KR102632488B1 - Synthetic method for 3,3-bis(bromomethyl)oxetane via continuous flow chemistry - Google Patents

Abstract

The present invention relates to a method for synthesizing BBMO by continuous flow chemistry, and more specifically to the synthesis of BBPO (3- Obtaining halogen-2,2-bis (bromomethyl) propan-1-ol); And obtaining BBMO (3,3-bis(bromomethyl)oxetane) from the BBPO through a cyclization reaction; It relates to a method of synthesizing BBMO by continuous flow chemistry, comprising: obtaining the BBPO and obtaining the BBMO, wherein the synthesis occurs in a continuous flow reactor.

Description

Method for synthesis of BBMO by continuous flow chemistry {SYNTHETIC METHOD FOR 3,3-BIS(BROMOMETHYL)OXETANE VIA CONTINUOUS FLOW CHEMISTRY}

The present invention relates to a method for synthesizing BBMO using continuous flow chemistry.

When casting solid propellants or composite explosives, the use of binders is one of the important substances because it can control the mechanical or chemical properties of the manufactured materials. Although the raw materials used in energy binder systems contain high energy, they have the disadvantage of having weak mechanical properties. As one of the studies to improve these shortcomings, energy-generating oxetane-type materials have been studied. Energized oxetane-type materials are characterized by containing nitro, nitramino, difluoroamino, azide, or nitrate ester groups in the molecule.

Among these materials, oxetane, which contains an azide group in the molecule, has high heat of formation and good oxygen balance, and can improve mechanical properties while containing higher energy than inert materials used in existing propellants and composite explosives. There is an advantage to having it. Among oxetane materials containing an azide group, 3,3-bis(azidomethyl)oxetane (BAMO) is an important polymer or copolymer applied to energy binder systems. It can be used as a raw material. This material contains two azide groups in a single molecule, so it contains higher energy than glycidyl azide polymer.

The polymer of the BAMO material can be produced through an azidation method after first preparing a polymer containing 3,3-bis(bromomethyl)oxetane (BBMO). there is. In order to manufacture a polymer containing a BBMO material, a BBMO single molecule material is essentially required, and this material is 3-bromo-2,2-bis(bromomethyl)propan-1-ol (3-bromo-2 It is manufactured from ,2-bis(bromomethyl)propan-1-ol; BBPO).

Methods for synthesizing BBPO and BBMO using batch reactions have been reported ( Chemistry of Heterocyclic Compounds 2017, 53, 811-821 and Journal of Energetic Materials 2016, 34, 318-341), but the mixture containing BBPO in the reported batch reactions The manufacturing method has the disadvantage of requiring a long reaction under high temperature conditions, resulting in poor heat transfer efficiency to the reaction solution, and the formation of many other by-products, resulting in the BBPO ratio in the solution being as low as 49%. The lower the ratio, the lower the yield at the stage of acquiring BBMO. In addition, when sulfuric acid is added dropwise, the exothermic reaction is severe, which may cause safety issues for the experimenter, and the bromine generated during the reaction may be continuously exposed to the human body and the environment. The method for producing BBMO in the batch reaction is to produce (3-(bromomethyl)oxetan-3-nyl)methanol, 3-(bromomethyl)oxetan- through a bimolecular nucleophilic substitution reaction during a long-time reaction at high temperature conditions. 3-yl)methanol) may be formed. These by-products are difficult to remove during the vacuum distillation purification process and thus affect the final purity of the obtained product.

To date, BBPO and BBMO materials are synthesized by batch reactions through batch chemistry. However, the manufacturing method through batch reaction has problems in scale-up, yield, and synthesis amount, and not only can large amounts of synthetic by-products that are harmful to the environment or the human body be formed, but safety issues for workers may also occur. Accordingly, the present invention is intended to solve the above-mentioned problems, and provides a method for synthesizing BBMO by continuous flow reaction, which can improve process efficiency and productivity and improve process stability using continuous flow reaction. .

However, the problems to be solved by the present invention are not limited to those mentioned above, and other problems not mentioned will be clearly understood by those skilled in the art from the description below.

According to one embodiment of the present invention, BBPO (3-halogen-2,2-bis (bromomethyl ) Obtaining propan-1-ol); And obtaining BBMO (3,3-bis(bromomethyl)oxetane) from the BBPO through a cyclization reaction; It relates to a method of synthesizing BBMO by a continuous flow reaction, comprising: obtaining the BBPO and obtaining the BBMO using a continuous flow reactor.

According to one embodiment of the present invention, the continuous flow reactor includes a single or a plurality of coiled tube reactors, and the plurality of coiled tube reactors may be arranged in series or parallel.

