4-butoxy-3-piperidinyl propiophenone hydrochloride and preparation method thereof
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- BEIJING SUN-NOVO PHARM RES CO LTD
- Filing Date
- 2024-11-18
- Publication Date
- 2026-05-19
AI Technical Summary
在中国专利CN101544616B对该技术进行了改进，使用低廉的苯酚为起始原料，通过苯酚与溴丁烷反应得到苯丁醚，然后再与醋酐反应制得对丁氧基苯乙酮，收率有所提高，克服了原对羟基苯乙酮为起始原料收率偏低问题
[0016]本发明人通过多次实验发现，将4-丁氧基-3-哌啶基苯丙酮盐酸盐粗品置于4-丁氧基-3-哌啶基苯丙酮盐酸盐不溶性有机溶剂中，未反应的反应原料(主要是哌啶盐酸盐)和降解杂质溶解于该有机溶剂中，加入酰基化试剂，在一定的PH下，发生酰基化反应，通过过滤后，获得4-丁氧基-3-哌啶基苯丙酮盐酸盐精品，该精制过程能明显降低成品中的杂质残留，提高成品的纯度和收率。
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Abstract
Description
Technical Field
[0001] This application belongs to the field of pharmaceutical synthesis technology, and specifically relates to a method for synthesizing 4-butoxy-3-piperidinylphenylacetone hydrochloride. Background Technology
[0002] 4-Butoxy-3-piperidinylphenylacetone hydrochloride is a white crystalline or crystalline powder with a slight odor and a numbing sensation. It is slightly soluble in water, soluble in ethanol, acetone, chloroform, and water at 60°C, and stable in air. In the medical field, it has various applications. Because it can block nerve conduction, it is often used as a local anesthetic. It can be used for anesthesia of the skin and mucous membranes, such as laryngeal anesthesia before gastroscopy to reduce patient pain and discomfort. For skin problems such as burns, abrasions, pruritus, and insect bites, 4-butoxy-3-piperidinylphenylacetone hydrochloride has analgesic and antipruritic effects. It can reduce pain and itching and promote wound healing. 4-Butoxy-3-piperidinylphenylacetone hydrochloride also has some bactericidal properties and can be used to treat some skin infections caused by bacteria.
[0003] In existing technology, Indian patent IN172270A (1993) uses p-hydroxyacetophenone as a starting material. The process involves reacting p-hydroxyacetophenone with bromobutane in an ethanol solution, followed by vacuum distillation to obtain p-butoxyacetophenone. This is then reacted with piperidine and formalin solution in a mixed solution of isopropanol hydrochloride and water to obtain crude 4-butoxy-3-piperidinylacetone hydrochloride, which is then recrystallized from methanol-water to obtain a pharmaceutically acceptable product. Chinese patent CN101544616B improved this technology by using inexpensive phenol as a starting material. The reaction of phenol with bromobutane yields phenylbutyl ether, which is then reacted with acetic anhydride to obtain p-butoxyacetophenone. This improved the yield and overcame the low yield problem of the original p-hydroxyacetophenone-based starting material. In the preparation of 4-butoxy-3-piperidinyl phenylacetone hydrochloride, replacing formalin solution with paraformaldehyde and isopropanol with anhydrous ethanol improved the product yield. However, in the post-processing, it was difficult to remove residual reaction raw materials and degradation impurities, resulting in high production costs in the purification process. Summary of the Invention
[0004] This application provides a method for preparing 4-butoxy-3-piperidinylphenylacetone hydrochloride, which improves the post-processing of crude 4-butoxy-3-piperidinylphenylacetone hydrochloride and increases the actual yield and purity of 4-butoxy-3-piperidinylphenylacetone hydrochloride.
[0005] This application provides a method for preparing 4-butoxy-3-piperidinylphenylacetone hydrochloride, comprising: dissolving 4-(n-butoxy)acetophenone in anhydrous ethanol, adding piperidine hydrochloride, paraformaldehyde and hydrochloric acid to generate crude 4-butoxy-3-piperidinylphenylacetone hydrochloride; placing the crude 4-butoxy-3-piperidinylphenylacetone hydrochloride in an organic solvent, adding an acylation reagent, adjusting the pH to 2-4, filtering and drying to obtain 4-butoxy-3-piperidinylphenylacetone hydrochloride, wherein the molar ratio of the acylation reagent to the molar difference between 4-(n-butoxy)acetophenone and piperidine hydrochloride is 1.5-3:1, the molar difference between 4-(n-butoxy)acetophenone and piperidine hydrochloride is greater than zero, and the 4-butoxy-3-piperidinylphenylacetone hydrochloride is insoluble in organic solvents.
