阅读说明：本技术 一种氰乙酸叔丁酯的连续流制备方法 (Continuous flow preparation method of tert-butyl cyanoacetate ) 是由 陈芬儿 程荡 刘敏杰 黄华山 姜梅芬 于 2020-12-25 设计创作，主要内容包括：本发明属于有机化学技术领域,具体为一种氰乙酸叔丁酯的连续流制备方法。本发明将含氰乙酸和路易斯酸的底物液与异丁烯同时输送到包括依次连通的微混合器和微通道反应器的微反应系统内,进行连续催化酯化反应得到氰乙酸叔丁酯。本发明的连续流制备方法相比传统间歇釜式合成方法,具有反应时间短,产物收率高,自动化程度高,过程连续效率高,时空产率高,能耗低和易于工业放大的优势,易于工业化应用。(The invention belongs to the technical field of organic chemistry, and particularly relates to a continuous flow preparation method of tert-butyl cyanoacetate. The invention simultaneously conveys substrate liquid containing cyanoacetic acid and Lewis acid and isobutene into a micro-reaction system comprising a micro-mixer and a micro-channel reactor which are sequentially communicated, and the tert-butyl cyanoacetate is obtained by continuous catalytic esterification reaction. Compared with the traditional batch kettle type synthesis method, the continuous flow preparation method has the advantages of short reaction time, high product yield, high automation degree, high process continuous efficiency, high space-time yield, low energy consumption and easy industrial amplification, and is easy for industrial application.)

1. A continuous flow preparation method of tert-butyl cyanoacetate is characterized in that a micro-reaction system consisting of a micro-mixer and a micro-channel reactor which are sequentially communicated is used, and the method comprises the following specific steps:

(1) respectively and simultaneously conveying substrate liquid containing cyanoacetic acid and Lewis acid and isobutene into a micro mixer for mixing to obtain a mixed reaction material;

(2) the mixed reaction material flowing out of the micro mixer in the step (1) directly enters a micro-channel reactor to carry out continuous catalytic esterification reaction;

(3) collecting reaction mixed liquid flowing out of the micro-reaction system, and performing separation and purification treatment to obtain a target product, namely tert-butyl cyanoacetate (I);

wherein, the tert-butyl cyanoacetate is a compound shown in a formula (I), and the cyanoacetic acid is a compound shown in a formula (II); the method relates to a chemical reaction formula as follows:

。

2. the method according to claim 1, wherein the substrate solution in step (1) is a solution prepared by dissolving cyanoacetic acid and Lewis acid in an organic solvent; the organic solvent is any one of ether, ester and ketone solvents; the ether solvent is selected from isopropyl ether, tetrahydrofuran and 1, 4-dioxane, the ester solvent is selected from methyl acetate, ethyl acetate and tert-butyl acetate, and the ketone solvent is selected from acetone, methyl butanone and methyl isobutyl ketone.

3. The method according to claim 1, wherein the Lewis acid in the step (1) is any one of aluminum trichloride, an aluminum trichloride complex, boron trifluoride, a boron trifluoride complex, antimony pentachloride, an antimony pentachloride complex, iron tribromide, an iron tribromide complex, iron trichloride, an iron trichloride complex, tin tetrachloride, a tin tetrachloride complex, titanium tetrachloride, a titanium tetrachloride complex, zinc dichloride and a zinc dichloride complex.

4. The method according to claim 1, wherein the molar ratio of cyanoacetic acid to Lewis acid in the substrate solution in step (1) is 1: 0.01-0.5; in the step (1), the flow ratio of the substrate liquid and the isobutene conveyed into the micro mixer is controlled so that the molar ratio of the cyanoacetic acid to the isobutene is in the range of 1 (1.0-1.5).

5. The method according to claim 1, wherein the micromixer in step (1) is any one of a static mixer, a T-type micromixer, a Y-type micromixer, a coaxial flow micromixer, and a flow focusing micromixer.

6. The method according to claim 1, wherein the temperature in the micromixer in step (1) is controlled to be in the range of-20 to 50 ℃.

7. The process of claim 1 wherein the microchannel reactor of step (2) is a tubular microchannel reactor or a plate microchannel reactor.

