Preparation method of phloroglucinol trimethyl ether

Abstract

The invention discloses a preparation method of phloroglucinol trimethyl ether, which comprises the following step: by taking phloroglucinol and trimethyl orthoester as raw materials, preparing the phloroglucinol trimethyl ether in an organic solvent under the catalytic action. According to the invention, phloroglucinol and trimethyl orthoate are taken as raw materials, so that the production safety is greatly improved, and the yield of a final finished product is improved; in the preparation process, byproducts are few, the operation is simple and safe, post-treatment is easy, safety and product yield are both considered, the process is simple, and the method is suitable for industrial production requirements.

Description

Technical Field

[0001] The invention belongs to the technical field of medicine preparation, and particularly relates to a method for preparing phloroglucinol trimethyl ether. Background Art

[0002] Phloroglucinol injection was first developed by Laboratoires L.Lafon of France under the trade name Spasfon, with a specification of 4ml:40mg. After analysis, the original Spasfon injection is a compound injection containing phloroglucinol and phloroglucinol trimethyl ether, with each vial containing 40mg of phloroglucinol and 0.04mg of phloroglucinol trimethyl ether. Phloroglucinol trimethyl ether has similar pharmacological and toxicological characteristics to phloroglucinol, but its duration of action is about six times that of phloroglucinol.

[0003] Huang Zhihong, Synthesis of 1,3,5-trimethoxybenzene [J]. Chinese Journal of Pharmaceutical Industry, 2005, 35(11): 676-676. The synthesis of phloroglucinol trimethyl ether was reported to be simple and efficient by methoxylation reaction using 1,3,5-tribromobenzene as raw material. First, methanol and metallic sodium were used to prepare sodium methoxide, and then DMF, 1,3,5-tribromobenzene and cuprous chloride were added, and the reaction was refluxed vigorously. The post-treatment was to evaporate the solvent, and then extract with benzene, wash, acidify, dry, distill, and purify with petroleum ether to finally obtain the target product.

[0004]

[0005] This route has the following disadvantages:

[0006] (1) Sodium metal is used in the process. Sodium metal has active chemical properties. The storage and use of sodium metal in the later scale-up production process are very dangerous.

[0007] (2) According to the process description in the literature, the reaction solvent is DMF, which needs to be distilled off in post-treatment. However, its boiling point is too high, making the distillation operation difficult.

[0008] (3) The post-processing extraction solvent is benzene, which is a Class I solvent in the residual solvent guidelines and should be avoided.

[0009] Hu Yimin, Wang Xiuran, Ye Zhongwen, et al. Study on a new method for synthesizing 1,3,5-trimethoxybenzene [J]. Synthetic Chemistry, 1999, 7(2): 191-193. A method for synthesizing phloroglucinol trimethyl ether using hexachlorobenzene as raw material through two steps of etherification and dechlorination was reported. Step 1 is to reflux hexachlorobenzene, pyridine and sodium methoxide, add acid after the reaction, extract with carbon tetrachloride, evaporate the carbon tetrachloride after drying, distill the residue at high temperature of 180-200°C to obtain a crude intermediate, and recrystallize from methanol to obtain the intermediate 1,3,5-trimethoxy-2,4,6-trichlorobenzene. Step 2 is to reflux the intermediate, methanol and metallic sodium, extract with formic acid and ether after the reaction, evaporate the ether after drying, distill the residue at high temperature of 130-150°C to obtain a crude product, and recrystallize from methanol to obtain the target product.

[0010]

[0011] This route has the following disadvantages:

[0012] (1) When synthesizing 1,3,5-trimethoxy-2,4,6-trichlorobenzene in step 1, the post-treatment extraction solvent is carbon tetrachloride and the reaction solvent is pyridine. According to the residual solvent guidelines, carbon tetrachloride is a Class I solvent and should be avoided, while pyridine is a Class II solvent and its use should be restricted.

[0013] (2) Metallic sodium is used in the synthesis of phloroglucinol trimethyl ether in step 2. Metallic sodium has an active chemical property. The storage and use of metallic sodium in the subsequent scale-up production process are both very dangerous.

[0014] (3) Both steps 1 and 2 involve high-temperature distillation operations, which place high demands on production equipment.

[0015] The literature Catalán LE, Maturana EB, Marín KC, et al. Synthesis and antitumoractivity of diterpenylhydroquinone derivatives of natural Ent-Labdanes [J]. Molecules, 2010, 15(9): 6502-6511. reported a method for synthesizing phloroglucinol trimethyl ether by using phloroglucinol as a raw material and reacting it with dimethyl sulfate in the presence of acetone and potassium carbonate.

[0016]

[0017] This route has the following disadvantages: the process uses highly toxic dimethyl sulfate, which is not conducive to industrial production.

