Preparation method of trimethylphloroglucinol

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of trimethyl phloroglucinol. The invention provides a preparation method of trimethyl phloroglucinol, which comprises the following steps: preparing a crude product: mixing 1, 3, 5-tribromobenzene, sodium methoxide, methanol, N, N-dimethylformamide and cuprous chloride, uniformly stirring, reacting for 6-12 hours, after the reaction is finished, transferring a reaction solution into a sulfuric acid solution, crystallizing, and filtering to obtain the trimethyl phloroglucinol crude product; and crude product purification: adding the trimethyl phloroglucinol crude product and sodium dithionite into a recrystallization solvent, heating and stirring to dissolve the trimethyl phloroglucinol crude product and sodium dithionite, dropwise adding into water to crystallize, and filtering and drying to obtain trimethyl phloroglucinol. The preparation method provided by the invention has the advantages that the steps are simple, the preparation process is safe and controllable, the yield of the obtained trimethylphloroglucinol is more than 90%, the liquid phase purity is higher than 99.9%, the color meets the pharmacopoeia standard requirement, and the industrial batch production is more favorably realized.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical synthesis, and particularly relates to a method for preparing trimethylphloroglucinol. Background Art

[0002] Trimethyl phloroglucinol, chemically known as 1,3,5-trimethoxybenzene, is an effective antispasmodic drug that can directly act on smooth muscle. At the same time, trimethyl phloroglucinol is also one of the ingredients of phloroglucinol injection, which is widely used to treat diseases such as smooth muscle spasms. It has the characteristics of rapid antispasmodic effect, significant effect and no toxic side effects. The presence of a small amount of trimethyl phloroglucinol in the phloroglucinol injection prescription can make the sphincter and urethral smooth muscle more sensitive to the drug through a synergistic effect, thereby enhancing the antispasmodic and analgesic effect of phloroglucinol injection.

[0003] At present, there are many methods for preparing trimethylphloroglucinol, but all of them have some defects or disadvantages. For example, in the method disclosed by Ji Yafei et al. (DOI: 10.19500 / j.cnki.0367-6358.2001.07.012), metallic sodium and highly toxic benzene are used; in the method disclosed by Qian Wang et al. (DOI: 10.1080 / 00304940309355837), ethyl acetate is needed to extract the reaction solution; The method disclosed by Guo et al. (DOI: 10.1007 / s11164-014-1917-x) requires a high-pressure reaction; Chinese patent CN102476981 discloses a method for preparing trimethylphloroglucinol, in which metallic sodium is used in the reaction process, and the target product is obtained by steam distillation in the post-treatment process; the method disclosed by Chinese patent CN109487297 requires the reaction solution to be concentrated; the method disclosed by Chinese patent CN112538005 requires continuous nitrogen gas to be introduced during a long purification operation to ensure product quality.

[0004] In summary, the existing preparation methods of trimethylphloroglucinol have complicated steps, are not conducive to workshop operation or require the use of dangerous / toxic chemical reagents, which is not conducive to industrial production. Summary of the invention

[0005] In view of this, the present invention provides a preparation method of trimethylphloroglucinol. The preparation method is simple to operate, does not require steps such as distillation, extraction or high-pressure reaction that are not conducive to workshop production operations, does not require the use of dangerous or highly toxic reagents for reaction, and does not require continuous introduction of nitrogen during the purification process. The yield is successfully obtained to be more than 90%, the liquid phase purity is more than 99.9%, and the color meets the pharmacopoeia standard description of white or off-white.

[0006] In order to solve the above technical problems, the present invention provides a method for preparing trimethyl phloroglucinol, comprising the steps of:

[0007] S1. Preparation of crude product: 1,3,5-tribromobenzene, sodium methoxide, methanol, N,N-dimethylformamide and cuprous chloride were mixed, stirred evenly and reacted for 6 to 12 hours. After the reaction was completed, the reaction solution was transferred to a sulfuric acid solution for crystallization, and filtered to obtain a crude product of trimethylphloroglucinol;

[0008] S2, crude product purification: the crude trimethylphloroglucinol and sodium dithionite are added to a recrystallization solvent, heated and stirred to dissolve, then dropped into water for crystallization, filtered and dried to obtain trimethylphloroglucinol.