8. The method of claim 7, wherein the tubular microchannel reactor has an inner diameter of 100 micrometers to 10 millimeters; the plate-type microchannel reactor comprises a first heat exchange layer, a reaction layer and a second heat exchange layer which are sequentially arranged from top to bottom; the reaction layer is provided with a reaction fluid channel, and the hydraulic diameter of the reaction fluid channel is 100 micrometers-10 millimeters.

9. The method of claim 1, wherein the temperature in the microchannel reactor in step (2) is controlled to be in the range of-20 to 50 ℃, and the residence time of the mixed reaction material in the microchannel reactor is 0.1 to 30 minutes.

10. The method of claim 1, wherein the micro-reaction system further comprises a feed pump, a gas mass flow controller, a gas-liquid separator and a back pressure valve, wherein one inlet of the micro-mixer is connected with the substrate liquid feed pump, the other inlet of the micro-mixer is connected with the gas mass flow controller, the outlet of the micro-mixer is connected with the inlet of the micro-channel reactor, the outlet of the micro-channel reactor is connected with a first top interface of the gas-liquid separator, a second top interface of the gas-liquid separator is connected with nitrogen for providing pressure for the gas-liquid separator, the adjustable range of the pressure of the connected nitrogen is 0.1-2.5 Mpa, and the back pressure valve is connected with a third top interface of the gas-liquid separator; the backpressure range of the backpressure valve is 0.1-2 Mpa; the pressure value of the accessed nitrogen is 0.2-0.5 MPa greater than the set back pressure value of the back pressure valve.

11. The method according to claim 1, wherein the step (3) of collecting the reaction mixture flowing out of the micro-reaction system and performing separation and purification treatment to obtain the target product, i.e. t-butyl cyanoacetate (I), specifically comprises: and collecting the reaction mixed liquid flowing out of the micro-reaction system, adding an aqueous solution of inorganic base into the reaction mixed liquid for neutralization, recovering an organic phase after the reaction mixture is layered, and distilling the organic phase to obtain a colorless oily product, namely tert-butyl cyanoacetate.

12. The method of claim 11, wherein the inorganic base is at least one of lithium carbonate, sodium carbonate, potassium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, lithium hydroxide, sodium hydroxide, and potassium hydroxide.

Technical Field

The invention belongs to the technical field of organic chemistry, and particularly relates to a preparation method of tert-butyl cyanoacetate.

Background

The tert-butyl cyanoacetate is an important fine chemical intermediate, and has wide application prospect in the industries of medicine, pesticide, dye and the like. The structural formula of the tert-butyl cyanoacetate is shown as the formula (I):

。

bowie et al (Tetrahedron1967, 23, 305) reported a process for the direct esterification of cyanoacetic acid and tert-butanol under the catalysis of concentrated sulfuric acid to synthesize compound (I). The yield of compound (I) in this process is only 20%. Shelkov et al (J. Org. Chem.2002, 67, 8975) reported the reaction of cyanoacetic acid with tert-butanol inN,N' -Dicyclohexylcarbodiimide (DCC) in the presence of water to prepare tert-butyl cyanoacetate. DCC used in the method is expensive, and generates a large amount of solid waste 1, 3-Dicyclohexylurea (DCU). Chinese patents CN 102633681, ZL 94191232.9, Japanese patent JP 3026407, Imwinkelried, etc. ((Org. Synth.,1987, 65, 230), Schnurrenberger et al (Helv. Chim. Acta1982, 65, 1197) and Seebach et al (Synthesis1982, 2, 138) describe the preparation of compounds (I) by transesterification of cyanoacetate with tert-butanol in the presence of catalysts such as sodium/potassium tert-butoxide, tin compounds and titanates, respectively. The method has the defects of long reaction time, high temperature, high energy consumption, complex operation, low yield, complex preparation of catalysts such as tin compounds, titanate and the like, high cost and the like. Beech et al (J. Chem. Soc.1955, 423) and Ireland et al (Org. Synth.1961, 41, 5) describes a process for preparing the compounds (I) by reacting cyanoacetyl chloride with tert-butanol. The raw material used in the method is limited in source of cyanoacetyl chloride, and the yield of the product (I) is only 63-67%. Dahn et al (Helv. Chim. Acta1959, 42, 1214) and US 3773808 describe the preparation of compound (I) by reacting tert-butyl haloacetate with cyanide. This method is not only usedThe cyanide is extremely toxic, cyanide-containing waste water which is extremely difficult to treat is generated, and the yield of the product (I) is low. DE2403483 discloses a process for preparing compounds (I) by the alkoxycarbonylation of chloroacetonitrile with carbon monoxide and tert-butanol, but the process is very demanding and requires high pressure and yields of not more than 66%.