[0018] Chinese patent CN202110760402 discloses a method for preparing phloroglucinol trimethyl ether, which uses phloroglucinol as a raw material, generates a partially methylated product by using sulfuric acid as a catalytic reaction; then uses potassium carbonate as a catalyst and uses dimethyl carbonate to carry out a second step methylation reaction to prepare phloroglucinol trimethyl ether. Dimethyl carbonate is non-toxic and non-corrosive, which greatly improves the safety of production; it can replace the highly toxic reagent dimethyl sulfate. However, this process operation is relatively cumbersome.

[0019]

[0020] Therefore, it is urgent to provide a new preparation method of phloroglucinol trimethyl ether to overcome the shortcomings of the existing synthesis method. In view of this, this patent application is proposed. Summary of the invention

[0021] The purpose of this patent application is to solve the technical problems in the current preparation process of phloroglucinol trimethyl ether, which cannot take into account the process safety, process complexity and low finished product yield.

[0022] The present invention is achieved through the following technical solutions:

[0023]

[0024] The object of the present invention is to provide a method for preparing phloroglucinol trimethyl ether, which adopts phloroglucinol and trimethyl orthoester as raw materials, and prepares phloroglucinol trimethyl ether in an organic solvent under the catalysis of Lewis acid.

[0025] Preferably, the molar ratio of phloroglucinol to trimethyl orthoester is 1:1.0-6.0.

[0026] Preferably, the molar ratio of phloroglucinol to trimethyl orthoester is 1:3.6.

[0027] Preferably, the organic solvent is any one of methanol, acetone, acetonitrile, tetrahydrofuran, toluene and DMF, or a mixture of several of them.

[0028] Preferably, the catalyst is a Lewis acid.

[0029] Preferably, the Lewis acid is p-toluenesulfonic acid.

[0030] Preferably, the molar ratio of the Lewis acid to trimethyl orthoester is 0.005-0.2:1.0.

[0031] Preferably, the molar ratio of the Lewis acid to trimethyl orthoester is 0.1:1.0.

[0032] Preferably, in the preparation process, the reaction temperature is 20 to 120° C. and the reaction time is 3 to 30 hours.

[0033] Preferably, after the reaction is completed, the reaction is concentrated under reduced pressure, ethyl acetate is added to the residue, and the organic layer is washed with sodium carbonate until it is neutral. The organic layer is dried, filtered, concentrated under reduced pressure, and then slurried in a mixed solvent of ethyl acetate / n-heptane to obtain a crude product;

[0034] The crude product is decolorized, filtered, stirred and crystallized to obtain the fine product of phloroglucinol trimethyl ether.

[0035] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0036] 1. The preparation method of phloroglucinol trimethyl ether provided in the present invention uses phloroglucinol and trimethyl orthoester as raw materials, greatly improves the safety of production, and improves the yield of the final product. There are few by-products in the preparation process, the operation is simple and safe, and the post-processing is easy.

[0037] 2. The present invention can take into account the requirements of safety, product yield, simple process and suitability for industrial production by selecting raw materials, designing reasonable ratios of each raw material and selecting appropriate reaction conditions. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] In order to more clearly illustrate the technical solutions of the exemplary embodiments of the present invention, the following briefly introduces the drawings required for use in the embodiments. It should be understood that the following drawings only illustrate certain embodiments of the present invention and should not be regarded as limiting the scope. For those of ordinary skill in the art, other relevant drawings can be obtained based on these drawings without creative work. In the drawings:

[0039] Figure 1 It is the high performance liquid chromatogram of phloroglucinol trimethyl ether obtained in Example 1.

[0040] Figure 2 It is the high performance liquid chromatogram of phloroglucinol trimethyl ether obtained in Example 2.

[0041] Figure 3 It is the high performance liquid chromatogram of phloroglucinol trimethyl ether obtained in Example 3.

[0042] Figure 4 It is the high performance liquid chromatogram of phloroglucinol trimethyl ether obtained in Example 4.

[0043] Figure 5 It is the high performance liquid chromatogram of phloroglucinol trimethyl ether obtained in Example 5.

[0044] Figure 6 It is the high performance liquid chromatogram of phloroglucinol trimethyl ether obtained in Example 6.

[0045] Figure 7 It is the high performance liquid chromatogram of phloroglucinol trimethyl ether obtained in Example 7.

[0046] Figure 8 It is the high performance liquid chromatogram of phloroglucinol trimethyl ether obtained in Example 8.

[0047] Fig. 9 It is the high performance liquid chromatogram of phloroglucinol trimethyl ether obtained in Example 9.

[0048] Fig.10 It is the high performance liquid chromatogram of phloroglucinol trimethyl ether obtained in Example 10.

[0049] Fig.11 It is the high performance liquid chromatogram of phloroglucinol trimethyl ether obtained in Example 11.

[0050] Fig.12 It is the high performance liquid chromatogram of phloroglucinol trimethyl ether obtained in Comparative Example 1.

