A preparation method of neostigmine intermediate

Abstract

This invention discloses a method for preparing a neostigmine intermediate, belonging to the field of pharmaceutical synthesis technology research. This method utilizes homemade Cu-siloxane zeolite as a catalyst and m-aminophenol as a raw material. Through a first-step quaternization reaction and a second-step demethylation reaction, m-dimethylaminophenol, a key intermediate in neostigmine synthesis, is obtained. The product yield exceeds 90%, and the content can reach over 99.9% (HPLC). Compared with existing m-dimethylaminophenol synthesis technologies, this method offers high product yield, mild reaction conditions, simple operation, and scalable production. #imgabs0#

Description

Technical Field

[0001] The invention relates to a preparation method of m-dimethylaminophenol, an intermediate of neostigmine, and belongs to the technical field of drug synthesis. Background Art

[0002] Neostigmine methylsulfate (Formula I) is a reversible anticholinesterase drug primarily used clinically to treat myasthenia gravis and as an antagonist for muscle relaxants. Neostigmine methylsulfate is often synthesized using m-dimethylaminophenol (Formula I) as a key intermediate (Ref. ① Indian Patent IN20162102205; ② Indian Patent IN2014MU01078; ③ World Patent WO2012131699).

[0003]

[0004] There are many methods for synthesizing m-dimethylaminophenol:

[0005] Method 1 (Document 4, Chinese Patent CN102381993A) uses a dimethylamine aqueous solution to react with resorcinol to produce a crude meta-dimethylaminophenol product. Industrial liquid caustic soda is then added to the crude product, followed by extraction of byproducts with toluene. After neutralization with the aqueous phase, unreacted resorcinol is washed away, and the meta-dimethylaminophenol is then distilled under reduced pressure to obtain the product. This method produces a product with a purity of 98% and a yield of only 40%. Furthermore, the reaction conditions, which are harsh and difficult to scale up, are based on high temperature and high pressure.

[0006] Method 2 (Document 5, Chinese Patent CN102924304A) uses resorcinol, dimethylamine, and benzyltriethylamine as raw materials, reacts at 190°C ± 10°C under a nitrogen pressure of 1.8 mPa ± 0.2, and then undergoes vacuum distillation to obtain m-dimethylaminophenol. This method achieves a product purity of 99.2% and a yield of approximately 50%. The same high-temperature and high-pressure reaction conditions are demanding and unsuitable for large-scale production.

[0007] Method 3 (Reference ⑥ Mao Shunyuan, Shen Shanming. Chemical World, 1958(08):43-44) uses dimethylaniline as the raw material, sulfonates it with fuming sulfuric acid to produce m-dimethylaminobenzenesulfonic acid, and then alkali-fuses it at 250°C to 300°C to obtain m-dimethylaminophenol in a yield of 76-81%. This method has complicated steps, requires a large amount of fuming sulfuric acid, and requires high temperature treatment. The reaction conditions are harsh and are not conducive to large-scale preparation.

[0008] Method 4 (Indian Patent IN2014MU01078) uses m-aminophenol as the raw material, dimethyl sulfate as the methylating agent, and sodium bicarbonate as the acid-binding agent. The reaction is carried out at 5-15°C. Subsequently, ethanolamine is added, refluxed, and treated with sodium hydroxide solution. After neutralization, filtration, washing, and drying, m-dimethylaminophenol is obtained with a yield of 79% and a purity of 99.9%. This method uses dimethyl sulfate as the methylating agent. Dimethyl sulfate was classified as a Class 2A carcinogen by the World Health Organization's International Agency for Research on Cancer in 2017. Therefore, this method uses a highly toxic reagent, which does not meet the requirements of green chemistry and poses a health threat to experimental operators.

[0009] As can be seen from the above, the synthesis of m-dimethylaminophenol reported in the literature generally has the defects of requiring high temperature and high pressure conditions or the use of highly toxic chemicals, and the reaction yield is between 40-81%. The preparation method needs to be improved. Summary of the Invention

[0010] In view of the shortcomings of the current prior art, the present invention aims to provide a method for synthesizing m-dimethylaminophenol, which has mild reaction conditions, low toxicity of the reagents used, high yield and purity, simple post-processing, and can be used for large-scale preparation.