Disclosure of Invention

In order to overcome the defects of long reaction time, large potential safety hazard, high energy consumption and low efficiency of the traditional batch kettle type synthesis mode, the invention provides the continuous flow preparation method of the tert-butyl cyanoacetate.

The invention provides a continuous flow preparation method of tert-butyl cyanoacetate, which uses a micro-reaction system consisting of a micro-mixer and a micro-channel reactor which are sequentially communicated, and the method comprises the following specific steps:

(1) respectively and simultaneously conveying substrate liquid containing cyanoacetic acid and Lewis acid and isobutene into a micro mixer for mixing to obtain a mixed reaction material;

(2) the mixed reaction material flowing out of the micro mixer in the step (1) directly enters a micro-channel reactor to carry out continuous catalytic esterification reaction;

(3) collecting reaction mixed liquid flowing out of the micro-reaction system, and performing separation and purification treatment to obtain a target product, namely tert-butyl cyanoacetate (I);

wherein, the tert-butyl cyanoacetate is a compound shown in a formula (I), and the cyanoacetic acid is a compound shown in a formula (II); the method relates to a chemical reaction formula as follows:

。

the substrate solution in the step (1) is a solution prepared by dissolving cyanoacetic acid and Lewis acid in an organic solvent; the organic solvent is any one of ethers (such as isopropyl ether, tetrahydrofuran, 1, 4-dioxane and the like), esters (such as methyl acetate, ethyl acetate, tert-butyl acetate and the like) and ketones (such as acetone, methyl butanone, methyl isobutyl ketone and the like) solvents and the like; preferably, the organic solvent is an ether solvent.

The Lewis acid in the step (1) is any one of aluminum trichloride, an aluminum trichloride complex, boron trifluoride, a boron trifluoride complex, antimony pentachloride, an antimony pentachloride complex, iron tribromide, an iron tribromide complex, ferric trichloride, an iron trichloride complex, tin tetrachloride, a tin tetrachloride complex, titanium tetrachloride, a titanium tetrachloride complex, zinc dichloride, a zinc dichloride complex and the like; preferably, the lewis acid is a boron trifluoride complex such as boron trifluoride diethyl etherate complex, boron trifluoride tetrahydrofuran complex, boron trifluoride dimethyl ether complex, boron trifluoride dibutyl ether complex, boron trifluoride piperidine complex, and the like.

The molar ratio of cyanoacetic acid to Lewis acid in the substrate solution in the step (1) is 1 (0.01-0.5).

The micro mixer in the step (1) is any one of a static mixer, a T-shaped micro mixer, a Y-shaped micro mixer, a coaxial flow micro mixer, a flow-focusing micro mixer and the like.

In the step (1), the flow ratio of the substrate liquid conveyed into the micro mixer and the isobutene is controlled so that the molar ratio of the cyanoacetic acid to the isobutene is within the range of 1 (1.0-1.5).

Controlling the temperature in the micro mixer in the step (1) within the range of-20 to 50 ℃; preferably, the temperature in the micro mixer is controlled within the range of 0-30 ℃.

The microchannel reactor in the step (2) is a tubular microchannel reactor or a plate microchannel reactor; the inner diameter of the tubular microchannel reactor is 100 micrometers-10 millimeters; preferably, the inner diameter of the tubular microchannel reactor is 120 micrometers-5.35 millimeters; the plate-type microchannel reactor comprises a first heat exchange layer, a reaction layer and a second heat exchange layer which are sequentially arranged from top to bottom; the reaction layer is provided with a reaction fluid channel; the hydraulic diameter of the reaction fluid channel is 100 micrometers-10 millimeters; preferably, the hydraulic diameter of the reaction fluid channel is 120 micrometers-5.35 millimeters.

Controlling the temperature in the microchannel reactor to be within a range of-20 to 50 ℃ in the step (2), and controlling the retention time of the mixed reaction material in the microchannel reactor to be 0.1 to 30 minutes; preferably, the temperature in the microchannel reactor is controlled within the range of 0-30 ℃, and the residence time of the mixed reaction materials in the microchannel reactor is controlled within 0.2-25 minutes.