[0051] Fig.13 It is the high performance liquid chromatogram of phloroglucinol trimethyl ether obtained in Comparative Example 2. DETAILED DESCRIPTION

[0052] The following is a further detailed description of the implementation of the present application in conjunction with the embodiments and drawings. The detailed description of the following embodiments is used to exemplarily illustrate the principles of the present application, but cannot be used to limit the scope of the present application, that is, the present application is not limited to the described embodiments.

[0053] Unless otherwise specified, all embodiments and optional embodiments of the present application can be combined with each other to form a new technical solution.

[0054] Unless otherwise specified, all technical features and optional technical features of this application can be combined with each other to form a new technical solution.

[0055] If there is no special explanation, all steps of the present application can be performed sequentially or randomly, preferably sequentially. For example, the method includes steps (a) and (b), which means that the method may include steps (a) and (b) performed sequentially, or may include steps (b) and (a) performed sequentially. For example, the method may further include step (c), which means that step (c) may be added to the method in any order. For example, the method may include steps (a), (b) and (c), or may include steps (a), (c) and (b), or may include steps (c), (a) and (b), etc.

[0056] If there is no special explanation, the "include" and "comprising" mentioned in this application are open-ended or closed-ended. For example, the "include" and "comprising" may mean that other components not listed may also be included or only the listed components may be included or only the listed components may be included.

[0057] If not specifically stated, in this application, the term "or" is inclusive. For example, the phrase "A or B" means "A, B, or both A and B". More specifically, any of the following conditions satisfies the condition "A or B": A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); or both A and B are true (or exist).

[0058] Example 1

[0059] In a 250ml three-necked flask, add phloroglucinol (16.21g, 0.10mol), methanol (200ml), HC(OMe)3 (63.66g, 0.60mol), stir to dissolve, add anhydrous p-toluenesulfonic acid (TsOH) (1.77g, 0.01mol) and reflux for 8 hours. After the reaction, concentrate under reduced pressure; add 200ml of ethyl acetate to the residue, and wash the organic layer with 5% sodium carbonate until neutral. Separate the liquid and discard the water layer; add 10.00g of anhydrous sodium sulfate to the organic layer and dry it. Filter, concentrate the filtrate under reduced pressure, and add 100ml of ethyl acetate / n-heptane mixed solvent (1:4) to the residue for pulping. Filter and dry the filter cake (t=60℃) to obtain 14.62g of crude phloroglucinol trimethyl ether, with a yield of 86.90%.

[0060] Take 14.00g crude phloroglucinol trimethyl ether, add 140ml 25% (v / v) methanol / water solution, heat at 50℃ to dissolve. Add 1.40g activated carbon to decolorize for 30 minutes, filter while hot; cool the filtrate to 0-5℃, stir and crystallize. Filter to obtain 11.90g refined phloroglucinol trimethyl ether. Yield: 85.00%. HPLC: 99.69%. See the HPLC chromatogram Figure 1 .

[0061] right Figure 1 The description is shown in Table 1 below.

[0062] Table 1:

[0063] Peak Compound Name Retention time area% Resolution (USP) 1 Phloroglucinol trimethyl ether 5.363 99.690 -- 2 Unknown impurities 6.690 0.006 5.323 3 Impurity c 7.539 0.184 3.140 4 Unknown impurities 7.888 0.049 1.349 5 Impurity d 9.728 0.027 6.894 6 Impurity b 10.78 0.044 3.063 total - - 100.000 -

[0064] Example 2

[0065] In a 250m three-necked flask, add phloroglucinol (16.21g, 0.10mol), DMF (200ml), HC (OMe) 3 (63.22g, 0.60mol), stir to dissolve, add anhydrous p-toluenesulfonic acid (TsOH) (1.77g, 0.01mol); react at 100-120℃ for 3 hours. After the reaction, add 200ml of ethyl acetate to the residue, and wash the organic layer with 5% sodium carbonate until neutral. Separate the liquid and discard the water layer; add 10.00g of anhydrous sodium sulfate to the organic layer and dry it. Filter, concentrate the filtrate under reduced pressure, and add 100ml of ethyl acetate / n-heptane mixed solvent (1:4) to the residue for pulping. Filter and dry the filter cake (t=60℃) to obtain 11.35g of crude phloroglucinol trimethyl ether, with a yield of 67.50%.

[0066] Take 11.00g crude phloroglucinol trimethyl ether, add 110ml 25% (v / v) methanol / water solution, heat at 50℃ to dissolve. Add 1.10g activated carbon to decolorize for 30 minutes, filter while hot; cool the filtrate to 0-5℃, stir and crystallize. Filter to obtain 8.64g refined phloroglucinol trimethyl ether. Yield: 78.54%. HPLC: 88.41%. High performance liquid chromatography is shown in Figure 2 .

[0067] right Figure 2 The description is shown in Table 2 below.

