A preparation method of trimethylphloroglucinol

Abstract

The present invention belongs to the field of pharmaceutical synthesis technology, and in particular to a method for preparing trimethyl phloroglucinol. The present invention provides a method for preparing trimethyl phloroglucinol, and the steps include: preparing a crude product: 1,3,5-tribromobenzene, sodium methoxide, methanol, N, N-dimethylformamide and cuprous chloride are mixed, stirred and then reacted for 6-12h, the reaction terminates, the reaction solution is transferred to a sulfuric acid solution for crystallization, and the crude trimethyl phloroglucinol product is filtered to obtain the crude product; crude product purification: the crude trimethyl phloroglucinol product and sodium dithionite are added to a recrystallization solvent, heated and stirred to dissolve it, then dropped into water for crystallization, filtered, dried, and trimethyl phloroglucinol is obtained. The preparation method step provided by the present invention is simple, and the preparation process is safe and controllable. The yield of the obtained trimethyl phloroglucinol is more than 90%, the liquid phase purity is higher than 99.9%, and the color meets the pharmacopoeia standard requirements, which is more conducive to realizing industrialized batch production.

Description

Technical Field

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

[0002] Trimethylphloroglucinol, also known as 1,3,5-trimethoxybenzene, is an effective antispasmodic drug that acts directly on smooth muscle. It is also an ingredient in phloroglucinol injection, which is widely used to treat conditions such as smooth muscle spasms. It has a rapid, effective, and non-toxic antispasmodic effect. The presence of a small amount of trimethylphloroglucinol in phloroglucinol injection can enhance the antispasmodic and analgesic effects of phloroglucinol injection through a synergistic effect, making the sphincter and urethral smooth muscle more sensitive to the drug.

[0003] Currently, there are many methods for preparing trimethylphloroglucinol, but all of them have some defects or disadvantages. For example, the method disclosed by Ji Yafei et al. (DOI: 10.19500 / j.cnki.0367-6358.2001.07.012) uses metallic sodium and benzene, which is highly toxic; the method disclosed by Qian Wang et al. (DOI: 10.1080 / 00304940309355837) requires the use of ethyl acetate 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, which uses metallic sodium in the reaction process and obtains the target product by steam distillation during 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 are not conducive to industrial production. Summary of the Invention

[0005] In view of this, the present invention provides a method for preparing trimethylphloroglucinol. This method is simple to operate and does not require steps such as distillation, extraction, or high-pressure reaction that are not conducive to workshop production operations. It does not require the use of dangerous or highly toxic reagents for the reaction, nor does it require the continuous introduction of nitrogen during the purification process. It successfully achieves a yield of over 90%, a liquid phase purity of over 99.9%, and a color that meets the pharmacopoeial 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 6-12 hours. After the reaction was completed, the reaction solution was transferred to sulfuric acid solution for crystallization, and filtered to obtain crude trimethylphloroglucinol;

[0008] S2. Purification of crude product: adding the crude trimethylphloroglucinol and sodium dithionite into a recrystallization solvent, heating and stirring to dissolve them, then dropping into water for crystallization, filtering and drying to obtain trimethylphloroglucinol.

[0009] The invention provides a method for preparing trimethyl phloroglucinol. The method comprises the following steps: using methanol as a solvent to dissolve sodium methoxide; using sodium methoxide as one of the reactants; reacting with 1,3,5-tribromobenzene under the catalytic action of cuprous chloride as a catalyst to methoxylate the 1,3,5-tribromobenzene; and using N,N-dimethylformamide as a solvent to dissolve crude trimethyl phloroglucinol obtained by the reaction; and then cleverly utilizing the principle of recrystallization to drop a solution containing the crude trimethyl phloroglucinol and sodium dithionite having a decolorizing effect into water to precipitate the trimethyl phloroglucinol. The purified trimethyl phloroglucinol can be obtained by filtration.

[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 1 kg:2L~6L, and the mass volume ratio of the 1,3,5-tribromobenzene to N,N-dimethylformamide is 1 kg:4L~8L.

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

[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 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 the 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 1 kg:3 L to 6 L, and the concentration of the sulfuric acid solution is 0.5 to 2 mol / L, preferably 1 mol / L.