[0011] To achieve the purpose of the present invention, the technical solution is as follows:

[0012] First, prepare Cu-silicone zeolite: weigh diatomaceous earth, Na2SiO3·9H2O, tetraethylammonium bromide and sodium chloride respectively, place them in a mortar, grind to obtain a paste. The molar ratio of each component is: SiO2: Na2O: tetraethylammonium bromide: sodium chloride = 1: 0.32: 0.20: 0.55 (mol: mol: mol: mol). Transfer the paste into an eggplant-shaped bottle, heat to react, and cool to room temperature after the reaction is completed. Add a small amount of deionized water to grind and dissolve, wash the insoluble matter until it is neutral, filter, dry, roast, and cool with the furnace to obtain silica-type zeolite. The characterization of the obtained silica-zeolite is shown in the attached Figure 1-3 . Then, the silica zeolite and ammonium chloride solution are placed at room temperature and stirred, and then filtered, washed, and vacuum dried to obtain ammonium-exchanged silica zeolite. The ammonium-exchanged silica zeolite is mixed evenly with the copper chloride solution, magnetically stirred, cooled to room temperature, filtered, washed several times, vacuum dried, and then calcined and cooled to room temperature in the furnace to obtain Cu-silicone zeolite. The characterization of the obtained Cu-silicone zeolite is shown in the attached Figure 4-5 .

[0013] Then, m-dimethylaminophenol was synthesized using homemade Cu-siloxane zeolite as a catalyst:

[0014] The synthesis of m-aminophenol is carried out in two steps, and the reaction formula is shown in Formula II:

[0015]

[0016] (1) The first step: m-aminophenol, a methylating agent, potassium carbonate, the Cu-siloxane zeolite prepared above and an organic solvent are mixed and reacted.

[0017] The methylating agent is methyl iodide, dimethyl sulfate, or dimethyl carbonate, preferably methyl iodide; the molar ratio of methyl iodide to m-aminophenol is 3-5:1, preferably 3.5:1; the amount of homemade Cu-siloxane zeolite added is 0.2-3 times the mass of m-aminophenol, preferably 0.5 times; the organic solvent is tetrahydrofuran, acetonitrile, or N,N-dimethylformamide (DMF), preferably tetrahydrofuran; the reaction temperature is preferably 5-10°C; and the reaction time is preferably 30 hours.

[0018] (2) Step 2: Add an organic amine to the mixture obtained from the first step, heat and react. After the reaction is complete, add ethyl acetate and stir, filter with suction, and let the filtrate stand to separate the organic phase. The organic phase is extracted, and the aqueous phase is collected and combined. The pH value of the organic phase is adjusted to neutral with concentrated hydrochloric acid to precipitate an oily liquid. After standing, the oil solidifies and is filtered to obtain a crude product of m-dimethylaminophenol. Finally, the obtained crude product of m-dimethylaminophenol is recrystallized and dried to obtain the target product m-dimethylaminophenol. The structural characterization of the target product m-dimethylaminophenol is shown in the attached Figure 6-8 .

[0019] The organic amine is hydroxyethylethylenediamine, isopropanolamine, 1,3-propylenediamine and ethylenediamine, preferably hydroxyethylethylenediamine; the molar ratio of hydroxyethylethylenediamine to m-aminophenol is 6-10:1, preferably 7:1; the reaction temperature is preferably 110°C; and the reaction time is preferably 20 hours.

[0020] The method of the present invention has the following beneficial effects:

[0021] 1. The present invention uses m-aminophenol as raw material, uses a methylating agent to carry out a quaternary ammonium reaction under the catalysis of homemade Cu-siloxane zeolite to generate a quaternary ammonium compound, and directly reacts with an organic amine to carry out a demethylation reaction without separation and purification, and obtains m-dimethylaminophenol after post-treatment. The yield of the product prepared by this method is greater than 90%, and the purity can reach 99.9% (HPLC, attached Figure 9 )above.

[0022] 2. Compared with the existing m-dimethylaminophenol synthesis technology, the present invention has the characteristics of high product yield, mild reaction conditions, simple operation and scalable preparation. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is the FT-IR spectrum of the silica zeolite prepared in the present invention;

[0024] Figure 2 The XRD spectrum of the silica zeolite prepared in the present invention is shown below:

[0025] Figure 3 TG-DSC spectrum of the silica zeolite prepared in the present invention;

[0026] Figure 4 FT-IR spectrum of Cu-loaded silica zeolite prepared in the present invention;

[0027] Figure 5 The XRD spectrum of the Cu-loaded silica zeolite prepared in the present invention is shown in FIG.

[0028] Figure 6 The m-dimethylaminophenol prepared by the present invention 1 H-NMR spectrum;

[0029] Figure 7 The m-dimethylaminophenol prepared by the present invention 13 C-NMR spectrum;

[0030] Figure 8 This is the TG-DSC spectrum of m-dimethylaminophenol prepared in the present invention;

[0031] Figure 9 The HPLC spectrum of m-dimethylaminophenol prepared by the present invention is shown. DETAILED DESCRIPTION

[0032] The present invention will be further described below with reference to specific embodiments.

