Preparation method of 2, 5-disubstituted benzyl chloride

Abstract

The invention provides a preparation method of 2, 5-disubstituted benzyl chloride, and belongs to the technical field of preparation of drug intermediates. The chloromethyl solution is prepared from concentrated hydrochloric acid and paraformaldehyde, the concentration of hydrochloric acid is gradually reduced along with the reaction, and the reaction progress is slow due to the reduction of the concentration of concentrated hydrochloric acid; therefore, the chloromethylation reaction is carried out on the chloromethyl liquid and the disubstituted benzene in the hydrogen chloride gas, and the hydrogen chloride gas is supplemented, so that the concentration of the hydrogen chloride is increased, and the chloromethylation reaction is accelerated; meanwhile, a gradient heating mode is adopted, disubstituted benzene and chloromethyl liquid are subjected to chloromethylation reaction for 2-3 hours at the temperature of 50-60 DEG C, and the temperature is increased to 70-80 DEG C after the concentration of hydrogen chloride is reduced, so that the chloromethylation reaction is accelerated again, and the yield of the product is increased. According to the method, the volatilization and consumption of concentrated hydrochloric acid can be reduced, the generation of wastewater is reduced, the reaction time is shortened, and meanwhile, the yield of 2, 5-disubstituted benzyl chloride is also improved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediate preparation technology, specifically relating to a method for preparing 2,5-disubstituted benzyl chloride. Background Technology

[0002] 2,5-Disubstituted benzyl chloride (such as 2,5-dimethylbenzyl chloride) is an important chemical raw material and intermediate. It can be used as an important intermediate for the insecticide and acaricide spirotetramat. For example, 2,5-dimethylphenylacetic acid can be prepared by using 2,5-dimethylbenzyl chloride, and then 2,5-dimethylphenylacetyl chloride can be synthesized. Then, it can be reacted with 1,4-substituted cyclohexane amino acids to synthesize spirotetramat intermediate.

[0003] One existing technique for preparing 2,5-dimethylbenzyl chloride involves preparing a chloromethyl reagent from formaldehyde and concentrated hydrochloric acid. This chloromethyl reagent is then reacted with p-xylene, and the amount of p-xylene is increased to three times the molar amount of formaldehyde to improve reaction selectivity and reduce the content of disubstituted impurities. However, this method is not ideal in practice and still exhibits some instability. The specific steps are as follows: First, concentrated hydrochloric acid is added to a reaction flask and heated to 70-75°C. After stabilizing the temperature, formaldehyde solution is added dropwise, and the mixture is kept warm and stirred to prepare a highly reactive chloromethyl reagent. Then, p-xylene is placed in another reaction flask and heated to 55-65°C. The chloromethyl reagent is added dropwise while controlling the temperature, and the reaction is maintained at this temperature for 4 hours after the addition is complete. The reaction temperature of concentrated hydrochloric acid with formaldehyde is 70-75℃. At this temperature, a large amount of hydrogen chloride gas in the concentrated hydrochloric acid volatilizes, and the amount of effective hydrogen chloride in the system is greatly reduced, which affects the reaction rate and yield. The yield of 2,5-dimethylbenzyl chloride in this method is only 83.6%, which does not reach the ideal yield level in industry and is not conducive to the control of large-scale production costs. Summary of the Invention

[0004] The purpose of this invention is to provide a method for preparing 2,5-disubstituted benzyl chloride, which yields a high amount of 2,5-disubstituted benzyl chloride.