[0068] Table 2:

[0069] Peak Compound Name Retention time area% Resolution (USP) 1 Phloroglucinol trimethyl ether 5.395 88.414 -- 2 Impurity c 7.579 8.620 9.196 3 Unknown impurities 9.264 0.231 6.087 4 Impurity d 9.709 1.619 1.621 5 Impurity b 10.772 0.300 3.404 6 Impurity a 19.638 0.596 19.370 7 Unknown impurities 22.278 0.218 4.006 total - - 100.000 -

[0070] Example 3

[0071] In a 250m three-necked flask, add phloroglucinol (16.21g, 0.10mol), toluene (200ml), HC(OMe)3 (63.66g, 0.20mol), stir to dissolve, add anhydrous p-toluenesulfonic acid (TsOH) (1.77g, 0.01mol) and reflux for 3 hours. After the reaction, concentrate under reduced pressure; add 200ml of ethyl acetate to the residue, and wash the organic layer with 5% sodium carbonate until neutral. Separate the liquid and discard the water layer; add 10.00g of anhydrous sodium sulfate to the organic layer and dry it. Filter, concentrate the filtrate under reduced pressure, and add 100ml of ethyl acetate / n-heptane mixed solvent (1:4) to the residue for pulping. Filter and dry the filter cake (t=60℃) to obtain 12.20g of crude phloroglucinol trimethyl ether, with a yield of 72.53%.

[0072] Take 12.00g crude phloroglucinol trimethyl ether, add 120ml 25% (v / v) methanol / water solution, heat at 50℃ to dissolve. Add 1.20g activated carbon to decolorize for 30 minutes, filter while hot; cool the filtrate to 0-5℃, stir and crystallize. Filter to obtain 9.09g refined phloroglucinol trimethyl ether; yield: 75.80%. HPLC: 90.57%. High performance liquid chromatography is shown in Figure 3 .

[0073] right Figure 3 The description is shown in Table 3 below.

[0074] Table 3:

[0075]

[0076]

[0077] Example 4

[0078] In a 250ml three-necked flask, add phloroglucinol (16.21g, 0.10mol), anhydrous acetonitrile (160ml), HC(OMe)3 (63.66g, 0.60mol), stir to dissolve, add anhydrous p-toluenesulfonic acid (TsOH) (1.77g, 0.01mol), and reflux for 6 hours. After the reaction is completed, concentrate under reduced pressure; add 200ml of ethyl acetate to the residue, and wash the organic layer with 5% sodium carbonate until neutral. Separate the liquid and discard the water layer; add 10.00g of anhydrous sodium sulfate to the organic layer and dry it. Filter, concentrate the filtrate under reduced pressure, and add 100ml of ethyl acetate / n-heptane mixed solvent (1:4) to the residue for pulping. Filter and dry the filter cake (t=60℃) to obtain 13.20g of crude phloroglucinol trimethyl ether, with a yield of 78.50%.

[0079] Take 13.00g crude phloroglucinol trimethyl ether, add 130ml 25% (v / v) methanol / water solution, heat at 50℃ to dissolve. Add 1.30g activated carbon to decolorize for 30 minutes, filter while hot; cool the filtrate to 0-5℃, stir and crystallize. Filter to obtain 10.60g refined phloroglucinol trimethyl ether. Yield: 81.50%. HPLC: 97.98%. High performance liquid chromatography is shown in Figure 4 .

[0080] right Figure 4 The description is shown in Table 4 below.

[0081] Table 4:

[0082] Peak Compound Name Retention time area% Resolution (USP) 1 Phloroglucinol trimethyl ether 5.729 97.989 -- 2 Unknown impurities 8.097 0.032 10.517 3 Impurity c 8.498 1.701 1.520 4 Impurity d 8.937 0.056 1.492 5 Impurity b 11.845 0.222 10.056 total - - 100.000 -

[0083] Example 5

[0084] In a 250m three-necked flask, add phloroglucinol (16.21g, 0.10mol), methanol (200ml), HC(OMe)3 (63.66g, 0.60mol), stir to dissolve, add anhydrous p-toluenesulfonic acid (TsOH) (1.77g, 0.01mol) and stir at room temperature for 30 hours. After the reaction is completed, concentrate under reduced pressure; add 200ml of ethyl acetate to the residue, and wash the organic layer with 5% sodium carbonate until neutral. Separate the liquid and discard the water layer; add 10.00g of anhydrous sodium sulfate to the organic layer and dry it. Filter, concentrate the filtrate under reduced pressure, and add 100ml of ethyl acetate / n-heptane mixed solvent (1:4) to the residue for pulping. Filter and dry the filter cake (t=60℃) to obtain 13.64g of crude phloroglucinol trimethyl ether, with a yield of 81.10%.

[0085] Take 13.00g crude phloroglucinol trimethyl ether, add 130ml 25% (v / v) methanol / water solution, heat at 50℃ to dissolve. Add 1.30g activated carbon to decolorize for 30 minutes, filter while hot; cool the filtrate to 0-5℃, stir and crystallize. Filter to obtain 10.46g refined phloroglucinol trimethyl ether. Yield: 80.50%. HPLC: 99.10%. See the HPLC chromatogram Figure 5 .