The micro-reaction system used in the invention also comprises a feed pump, a gas mass flow controller, a gas-liquid separator and a back pressure valve, wherein one inlet of the micro-mixer is connected with the substrate liquid feed pump, the other inlet of the micro-mixer is connected with the gas mass flow controller, the outlet of the micro-mixer is connected with the inlet of the micro-channel reactor, the outlet of the micro-channel reactor is connected with the first interface at the top of the gas-liquid separator, the second interface at the top of the gas-liquid separator is connected with nitrogen for providing pressure for the gas-liquid separator, the adjustable range of the pressure of the connected nitrogen is 0.1-2.5 MPa, and the back pressure valve is connected with the third interface at the top of the gas-liquid separator; the backpressure range of the backpressure valve is 0.1-2 Mpa; the pressure value of the accessed nitrogen is 0.2-0.5 MPa greater than the set back pressure value of the back pressure valve.

In the step (3), "collecting the reaction mixture flowing out from the micro-reaction system, and performing separation and purification treatment to obtain the target product tert-butyl cyanoacetate (I)" specifically includes: and collecting the reaction mixed liquid flowing out of the micro-reaction system, adding an aqueous solution of inorganic base into the reaction mixed liquid for neutralization, recovering an organic phase after the reaction mixture is layered, and distilling the organic phase to obtain a colorless oily product, namely tert-butyl cyanoacetate.

The inorganic base is at least one of lithium carbonate, sodium carbonate, potassium carbonate, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, lithium hydroxide, sodium hydroxide and potassium hydroxide.

The method for continuously preparing the tert-butyl cyanoacetate (I) by using the micro-reaction system can conveniently realize the industrial large-scale production of the tert-butyl cyanoacetate by the continuous catalytic esterification reaction of the cyanoacetic acid and the isobutene through a multi-channel parallel amplification strategy.

Advantageous effects

Compared with the traditional synthesis method of a batch reactor, the method for preparing tert-butyl cyanoacetate by carrying out continuous catalytic esterification reaction of cyanoacetic acid and isobutene by adopting the micro-reaction system comprising the micro-mixer and the micro-channel reactor which are sequentially communicated has the following advantages:

1. the microchannel reactor has excellent mass transfer, heat transfer and material molecule mixing performance, so that the reaction time of continuous catalytic esterification of cyanoacetic acid and isobutene is greatly shortened, the reaction can be quantitatively completed within ten minutes from several hours of the traditional batch kettle type reaction, side reactions are inhibited to the maximum extent, and the yield of the product, i.e. tert-butyl cyanoacetate, is improved to more than 95 percent from about 85 to 90 percent of the traditional batch kettle type synthesis method;

2. the continuous preparation of the tert-butyl cyanoacetate by adopting the micro-reaction system can accurately control the using amount of the isobutene gas, realize the complete quantitative conversion of the isobutene in the microchannel reactor and avoid the problems of excessive gas, serious waste and difficult recovery in the aeration reaction process in the traditional intermittent kettle type synthesis mode;

3. the method has the advantages that the continuous synthesis from the raw materials to the products is realized, the technological process is continuously carried out, the automation degree is high, external intervention is not needed in the middle, the space-time efficiency is high, the number of operators and the labor intensity are greatly reduced, and the production cost is obviously reduced;

4. the continuous catalytic esterification reaction of cyanoacetic acid and isobutene is completed in a reaction fluid channel of the microchannel reactor, and the total reaction volume is small, so that the online liquid holdup is small, and the reaction process is intrinsically safe;

5. the multiphase mixing, mass transfer and reaction processes in the reaction process are finished in the micro mixer and the micro channel reactor, the operation is simple and convenient, a stirring device is not needed, and the energy consumption in the process is greatly reduced;

6. the industrial amplification of the synthesis method can be conveniently realized by adopting a multichannel reactor through a multichannel parallel amplification strategy, and the industrial production can be quickly realized.

Drawings

FIG. 1 is a schematic view of a micro-reaction system used in an embodiment of the present invention.

FIG. 2 is a schematic view of a plate microchannel reactor used in embodiments of the invention.