According to one embodiment of the present invention, the tube reactor may have an inner diameter of 0.5 mm to 2 mm.

According to one embodiment of the present invention, the step of obtaining the BBPO includes: a first stream containing 2,2-bis(hydroxymethyl)propane-1,3-diol and an aqueous sulfuric acid solution; and simultaneously supplying a second stream containing an aqueous hydrogen bromide solution and an organic acid to a continuous flow reactor to proceed with a synthesis reaction of BBPO; And extracting the reaction mixture with an organic solvent and phase separating to obtain crude BBPO; It may include.

According to an embodiment of the present invention, the step of carrying out the synthesis reaction of BBPO may be performed at a reaction temperature of 100 ° C. to 160 ° C. and a residence time of 100 minutes to 200 minutes.

According to one embodiment of the present invention, the aqueous sulfuric acid solution is a 6 M to 11 M aqueous sulfuric acid solution, and the organic acid may include an organic acid having one carboxyl group in the molecule.

According to one embodiment of the present invention, the aqueous hydrogen bromide solution may be a 45% to 55% aqueous hydrogen bromide solution.

According to one embodiment of the present invention, the molar ratio of the 2,2-bis(hydroxymethyl)propane-1,3-diol to the aqueous hydrogen bromide solution may be 1:10 to 45.

According to one embodiment of the present invention, the flow rate ratio of the first stream to the second stream may be 1:2 to 5.

According to one embodiment of the present invention, the BBPO is 70% by weight or more in the crude BBPO, the yield of the BBPO in the step of synthesizing the BBPO is 60% or more, and the production rate may be 1.7 g/h or more. .

According to one embodiment of the present invention, a step of washing the continuous flow reactor is further included after the step of obtaining the BBPO, and the washing step may be using an aqueous acid solution of 1 M or more.

According to one embodiment of the present invention, the step of obtaining the BBMO includes simultaneously supplying a third stream containing crude BBPO and an alcohol, and a fourth stream containing an alkali hydroxide and an alcohol to a continuous flow reactor to produce BBMO. Proceeding with a synthesis reaction; Extracting the reaction mixture with an organic solvent and phase separating to obtain crude BBMO; and purifying the crude BBMO; It may include.

According to one embodiment of the present invention, the step of carrying out the synthesis reaction of BBMO may be performed at a reaction temperature of 40 ° C. to 50 ° C. and a residence time of 40 minutes to 80 minutes.

According to one embodiment of the present invention, the molar ratio of BBPO to the alkali hydroxide in the crude BBPO may be 1:1.5 to 3.0.

According to one embodiment of the present invention, the alcohol may be added to the third stream as a 40% to 60% alcohol aqueous solution.

According to one embodiment of the present invention, the flow rate ratio of the third stream to the fourth stream may be 1:0.6 to 4.2.

According to one embodiment of the present invention, the content of BBMO in the crude BBMO may be 98% or more.

According to one embodiment of the present invention, the purifying step may use a reduced pressure distillation process.

According to one embodiment of the present invention, the yield of the BBMO may be 65% or more, and the production rate may be 30 g/h or more.

The present invention can synthesize 3,3-bis(bromomethyl)oxetane (BBMO) using a continuous flow reaction in a more efficient and practical method than the existing batch reaction. In addition, worker safety can be ensured by minimizing workers' exposure to synthetic by-products that may have negative effects on the environment or the human body.

Figure 1 shows the production of 3-bromo-2,2-bis(bromomethyl)propan-1-ol (3) by continuous flow reaction in the continuous flow reactor of Example 1 of the present invention, according to an embodiment of the present invention. This shows the process for synthesizing -bromo-2,2-bis(bromomethyl)propan-1-ol, BBPO).
Figure 2 shows 3,3-bis(bromomethyl)oxetane by continuous flow reaction in the continuous flow reactor of Example 2 of the present invention, according to an embodiment of the present invention. , BBMO) is synthesized.

Hereinafter, embodiments of the present invention will be described in detail with reference to the attached drawings. In describing the present invention, if a detailed description of a related known function or configuration is judged to unnecessarily obscure the gist of the present invention, the detailed description will be omitted. In addition, the terms used in this specification are terms used to appropriately express preferred embodiments of the present invention, and may vary depending on the intention of the user or operator or the customs of the field to which the present invention belongs. Therefore, definitions of these terms should be made based on the content throughout this specification. The same reference numerals in each drawing indicate the same members.

Throughout the specification, when a member is said to be located “on” another member, this includes not only cases where a member is in contact with another member, but also cases where another member exists between the two members.