[0033] The instruments used for the detection and analysis of the present invention are as follows:

[0034] Fourier transform infrared spectroscopy (FT-IR) analysis was performed using a Nicolet iS10 Fourier transform infrared spectrometer from Thermo Fisher Scientific using the potassium bromide pellet method with a scanning wavelength range of 400–4000 cm -1 , step length 4cm- 1 .

[0035] X-ray powder diffraction (XRD) analysis was performed using a Bruker D8 Advance X-ray diffractometer with a Cu target X-ray tube and a K α1 ray The acceleration voltage was 40 kV, the tube current was 40 mA, the step size was 0.02°, and the scanning angle was 10-50° / 2θ.

[0036] Thermogravimetric analysis (TG-DSC) was performed using a Q600 thermogravimetric analyzer from TA Instruments, USA, with a heating rate of 10 K / min and N2 protection passing through the DSC cell at a rate of 10 mL / min.

[0037] 1 H-NMR and 13 C-NMR spectra were obtained using an Advance Digital 400 nuclear magnetic resonance instrument from Bruker, Switzerland.

[0038] Purity was determined using a Shimadzu KF-062 high-performance liquid chromatograph. High-pressure liquid chromatography (HPLC) assay conditions employed a C18 column (250 mm × 4.6 mm, 5 μm) with a mobile phase consisting of methanol-acetonitrile-0.02 M potassium dihydrogen phosphate solution (volume ratio 5:24:75), UV full-wavelength detection, a column temperature of 30°C, a flow rate of 1.0 mL / min, and an injection volume of 10 μL.

[0039] Example 1: Preparation of Cu-siloxane zeolite

[0040] Weigh 11.8g of diatomaceous earth (85% silica content), 21.8g of Na2SiO3·9H2O, 10.1g of tetraethylammonium bromide, and 7.7g of sodium chloride in a mortar and grind for 40 minutes to obtain a paste. Transfer the paste to an eggplant-shaped bottle, react at 170°C for 40 hours, and then cool to room temperature. Add a small amount of deionized water to grind and dissolve. Wash the insoluble matter until neutral, filter, dry at 100°C for 8 hours, calcine at 560°C for 3 hours, and cool in the furnace to obtain silica zeolite. Then, 5 g of silica zeolite and 50 ml of 1.5 mol / L ammonium chloride solution were placed at room temperature and stirred for 3 hours, filtered, washed, and vacuum-dried at 45°C for 2 hours. The mixture was then mixed with 15 ml of 0.2564 mol / L copper chloride solution and magnetically stirred at 70°C for 4 hours. The mixture was cooled to room temperature, filtered, washed several times, vacuum-dried at 45°C for 3 hours, calcined at 400°C for 4 hours, and furnace-cooled to room temperature to obtain Cu-silica zeolite.

[0041] Example 2: Preparation of Cu-siloxane zeolite

[0042] Weigh 15.0g of diatomaceous earth (85% silica content), 27.7g of Na2SiO3·9H2O, 12.8g of tetraethylammonium bromide, and 9.8g of sodium chloride in a mortar and grind for 40 minutes to obtain a paste. Transfer the paste to an eggplant-shaped bottle, react at 170°C for 40 hours, and then cool to room temperature. Add a small amount of deionized water to grind and dissolve. Wash the insoluble matter until neutral, filter, dry at 100°C for 8 hours, calcine at 560°C for 3 hours, and cool in the furnace to obtain silica zeolite. Then, 10 g of silica zeolite and 100 ml of 1.5 mol / L ammonium chloride solution were placed at room temperature and stirred for 3 hours, filtered, washed, and vacuum-dried at 45°C for 2 hours. The mixture was then mixed with 30 ml of 0.2564 mol / L copper chloride solution and magnetically stirred at 70°C for 4 hours. The mixture was cooled to room temperature, filtered, washed several times, vacuum-dried at 45°C for 3 hours, calcined at 400°C for 4 hours, and furnace-cooled to room temperature to obtain Cu-silica zeolite.