[0086] right Figure 5 The description is shown in Table 5 below.

[0087] Table 5:

[0088] Peak Compound Name Retention time area% Resolution (USP) 1 Phloroglucinol trimethyl ether 5.733 99.108 -- 2 Unknown impurities 7.997 0.024 6.788 3 Impurity c 8.588 0.731 1.600 4 Impurity d 8.993 0.082 1.422 5 Impurity b 10.645 0.047 5.457 6 Impurity a 25.945 0.009 31.165 total - - 100.000 -

[0089] Example 6

[0090] In a 250ml three-necked flask, add phloroglucinol (16.21g, 0.10mol), methanol (200ml), HC(OMe)3 (63.66g, 0.60mol), stir to dissolve, add concentrated sulfuric acid (0.98g, 0.01mol) and reflux for 8 hours. After the reaction, concentrate under reduced pressure; add 200ml of ethyl acetate to the residue, and wash the organic layer with 5% sodium carbonate until neutral. Separate the liquid and discard the water layer; add 10.00g of anhydrous sodium sulfate to the organic layer and dry it. Filter, concentrate the filtrate under reduced pressure, and add 100ml of ethyl acetate / n-heptane mixed solvent (1:4) to the residue for pulping. Filter and dry the filter cake (t=60℃) to obtain 13.86g of crude phloroglucinol trimethyl ether, with a yield of 82.50%.

[0091] Take 13.00g crude phloroglucinol trimethyl ether, add 130ml 25% (v / v) methanol / water solution, heat at 50℃ to dissolve. Add 1.30g activated carbon to decolorize for 30 minutes, filter while hot; cool the filtrate to 0-5℃, stir and crystallize. Filter to obtain 10.08g refined phloroglucinol trimethyl ether. Yield: 77.53%. HPLC: 99.37%. High performance liquid chromatography is shown in Figure 6 .

[0092] right Figure 6 The description is shown in Table 6 below.

[0093] Table 6:

[0094] Peak Compound Name Retention time area% Resolution (USP) 1 Phloroglucinol trimethyl ether 5.329 99.379 -- 2 Impurity c 7.471 0.592 8.702 3 Impurity d 9.141 0.010 5.597 4 Impurity b 10.191 0.003 3.346 5 Unknown impurities 10.715 0.003 1.565 6 Impurity a 19.580 0.014 19.797 total - - 100.000 -

[0095] Example 7

[0096] In a 250ml three-necked flask, add phloroglucinol (16.21g, 0.10mol), HC(OMe)3 (63.66g, 0.60mol), acetone / tetrahydrofuran mixed solution (150ml / 150ml), stir to dissolve, add anhydrous p-toluenesulfonic acid (TsOH) (1.77g, 0.01mol) and reflux for 10 hours. After the reaction, concentrate under reduced pressure; add 200ml of ethyl acetate to the residue, and wash the organic layer with 5% sodium carbonate until neutral. Separate the liquid and discard the water layer; add 10.00g of anhydrous sodium sulfate to the organic layer and dry it. Filter, concentrate the filtrate under reduced pressure, and add 100ml of ethyl acetate / n-heptane mixed solvent (1:4) to the residue for pulping. Filter and dry the filter cake (t=60℃) to obtain 12.48g of crude phloroglucinol trimethyl ether, with a yield of 74.20%.

[0097] Take 12.00g crude phloroglucinol trimethyl ether, add 120ml 25% (v / v) methanol / water solution, heat at 50℃ to dissolve. Add 1.20g activated carbon to decolorize for 30 minutes, filter while hot; cool the filtrate to 0-5℃, stir and crystallize. Filter to obtain 9.85g refined phloroglucinol trimethyl ether. Yield: 82.08%. HPLC: 96.22%. High performance liquid chromatography is shown in Figure 7 .

[0098] right Figure 7 The description is shown in Table 7 below.

[0099] Table 7:

[0100] Peak Compound Name Retention time area% Resolution (USP) 1 Phloroglucinol trimethyl ether 5.700 96.223 -- 2 Impurity c 8.525 3.040 10.517 3 Impurity d 10.541 0.031 6.274 4 Impurity b 11.759 0.657 3.684 5 Unknown impurities 13.330 0.048 4.561 total - - 100.000 -

[0101] Example 8

[0102] In a 250ml three-necked flask, add phloroglucinol (16.21g, 0.10mol), methanol (200ml), HC(OMe)3 (47.76g, 0.45mol), stir to dissolve, add anhydrous p-toluenesulfonic acid (TsOH) (1.77g, 0.01mol) and reflux for 8 hours. After the reaction, concentrate under reduced pressure; add 200ml of ethyl acetate to the residue, and wash the organic layer with 5% sodium carbonate until neutral. Separate the liquid and discard the water layer; add 10.00g of anhydrous sodium sulfate to the organic layer and dry it. Filter, concentrate the filtrate under reduced pressure, and add 100ml of ethyl acetate / n-heptane mixed solvent (1:4) to the residue for pulping. Filter and dry the filter cake (t=60℃) to obtain 14.55g of crude phloroglucinol trimethyl ether, with a yield of 86.50%.