Throughout the specification, when a part “includes” a certain component, this does not mean excluding other components, but rather means that it can further include other components.

The present invention relates to a method for producing BBMO (3,3-bis(bromomethyl)oxetane) using continuous flow chemistry. According to one embodiment of the present invention, the production method is 3,3-bis(bromomethyl)oxetane) using continuous flow chemistry. - Obtaining bromo-2,2-bis(bromomethyl)propan-1-ol (3-bromo-2,2-bis(bromomethyl)propan-1-ol, hereinafter referred to as BBPO); And it may include obtaining 3,3-bis(bromomethyl)oxetane (hereinafter referred to as BBMO) using a continuous flow reaction.

According to one embodiment of the present invention, the continuous flow reaction (or continuous flow chemistry) is a synthesis reaction carried out continuously in a continuous flow reactor. As an example of the present invention, the continuous flow reaction is a continuous flow reaction in which process conditions are set. The reaction proceeds as a stream flows within the flow reactor. For example, a stream for a chemical reaction may be supplied into a continuous flow reactor and may be contacted to proceed with the reaction. The continuous flow reaction has a very superior heat transfer ability compared to existing methods (e.g., batch reaction), which can reduce heat loss during the manufacturing process, which can contribute to improving the yield and process efficiency of BBPO and BBMO.

As an example of the present invention, the continuous flow reactor may include a single or a plurality of coiled tube reactors. For example, a plurality of coiled tube reactors can be arranged and connected in series or parallel. In some examples, each coiled tube reactor is further equipped with connectors, supply pipes, etc. for supplying suitable streams (e.g., reaction raw materials, solvents, catalysts, etc.) to induce a desired chemical reaction, and has an inlet and outlet, etc. Can be installed. In some examples, process conditions (e.g., temperature, flow rate, residence time, etc.) may be set independently for each of the plurality of coiled tube reactors.

In one example of the present invention, the tube reactor has a diameter of 0.5 mm to 2 mm; 0.5 mm to 1 mm; or has an inner diameter of 1 mm to 1.5 mm, and the total volume of the tube reactor used in the reaction process is 1 ml or more; More than 5 ml; More than 10 ml; Or it may be 8 ml to 10 ml. If it is within the above range, it can provide an appropriate contact area with reaction raw materials, etc. in the stream flowing into the reactor, improve reaction efficiency, and improve the yield of the desired product.

According to one embodiment of the present invention, the step of obtaining the BBPO is 2,2-bis (hydroxymethyl) propane-1,3-diol (2,2-bis (hydroxymethyl) using a continuous flow reaction. A step of obtaining BBPO through a bromination reaction from propane-1,3-diol), wherein the step of obtaining BBPO includes 2,2-bis(hydroxymethyl)propane-1,3-diol. preparing a first stream; preparing a second stream comprising hydrogen bromide and an organic acid; And supplying the second stream to a continuous flow reactor and proceeding with a synthesis reaction of BBPO.

As an example of the present invention, the step of preparing the first stream is the step of preparing a first stream containing 2,2-bis (hydroxymethyl) propane-1,3-diol and an aqueous sulfuric acid solution, for example For example, the sulfuric acid aqueous solution is 6 M to 11 M; 8.0 M to 11.0; Or it may be an aqueous solution of sulfuric acid of 9.0 M to 11.0 M. In some instances, a 9.0 M to 11.0 M aqueous solution of sulfuric acid may be used to control stream flow and increase the efficiency of the synthesis process, preferably in a continuous flow reactor (e.g., tube reactor).

In one example of the present invention, the step of preparing the second stream is a step of preparing a second stream containing an aqueous hydrogen bromide solution and an organic acid. For example, the organic acid may include an organic acid having one carboxyl group in the molecule. It may be, for example, acetic acid. For example, the hydrogen bromide is 45% to 55%; Alternatively, a 45% to 52% aqueous solution of hydrogen bromide may be applied.

According to one embodiment of the present invention, the step of carrying out the synthesis reaction of BBPO is performed by supplying the first stream and the second stream simultaneously through different stream lines and then contacting them in a continuous flow reactor (e.g., a tube reactor). can do. For example, through the stream line of the first stream and the stream line of the second stream, the first stream and the second stream are simultaneously supplied to a continuous flow reactor (e.g., a tube reactor) and the continuous flow reactor (e.g., a tube reactor) ), a synthesis reaction can be achieved by their contact within.