Reference numbers in the figures: the device comprises a isobutene pipeline 1, a substrate liquid storage tank 2, a gas mass flow controller 3, a feeding pump 4, a micro mixer 5, a micro channel reactor 6, a gas-liquid separator 7, a nitrogen pipeline 8, a product liquid storage tank 9 and a back pressure valve 10. 6-1 is a first temperature control medium layer, 6-2 is a reaction layer, and 6-3 is a second temperature control medium layer.

Detailed Description

To explain technical contents, structural features, achieved objects and effects of the technical solutions in detail, the following description is further made with reference to the embodiments and accompanying drawings. The present embodiment is implemented on the premise of the technical solution of the present invention, and a detailed implementation manner and a specific operation process are given, but the protection scope of the present invention is not limited to the following embodiments.

The structure of the micro-reaction system used in the example is shown in figure 1, and comprises an isobutene pipeline 1, a substrate liquid storage tank 2, a gas mass flow controller 3, a feed pump 4, a micro-mixer 5, a micro-channel reactor 6, a gas-liquid separator 7, a nitrogen pipeline 8, a product liquid storage tank 9 and a back pressure valve 10.

One inlet of the micro mixer 5 is connected with the gas mass flow controller 3, the other inlet of the micro mixer 5 is connected with the feed pump 4, the outlet of the micro mixer 5 is connected with the inlet of the micro channel reactor 6, the outlet of the micro channel reactor 6 is connected with the first interface at the top of the gas-liquid separator 7, the second interface at the top of the gas-liquid separator 7 is connected with the nitrogen pipeline 8 to access nitrogen, and the backpressure valve 10 is connected with the third interface at the top of the gas-liquid separator 7.

The working process is as follows:

(A) preparing a substrate solution containing cyanoacetic acid and Lewis acid, and placing the substrate solution in a substrate solution storage tank 2;

(B) respectively and simultaneously conveying substrate liquid and isobutene into a micro mixer 5 by using a feed pump 4 and a gas mass flow controller 3, mixing the substrate liquid and the isobutene by the micro mixer 5 to form a mixed reaction material, directly feeding the mixed reaction material flowing out of the micro mixer 5 into a micro-channel reactor 6 for continuous catalytic esterification, feeding the mixed material flowing out of the micro-channel reactor 6 into a gas-liquid separator 7, discharging waste gas through a third interface at the top of the gas-liquid separator 7 and a back pressure valve 10, leading out and collecting reaction mixed liquid from a bottom outlet of the gas-liquid separator 7, and performing separation and purification treatment to obtain a target product, namely tert-butyl cyanoacetate.

To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to specific examples.

Example 1

Mixing solid cyanoacetic acid (3.4 kg, 40 mol) and boron trifluoride diethyl etherate (0.284 kg, 2 mol) with 17L tetrahydrofuran to prepare a substrate liquid, then respectively and simultaneously conveying the substrate liquid and isobutene to a T-shaped micro mixer, controlling the temperature in the T-shaped micro mixer to be 10 ℃, adjusting the flow ratio of the substrate liquid and isobutene to ensure that the molar ratio of the cyanoacetic acid substrate to the isobutene is 1:1.1, mixing the substrate liquid and the isobutene through the T-shaped micro mixer, then directly feeding the mixture into a tubular micro-channel reactor (the length is 20 cm, the inner diameter is 0.6 mm), setting the backpressure value of a backpressure valve to be 1.6 MPa, adjusting the pressure of a gas-liquid separator connected with nitrogen to be 1.9 MPa, controlling the temperature in the micro-channel reactor to be 10 ℃, reacting for 8 minutes (namely, keeping the residence time of the mixed reaction material in the micro-channel reactor to be 8 minutes), and allowing the mixed reaction material to flow out of an outlet of the micro-channel reactor, and after gas components are separated by a gas-liquid separator, collecting the gas components in a product liquid collecting tank, adding saturated sodium bicarbonate solution for neutralization and layering, recovering an organic phase, distilling to obtain colorless oily tert-butyl cyanoacetate, analyzing, completely converting a substrate cyanoacetic acid, and obtaining the product, namely the tert-butyl cyanoacetate, with the yield of 97.8 percent and the purity of more than 99 percent (GC).

Example 2

The present embodiment is the same as embodiment 1, except that a Y-type micromixer is used for the micromixer in the present embodiment. In the example, the substrate cyanoacetic acid is completely converted, and the yield of the obtained product, namely tert-butyl cyanoacetate, is 97.2 percent, and the purity is more than 99 percent (GC).