[0005] To achieve the objectives of this invention, the following technical solutions are provided: A method for preparing 2,5-disubstituted benzyl chloride includes the following steps: Paraformaldehyde and concentrated hydrochloric acid are mixed and subjected to a condensation reaction to obtain a chloromethylating agent; The chloromethylating agent and the para-disubstituted benzene of Formula I were mixed and chloromethylated in hydrogen chloride gas to obtain 2,5-disubstituted benzyl chloride of Formula II. Formula I; Formula II; Among them, R1 and R2 are independently alkyl groups having 1 to 10 carbon atoms; The concentration of the concentrated hydrochloric acid is 36~38wt%; based on the molar amount of formaldehyde monomer in paraformaldehyde and the molar amount of HCl in the concentrated hydrochloric acid, the molar ratio of the concentrated hydrochloric acid to paraformaldehyde is 1~2:1. The chloromethylation reaction includes sequentially performing a first reaction and a second reaction; the temperature of the first reaction is 50~60℃; the temperature of the second reaction is 70~80℃.

[0006] Preferably, the para-disubstituted benzene is one of 1,4-dimethylbenzene, 1,4-diethylbenzene, and 1,4-dipropylbenzene.

[0007] Preferably, the molar ratio of para-disubstituted benzene to paraformaldehyde is 2 to 5:1, based on the molar amount of formaldehyde monomer in paraformaldehyde.

[0008] Preferably, the molar ratio of hydrogen chloride gas to paraformaldehyde is 0.5 to 2:1, based on the molar amount of formaldehyde monomer in paraformaldehyde.

[0009] Preferably, the reaction time for the first reaction is 2 to 3 hours.

[0010] Preferably, the second reaction takes 4 to 8 hours.

[0011] Preferably, the condensation reaction is carried out at a temperature of 40-60°C for 0.5-2 hours.

[0012] This invention provides a method for preparing 2,5-disubstituted benzyl chloride, comprising the following steps: mixing paraformaldehyde and concentrated hydrochloric acid to perform a condensation reaction to obtain a chloromethylating agent; mixing the chloromethylating agent with a para-disubstituted benzene of Formula I and performing a chloromethylation reaction in hydrogen chloride gas to obtain 2,5-disubstituted benzyl chloride of Formula II; wherein R1 and R2 are independently alkyl groups having 1 to 10 carbon atoms; the concentration of the concentrated hydrochloric acid is 36 to 38 wt%; the molar ratio of the concentrated hydrochloric acid to paraformaldehyde is 1 to 2:1, based on the molar amount of formaldehyde monomer in paraformaldehyde and the molar amount of HCl in the concentrated hydrochloric acid; the chloromethylation reaction includes sequentially performing a first reaction and a second reaction; the temperature of the first reaction is 50 to 60°C; the temperature of the second reaction is 70 to 80°C. This invention uses 36-38 wt% concentrated hydrochloric acid and paraformaldehyde to prepare a chloromethyl liquid. As the reaction proceeds, the hydrochloric acid concentration gradually decreases, slowing the reaction. Therefore, this invention performs the chloromethylation reaction of the chloromethyl liquid and disubstituted benzene in a hydrogen chloride gas atmosphere. By adding hydrogen chloride gas, the concentration of hydrogen chloride is increased, thereby accelerating the chloromethylation reaction. Simultaneously, this invention employs a gradient heating method: the disubstituted benzene and chloromethyl liquid undergo chloromethylation at 50-60°C, and after the hydrogen chloride concentration decreases, the temperature is raised to 70-80°C to further accelerate the chloromethylation reaction, thereby improving the product yield. This invention reduces the volatilization and consumption of concentrated hydrochloric acid, reduces wastewater generation, shortens the reaction time, and also improves the yield of 2,5-disubstituted benzyl chloride. Detailed Implementation

[0013] This invention provides a method for preparing 2,5-disubstituted benzyl chloride, comprising the following steps: Paraformaldehyde and concentrated hydrochloric acid are mixed and subjected to a condensation reaction to obtain a chloromethylating agent; The chloromethylating agent and the para-disubstituted benzene of Formula I were mixed and chloromethylated in hydrogen chloride gas to obtain 2,5-disubstituted benzyl chloride of Formula II. Formula I; Formula II; Among them, R1 and R2 are independently alkyl groups having 1 to 10 carbon atoms; The concentration of the concentrated hydrochloric acid is 36~38wt%; based on the molar amount of formaldehyde monomer in paraformaldehyde and the molar amount of HCl in the concentrated hydrochloric acid, the molar ratio of the concentrated hydrochloric acid to paraformaldehyde is 1~2:1. The chloromethylation reaction includes sequentially performing a first reaction and a second reaction; the temperature of the first reaction is 50~60℃; the temperature of the second reaction is 70~80℃.