[0009] The invention provides a method for preparing trimethyl phloroglucinol. Methanol is used as a solvent to dissolve sodium methoxide, which is one of the reactants. Under the catalytic action of cuprous chloride, the sodium methoxide reacts with 1,3,5-tribromobenzene to methoxylate the 1,3,5-tribromobenzene. N,N-dimethylformamide is used as a solvent to dissolve a crude trimethyl phloroglucinol product obtained by the reaction. Then, the principle of recrystallization is cleverly utilized to drop a solution containing the crude trimethyl phloroglucinol and sodium dithionite having a decolorizing effect into water to precipitate the trimethyl phloroglucinol. After filtering, the purified trimethyl phloroglucinol can be obtained.

[0010] In combination with the first aspect, the molar ratio of the 1,3,5-tribromobenzene to sodium methoxide is 1:3-10, and the mass ratio of the 1,3,5-tribromobenzene to cuprous chloride is 1:0.01-0.2.

[0011] Preferably, the molar ratio of the 1,3,5-tribromobenzene to sodium methoxide is 1:5-8, and the mass ratio of the 1,3,5-tribromobenzene to cuprous chloride is 1:0.1-0.2.

[0012] In combination with the first aspect, the mass volume ratio of the 1,3,5-tribromobenzene to methanol is 1kg:2L~6L, and the mass volume ratio of the 1,3,5-tribromobenzene to N,N-dimethylformamide is 1kg:4L~8L.

[0013] Preferably, the mass volume ratio of the 1,3,5-tribromobenzene to methanol is 1kg:4L, and the mass volume ratio of the 1,3,5-tribromobenzene to N,N-dimethylformamide is 1kg:6L.

[0014] In combination with the first aspect, the mass ratio of 1,3,5-tribromobenzene to sodium dithionite is 1:0.0005-0.005. This amount of added sodium dithionite can remove colored impurities in the trimethylphloroglucinol product, thereby further increasing the product purity without affecting the yield.

[0015] Preferably, the mass ratio of 1,3,5-tribromobenzene to sodium dithionite is 1:0.001-0.002.

[0016] In combination with the first aspect, the mass volume ratio of the 1,3,5-tribromobenzene to the sulfuric acid solution is 1kg:3L~6L, and the concentration of the sulfuric acid solution is 0.5~2mol / L, preferably 1mol / L.

[0017] In combination with the first aspect, the mass volume ratio of the 1,3,5-tribromobenzene to the recrystallization solvent is 1kg:1L~3L, and the mass volume ratio of the 1,3,5-tribromobenzene to water is 1kg:1L~3L.

[0018] In combination with the first aspect, the recrystallization solvent is at least one of methanol, ethanol, isopropanol, N,N-dimethylformamide, acetonitrile and acetone.

[0019] In combination with the first aspect, in step S1, the reaction temperature is 80-120°C, preferably 100-110°C.

[0020] In combination with the first aspect, in step S2, the heating temperature is 35-65°C, preferably 50°C.

[0021] In combination with the first aspect, the temperature of the sulfuric acid solution and the water are both 30-40°C, preferably 35°C.

