Process for the preparation of bis-ethylhexyloxyphenol-methoxyphenyl-triazine (bemotrizinol)

Abstract

This paper falls within the technical field of organic synthesis and specifically concerns a process for preparing bis-ethylhexyloxyphenol-methoxyphenyl-triazine (bemotrizinol). In this paper, a Friedel-Crafts alkylation is carried out in a single step using 2,4-dichloro-6-(4-methoxyphenyl)triazine as a starting material and supercritical carbon dioxide as a solvent to obtain bemotrizinol. This paper avoids the pressure of wastewater, exhaust gas, and solid waste treatment due to the high concentration of aluminum trichloride in wastewater resulting from the anhydrous aluminum trichloride catalyst used in the post-treatment stage of a conventional preparation process.This design also avoids the large quantity of wastewater containing salts and N,N-dimethylformamide (DMF) produced in a second step of the traditional preparation process. Therefore, this design meets environmental protection requirements. Abstract figure: Figure 1.

Description

Description Title of the invention: Process for the preparation of bis- ethylhexyloxyphenol-methoxyphenyl-triazine (bemotrizinol) Technical field

[0001] = This presentation belongs to the technical field of organic synthesis, and relates in particular to a process for the preparation of bis-ethylhexy- loxyphenol-methoxyphenyl-triazine (bemotrizinol). Background

[0002] — Bis-ethylhexyloxyphenol-methoxyphenyl-triazine (III) (bemotrizinol) is a highly efficient, broad-spectrum ultraviolet (UV) absorber that has strong absorption over a wide range of UVA (320 nm to 400 nm) and UVB (280 nm to 320 nm). Moreover, bemotrizinol has a high molecular weight and strong stability, and is not easily absorbed through the skin. Therefore, bemotrizinol is widely used in personal hygiene and cosmetic products to reduce damage UV rays to the skin under sunlight.

[0003] — US patent 5955060 provides a traditional process for synthesizing be- motrizinol. In this technology, in a first step, a Friedel-alkylation Crafts is made by using 2,4-dichloro-6-(4-methoxyphenyl)triazine (I) and resorcinol as raw materials, aluminum trichloride as ca- talyser, and a halogenated hydrocarbon such as sulfones or chlorobenzene as as a solvent. Once the alkylation is complete, deactivation is carried out with water, and is followed by a solid-liquid separation to obtain an intermediate, the 2,6-(2,4-dihydroxyphenyl)-4-(4-methoxyphenyl)triazine (IT). In a second step, the intermediate 2,6-(2,4-dihydroxyphenyl)-4-(4-methoxyphenyl)triazine (II) reacts with a halogenated isooctane (such as chloroisooctane or bromoisooctane) in N,N-dimethylformamide (DMF) under alkaline catalysis conditions for that a finished product, bemotrizinol, is obtained.

[0004] [Chem.1] English wise NES M 3, DMF and alsali SN SE = a Resorcinal Do Su gen = ce ; ne pol à = DMF etalcali a 404, 3 ES CD MN Pre postage Fe A grrat # re An @ %,