[0014] In this invention, unless otherwise specified, all raw materials used in the preparation are commercially available products well known to those skilled in the art.

[0015] In this invention, the para-disubstituted benzene is one of 1,4-dimethylbenzene, 1,4-diethylbenzene, 1,4-dipropylbenzene, and other 1,4-disubstituted benzene structures. In a specific embodiment, it can be 1,4-dimethylbenzene.

[0016] In this invention, paraformaldehyde has the molecular formula (CH2O). n Where n is 8~100, and in a specific embodiment of the present invention, 30g of paraformaldehyde is 1mol.

[0017] In this invention, based on the molar amount of formaldehyde monomer in paraformaldehyde, the molar ratio of para-disubstituted benzene to paraformaldehyde is 2-5:1, and in specific embodiments it can be 3:1 or 4:1. This invention controls the molar ratio of para-disubstituted benzene to paraformaldehyde within the above range to prevent low reaction selectivity and excessive disubstituted impurities when the molar amount is too low; on the other hand, it prevents the effect of excessively high molar amount on improving reaction selectivity from being limited, and also prevents increased post-processing time and cost due to excessive para-disubstituted benzene.

[0018] In this invention, the molar ratio of concentrated hydrochloric acid to paraformaldehyde is 1-2:1, based on the molar amount of formaldehyde monomer in paraformaldehyde. In specific embodiments, it can be 1.0:1, 1.5:1, or 2.0:1. The molar ratio of hydrogen chloride gas to paraformaldehyde is 0.5-2:1, based on the molar amount of formaldehyde monomer in paraformaldehyde. In specific embodiments, it can be 0.5:1, 0.75:1, or 1:1. This invention controls the molar ratio of concentrated hydrochloric acid to paraformaldehyde within the above range. When the amount of concentrated hydrochloric acid added is less than 1:1, it is not conducive to the reaction and it is difficult to achieve the ideal yield. When it is greater than 2:1, the amount of wastewater generated increases significantly. On the other hand, by introducing hydrogen chloride to increase the concentration of hydrogen chloride in the reaction of chloromethyl liquid with disubstituted benzene, the reaction temperature of paraformaldehyde and concentrated hydrochloric acid can be significantly reduced, which can effectively reduce the generation of disubstituted impurities and thus reduce the consumption of hydrochloric acid. Therefore, the amount of concentrated hydrochloric acid added should be 2 times the molar amount of paraformaldehyde or less. Adding more than 2 times the molar amount of concentrated hydrochloric acid not only increases the cost of raw materials, but also leads to a significant increase in the amount of post-treatment wastewater, increasing wastewater costs and being environmentally unfriendly.

[0019] In this invention, the temperature of the condensation reaction is 40~60℃, and in a specific embodiment, it can be 50℃; the time is 0.5~2h, and in a specific embodiment, it can be 1 or 1.5h. In the initial stage of this invention, formaldehyde and hydrochloric acid are used to obtain CH2OH through a condensation reaction. + or CH2Cl + Intermediates, etc.

[0020] In this invention, the chloromethylation reaction includes a first reaction and a second reaction performed sequentially. The temperature of the first reaction is 50-60°C, and the time is 2-3 hours. The temperature of the second reaction is 70-90°C, and the time is 4-8 hours. This invention employs a gradient heating method, where the disubstituted benzene and chloromethyl liquid are first subjected to a chloromethylation reaction at 50-60°C for 2-3 hours. After the hydrogen chloride concentration is reduced, the temperature is raised to 70-80°C to further accelerate the chloromethylation reaction, thereby improving the product yield.

