minutes to check pH 3 to 4, and allowed to stand to separate the layers, and the aqueous layer (about 100 mL) was discarded. A 1wt% NaHCO ₃ (400 mL) aqueous solution was injected into the separated organic layer, stirred at an internal temperature of 20° C. for 30 minutes to check pH 7, and allowed to stand to separate the layers, and the aqueous layer (about 400 mL) was discarded. _{H 2} O (100 mL) was injected into the separated organic layer, stirred at an internal temperature of 20° C. for 30 minutes, left to stand for separation, and the aqueous layer (about 100 mL) was discarded. The separated organic layer was concentrated under reduced pressure and distilled to remove toluene, and methyl (S)-methyl 2-((methylsulfonyl)oxy)propanoate was added to 158.5 g of a colorless and transparent liquid (GC area% = 99%, yield 87 mol). %).

<Comparative Example 1>

(S)-methyl 2-hydroxypropanoate (104.11 g, 1 mol) and triethylamine (181.20 mL, 1.30 mol) were added to a reactor containing toluene (500 mL) at room temperature, and the internal temperature was- Cool to 5°C. Methanesulfonyl chloride (117.98 g, 1.03 mol) was slowly added dropwise for 5 hours at an internal temperature of -5°C. When the addition of methanesulfonyl chloride is complete, the mixture is stirred for 3 hours so that the internal temperature does not exceed 0°C. By GC analysis, it is checked whether (S)-methyl 2-hydroxypropanoate is exhausted to 0.1% or less to confirm the completion of the reaction. When the reaction is complete, 1N HCl (300 mL) aqueous solution is injected into the reaction solution, and the mixture is stirred at an internal temperature of 20° C. for 30 minutes to check pH 2 and then settled to separate layers, and the aqueous layer (about 400 mL) is discarded. _{H 2} O (100 mL) was injected into the separated organic layer, stirred at an internal temperature of 20° C. for 30 minutes to check pH 3 to 4, and allowed to stand to separate the layers, and the aqueous layer (about 100 mL) was discarded. A 1wt% NaHCO ₃ (400 mL) aqueous solution was injected into the separated organic layer, stirred at an internal temperature of 20° C. for 30 minutes to check pH 7, and allowed to stand to separate the layers, and the aqueous layer (about 400 mL) was discarded. _{H 2} O (100 mL) was injected into the separated organic layer, stirred at an internal temperature of 20° C. for 30 minutes, left to stand for separation, and the aqueous layer (about 100 mL) was discarded. The separated organic layer was concentrated under reduced pressure and distilled to remove toluene, 154.86g (S)-methyl 2-((methylsulfonyl)oxy)propanoate (Pale yellow liquid, GC area% = 96%, yield 84 mol%) Got it.

Comparing Example 1 and Comparative Example 1, it can be seen that when the production method according to an exemplary embodiment of the present invention is used, it is possible to obtain a compound having a high purity of 99% or more in terms of GC area %, and the yield is also improved.

100: continuous reactor
101a, 101b: raw material container
102a, 102b: pump
103a, 103b: raw material supply line
110a, 110b: cooler
104a, 104b: jacket
105: mixing device
110: reactor (z)
111: mixture transfer line

Claims (11)

(A) preparing a mixture by adding a compound of the following formula 1 and a compound of the following formula 2 to a continuous reactor; And (b) supplying the mixture formed in step (a) to a reactor (z) connected in series with the continuous reactor to obtain a compound of formula 3 below:
[Formula 1]

[Formula 2]

[Formula 3]

In Formulas 2 and 3, R is an alkyl group; Or an aryl group unsubstituted or substituted with one or more substituents selected from the group consisting of an alkyl group, a halogen group, and a nitro group. The method of claim 1, wherein the continuous reactor includes at least one selected from the group consisting of a static mixer and a micromixer. The method according to claim 1, wherein the compound of Formula 1 is introduced into the continuous reactor in the form of a first solution containing the compound of Formula 1 and a first solvent, and the compound of Formula 2 is 2 A method for producing a compound of Formula 3 that is introduced into the continuous reactor in the form of a second solution containing a solvent. The method of claim 3, wherein the first solution further contains a base. The method according to claim 4, wherein the base is an amine; Or a method for producing a compound of Formula 3 that is a nitrogen-containing heterocycle. The method of claim 1, wherein the temperature of the continuous reactor is -5°C to 0°C. The method of claim 1, wherein the temperature of the compound of Formula 1 introduced into the continuous reactor is -5°C to 0°C. The method of claim 1, wherein the temperature of the compound of Formula 2 introduced into the continuous reactor is -5°C to 0°C. The method of claim 1, wherein the reactor (z) is a batch reactor. The method according to claim 1, wherein the step (b) comprises the step (b1) of supplying the mixture obtained in the step (a) to a reactor (z) at -5°C to 0°C connected in series with the continuous reactor; A step (b2) of working-up the mixture obtained in step (b1); And (b3) extracting the compound of Formula 3 from the mixture obtained in step (b2). The method of claim 10, wherein the step (b2) comprises: mixing an aqueous solution having a pH of less than 7 with the mixture of step (b1) (b2-1); And removing the aqueous solution from the mixture obtained in step (b2-1) (b2-2).

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