[0005] — In the traditional synthesis process above, the first step has pri- The following disadvantages are clearly observed. 1. When Friedel Crafts alkylation is carried out, the aluminum trichloride catalyst has poor solubility in the solvent. Therefore, even if a large amount of the solvent is added, the resulting reaction system is still a heterogeneous reaction, leading to a long reaction time and various by-products. 2. When deactivation is carried out after alkylation, it is necessary to precipitate the product by adding a large amount of water. Furthermore, the residual aluminum trichloride must be washed off with a large amount of water, so that the residual aluminum salt will not affect subsequent reactions. In this step, a large amount of wastewater containing aluminum trichloride is produced. It is difficult to treat the wastewater, which may cause significant environmental pollution. Therefore, this step does not meet the environmental protection requirements. In the above traditional synthesis process, the second step also has the following disadvantages: 1. For the 2,6-(2,4-dihydroxyphenyl)-4-(4-methoxyphenyl)triazine (II), DMF is used as a solvent while alkali is used as an acid-binding agent, and etherification is carried out with halogenated isooctane at a high temperature of 100°C to 130°C. In the presence of strong alkali, the halogenated isooctane raw material is severely damaged. 2. There are multiple reaction sites during the reaction, and mono-substitution, di-substitution, tri-substitution, and tetra-substitution products can be generated. Due to a high reaction temperature, there is poor selectivity, more impurities are generated, and an undesirable yield. 3. After the reaction is completed, the product must be separated by water and extraction solvents. In this stage, a large amount of wastewater containing DMF is produced.It is not easy to treat wastewater, which can cause significant environmental pollution. Therefore, this step does not meet environmental protection requirements. In view of the above disadvantages in the traditional method, Rong Wang et al. proposed in 2020 (CN112321520A, Preparation method for synthesizing bemotrizinol by a one-pot method) proposed a one-pot method for synthesizing bemotrizinol. In this method, a first step is improved by using toluene as a solvent, and introducing benzonitrile as a co-solvent of aluminum trichloride for the heterogeneity problem. After alkylation, a reaction system is diluted with water and a large amount of DMF (with a mass of 12.5 times that of 2,4-dichloro-6-(4-methoxyphenyl)triazine). After heating until the solution becomes clarified, the pH value of the reaction system is adjusted to 7 to 8, and the chloroisooctane is subjected to a reaction using potassium carbonate as an alkali. After the reaction is completed, a pump Water is adjusted to a vacuum degree of -0.01 MPa, and the solvent is recovered under reduced pressure until the reactor temperature is 140°C. After solvent recovery, the system is brought back to a temperature of 50°C to 60°C, toluene and tap water are added, an aqueous layer is separated, and an organic layer is washed twice with tap water. After precipitation, crystallization, recrystallization and drying of the resulting oily layer, a finished product of bemotrizinol is obtained. This process mainly has the following disadvantages: 1. The high-boiling solvent DMF is used in a large amount, and the product of a single batch has a poor production yield (because DMF is 12.5 times the mass of 2,4-dichloro-6-(4-methoxyphenyl)triazine, and there are also benzonitrile and toluene, so the reaction is a high-dilution reaction). 2. Long-term distillation under high vacuum and high temperature is required to remove DMF. 3. In addition, a large amount of aluminum-containing wastewater containing salts is produced. Basically, this process is an uneconomical and environmentally friendly production process with high production and raw material costs, which is not suitable for industrial production. In 2018, Jiwen Meng et al. (CN108947921A, Preparation Method for 2,4 bis(2,4-dihydroxyphenyl)-6-(4-methoxyphenyl)-s-triazine) proposed to adopt chloroaluminate ionic liquid as a reaction solvent as well as a catalyst. In this method, a product is extracted from the ionic liquid catalyst with an extractant after the reaction, thus realizing separation of the product and the catalyst. The chloroaluminate ionic liquid can be recycled, thus avoiding the pressure that the traditional anhydrous aluminum trichloride catalyst brings to the treatment of wastewater, exhaust gas, and solid waste, thus meeting the environmental protection requirements. The method preferably avoids the treatment of a large amount of wastewater containing aluminum trichloride in the traditional Friedel-Crafts alkylation in the first step.However, the process does not perform the second step to prepare bemotrizinol, so the problems cannot be solved during etherification in the second step. Abstract . In view of this, an objective of the present disclosure is to provide a process for the preparation of bemotrizinol. In the present disclosure, bemotrizinol is prepared in a single step with supercritical carbon dioxide as a solvent. The present disclosure avoids a large amount of wastewater containing aluminum trichloride during conventional Friedel-Crafts alkylation in a first step. The present disclosure also avoids a large amount of wastewater containing salts and DMF, produced in a second step. Therefore, the present disclosure meets environmental protection requirements. To achieve the above