[0021] To further illustrate the present invention, the preparation method of 2,5-disubstituted benzyl chloride provided by the present invention will be described in detail below with reference to the embodiments, but these should not be construed as limiting the scope of protection of the present invention.

[0022] The high-performance liquid chromatography (HPLC) measurement conditions are as follows in the examples: The instrument is an Agilent phase chromatograph with a UV detector; The chromatographic column is a stainless steel C18 column, 4.6×250mm; The mobile phase is acetonitrile:water = 7:3 (V / V); The column temperature was 30℃; the flow rate was 1.0 mL / min. The detection wavelength is 225nm.

[0023] Example 1 150 g of paraformaldehyde and 750 g of concentrated hydrochloric acid (36.5 wt%) were added to a reaction vessel. The temperature was raised to 55℃±5℃, and the mixture was stirred for 1-2 h. Then, 1590 g of p-xylene was added, and 91.25 g (2.5 mol) of hydrogen chloride was introduced. The reaction was continued at 55±5℃ for 2-3 h, and then raised to 75±5℃ for 4-8 h. A sample was taken, and the upper organic phase was analyzed by high-performance liquid chromatography (HPLC). The reaction ended when 2,5-dimethylbenzyl chloride was detected and no further increase was observed. After standing, the mixture was separated, and the organic phase was transferred to a solvent removal reactor. After vacuum distillation, 2,5-dimethylbenzyl chloride was obtained.

[0024] Five batches were prepared according to the above method. The purity and yield of 2,5-dimethylbenzyl chloride obtained from the five batches are shown in Table 1. The yield is relative to paraformaldehyde (calculated as formaldehyde monomer).

[0025] Table 1. Purity and yield results of 2,5-dimethylbenzyl chloride obtained from 5 batches in Example 1.

[0026] Example 2 150 g of paraformaldehyde and 750 g of concentrated hydrochloric acid (36.5 wt%) were added to a reaction vessel. The temperature was raised to 55℃±5℃, and the mixture was stirred for 1-2 h. Then, 1590 g of p-xylene was added, and 45.6 g (1.25 mol) of hydrogen chloride was introduced. The reaction was continued at 55±5℃ for 2-3 h, and then raised to 75±5℃ for 4-8 h. A sample was taken, and the upper organic phase was analyzed by high-performance liquid chromatography (HPLC). The reaction ended when 2,5-dimethylbenzyl chloride was no longer detected. After standing, the mixture was separated, and the organic phase was transferred to a solvent extraction vessel and distilled under reduced pressure to obtain 626.9 g of 2,5-dimethylbenzyl chloride with a purity of 97.8% and a yield of 81.15%.

[0027] Example 3 150 g of paraformaldehyde and 750 g of concentrated hydrochloric acid (36.5 wt%) were added to a reaction vessel. The temperature was raised to 55℃±5℃, and the mixture was stirred for 1-2 h. Then, 1590 g of p-xylene was added, and 182.5 g (5 mol) of hydrogen chloride was introduced. The reaction was continued at 55±5℃ for 2-3 h, and then raised to 75±5℃ for 4-8 h. A sample was taken, and the upper organic phase was analyzed by high-performance liquid chromatography (HPLC). The reaction ended when 2,5-dimethylbenzyl chloride was no longer detected. After standing, the mixture was separated, and the organic phase was transferred to a solvent extraction vessel and distilled under reduced pressure to obtain 724.7 g of 2,5-dimethylbenzyl chloride with a purity of 98.1% and a yield of 93.81%.

[0028] Example 4 150 g of paraformaldehyde and 750 g of concentrated hydrochloric acid (36.5 wt%) were added to a reaction vessel. The temperature was raised to 55℃±5℃, and the mixture was stirred for 1-2 h. Then, 1590 g of p-xylene was added, and 136.9 g (7.5 mol) of hydrogen chloride was introduced. The reaction was continued at 55±5℃ for 2-3 h, and then raised to 75±5℃ for 4-8 h. A sample was taken, and the upper organic phase was analyzed by high-performance liquid chromatography (HPLC). The reaction ended when 2,5-dimethylbenzyl chloride was no longer detected. After standing, the mixture was separated, and the organic phase was transferred to a solvent extraction vessel and distilled under reduced pressure to obtain 719.9 g of 2,5-dimethylbenzyl chloride with a purity of 97.9% and a yield of 93.2%.