As an example of the present invention, in the step of carrying out the synthesis reaction of BBPO, the flow rate ratio of the first stream to the second stream is 1:2 to 5; 1:2 to 4; Or it may be 1:2.5 to 4. In some instances it may preferably be 1:2.5 to 4. By controlling the flow rate ratio of the first stream and the second stream, the efficiency and yield of the synthesis process can be improved in a continuous flow reactor (eg, a tube reactor), and the synthesis process time can be reduced.

As an example of the present invention, in the step of conducting the synthesis reaction of BBPO, 2,2-bis(hydroxymethyl)propane-1,3-diol of the first stream and an aqueous hydrogen bromide solution of the second stream (e.g. : 45% to 55%; or 45% to 52% aqueous solution of hydrogen bromide) the molar ratio is 1:10 to 45; Or it may be 1:10.6 to 44.0. This can improve the efficiency and yield of the synthesis process in a continuous flow reactor (e.g., tube reactor) and reduce the production of side reactants.

As an example of the present invention, in the step of synthesizing BBPO, 2,2-bis(hydroxymethyl)propane-1,3-diol of the first stream and an organic acid (e.g., acetic acid) of the second stream The molar ratio is 1:2 to 11.0; Or it may be 1:2.8 to 11.0. This can improve the efficiency and yield of the synthesis process in a continuous flow reactor (e.g., tube reactor) and reduce the production of side reactants.

As an example of the present invention, the step of carrying out the synthesis reaction of BBPO is 100 ℃ to 160 ℃; 120°C to 150°C; or a reaction temperature of 130°C to 140°C; and 100 to 200 minutes; Alternatively, the synthesis reaction may proceed within a residence time of 120 to 200 minutes. In some examples, the residence time may be the total residence time of the stream within a continuous flow reactor. In some examples, a plurality of tube reactors configured within the continuous flow reactor may each have the same or different reaction temperature and/or residence time settings.

According to one embodiment of the present invention, the step of separating the product may be further included after performing the synthesis reaction of BBPO. For example, extraction and phase separation; And it may further include a purification step if necessary.

In one example of the present invention, the extraction and phase separation steps obtain a stream containing the reaction mixture in a continuous flow reactor (e.g., a tube reactor) after the step of performing the synthesis reaction of BBPO, and mix the reaction mixture with an organic solvent. Crude BBPO can be obtained by extraction and phase separation. The organic solvent may be applied without limitation as long as it extracts a product (e.g., organic matter) (e.g., BBPO) from an aqueous solution-based stream and is capable of phase separation from the aqueous solution. For example, it may be chloroform, dichloromethane, etc. In addition, the phase-separated organic solvent-based solution can have the solvent removed through evaporation, drying, etc., and can be further subjected to a filtration process if necessary.

As an example of the present invention, the crude BBPO may be in the form of a mixture containing impurities (e.g., an organic mixture containing residual raw materials, side reactants, etc.) in addition to BBPO, which is the desired product. For example, the BBPO is 70% by weight or more of the crude BBPO among the crude BBPO; preferably more than 75%; Or it may be 80% or more. That is, the yield of BBPO in the step of carrying out the synthesis reaction of BBPO is 64% or more; 70%, and the production rate can be more than 1.7 g/h.

As an example of the present invention, the purifying step may be performed when the BBPO obtained in the step of synthesizing BBPO is the final product or to proceed with an organic purification process (clean-up, purification) to obtain high purity or pure BBPO. You can. Preferably, the purification step can be omitted considering the efficiency, productivity, process time, etc. of the synthesis process using the continuous flow reactor of the present invention. For example, the purification process may use chromatography (GC/HPLC), recrystallization process, reduced pressure distillation, purification equipment, etc., but is not specifically mentioned in this document.

As an example of the present invention, the step of cleaning the continuous flow reactor before or after the step of obtaining the BBPO may be further included. In the washing step, the washing solution is 1M or more; Preferably, an aqueous acid solution of 1 M to 5 M (e.g., aqueous sulfuric acid solution) can be used.

According to one embodiment of the present invention, the step of obtaining BBMO is a step of obtaining BBMO (3,3-bis(bromomethyl)oxetane) by performing a cyclization reaction from the BBPO, preferably the Crude BBPO is available. As an example of the present invention, acquiring the BBMO includes preparing a third stream including the crude BBPO; preparing a fourth stream containing alkali hydroxide; And supplying the third stream and the fourth stream to a continuous flow reactor and proceeding with the synthesis reaction of BBMO; may include.

As an example of the present invention, the step of preparing the third stream is to prepare a third stream containing crude BBPO and alcohol, wherein the crude BBPO may be a powder, and the alcohol may be an alcohol having 1 to 2 carbon atoms. For example, the alcohol may be a 40% to 60% alcohol aqueous solution (eg, an ethanol aqueous solution).