[0103] Take 14.00g crude phloroglucinol trimethyl ether, add 140ml 25% (v / v) methanol / water solution, heat at 50℃ to dissolve. Add 1.40g activated carbon to decolorize for 30 minutes, filter while hot; cool the filtrate to 0-5℃, stir and crystallize. Filter to obtain 11.92g refined phloroglucinol trimethyl ether. Yield: 85.14%. HPLC: 99.82%. High performance liquid chromatography is shown in Figure 8 .

[0104] right Figure 8 The description is shown in Table 8 below.

[0105] Table 8:

[0106] Peak Compound Name Retention time area% Resolution (USP) 1 Phloroglucinol trimethyl ether 5.309 99.824 -- 2 Unknown impurities 7.141 0.005 7.837 3 Impurity c 7.432 0.103 1.130 4 Unknown impurities 7.802 0.023 1.419 5 Impurity d 9.100 0.011 4.644 6 Impurity b 9.698 0.015 2.042 7 Unknown impurities 10.697 0.007 3.261 8 Impurity a 19.616 0.012 20.722 total - - 100.000 -

[0107] Example 9

[0108] In a 250ml three-necked flask, add phloroglucinol (16.21g, 0.10mol), methanol (200ml), HC(OMe)3 (38.19g, 0.36mol), stir to dissolve, add anhydrous p-toluenesulfonic acid (TsOH) (1.77g, 0.01mol) and reflux for 8 hours. After the reaction, concentrate under reduced pressure; add 200ml of ethyl acetate to the residue, and wash the organic layer with 5% sodium carbonate until neutral. Separate the liquid and discard the water layer; add 10.00g of anhydrous sodium sulfate to the organic layer and dry it. Filter, concentrate the filtrate under reduced pressure, and add 100ml of ethyl acetate / n-heptane mixed solvent (1:4) to the residue for pulping. Filter and dry the filter cake (t=60℃) to obtain 14.50g of crude phloroglucinol trimethyl ether, with a yield of 86.20%.

[0109] Take 14.00g crude phloroglucinol trimethyl ether, add 140ml 25% (v / v) methanol / water solution, heat at 50℃ to dissolve. Add 1.40g activated carbon to decolorize for 30 minutes, filter while hot; cool the filtrate to 0-5℃, stir and crystallize. Filter to obtain 12.25g refined phloroglucinol trimethyl ether. Yield: 87.50%. HPLC: 99.93%. High performance liquid chromatography is shown in Fig. 9 .

[0110] right Fig. 9 The description is shown in Table 9 below.

[0111] Table 9:

[0112]

[0113]

[0114] Example 10

[0115] In a 250ml three-necked flask, add phloroglucinol (16.21g, 0.10mol), methanol (200ml), HC(OMe)3 (38.19g, 0.36mol), stir to dissolve, add anhydrous p-toluenesulfonic acid (TsOH) (0.88g, 0.005mol) and reflux for 10 hours. After the reaction, concentrate under reduced pressure; add 200ml of ethyl acetate to the residue, and wash the organic layer with 5% sodium carbonate until neutral. Separate the liquid and discard the water layer; add 10.00g of anhydrous sodium sulfate to the organic layer and dry it. Filter, concentrate the filtrate under reduced pressure, and add 100ml of ethyl acetate / n-heptane mixed solvent (1:4) to the residue for pulping. Filter and dry the filter cake (t=60℃) to obtain 14.43g of crude phloroglucinol trimethyl ether, with a yield of 85.80%.

[0116] Take 14.00g crude phloroglucinol trimethyl ether, add 140ml 25% (v / v) methanol / water solution, heat at 50℃ to dissolve. Add 1.40g activated carbon to decolorize for 30 minutes, filter while hot; cool the filtrate to 0-5℃, stir and crystallize. Filter to obtain 11.76g refined phloroglucinol trimethyl ether. Yield: 84.00%. HPLC: 99.69%. High performance liquid chromatography is shown in Fig.10 .

[0117] right Fig.10 The description is shown in Table 10 below.