[0029] Comparative Example 1 150 g of paraformaldehyde and 750 g of concentrated hydrochloric acid (36.5 wt%) were added to a reaction vessel, the temperature was raised to 55℃±5℃, and the reaction was stirred for 1-2 h. Then, 1590 g of p-xylene was added, and the temperature was raised to 75±5℃, and the reaction was carried out for 4-8 h. A sample was taken, and the resulting upper organic phase was analyzed by high-performance liquid chromatography. After the reaction was completed, the mixture was allowed to stand and then separated. The organic phase was transferred to a solvent extraction vessel and distilled under reduced pressure to obtain 356.1 g of 2,5-dimethylbenzyl chloride with a purity of 97.5% and a yield of 46.1%.

[0030] Comparative Example 2 150 g of paraformaldehyde and 500 g of concentrated hydrochloric acid (36.5 wt%) were added to a reaction vessel. The temperature was raised to 55℃±5℃, and the mixture was stirred for 1-2 h. Then, 1590 g of p-xylene was added, and 91.2 g (5 mol) of hydrogen chloride was introduced. The reaction was continued at 55±5℃ for 2-3 h, and then raised to 75±5℃ for 4-8 h. A sample was taken, and the resulting upper organic phase was analyzed by high-performance liquid chromatography. After the reaction was completed, the mixture was allowed to stand and then separated. The organic phase was transferred to a solvent extraction vessel and distilled under reduced pressure to obtain 565.5 g of 2,5-dimethylbenzyl chloride with a purity of 97.6% and a yield of 73.2%.

[0031] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. People can obtain other embodiments based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A method for preparing 2,5-disubstituted benzyl chloride, characterized in that, Includes the following steps: Paraformaldehyde and concentrated hydrochloric acid are mixed and subjected to a condensation reaction to obtain a chloromethylating agent; The chloromethylating agent and the para-disubstituted benzene of Formula I were mixed and chloromethylated in hydrogen chloride gas to obtain 2,5-disubstituted benzyl chloride of Formula II. Formula I; Formula II; Among them, R1 and R2 are independently alkyl groups having 1 to 10 carbon atoms; The concentration of the concentrated hydrochloric acid is 36~38wt%; based on the molar amount of formaldehyde monomer in paraformaldehyde and the molar amount of HCl in the concentrated hydrochloric acid, the molar ratio of the concentrated hydrochloric acid to paraformaldehyde is 1~2:

1. The chloromethylation reaction includes a first reaction and a second reaction performed sequentially; the temperature of the first reaction is 50-60°C; and the temperature of the second reaction is 70-80°C.

2. The preparation method according to claim 1, characterized in that, The para-disubstituted benzene is one of 1,4-dimethylbenzene, 1,4-diethylbenzene, and 1,4-dipropylbenzene.

3. The preparation method according to claim 1, characterized in that, The molar ratio of para-disubstituted benzene to paraformaldehyde is 2-5:1, based on the molar amount of formaldehyde monomer in paraformaldehyde.

4. The preparation method according to claim 1, characterized in that, The molar ratio of hydrogen chloride gas to paraformaldehyde is 0.5 to 2:1, based on the molar amount of formaldehyde monomer in paraformaldehyde.

5. The preparation method according to claim 1, characterized in that, The first reaction takes 2-3 hours.

6. The preparation method according to claim 1, characterized in that, The second reaction takes 4 to 8 hours.

7. The preparation method according to claim 1, characterized in that, The condensation reaction is carried out at a temperature of 40-60°C for a time of 0.5-2 hours.

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