As an example of the present invention, the step of preparing the fourth stream is to prepare a fourth stream containing an alkali hydroxide and an alcohol, and the alkali hydroxide may be selected from K and Na. The alcohol is an alcohol having 1 to 2 carbon atoms. For example, the alcohol may be a 40% to 60% aqueous alcohol solution (eg, an aqueous ethanol solution).

According to one embodiment of the present invention, the step of carrying out the synthesis reaction of the BBMO involves supplying the third stream and the fourth stream simultaneously through different stream lines and then contacting them in a continuous flow reactor (e.g., a tube reactor). can do. For example, through the stream line of the third stream and the stream line of the fourth stream, the third stream and the fourth stream are simultaneously supplied to a continuous flow reactor (e.g., a tube reactor) and a continuous flow reactor (e.g., a tube reactor) ), a synthesis reaction can be achieved by their contact within.

As an example of the present invention, in the step of carrying out the synthesis reaction of BBMO, the flow rate ratio of the third stream and the fourth stream is 1:0.6 to 42; 1:1 to 42; Or it may be 1:5 to 40. By controlling the flow rate ratio of the third stream and the fourth stream, the efficiency and yield of the synthesis process can be improved in a continuous flow reactor (eg, a tube reactor), and the synthesis process time can be reduced.

As an example of the present invention, in the step of carrying out the synthesis reaction of BBMO, the molar ratio of BBPO to the alkali hydroxide in the crude BBPO may be 1:1.5 to 3.0. This can improve the efficiency and yield of the synthesis process in a continuous flow reactor (e.g., tube reactor) and reduce the production of side reactants.

As an example of the present invention, the step of carrying out the synthesis reaction of BBMO includes a reaction temperature of 40°C to 50°C; And the synthesis reaction can proceed within a residence time of 40 to 80 minutes. In some examples, the residence time may be the total residence time of the stream within a continuous flow reactor (e.g., the residence time of the entire tube reactor). In some examples, the plurality of tube reactors may each have the same or different reaction temperature and/or residence time.

As an example of the present invention, the yield of BBMO in the step of synthesizing BBMO is 80% or more; or more than 90%, and the production rate is more than 30 g/h; Or it may be 30.4 g/h or more.

According to one embodiment of the present invention, the step of separating the product may be further included after performing the synthesis reaction of BBMO. For example, extraction and phase separation; And it may include a purifying step.

In one example of the present invention, the extraction and phase separation steps obtain a stream containing the reaction mixture in a continuous flow reactor (e.g., a tube reactor) after the step of performing the synthesis reaction of BBMO, and mix the reaction mixture with an organic solvent. Crude BBMO can be obtained by extraction and phase separation. The organic solvent can be applied without limitation as long as it extracts products (e.g., organic matter) (e.g., organic mixture containing BBMO and impurities (e.g., residual raw materials, etc.)) from an aqueous solution-based stream and is capable of phase separation from the aqueous solution. For example, it may be chloroform, dichloromethane, etc. In addition, the phase-separated organic solvent-based solution can have the solvent removed through evaporation, drying, etc., and can be further subjected to a filtration process if necessary. For example, the content of BBMO in the crude BBMO may be 98% or more. Based on the crude BBMO (i.e., the yield before the purification step), the yield of BBMO is 70% or more; More than 80%; Or it may be 90% or more.

As an example of the present invention, the purifying step is to purify crude BBMO, for example, a reduced pressure distillation process may be used. The yield of BBMO after the purification step is 65% or more; over 66%; More than 70%; It may be more than 80%.

As an example of the present invention, the step of cleaning the continuous flow reactor before or after the step of obtaining the BBMO may be further included. In the washing step, a 40% to 60% ethanol aqueous solution may be used as the washing solution.

Hereinafter, the present invention will be described in more detail through examples and comparative examples.

However, the following examples are only for illustrating the present invention, and the content of the present invention is not limited to the following examples.

<Experimental equipment>

The continuous flow chemistry equipment used in the present invention is the RS-100, manual control product from Vapourtec's R-series modular flow chemistry system. The pump is an HPLC-based R2C module and consists of two units, and the maximum pressure used is 42 bar. The reactor consists of a standard PFA (perfluoroalkoxy alkanes) coiled tube and can be heated up to 150°C. The tubing installed inside the reactor has an internal diameter of 1/16 inch and a volume of 10 mL. In other words, it has the following specifications: “Reactor tube material: PFA (polyfluoroalkoxy), reactor volume: 10ml, tube inner diameter: 1.0mm, total length: 12.73M.”