[0022] The beneficial effects obtained by the present invention are as follows: the preparation method of trimethyl phloroglucinol provided by the present invention is simple to operate, not only abandoning the operation steps that are not conducive to the workshop, such as distillation, extraction, and high-pressure reaction, but also avoiding the use of dangerous solid reagent sodium and highly toxic organic reagent benzene, making the reaction safer and controllable. In addition, the preparation method provided by the present invention does not need to perform a purification step in a nitrogen atmosphere, and the yield of the obtained trimethyl phloroglucinol can reach more than 90%, the liquid phase purity is higher than 99.9%, and the color meets the description of white or off-white in the pharmacopoeia standard. DETAILED DESCRIPTION

[0023] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with specific embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0024] In addition to the problems that the current method for preparing trimethylphloroglucinol has complicated steps, is not conducive to workshop operation or requires the use of dangerous / toxic chemical reagents, which is not conducive to industrial production, the inventors also found in the process of consulting literature and experiments that trimethylphloroglucinol easily turns yellow in the air, so it is often ensured to be white by continuously introducing nitrogen during the purification process, but the continuous introduction of nitrogen is not conducive to workshop operation and production.

[0025] In view of this, the present invention provides a preparation method of trimethyl phloroglucinol. The preparation method is simple to operate, does not require steps such as distillation, extraction or high-pressure reaction that are not conducive to workshop production operations, and does not require the use of dangerous or highly toxic reagents for reaction. At the same time, the obtained trimethyl phloroglucinol has ideal yield, purity and color.

[0026] In the following examples and comparative examples, the yield of the product is calculated based on the molar amount of 1,3,5-tribromobenzene, and the purity is the purity obtained by liquid chromatography.

[0027] The chromatographic conditions used for liquid chromatography are as follows: octadecylsilane bonded silica gel as filler (ZORBAX SB-C18, 4.6×250 mm, 5 μm or a chromatographic column with equivalent performance); water (pH adjusted to 2.8 with phosphoric acid) as mobile phase A, acetonitrile as mobile phase B; linear gradient elution according to the table below; detection wavelength of 230 mm; column temperature of 30°C, flow rate of 1 mL / mm; injection volume of 20 μL.

[0028] Time (minutes) Liquidity A(%) Liquidity B (%) 0 75 25 10 20 80 25 20 80 25.1 75 25 35 75 25 .

[0029] The chemical reaction formula for preparing trimethyl phloroglucinol provided by the present invention is as follows:

[0030]

[0031] Example 1

[0032] This embodiment provides a method for preparing trimethyl phloroglucinol, the steps comprising:

[0033] S1. Add 1kg of 1,3,5-tribromobenzene, 1.02kg of sodium methoxide, 4L of methanol, 6L of N,N-dimethylformamide and 0.1kg of cuprous chloride into the reaction bottle at once, stir evenly at a speed of 180rpm, and heat to 100℃ for 8h. After the reaction is completed, pour all the reaction liquid into 3L of 1mol / L dilute sulfuric acid at 35℃, filter, and obtain crude trimethylphloroglucinol.

[0034] S2. Dissolve the crude trimethylphloroglucinol in 1L of methanol, add 1g of sodium dithionite, raise the temperature to 50°C, stir at 180rpm to dissolve, then drop into 2L of 35°C purified water, filter, take the solid, and dry under reduced pressure to obtain 0.501kg of trimethylphloroglucinol (yield 93.77%, purity 99.92%, white).

[0035] Example 2

[0036] This embodiment provides a method for preparing trimethyl phloroglucinol, the steps comprising:

[0037] S1. Add 1 kg of 1,3,5-tribromobenzene, 0.51 kg of sodium methoxide, 4 L of methanol, 6 L of N,N-dimethylformamide and 0.1 kg of cuprous chloride into the reaction bottle at one time, stir evenly at a speed of 150 rpm, heat to 100 °C and react for 10 hours. After the reaction is completed, pour all the reaction liquid into 6 L of 1 mol / L dilute sulfuric acid at 30 °C, filter, and obtain crude trimethylphloroglucinol.

[0038] S2. Dissolve the crude trimethyl phloroglucinol in 3 L of ethanol, add 2 g of sodium dithionite, raise the temperature to 50°C, stir at 150 rpm to dissolve, then drop into 3 L of 30°C purified water, filter, take the solid, and dry under reduced pressure to obtain 0.490 kg of trimethyl phloroglucinol (yield 91.71%, purity 99.90%, white).