objective, this presentation provides the following technical solutions. This disclosure provides a process for preparing bemotrizinol, comprising the following steps: mixing 2,4-dichloro-6-(4-methoxyphenyl)triazine, resorcinol monoisooctyl ether, a Lewis acid catalyst, and supercritical carbon dioxide, and carrying out a Friedel-Crafts alkylation to obtain bemotrizinol. Preferably, the Lewis acid catalyst comprises aluminum trichloride. Preferably, 2,4-dichloro-6-(4-methoxyphenyl)triazine and resorcinol monoisooctyl ether are present in a molar ratio of 1 / (2 to 2.2). Preferably, the 2,4-dichloro-6-(4-methoxyphenyl)triazine and the Lewis acid catalyst are present in a molar ratio of 1 / (2 to 2.2). Preferably, 2,4-dichloro-6-(4-methoxyphenyl)triazine and supercritical carbon dioxide are present in a mass ratio of 1:(1 to 8). Preferably, the Friedel-Crafts alkylation is carried out at a temperature of 0°C to 30°C for 6 hours to 14 hours. Preferably, the Friedel-Crafts alkylation is carried out in a pressure reactor equipped with an external circulation temperature control system, a sampling valve, and an agitation device. Preferably, the preparation method further comprises the following steps after the Friedel-Crafts alkylation is completed: subjecting the material obtained after the Friedel-Crafts alkylation to carbon dioxide recovery, Lewis acid catalyst recovery, and purification and crystallization in sequence to obtain bemotrizinol. Preferably, the carbon dioxide recovery specifically comprises: connecting a carbon dioxide recovery system with the reactor after the Friedel-Crafts alkylation is completed, and recovering carbon dioxide at room temperature until the internal pressure of the reactor reaches normal pressure, to obtain a product from which carbon dioxide has been removed; and the Lewis acid catalyst recovery specifically comprises: mixing the product from which carbon dioxide has been removed with an organic solvent, and filtering to obtain the Lewis acid catalyst and an organic phase; and subjecting the organic phase to washing and vacuum distillation in sequence to obtain the organic solvent and a final product in a non-solid form. Preferably, the purification and crystallization specifically comprise: mixing the final product in a non-solid form with ethanol, and making crystallization, filtration and drying in sequence to obtain bemotrizinol. The present disclosure provides a process for preparing bemotrizinol, comprising the following steps: mixing 2,4-Dichloro-6-(4-methoxyphenyl)triazine, resorcinol monoisooctyl ether, a Lewis acid catalyst, and supercritical carbon dioxide, and performing Friedel-Crafts alkylation to obtain bemotrizinol. In the preparation method of the present disclosure, supercritical carbon dioxide is used as a reaction solvent to replace traditional petrochemical organic solvents. Supercritical carbon dioxide has low viscosity and surface tension, strong dissolving ability, and high safety. Supercritical carbon dioxide can enable alkylation to be carried out in a homogeneous phase, thereby increasing the reaction yield and shortening the reaction time. Supercritical carbon dioxide is used as a reaction solvent for the preparation of a bemotrizinol product in a single step.The present disclosure avoids the pressure of wastewater treatment, exhaust gas, and solid waste due to a large amount of wastewater containing aluminum trichloride resulting from the anhydrous aluminum trichloride catalyst used during post-treatment in a first step of a conventional preparation process. The present disclosure also avoids the large amount of wastewater containing salts and DMF produced in a second step of the conventional preparation process. Therefore, the present disclosure meets the environmental protection requirements. In addition, in the preparation process, the supercritical carbon dioxide solvent is a readily available, non-flammable, and non-explosive, low-cost material, which can reduce the synthesis costs and post-processing difficulties, and improve the safety during preparation. In addition, both carbon dioxide and the catalyst can be recycled, while other organic solvents are omitted in the reaction. Furthermore, a large amount of fossil organic solvents is not required, thus greatly reducing the costs of raw materials, production, and environmental protection. Furthermore, the safety during preparation is improved to promote the goal of carbon neutrality. In addition, the preparation method has mild reaction conditions, convenient operations, simple post-treatment, and high yield. Brief Description of the Drawings [Fig.1] [Fig.1] shows a high performance liquid chromatography (HPLC) graph of bemotrizinol prepared in Example |; and [Fig.2] [Fig.2] shows an HPLC graph of bemotrizinol prepared in Example 2. Detailed description of the embodiments This disclosure provides a process for preparing bemotrizinol, comprising the following steps: mixing 2,4-dichloro-6-(4-methoxyphenyl)triazine, resorcinol monoisooctyl ether, a Lewis acid catalyst, and supercritical carbon dioxide, and carrying out a Friedel-Crafts alkylation to obtain bemotrizinol. Unless otherwise stated, this disclosure has no particular limitations regarding the sources of the raw materials used, and commercially available products, well known to those skilled in the art, may be adopted. In this disclosure, 2,4-dichloro-6-(4-methoxyphenyl)triazine, resorcinol monoisooctyl ether, a Lewis acid catalyst, and supercritical carbon dioxide are mixed. In the present disclosure, the Lewis acid catalyst preferably comprises aluminum trichloride. In the present disclosure, 2,4-dichloro-6-(4-methoxyphenyl)triazine and resorcinol monoisooctyl ether are present in a molar ratio of preferably 1:(2 to 2.2), more preferably 1:(2 to 2.1). 