[0118] Table 10:

[0119] Peak Compound Name Retention time area% Resolution (USP) 1 Phloroglucinol trimethyl ether 5.664 99.692 -- 2 Impurity c 8.381 0.248 10.070 3 Impurity d 10.418 0.012 6.329 4 Impurity b 11.769 0.015 4.187 5 Unknown impurities 16.468 0.007 12.577 6 Impurity a 26.262 0.026 17.951 total - - 100.000 -

[0120] Embodiment 11

[0121] In a 250ml three-necked flask, add phloroglucinol (16.21g, 0.10mol), methanol (200ml), HC(OMe)3 (38.19g, 0.36mol), stir to dissolve, add anhydrous p-toluenesulfonic acid (TsOH) (3.52g, 0.02mol) and reflux for 7.5 hours. After the reaction, concentrate under reduced pressure; add 200ml of ethyl acetate to the residue, and wash the organic layer with 5% sodium carbonate until neutral. Separate the liquid and discard the water layer; add 10.00g of anhydrous sodium sulfate to the organic layer and dry it. Filter, concentrate the filtrate under reduced pressure, and add 50ml of ethyl acetate / n-heptane mixed solvent (1:4) to the residue for pulping. Filter and dry the filter cake (t=60℃) to obtain 14.56g of crude phloroglucinol trimethyl ether, with a yield of 86.60%.

[0122] Take 14.00g crude phloroglucinol trimethyl ether, add 140ml 25% (v / v) methanol / water solution, heat at 50℃ to dissolve. Add 1.40g activated carbon to decolorize for 30 minutes, filter while hot; cool the filtrate to 0-5℃, stir and crystallize. Filter to obtain 11.69g refined phloroglucinol trimethyl ether. Yield: 83.50%. HPLC: 99.37%. See the HPLC chromatogram Fig.11 .

[0123] right Fig.11 The description is shown in Table 11 below.

[0124] Table 11:

[0125] Peak Compound Name Retention time area% Resolution (USP) 1 Phloroglucinol trimethyl ether 5.657 99.373 -- 2 Impurity c 8.378 0.507 10.328 3 Impurity d 10.402 0.037 6.369 4 Impurity b 11.745 0.035 4.222 5 Unknown impurities 13.227 0.021 4.245 6 Impurity a 26.181 0.026 25.100 total - - 100.000 -

[0126] Comparative Example 1: Example described in CN113402364

[0127] The preparation method of Example 1 was used to prepare trimethyl phloroglucinol, which specifically comprised the following steps:

[0128] (1) Add 200 ml of methanol to a reaction flask, slowly drip 64.00 g of concentrated sulfuric acid under stirring; add 20.20 g of anhydrous phloroglucinol to a reactor, stir until dissolved, fill with nitrogen, heat to 80°C, and reflux for 6 hours. Cool to room temperature, add 200 ml of 20% sodium chloride solution, extract with methyl tert-butyl ether (100 ml + 50 ml + 50 ml), combine the extracts, and distill at 60°C to recover the solvent to obtain a concentrate.

[0129] (2) Take the above concentrate, add 180 ml of dimethyl sulfoxide to dissolve, fill with nitrogen, add 66.4 g of potassium carbonate, and heat to 130°C. Weigh 57.80 g of dimethyl carbonate and add it three times, with an interval of 0.5 h between each addition. After the addition is complete, continue to react for 1 h, then distill to remove the unreacted excess dimethyl carbonate, cool to 25°C, add 360 ml of cold water dropwise under stirring, cool to 5°C after the addition is complete, crystallize for 1 h, filter, and wash the residue with water to obtain crude phloroglucinol trimethyl ether.

[0130] (3) Take the crude product of phloroglucinol trimethyl ether, add 120 ml of 25% (v / v) ethanol aqueous solution, heat at 50°C to dissolve, add 2.40 g of activated carbon to decolorize for 10 min, filter while hot, cool to 5°C with stirring, continue stirring for 1 h, filter, and obtain a refined product.

[0131] (4) Take the first refined product, add 80 ml of 25% (v / v) ethanol aqueous solution, heat at 50°C to dissolve, add 0.80 g of activated carbon to decolorize for 10 min, filter while hot, cool to 5°C with stirring, continue stirring for 1 h, filter, wash the filter residue with 15 ml of 25% (v / v) ethanol aqueous solution, and dry under reduced pressure at 30°C to obtain 18.85 g of white crystals (yield 70.1%). HPLC: 97.36%. See the HPLC chromatogram for details. Fig.12 .

[0132] right Fig.12 The description is shown in Table 12 below.

[0133] Table 12:

[0134] Peak Compound Name Retention time area% Resolution (USP) 1 Phloroglucinol trimethyl ether 5.331 97.361 -- 2 Impurity c 7.473 2.155 8.606 3 Unknown impurities 7.834 0.032 1.531 4 Impurity d 9.710 0.423 7.782 5 Impurity b 10.724 0.029 3.162 total - - 100.000 -

[0135] Comparative Example 2: Example described in US3449503

[0136] In a 5L three-necked flask, add 2L of anhydrous methanol and 200.00g of phloroglucinol under stirring. Cool to below 30°C, introduce dry hydrogen chloride gas, and react in this temperature range for 10 hours. Concentrate under reduced pressure, add 800ml of dimethyl sulfate to the residue; after stirring evenly, add 1L of sodium carbonate solution (7.5N). Raise the temperature to 90°C and keep the reaction for 2 hours. Cool to room temperature, extract with 1L of methyl tert-butyl ether and separate the liquids; add 50g of anhydrous sodium sulfate to the organic phase and dry it. Filter, and concentrate the filtrate under reduced pressure to obtain the crude product of phloroglucinol trimethyl ether. Phloroglucinol trimethyl ether is obtained by recrystallization from methanol, with a yield of 65.0%, HPLC: 91.32%. See the HPLC chromatogram. Fig.13 .