[0039] Example 3

[0040] This embodiment provides a method for preparing trimethyl phloroglucinol, the steps comprising:

[0041] S1. Add 1 kg of 1,3,5-tribromobenzene, 1.02 kg of sodium methoxide, 4 L of methanol, 6 L of N,N-dimethylformamide and 0.1 kg of cuprous chloride into a reaction bottle at one time, stir evenly at a speed of 200 rpm, heat to 110 °C and react for 6 hours. After the reaction is completed, pour all the reaction liquid into 3 L of 1 mol / L dilute sulfuric acid at 40 °C, filter, and obtain crude trimethylphloroglucinol.

[0042] S2. Dissolve the crude trimethyl phloroglucinol in 2L of isopropanol, add 1g of sodium dithionite, raise the temperature to 50°C, stir at 200rpm to dissolve, then drop into 3L of purified water at 40°C, filter, take the solid, and dry under reduced pressure to obtain 0.522kg of trimethyl phloroglucinol (yield 97.70%, purity 99.92%, white).

[0043] Example 4

[0044] This embodiment provides a method for preparing trimethyl phloroglucinol, the steps comprising:

[0045] S1. Add 1 kg of 1,3,5-tribromobenzene, 1.02 kg of sodium methoxide, 4 L of methanol, 6 L of N,N-dimethylformamide and 0.1 kg of cuprous chloride into a reaction bottle at one time, stir evenly at a speed of 200 rpm, heat to 100 °C and react for 10 hours. After the reaction is completed, pour all the reaction liquid into 3 L of 1 mol / L dilute sulfuric acid at 35 °C, filter, and obtain crude trimethylphloroglucinol.

[0046] S2. Dissolve the crude trimethylphloroglucinol in 1 L of N,N-dimethylformamide, add 1 g of sodium dithionite, raise the temperature to 50°C, stir at 200 rpm to dissolve, then drop into 3 L of 30°C purified water, filter, take the solid, and dry under reduced pressure to obtain 0.505 kg of trimethylphloroglucinol (yield 94.52%, purity 99.93%, white).

[0047] Example 5

[0048] This embodiment provides a method for preparing trimethyl phloroglucinol, the steps comprising:

[0049] S1. Add 1 kg of 1,3,5-tribromobenzene, 1.72 kg of sodium methoxide, 2 L of methanol, 8 L of N,N-dimethylformamide and 0.01 kg of cuprous chloride into a reaction bottle at one time, stir evenly at a speed of 200 rpm, heat to 120 °C and react for 12 h. After the reaction is completed, pour all the reaction liquid into 5 L of 0.5 mol / L dilute sulfuric acid at 35 °C, filter, and obtain crude trimethylphloroglucinol.

[0050] S2. Dissolve the crude trimethylphloroglucinol in 1 L of acetonitrile, add 0.5 g of sodium dithionite, raise the temperature to 35° C., stir at 200 rpm to dissolve, then drop into 3 L of purified water at 40° C., filter, take the solid, and dry under reduced pressure to obtain 0.512 kg of trimethylphloroglucinol (yield 95.88%, purity 99.94%, white).

[0051] Example 6

[0052] This embodiment provides a method for preparing trimethyl phloroglucinol, the steps comprising:

[0053] S1. Add 1 kg of 1,3,5-tribromobenzene, 1.05 kg of sodium methoxide, 4 L of methanol, 6 L of N,N-dimethylformamide and 0.2 kg of cuprous chloride into a reaction bottle at one time, stir evenly at a speed of 200 rpm, heat to 80 °C and react for 8 hours. After the reaction is completed, pour all the reaction liquid into 3 L of 2 mol / L dilute sulfuric acid at 30 °C, filter, and obtain crude trimethylphloroglucinol.