[0043] Example 3: Preparation of m-dimethylaminophenol

[0044] Add 6.8g (0.0623mol) of m-aminophenol, 24.1g (0.1745mol) of potassium carbonate, and 1.4g of Cu-siloxane to 35.0ml of acetonitrile, stir evenly, and add 18.0ml (0.1994mol) of dimethyl carbonate dropwise in an ice bath maintained at 5°C-10°C. Let react for 28 hours. Add 36.4ml (0.4362mol) of 1,3-propylenediamine (99% content) to the reaction mixture, and reflux at 100°C for 23 hours. Cool to room temperature, add 40.8ml of ethyl acetate, stir for 10 minutes, filter, separate the organic phase, and extract with 20.4ml of saturated sodium carbonate solution (2 times: 13.6ml and 6.8ml). Combine the aqueous phases, adjust the pH to 7-8 with concentrated hydrochloric acid, let stand for 30 minutes, filter, and dry in vacuo. Recrystallization from toluene and vacuum drying gave 7.29 g of m-dimethylaminophenol with a yield of 85.3% and an HPLC content of 99.926% (Table 1, Figure 9 ), its TG-DSC spectrum ( Figure 8 ) Characteristic absorption peaks appear at 223.69℃ and 223.69℃.

[0045] Table 1 HPLC test results of m-dimethylaminophenol

[0046]

[0047] Example 4: Preparation of m-dimethylaminophenol

[0048] 11.2g (0.1026mol) of m-aminophenol, 39.7g (0.2874mol) of potassium carbonate, and 9.0g of Cu-siloxane zeolite were added to 67ml of tetrahydrofuran, stirred evenly, and 23.2ml (0.3591mol) of iodomethane was added dropwise in an ice bath maintained at 5°C-10°C. The reaction mixture was allowed to react for 33 hours. 72.7ml (0.7182mol) of hydroxyethylethylenediamine was added to the reaction mixture, and the mixture was refluxed at 110°C for 22 hours. The mixture was cooled to room temperature, and 60ml of ethyl acetate was added, stirred for 30 minutes, and filtered. The organic phase was separated and extracted with 28ml of saturated sodium carbonate solution (two times: 18.7ml and 9.3ml). The aqueous phases were combined, the pH was adjusted to 7-8 with concentrated hydrochloric acid, the mixture was allowed to stand for 40 minutes, filtered, and vacuum dried. Recrystallization from toluene and vacuum drying yielded 12.4g of m-dimethylaminophenol (87.8% yield).

[0049] Example 5: Preparation of m-dimethylaminophenol

[0050] 13.2g (0.1210 mol) of m-aminophenol, 46.8g (0.3387 mol) of potassium carbonate, and 6.6g of Cu-siloxane zeolite were added to 75ml of tetrahydrofuran, stirred evenly, and 27.3ml (0.4235 mol) of methyl iodide (99%) was added dropwise in an ice bath maintained at 5°C-10°C. The mixture was allowed to react for 30 hours. 85.7ml (0.8467 mol) of hydroxyethylethylenediamine was added to the reaction mixture, and the mixture was refluxed at 110°C for 20 hours. The mixture was cooled to room temperature, and 79ml of ethyl acetate was added, stirred for 30 minutes, and filtered. The organic phase was separated and extracted with 40ml of saturated sodium carbonate solution (27ml and 13ml, respectively). The aqueous phases were combined, the pH was adjusted to 7-8 with concentrated hydrochloric acid, the mixture was allowed to stand for 30 minutes, filtered, and vacuum dried. Recrystallization from toluene and vacuum drying yielded 15.1g of m-dimethylaminophenol (90.7% yield).

[0051] Example 6: Preparation of m-dimethylaminophenol

[0052] 8.0 g (0.0733 mol) of m-aminophenol, 28.3 g (0.2053 mol) of potassium carbonate, and 1.6 g of Cu-siloxane zeolite were added to 45 ml of DMF and stirred evenly. 17.5 ml (0.2712 mol) of methyl iodide was added dropwise in an ice bath maintained at 5°C-10°C and allowed to react for 28 hours. 34.3 ml (0.5132 mol) of ethylenediamine (99%) was added to the reaction solution and refluxed at 110°C for 22 hours. The mixture was cooled to room temperature, 42 ml of ethyl acetate was added, and stirred for 30 minutes. The mixture was filtered and the organic phase was separated. The mixture was extracted with 24 ml of saturated sodium carbonate solution (16 ml and 8 ml, respectively). The aqueous phases were combined, the pH was adjusted to 7-8 with concentrated hydrochloric acid, the mixture was allowed to stand for 30 minutes, filtered, and vacuum dried. Recrystallization from toluene and vacuum drying yielded 8.3 g of m-dimethylaminophenol (82.9% yield).