2,4-dichloro-6-(4-methoxyphenyl)triazine and Lewis acid catalyst are present in a molar ratio of preferably 1:(2 to 2.2), more preferably 1:(2 to 2.1). 2,4-dichloro-6-(4-methoxyphenyl)triazine and supercritical carbon dioxide are present in a mass ratio of preferably 1:(1 to 8), more preferably 1:5. In this disclosure, a method of mixing the 2,4-dichloro-6-(4-methoxyphenyl)triazine, resorcinol monoisooctyl ether, Lewis acid catalyst, and supercritical carbon dioxide preferably comprises: placing the 2,4-dichloro-6-(4-methoxyphenyl)triazine, resorcinol monoisooctyl ether, and Lewis acid catalyst in the reactor, sealing the reactor, venting with carbon dioxide, and injecting the supercritical carbon dioxide. In the present disclosure, once mixing is complete, the mixed material is subjected to Friedel-Crafts alkylation. In the present disclosure, the Friedel-Crafts alkylation is preferably carried out at a temperature of 0°C to 30°C, more preferably 25°C, preferably in a pressure reactor equipped with an external circulation temperature control system, a sampling valve, and a stirring device, and preferably with stirring. The stirring speed is not particularly limited, as long as the raw materials can be completely reacted during the reaction at a stirring speed well known in the art. In the present disclosure, preferably, the end point of the reaction is controlled by adjusting the time of the Friedel-Crafts alkylation or by performing detection by sampling through the sampling valve. When the end point is controlled by adjusting the time of the Friedel-Crafts alkylation, the Friedel-Crafts alkylation is preferably performed for 6 hours to 14 hours, more preferably 8 hours. When the end point is controlled by performing detection by sampling through the sampling valve, the Friedel-Crafts alkylation is preferably terminated after it has been detected by sampling through the sampling valve. sampling, that 2,4-dichloro-6-(4-methoxyphenyl)triazine has completely reacted. In the present disclosure, supercritical carbon dioxide is used as a reaction solvent to replace traditional petrochemical organic solvents. Supercritical carbon dioxide has low viscosity and surface tension, strong dissolving ability, and high safety. Supercritical carbon dioxide can enable alkylation to be carried out in a homogeneous phase, thereby increasing the reaction yield and shortening the reaction time. In addition, supercritical carbon dioxide is a readily available, non-flammable, and non-explosive material with low cost, which can reduce synthesis costs and post-processing difficulties, and improve safety during preparation. In the present disclosure, the preparation method preferably further comprises the following steps after the Friedel-Crafts alkylation is completed: subjecting the material obtained after the Friedel-Crafts alkylation to carbon dioxide recovery, Lewis acid catalyst recovery, and sequential purification and crystallization to obtain bemotrizinol. In the present disclosure, once the Friedel-Crafts alkylation is completed, carbon dioxide recovery is preferably carried out on a material obtained after the Friedel-Crafts alkylation. In the present disclosure, carbon dioxide recovery specifically preferably comprises: connecting a carbon dioxide recovery system with the reactor after the Friedel-Crafts alkylation is complete, and recovering carbon dioxide at room temperature until the internal pressure of the reactor reaches normal pressure, to obtain a product from which carbon dioxide has been removed. In this presentation, carbon dioxide recovery allows for the recycling of carbon dioxide, and can greatly reduce the use of fossil organic solvents. In the present disclosure, after carbon dioxide recovery is completed, Lewis acid catalyst recovery is preferably carried out on the material obtained after carbon dioxide recovery. In the present disclosure, the recovery of Lewis acid catalyst preferably comprises: mixing the product from which carbon dioxide has been removed with an organic solvent, and filtering to obtain the Lewis acid catalyst and an organic phase; and subjecting the organic phase to washing and vacuum distillation in sequence to obtain the organic solvent and a final product in a non-solid form. The organic solvent is preferably toluene. 2,4-Dichloro-6-(4-methoxyphenyl)triazine and the organic solvent are present in a mass ratio of preferably 1:(1 to 6), more preferably 1:4. Mixing of the material after carbon dioxide recovery with the organic solvent is preferably carried out under stirring, preferably at a temperature of 25°C to 30°C, more preferably 25°C.The filtration method is not particularly limited, and a filtration method well known in the art can be used. The cleaning is preferably carried out with water, preferably 2 times. The amount of the cleaning water, which can be determined according to actual needs, is not particularly limited. The vacuum distillation method is not particularly limited, as long as the organic solvent is evaporated to dryness. In this disclosure, carbon dioxide is used as a solvent. After carbon dioxide is recovered after the reaction, toluene is added to extract a product, so that the product is dissolved in the toluene. The aluminum trichloride catalyst and a resulting organic phase are separated by filtration (the aluminum trichloride catalyst is efficiently recycled). The organic phase only needs to be washed with a small amount of water to