[0054] S2. Dissolve the crude trimethylphloroglucinol in a mixture of 1L of acetone and methanol, add 5g of sodium dithionite, raise the temperature to 65°C, stir at 200rpm to dissolve, then drop into 1L of purified water at 40°C, filter, take the solid, and dry under reduced pressure to obtain 0.504kg of trimethylphloroglucinol (yield 94.38%, purity 99.93%, white).

[0055] Comparative Example 1

[0056] This comparative example provides a method for preparing trimethyl phloroglucinol, and its steps are basically similar to those of Example 1, except that the sodium dithionite in step S2 is replaced by an equal amount of activated carbon, and the other parameters are the same as those of Example 1. Finally, 0.509 kg of trimethyl phloroglucinol was obtained (yield 95.32%, purity 99.92%, yellow color).

[0057] Comparative Example 2

[0058] This comparative example provides a method for preparing trimethyl phloroglucinol, and its steps are basically similar to those of Example 1, except that sodium dithionite is not added in step S2, and the other parameters are the same as those of Example 1. Finally, 0.501 kg of trimethyl phloroglucinol (yield 93.82%, purity 99.91%, yellow color) was obtained.

[0059] What is described above is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A method for preparing trimethyl phloroglucinol, characterized in that the steps include: S1. Preparation of crude product: 1,3,5-tribromobenzene, sodium methoxide, methanol, N,N-dimethylformamide and cuprous chloride were mixed, stirred evenly and reacted for 6 to 12 hours. After the reaction was completed, the reaction solution was transferred to a sulfuric acid solution for crystallization, and filtered to obtain a crude product of trimethylphloroglucinol; S2. Purification of crude product: Add the crude trimethylphloroglucinol and a small amount of sodium dithionite into a recrystallization solvent, heat and stir to dissolve them, then drop into water for crystallization, filter and dry to obtain trimethylphloroglucinol.

2. The method for preparing trimethyl phloroglucinol as claimed in claim 1, wherein The molar ratio of the 1,3,5-tribromobenzene to sodium methoxide is 1:3-10, and the mass ratio of the 1,3,5-tribromobenzene to cuprous chloride is 1:0.01-0.

2.

3. The method for preparing trimethyl phloroglucinol according to claim 1 or 2, wherein: The mass volume ratio of the 1,3,5-tribromobenzene to methanol is 1kg:2L-6L, and the mass volume ratio of the 1,3,5-tribromobenzene to N,N-dimethylformamide is 1kg:4L-8L.

4. The method for preparing trimethyl phloroglucinol as claimed in claim 1, wherein The mass ratio of the 1,3,5-tribromobenzene to sodium dithionite is 1:0.0005-0.

005.

5. The method for preparing trimethyl phloroglucinol as claimed in claim 1, characterized in that: The mass volume ratio of the 1,3,5-tribromobenzene to the sulfuric acid solution is 1kg:3L-6L, and the concentration of the sulfuric acid solution is 0.5-2mol / L.

6. The method for preparing trimethyl phloroglucinol as claimed in claim 1, characterized in that: The mass volume ratio of the 1,3,5-tribromobenzene to the recrystallization solvent is 1kg:1L-3L, and the mass volume ratio of the 1,3,5-tribromobenzene to water is 1kg:1L-3L.

7. The method for preparing trimethyl phloroglucinol as claimed in claim 1, characterized in that: The recrystallization solvent is at least one of methanol, ethanol, isopropanol, N,N-dimethylformamide, acetonitrile and acetone.

8. The method for preparing trimethyl phloroglucinol as claimed in claim 1, characterized in that: In step S1, the reaction temperature is 80-120°C.

9. The method for preparing trimethyl phloroglucinol as claimed in claim 1, characterized in that: In step S2, the heating temperature is 35-65°C.

10. The method for preparing trimethyl phloroglucinol according to claim 1, characterized in that: The temperatures of the sulfuric acid solution and water are both 30-40°C.

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