[0053] Example 7: Preparation of m-dimethylaminophenol

[0054] 15.3g (0.1402mol) of m-aminophenol, 54.26g (0.3926mol) of potassium carbonate, and 4.6g of Cu-siloxane zeolite were added to 70.5ml of acetonitrile and stirred evenly. 50.5ml (0.5608mol) of dimethyl carbonate was added dropwise in an ice bath maintained at 5°C-10°C and allowed to react for 25 hours. 99.3ml (0.9814mol) of hydroxyethylethylenediamine (99% content) was added to the reaction solution and refluxed at 110°C for 28 hours. The mixture was cooled to room temperature, 90ml of ethyl acetate was added, and stirred for 20 minutes. The mixture was filtered and the organic phase was separated. Extraction was performed with 42ml of saturated sodium carbonate solution (28ml and 14ml, respectively). The aqueous phases were combined, the pH was adjusted to 7-8 with concentrated hydrochloric acid, the mixture was allowed to stand for 30 minutes, filtered, and vacuum dried. Recrystallization from toluene and vacuum drying yielded 15.5g of m-dimethylaminophenol (80.6% yield).

[0055] The method for preparing the neostigmine intermediate m-dimethylaminophenol disclosed and proposed in the present invention can be implemented by those skilled in the art by appropriately modifying the conditions and routes, drawing upon the contents herein. Although the methods and preparation techniques of the present invention have been described using preferred embodiments, it is apparent to those skilled in the art that modifications or recombinations of the methods and technical routes described herein can be made to achieve the ultimate preparation technology without departing from the content, spirit, and scope of the present invention. It is particularly important to note that all similar substitutions and modifications obvious to those skilled in the art are considered to be included within the spirit, scope, and content of the present invention.

Claims

1. A method for preparing meta-dimethylaminophenol, an intermediate of neostigmine, characterized in that: Synthesized by the following steps: m-Dimethylaminophenol (1) Mixing m-aminophenol, a methylating agent, potassium carbonate, Cu-siloxane zeolite and an organic solvent; reacting; (2) Adding an organic amine to the mixture obtained by the above reaction and heating the mixture for reaction; after the reaction is completed, adding ethyl acetate and stirring, filtering, and allowing the filtrate to stand for stratification to separate the organic phase. The organic phase is extracted, and the aqueous phase is collected and combined. The pH value is adjusted to neutral, and an oily liquid is precipitated. The oily liquid is allowed to stand for solidification and filtered to obtain a crude product of m-dimethylaminophenol; the target product m-dimethylaminophenol is obtained after recrystallization and drying; The methylating agent in step (1) is methyl iodide, dimethyl sulfate or dimethyl carbonate; The organic amine in step (2) is hydroxyethylethylenediamine, isopropanolamine, 1,3-propylenediamine or ethylenediamine; The Cu-silicone zeolite is prepared by the following method: diatomaceous earth, Na2SiO3·9H2O, tetraethylammonium bromide and sodium chloride are weighed separately, placed in a mortar, and ground to obtain a paste; the paste is transferred to an eggplant-shaped bottle, heated for reaction, and cooled to room temperature after the reaction is completed; a small amount of deionized water is added for grinding and dissolution, insoluble matter is washed until neutral, and then filtered, dried, calcined, and cooled in a furnace to obtain the silica-type zeolite; then, the silica-type zeolite and ammonium chloride solution are placed at room temperature and stirred, and then filtered, washed, and vacuum-dried to obtain ammonium-exchanged silica-type zeolite; the ammonium-exchanged silica-type zeolite is uniformly mixed with a copper chloride solution, magnetically stirred, cooled to room temperature, filtered, washed several times, vacuum-dried, calcined, and cooled in a furnace to obtain the Cu-silicone zeolite; the reactants have a molar ratio of SiO2:Na2O:tetraethylammonium bromide:sodium chloride = 1:0.32:0.20:0.

55.

2. The method for preparing the neostigmine intermediate m-dimethylaminophenol according to claim 1, wherein In the first reaction, the methylating agent in step (1) is selected from methyl iodide; the molar ratio of methyl iodide to m-aminophenol is 3-5:1; and the amount of Cu-siloxane zeolite added is 0.2-3 times the mass of m-aminophenol.

3. The method for preparing the neostigmine intermediate m-dimethylaminophenol according to claim 1, wherein The organic solvent in step (1) is tetrahydrofuran, acetonitrile or N,N-dimethylformamide.

4. The method for preparing the neostigmine intermediate m-dimethylaminophenol according to claim 1, wherein The organic amine in step (2) is selected from hydroxyethylethylenediamine, and the molar ratio of hydroxyethylethylenediamine to m-aminophenol is 6-10:1.

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