remove residual aluminum trichloride, and it is concentrated and added with ethanol for crystallization to obtain the high-purity final product. The Lewis acid catalyst can be recycled, which avoids the treatment of a large amount of catalyst-containing wastewater. In the present disclosure, after the recovery of Lewis acid catalyst is completed, purification and crystallization are preferably carried out on the material obtained after the recovery of Lewis acid catalyst, so that bemo-trizinol is obtained. In the present disclosure, the purification and crystallization specifically preferably comprise: mixing the final product in a non-solid form with ethanol, and carrying out crystallization, filtration and drying in sequence to obtain bemotrizinol. In this disclosure, 2,4-dichloro-6-(4-methoxyphenyl)triazine and ethanol are present in a mass ratio of preferably 1 / (2 to 5), more preferably 1 / (3 to 4). The filtration and drying method is not particularly limited, and a filtration and drying method well known in the art can be used. In the present disclosure, if the quality of the bemotrizinol obtained through purification and crystallization cannot meet the requirements, secondary purification and crystallization are preferably carried out on the bemotrizinol obtained through purification and crystallization. In the present disclosure, for the preparation process of bemotrizinol, Friedel-Crafts alkylation is carried out using 2,4-Dichloro-6-(4-methoxyphenyl)triazine as a starting material with supercritical carbon dioxide as a solvent. An environmentally friendly and efficient preparation of bemotrizinol is carried out by a one-step reaction, which is suitable for large-scale industrial production. Taking aluminum trichloride as an example of the Lewis acid catalyst, the synthetic route of bemotrizinol is as follows: [Chem.2] Bb Bone pe ANIELSERA ge ESS Se we Aug ea pe ke an RS DH + fe Se rraretate haha EU at In this presentation, compared with the traditional process, the preparation process of bemotrizinol does not produce a large amount of wastewater and does not use a large amount of fossil organic solvents. The preparation process reduces costs, and improves safety during preparation, which is advantageous for the purpose of carbon neutrality. The technical solutions of this presentation will be clearly and fully described below with reference to the examples of this presentation. Example 1 A pressure reactor is cleaned and dried. 383 g (1.5 mol) of 2,4-dichloro-6-(4-methoxyphenyl)triazine, 666 g (3 mol) of resorcinol monoisooctyl ether, and 400 g (3 mol) of anhydrous aluminum trichloride are added to the reactor. The reactor is sealed and, to remove the air in the reactor, it is replaced with carbon dioxide. 1915 g of supercritical carbon dioxide are injected into the reactor, an external circulation temperature control system is turned on, stirring is started, and the temperature in the reactor is controlled to no more than 25°C. Sampling is carried out with a sampling valve to detect the moment where 2,4-dichloro-6-(4-methoxyphenyl)triazine has completely reacted. At room temperature, the reactor is connected to a carbon dioxide recovery system to recover carbon dioxide until the reactor pressure is normal pressure. 1568.5 g of toluene is added to the reactor, stirred well at 25°C, aluminum trichloride is recovered by filtration, the resulting toluene phase is washed with 300 g of water twice, and then the toluene is recovered under reduced pressure to dryness. 1400 g of ethanol is added to achieve crystallization, and the resulting crystal is filtered and dried, giving 583.5 g of bemotrizinol product with a yield of 93% and a purity of not less than 99% (as shown in [Fig. 1]). If the product quality does not meet the requirements, secondary crystallization is carried out with ethanol solvent. Example 2 A pressure reactor is cleaned and dried. 383 g (1.5 mol) of 2,4-dichloro-6-(4-methoxyphenyl)triazine, 699.3 g (3.15 mol) of resorcinol monoisooctyl ether, and 420.5 g (3.15 mol) of anhydrous aluminum trichloride are added to the reactor. The reactor is sealed and, to remove the air in the reactor, it is replaced with carbon dioxide. 1915 g of supercritical carbon dioxide are injected into the reactor, an external circulation temperature control system is turned on, stirring is started, and the temperature in the reactor is controlled to no more than 25°C. Sampling is carried out with a sampling valve to detect when the 2,4-dichloro-6-(4-methoxyphenyl)triazine has completely reacted. At room temperature, the reactor is connected to a carbon dioxide recovery system to recover carbon dioxide until the reactor pressure is normal pressure.1568.5 g of toluene was added to the reactor, stirred well at 25°C, the aluminum trichloride was recovered by filtration, the resulting toluene phase was washed with 300 g of water twice, and then the toluene was recovered under reduced pressure to dryness. 1400 g of ethanol was added to carry out crystallization, and the resulting crystal was filtered and dried, giving 589.7 g of bemotrizinol product with a yield of 94% and a purity of not less than 99% (as shown in [Fig.2]). If the product quality does not meet the requirements, secondary crystallization was carried out with the solvent ethanol. Although the above example has described this disclosure in detail, it constitutes only a part, and not all, of the examples in this disclosure. Other examples may also be obtained by persons based on the example without creative efforts, and all such examples will fall within the scope of protection of this disclosure.