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

[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 present invention provides the following beneficial effects: The method for preparing trimethylphloroglucinol provided by the present invention is simple to operate. It not only eliminates workshop-inconvenient operation steps such as distillation, extraction, and high-pressure reaction, but also avoids the use of highly dangerous solid reagents such as sodium and highly toxic organic reagents such as benzene, making the reaction safer and more controllable. Furthermore, the preparation method provided by the present invention does not require a purification step in a nitrogen atmosphere, and the yield of the obtained trimethylphloroglucinol can reach over 90%, the liquid phase purity is higher than 99.9%, and the color meets the pharmacopoeial standard description of white or off-white. DETAILED DESCRIPTION

[0023] In order to make the purpose, technical solutions and advantages of the present invention more clearly understood, the present invention will be 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 intended to limit the present invention.

[0024] In addition to the problems that the current methods for preparing trimethylphloroglucinol have complex steps, are not conducive to workshop operations, or require the use of dangerous / toxic chemical reagents, which are therefore not conducive to industrial production, the inventors also found during literature review and experimental work that trimethylphloroglucinol easily turns yellow in the air. Therefore, nitrogen is often continuously introduced during the purification process to ensure its white color. However, the continuous introduction of nitrogen is not conducive to workshop operations and production.

[0025] In view of this, the present invention provides a method for preparing trimethylphloroglucinol. The method is simple to operate and does not require steps such as distillation, extraction, or high-pressure reaction that are not conducive to workshop production operations. It also does not require the use of dangerous or highly toxic reagents for the reaction. At the same time, the obtained trimethylphloroglucinol has an 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 were as follows: octadecylsilane bonded silica gel as the filler (ZORBAX SB-C18, 4.6×250 mm, 5 μm or a chromatographic column of equivalent performance); water (pH adjusted to 2.8 with phosphoric acid) as mobile phase A, and 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, comprising the following steps:

[0033] 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 to a reaction flask all at once. Stir evenly at 180 rpm. Heat to 100°C and react for 8 hours. After the reaction is complete, pour the entire reaction solution into 3 L of 1 mol / L dilute sulfuric acid at 35°C and filter to obtain crude trimethylphloroglucinol.

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

[0035] Example 2

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

[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 flask 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 and filter to obtain crude trimethylphloroglucinol.

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

[0039] Example 3

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

[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 the reaction flask 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 and filter to obtain crude trimethylphloroglucinol.

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

[0043] Example 4

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

[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 the reaction flask 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 and filter to 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 add dropwise 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, comprising the following steps:

[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 the reaction flask at one time, stir evenly at a speed of 200 rpm, heat to 120 ° C and react for 12 hours. After the reaction is completed, pour all the reaction liquid into 5 L of 0.5 mol / L dilute sulfuric acid at 35 ° C and filter to 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 add dropwise 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, comprising the following steps:

[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 the reaction flask 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 and filter to obtain crude trimethylphloroglucinol.

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

[0055] Comparative Example 1

[0056] This comparative example provides a method for preparing trimethyl phloroglucinol. The steps are basically similar to those in Example 1, except that the sodium dithionite in step S2 is replaced with an equal amount of activated carbon. The other parameters are the same as those in 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, the steps of which 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 was obtained (yield 93.82%, purity 99.91%, yellow color).

[0059] The above is only a preferred specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any technician familiar with this technical field, within the technical scope disclosed by the present invention, who makes equivalent replacements or changes based on the technical solutions and inventive concepts of the present invention, should be covered by the scope of protection 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 6-12 hours. After the reaction was completed, the reaction solution was transferred to sulfuric acid solution for crystallization, and filtered to obtain crude trimethylphloroglucinol; S2. Purification of crude product: adding the crude trimethylphloroglucinol and a small amount of sodium dithionite to a recrystallization solvent, heating and stirring to dissolve them, then dropping into water for crystallization, filtering and drying to obtain trimethylphloroglucinol; the mass ratio of the 1,3,5-tribromobenzene to sodium dithionite is 1:0.0005-0.

005.

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 1 kg:2 L to 6 L, and the mass volume ratio of the 1,3,5-tribromobenzene to N,N-dimethylformamide is 1 kg:4 L to 8 L.

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

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

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

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

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

9. The method for preparing trimethyl phloroglucinol as claimed in claim 1, wherein The temperatures of the sulfuric acid solution and water are both 30-40°C.

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