[0137] right Fig.13 The description is shown in Table 13 below.

[0138] Table 13:

[0139] Peak Compound Name Retention time area% Resolution (USP) 1 Phloroglucinol trimethyl ether 5.673 91.320 -- 2 Unknown impurities 6.579 0.294 4.259 3 Impurity c 8.393 1.856 7.319 4 Impurity d 10.416 3.157 6.594 5 Impurity b 11.775 0.769 4.186 6 Unknown impurities 12.883 0.031 1.924 7 Impurity a 26.192 2.573 17.337 total - - 100.000 -

[0140] As can be seen from Examples 1 to 11, the preparation method of the present invention uses phloroglucinol and trimethyl orthoester as raw materials, and trimethyl orthoester is low in toxicity, which greatly improves the safety of production, is green and environmentally friendly, and improves the yield of the final product. There are few by-products in the preparation process, the operation is simple and safe, and the post-processing is easy. Compared with the use of dimethyl carbonate as a raw material in Comparative Example 1, and compared with the use of highly toxic dimethyl sulfate in Comparative Example 2, the process is simplified, the safety of the process operation is improved, and it is green and environmentally friendly, and more suitable for industrial production. The preparation process of the present invention is highly controllable and easy to operate. In addition, compared with the methods of Comparative Examples 1 and 2, the yield of the finished product obtained by the preparation method of the embodiment of the present invention is also significantly higher than that of Comparative Examples 1 and 2 (the product yields of Comparative Examples 1 and 2 are: 70.1%, 65.0% respectively), all above 75%, up to 87.5%, and the purity also meets the requirements. It is shown that by selecting raw materials, designing the reasonable ratio of each raw material, and selecting appropriate reaction conditions, the requirements of safety, product yield, and simple process can be taken into account. Compared with various preparation methods in the prior art that cannot simultaneously take into account preparation safety, high finished product yield, simple operation, and suitability for industrial preparation, the preparation method of the present invention has obvious novelty and high degree of creativity.

[0141] The above specific implementation methods further illustrate the objectives, technical solutions and beneficial effects of the present invention in detail. It should be understood that the above are only specific implementation methods of the present invention and are not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for preparing phloroglucinol trimethyl ether, characterized in that: Phloroglucinol trimethyl ether is prepared by using phloroglucinol and trimethyl orthoester as raw materials in an organic solvent under the action of catalyst.

2. A method for preparing phloroglucinol trimethyl ether according to claim 1, characterized in that: The molar ratio of phloroglucinol to trimethyl orthoester is 1:1.0-6.

0.

3. A method for preparing phloroglucinol trimethyl ether according to claim 1, characterized in that: The molar ratio of phloroglucinol to trimethyl orthoester is 1:3.

6.

4. A method for preparing phloroglucinol trimethyl ether according to claim 1, characterized in that: The organic solvent is any one of methanol, acetone, acetonitrile, tetrahydrofuran, toluene and DMF or a mixture of several of them.

5. A method for preparing phloroglucinol trimethyl ether according to claim 1, characterized in that: The catalyst is a Lewis acid.

6. A method for preparing phloroglucinol trimethyl ether according to claim 1, characterized in that: The Lewis acid is p-toluenesulfonic acid.

7. A method for preparing phloroglucinol trimethyl ether according to claim 1, characterized in that: The molar ratio of the catalyst to trimethyl orthoester is 0.005-0.2:1.

0.

8. A method for preparing phloroglucinol trimethyl ether according to claim 1, characterized in that: The molar ratio of the catalyst to trimethyl orthoester is 0.1:1.

0.

9. A method for preparing phloroglucinol trimethyl ether according to claim 1, characterized in that: In the preparation process, the reaction temperature is 20 to 120° C. and the reaction time is 3 to 30 hours.

10. The method for preparing phloroglucinol trimethyl ether according to claim 1, characterized in that: After the reaction is completed, the mixture is concentrated under reduced pressure, ethyl acetate is added to the residue, and the organic layer is washed with sodium carbonate until it becomes neutral. The organic layer is dried, filtered, concentrated under reduced pressure, and then slurried with a mixed solvent of ethyl acetate / n-heptane to obtain a crude product; The crude product is decolorized, filtered, stirred and crystallized to obtain the fine product of phloroglucinol trimethyl ether.

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