Claims

Claims

1. Process for the preparation of bis-ethylhexy- loxyphenol-methoxyphenyl-triazine (bemotrizinol), including next steps: mixture of 2,4-dichloro-6-{4-methoxyphenyl)triazine, mono- ether isooctyl resorcinol, a Lewis acid catalyst, and dioxide of supercritical carbon, and realization of a Friedel-alkylation Crafts to obtain bemotrizinol.

2. Preparation process according to claim 1, wherein the ca- Lewis acid catalyzer comprises aluminum trichloride.

3. A preparation process according to claim 1, wherein the 2,4-dichloro-6-(4-methoxyphenyl)triazine and monoisooctyl ether of resorcinol are present in a molar ratio of 1 / (2 to 2.2).

4. A preparation process according to claim 1, wherein the 2,4-dichloro-6-(4-methoxyphenyl)triazine and the acid catalyst of Lewis are present in a molar ratio of 1 / (2 to 2.2).

5. A preparation method according to claim 1, wherein the 2,4-dichloro-6-(4-methoxyphenyl)triazine and carbon dioxide su- percritical are present in a molar ratio of 1 / (1 to 8).

6. Preparation process according to any one of claims 1 to 5, in which the Friedel-Crafts alkylation is carried out at a temperature from 0°C to 30°C for 6 hours to 14 hours.

7. A preparation process according to claim 1, wherein the alkylation Friedel-Crafts is carried out in a pressurized reactor equipped with a external circulation temperature control system, of a sampling valve, and a stirring device.

8. A preparation method according to claim 1, further comprising the Next steps after Friedel-Crafts alkylation is complete: subjecting the material obtained after Friedel-Crafts alkylation to a carbon dioxide recovery, to catalyst recovery Lewis acid, and to a purification and crystallization in sequence to obtain bemotrizinol.

9. Preparation process according to claim 8, wherein the recov- carbon dioxide operation specifically includes: the connection of a carbon dioxide recovery system with the reactor a once the Friedel-Crafts alkylation is complete, and the recovery of carbon dioxide at room temperature until the pressure internal pressure of the reactor reaches normal pressure, so that a product from which carbon dioxide has been removed; and the recovery of Lewis acid catalyst specifically includes: the mixture of the product from which carbon dioxide has been removed with a solvent organic, and filtration to obtain the acid catalyst Lewis and an organic phase; and the submission of the phase organic to washing and vacuum distillation in sequence for that the organic solvent and a final product are obtained under a non-solid form.

10. Preparation process according to claim 8, wherein the puri- fication and crystallization specifically include: mixing the final product in a non-solid form with ethanol, and the rea- Sequential crystallization, filtration and drying to obtain bemotrizinol.