<Material analysis>

The synthesized material was analyzed through GC/MS and NMR. GC/MS was a 7890A GC system and 5975C inert XL MSD with Triple-Axis Detector from Agilent Technology (San Diego, CA, USA). NMR was performed on a Bruker Avance 500 MHz instrument.

<Example: Synthesis through continuous flow reaction>

[Formula 1]

Example 1: Preparation of 3-bromo-2,2-bis(bromomethyl)propan-1-ol (3-bromo-2,2-bis(bromomethyl)propan-1-ol; BBPO)

Preparation of stream 1:

Dissolve 2,2-bis(hydroxymethyl)propane-1,3-diol (22.4g, 0.16mol) in 224mL of 10.0M sulfuric acid aqueous solution. At this time, the concentration of 2,2-bis(hydroxymethyl)propane-1,3-diol is 0.73M.

Preparation for stream 2:

Mix 48% aqueous hydrogen bromide solution (549 mL, 4.84 mol) with acetic acid (49.3 mL, 0.88 mol). Streams 1 and 2, respectively, were pumped into a 10 mL standard PFA coiled tube reactor. A total of 8 10mL standard PFA coiled tube reactors were used and connected in series (total length 80mL). The reaction process is referred to as Chemical Formula 1. The set temperature of the tube reactor is 140°C, the residence time per tube reactor is 15 minutes (total 120 minutes), and the flow rate ratio of the first stream and the second stream is 1:2.5. Depending on the ratio of residence time and flow rate, the flow rate of the first stream can be calculated to be 0.19 mL/min, and the flow rate of the second stream can be calculated to be 0.476 mL/min. To monitor the reaction, the conversion rate of starting materials and intermediates to BBPO was measured using GC/MS. The proportions in GC/MS were 0.3% for 2,2-bis(bromomethyl)propane-1,3-diol, 76.3% for BBPO, and 3-bromo-2-(bromomethyl)-2-(hyde), respectively. Roxymethyl)propyl acetate 4.0%, 3-bromo-2,2-bis(bromomethyl)propyl acetate 19.4%, 2,2-bis(bromomethyl)propane-1,3-dynyl diacetate 0.1% am. After completion of the reaction, 500 mL of distilled water was added to the mixture obtained in the reactor, and then extracted twice with 500 mL of dichloromethane (DCM), dried over anhydrous sodium sulfate, filtered, and evaporated under vacuum. 44.8 g of the mixture was obtained, the approximate yield was 64.0%, and the production rate was 1.73 g/h.

Example 2: Preparation of 3,3-bis(bromomethyl)oxetane (BBMO)

Preparation of stream 1:

Dissolve BBPO (44.8 g, 105.2 mmol) in the mixture in 34.2 mL of ethanol. At this time, the BBPO concentration is 3.1M.

Preparation for stream 2:

Dissolve sodium hydroxide (12.6 g, 315.6 mmol) in 79 mL of 50% ethanol aqueous solution. At this time, the concentration of sodium hydroxide was 4.0M. Streams 1 and 2, respectively, were pumped into a 10mL standard PFA coiled tube reactor. A total of eight 10mL standard PFA coiled tube reactors were used and connected in series (total length 80mL). The reaction process is referred to as Chemical Formula 1. The set temperature of the tube reactor is 50°C, the residence time per tube reactor is 5 minutes (total 40 minutes), and the flow rate ratio of the first stream and the second stream is 1:1.46. Depending on the ratio of residence time and flow rate, the flow rate of the first stream can be calculated to be 0.826 mL/min, and the flow rate of the second stream can be calculated to be 1.174 mL/min.

To monitor the reaction, the conversion of BBPO to BBMO was measured using GC/MS. The proportions in GC/MS are (3-(bromomethyl)oxetan-3-yl)methanol 1.6%, BBMO 98.2%, and BBPO 0.2%, respectively. After completion of the reaction, 100 mL of distilled water was added to the mixture obtained in the reactor, and then extracted twice with 200 mL of dichloromethane (DCM), dried over anhydrous sodium sulfate, filtered, and evaporated under vacuum. 27.7 g of the mixture was obtained, the approximate yield was 80.9%, and the production rate was 30.4 g/h.

Unpurified BBMO is finally obtained by using a vacuum distillation purification method to obtain 26.8 g of purified BBMO. The two-step yield of BBMO obtained through the processes of Examples 1 and 2 is 66.8%.

¹ H-NMR (DMSO- d ₆ ) δ 4.36 (s, 4H), 3.95 (s, 4H).