Example 3

This example is the same as example 1, except that a coaxial flow micromixer is used for the micromixer in this example. In the example, the substrate cyanoacetic acid is completely converted, and the yield of the obtained product, namely tert-butyl cyanoacetate, is 97.5 percent, and the purity is more than 99 percent (GC).

Example 4

This example is the same as example 1, except that a flow focusing micromixer is used for the micromixer in this example. In the example, the substrate cyanoacetic acid is completely converted, and the yield of the obtained product, namely tert-butyl cyanoacetate, is 97.6 percent, and the purity is more than 99 percent (GC).

Example 5

This example is the same as example 1, except that a static mixer was used for the micromixer in this example. In the example, the substrate cyanoacetic acid is completely converted, and the yield of the obtained product, namely tert-butyl cyanoacetate, is 98 percent, and the purity is more than 99 percent (GC).

Example 6

This embodiment is the same as embodiment 1, except that the microchannel reactor in this embodiment is

316L stainless steel plate type microchannel reactor. The plate-type microchannel reactor is a cuboid (figure 2) with the length of 12 cm, the width of 10 cm and the height of 3 cm, and comprises a first temperature control medium layer, a reaction layer and a second temperature control medium layer which are sequentially arranged from top to bottom; the first temperature control medium layer and the second temperature control medium layer are used for adjusting and controlling the temperature of the reaction layer, and the reaction fluid channel is arranged on the reaction layer. The cross-sectional dimensions of the reaction flow channel were 400 microns (width) by 600 microns (depth), the hydraulic diameter was 480 microns, and the total reaction flow channel length was 100 mm. In the example, the substrate cyanoacetic acid is completely converted, and the yield of the obtained product, namely tert-butyl cyanoacetate, is 97.9 percent, and the purity is more than 99 percent (GC).

Example 7

This example is the same as example 1, except that in this example the temperature in the micromixer and microchannel reactor was controlled at 20 ℃ and the reaction was carried out for 7.3 minutes (i.e., the residence time of the mixed reaction mass in the microchannel reactor was 7.3 minutes) the substrate cyanoacetic acid was completely converted, resulting in a yield of t-butyl cyanoacetate of 97.2% and a purity of greater than 99% (GC).

Example 8

This example is the same as example 1, except that in this example the temperature in the micromixer and microchannel reactor was controlled at 30 ℃ and the reaction was carried out for 6.6 minutes (i.e. the residence time of the mixed reaction mass in the microchannel reactor was 6.6 minutes) the substrate cyanoacetic acid was completely converted, giving a yield of 96.7% t-butyl cyanoacetate and a purity of greater than 99% (GC).

Example 9

This example is the same as example 1, except that the solvent used in this example was acetone (17L). In the example, the substrate cyanoacetic acid is completely converted, and the yield of the obtained tert-butyl cyanoacetate is 97.6 percent, and the purity is more than 99 percent (GC).

Example 10

This example is the same as example 1, except that the solvent used in this example was t-butyl acetate (17L). In the example, the substrate cyanoacetic acid is completely converted, and the yield of the obtained tert-butyl cyanoacetate is 97.1 percent, and the purity is more than 99 percent (GC).

Example 11

This example is the same as example 1, except that boron trifluoride dimethyl ether complex (0.228 kg, 2 mol) was used as the Lewis acid in this example. In the example, the substrate cyanoacetic acid is completely converted, and the yield of the obtained tert-butyl cyanoacetate is 97.8 percent, and the purity is more than 99 percent (GC).

Example 12

This example is identical to example 1, except that in this example boron trifluoride diethyl etherate is used in an amount of 0.568 kg (4 mol). The reaction time is 7.2 minutes (namely the retention time of the mixed reaction material in the microchannel reactor is 7.2 minutes), the substrate cyanoacetic acid is completely converted, the yield of the obtained tert-butyl cyanoacetate is 97.9 percent, and the purity is more than 99 percent (GC).

It should be noted that, although the above embodiments have been described herein, the invention is not limited thereto. Therefore, based on the innovative concepts of the present invention, the technical solutions of the present invention can be directly or indirectly applied to other related technical fields by making changes and modifications to the embodiments described herein, or by using equivalent structures or equivalent processes performed in the content of the present specification and the attached drawings, which are included in the scope of the present invention.