¹³ C-NMR (DMSO- d ₆ ) δ 76.9, 44.5, 38.6.

<Comparative example: synthesis through batch reaction>

Comparative Example 1: Preparation of 3-bromo-2,2-bis(bromomethyl)propan-1-ol (3-bromo-2,2-bis(bromomethyl)propan-1-ol; BBPO)

2,2-bis(hydroxymethyl)propane-1,3-diol (20.0g, 146.9mmol) and 48% aqueous hydrogen bromide solution (148.6g, 881.4mmol) were mixed in 500mL volume 3 equipped with a thermometer and condenser. Place it in a 3 neck round bottom flask and stir at room temperature for 10 minutes. After cooling the temperature to 3-5℃ in an ice bath, acetic acid (15.4g, 257.1mmol) was slowly added dropwise over 5 minutes. Afterwards, while maintaining the temperature below 20°C, concentrated sulfuric acid (64.8g, 661.1mmol) was slowly added dropwise over 1 hour. The solution is raised to reflux temperature (approximately 116°C) and then stirred at that temperature for 20 hours. After about 20 hours, the temperature is cooled to 80°C, and then 48% aqueous hydrogen bromide solution (74.3g, 440.7mmol) is additionally added. The temperature was raised to 116°C and stirred at that temperature for an additional 20 hours. After completion of the reaction, the solution is cooled to room temperature and the layers are separated (save the organic layer). After adding dichloromethane (DCM) to the aqueous layer, the extraction process is performed once and the layers are separated. Combine the stored organic layer with the organic layer generated after layer separation. This organic layer is washed twice with distilled water and then separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to obtain 43.9 g of BBPO in the mixture (ratio of BBPO in the mixture: 63.2%).

Comparative Example 2: Preparation of 3,3-bis(bromomethyl)oxetane (BBMO)

BBPO (43.9 g, 143.8 mmol) and 70 mL ethanol from the mixture obtained in Comparative Example 1 were added to a 250 mL 3 neck round bottom flask equipped with a thermometer and a condenser and stirred at room temperature for 10 minutes. do. Dissolve sodium hydroxide (10.4 g, 258.9 mmol) in 20 mL distilled water in a 50 mL round bottom flask to prepare a 13.0 M sodium hydroxide solution. After cooling the temperature to 3-5 ℃ in an ice bath, add sodium hydroxide aqueous solution slowly dropwise to the BBPO solution in the mixture for 15 minutes. At this time, the internal temperature is maintained below 20°C. After raising the temperature to room temperature, stir for about 5 to 7 hours. After completion of the reaction, about half of the ethanol is distilled under reduced pressure and then dichloromethane (DCM) is added to the solution. Distilled water is added to the solution, washed twice, and the organic layer is separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to obtain 21.8 g of crude BBMO. Unpurified BBMO was obtained using a vacuum distillation purification method to obtain 20.4 g of finally purified BBMO. The two-step yield of BBMO obtained through the processes of Comparative Examples 1 and 2 was 56.9%.

Example 1 compared to the batch reaction as in Comparative Example 1, the synthesis time of 3-bromo-2,2-bis (bromomethyl) propan-1-ol (BBPO) was reduced from 40 hours to 120 minutes, and BBPO in the mixture was By improving the ratio from 63% to 76%, the amount of by-products can be reduced.

Example 2 can reduce the 3,3-bis(bromomethyl)oxetane (BBMO) synthesis time from 5-7 hours to 40 minutes compared to Comparative Example 2. Moreover, Example 2 not only excels in cost reduction by improving the two-step synthesis yield from 59.6% (batch synthesis of Comparative Example 2) to 66.8%, but also enables stable production of BBMO on an industrially usable scale. there is.

The present invention minimizes the production of by-products through a continuous flow chemical process, thereby improving the overall synthesis yield by obtaining BBPO at a high rate of 75% or more from the mixture (e.g. crude) BBPO obtained in the BBPO synthesis process. It is excellent in terms of cost reduction by dramatically reducing the manufacturing time required in existing batch reactions. In addition, it is possible to provide a method for manufacturing BBMO that increases worker safety, is environmentally friendly, is economical, and has improved yield.

Although the embodiments have been described with limited drawings as described above, those skilled in the art can apply various technical modifications and variations based on the above. For example, the described techniques are performed in a different order than the described method, and/or components of the described system, structure, device, circuit, etc. are combined or combined in a different form than the described method, or other components are used. Alternatively, appropriate results may be achieved even if substituted or substituted by an equivalent. Therefore, other implementations, other embodiments, and equivalents of the claims also fall within the scope of the following claims.

Claims (19)

Obtain BBPO (3-halogen-2,2-bis (bromomethyl)propan-1-ol) from 2,2-bis(hydroxymethyl)propane-1,3-diol through halogenation reaction. steps;
And obtaining BBMO (3,3-bis(bromomethyl)oxetane) from the BBPO through a cyclization reaction;
Including,
Wherein the step of obtaining BBPO and the step of obtaining BBMO use a continuous flow reactor,
Method for synthesis of BBMO by continuous flow reaction.
According to paragraph 1,
The continuous flow reactor includes a single or plural coiled tube reactor,
The plurality of coiled tube reactors are arranged in series or parallel,
Method for synthesis of BBMO by continuous flow reaction.
According to paragraph 2,
The tube reactor,
Having an inner diameter of 0.5 mm to 2 mm,
Method for synthesis of BBMO by continuous flow reaction.
According to paragraph 1,
The step of acquiring the BBPO is,
A first stream comprising 2,2-bis(hydroxymethyl)propane-1,3-diol and an aqueous sulfuric acid solution; and simultaneously supplying a second stream containing an aqueous hydrogen bromide solution and an organic acid to a continuous flow reactor to proceed with the synthesis reaction of BBPO; and
Extracting the reaction mixture with an organic solvent and phase separating to obtain crude BBPO;
which includes,
Method for synthesis of BBMO by continuous flow reaction.
According to clause 4,
The step of carrying out the synthesis reaction of BBPO is,
At a reaction temperature of 100°C to 160°C and a residence time of 100 to 200 minutes,
Method for synthesis of BBMO by continuous flow reaction.
According to paragraph 4,
The aqueous sulfuric acid solution is a 6 M to 11 M aqueous sulfuric acid solution,
The organic acid includes an organic acid having one carboxyl group in the molecule,
Method for synthesis of BBMO by continuous flow reaction.
According to paragraph 4,
The aqueous hydrogen bromide solution is a 45% to 55% aqueous hydrogen bromide solution,
Method for synthesis of BBMO by continuous flow reaction.
According to paragraph 4,
The molar ratio of the 2,2-bis(hydroxymethyl)propane-1,3-diol to the aqueous hydrogen bromide solution is 1:10 to 45,
Method for synthesis of BBMO by continuous flow reaction.
According to clause 4,
The flow rate ratio of the first stream to the second stream is 1:2 to 5,
Method for synthesis of BBMO by continuous flow reaction.
According to paragraph 4,
The BBPO is more than 70% by weight of crude BBPO,
In the step of synthesizing the BBPO, the yield of the BBPO is more than 64% and the production rate is more than 1.7 g / h,
Method for synthesis of BBMO by continuous flow reaction.
According to paragraph 1,
Cleaning the continuous flow reactor after obtaining the BBPO
It further includes,
The washing step uses an aqueous acid solution of 1 M or more,
Method for synthesis of BBMO by continuous flow reaction.
According to paragraph 1,
The step of acquiring the BBMO is,
simultaneously supplying a third stream containing crude BBPO and alcohol, and a fourth stream containing alkali hydroxide and alcohol to a continuous flow reactor to proceed with a synthesis reaction of BBMO;
Extracting the reaction mixture with an organic solvent and phase separating to obtain crude BBMO; and
Purifying crude BBMO;
which includes,
Method for synthesis of BBMO by continuous flow reaction.
According to clause 12,
The step of carrying out the synthesis reaction of BBMO is,
At a reaction temperature of 40°C to 50°C and a residence time of 40 to 80 minutes,
Method for synthesis of BBMO by continuous flow chemistry.
According to clause 12,
The molar ratio of BBPO to the alkali hydroxide in the crude BBPO is 1:1.5 to 3.0,
Method for synthesis of BBMO by continuous flow reaction.
According to clause 12,
The alcohol is added to the third stream as an aqueous alcohol solution of 40% to 60%,
Method for synthesis of BBMO by continuous flow reaction.
According to clause 12,
The flow rate ratio of the third stream to the fourth stream is 1:0.6 to 4.2,
Method for synthesis of BBMO by continuous flow reaction.
According to clause 12,
The content of BBMO in the crude BBMO is 98% or more,
Method for synthesis of BBMO by continuous flow reaction.
According to clause 12,
The purifying step uses a reduced pressure distillation process,
Method for synthesis of BBMO by continuous flow reaction.
According to paragraph 1,
The yield of the BBMO is more than 65% and the production rate is more than 30 g/h,
Method for synthesis of BBMO by continuous flow reaction.