[0006] Preferably, the molar ratio of 4-(n-butoxy)acetophenone to piperidine hydrochloride is 1.5 to 4:1.
[0007] Preferably, the molar ratio of the acylation reagent to the molar difference between 4-(n-butoxy)acetophenone and piperidine hydrochloride is 1.8 to 2.5:1.
[0008] Preferably, the molar ratio of the acylation reagent to the molar difference between 4-(n-butoxy)acetophenone and piperidine hydrochloride is 2:1.
[0009] Preferably, the pH is 2.5 to 3.5.
[0010] Preferably, the pH is 2.
[0011] Preferably, the acylation reagent is one or both of acetyl chloride and acetic anhydride.
[0012] Preferably, the organic solvent is one or more of dichloromethane, ethyl acetate, tetrahydrofuran, and acetone.
[0013] Preferably, the paraformaldehyde and hydrochloric acid are added in one or more batches.
[0014] This application also provides a 4-butoxy-3-piperidinylphenylacetone hydrochloride, which is prepared using the above method.
[0015] Beneficial effects:
[0016] Through multiple experiments, the inventors discovered that placing crude 4-butoxy-3-piperidinylphenylacetone hydrochloride in an insoluble organic solvent of 4-butoxy-3-piperidinylphenylacetone hydrochloride dissolves unreacted reaction raw materials (mainly piperidine hydrochloride) and degradation impurities in the organic solvent. Adding an acylation reagent and conducting an acylation reaction at a specific pH allows for the extraction of refined 4-butoxy-3-piperidinylphenylacetone hydrochloride after filtration. This purification process significantly reduces residual impurities in the finished product, improving its purity and yield. Detailed Implementation
[0017] The technical solutions in the embodiments of this application are clearly described below. Obviously, the described embodiments are only some, not all, of the embodiments of this application. All other embodiments obtained by those skilled in the art based on the embodiments of this application are within the scope of protection of this application.
[0018] The terms "first," "second," etc., used in the specification and claims of this application are used to distinguish similar objects and not to describe a specific order or sequence. It should be understood that such use of data can be interchanged where appropriate so that embodiments of this application can be implemented in orders other than those illustrated or described herein, and the objects distinguished by "first," "second," etc., are generally of the same class and the number of objects is not limited; for example, a first object can be one or more. Furthermore, in the specification and claims, "and / or" indicates at least one of the connected objects, and the character " / " generally indicates that the preceding and following objects are in an "or" relationship.
[0019] This application is not limited to the specific embodiments described above. The specific embodiments described above are merely illustrative and not restrictive. Those skilled in the art can make many other forms under the guidance of this application without departing from the spirit and scope of the claims, and all of these forms are within the protection scope of this application.
[0020] This application provides a method for preparing 4-butoxy-3-piperidinylphenylacetone hydrochloride, comprising: dissolving 4-(n-butoxy)acetophenone in anhydrous ethanol, adding piperidine hydrochloride, paraformaldehyde and hydrochloric acid to generate crude 4-butoxy-3-piperidinylphenylacetone hydrochloride; placing the crude 4-butoxy-3-piperidinylphenylacetone hydrochloride in an organic solvent, adding an acylation reagent, adjusting the pH to 2-4, filtering and drying to obtain 4-butoxy-3-piperidinylphenylacetone hydrochloride, wherein the molar ratio of the acylation reagent to the molar difference between 4-(n-butoxy)acetophenone and piperidine hydrochloride is 1.5-3:1, the molar difference between 4-(n-butoxy)acetophenone and piperidine hydrochloride is greater than zero, and the 4-butoxy-3-piperidinylphenylacetone hydrochloride is insoluble in organic solvents. The ratio of the molar amount of the acylation reagent to the molar difference between 4-(n-butoxy)acetophenone and piperidine hydrochloride can be 1.5:1, 1.8:1, 2.0:1, 2.5:1, or 3:1; the pH can be 2, 2.5, 3, 3.5, 4, 4.5, or 5.
[0021] The molar ratio of 4-(n-butoxy)acetophenone to piperidine hydrochloride is 1.5 to 4:1, and this molar ratio can be 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, or 4:1.
[0022] The acylation reagent is one or both of acetyl chloride and acetic anhydride.
[0023] The organic solvent is one or more of dichloromethane, ethyl acetate, tetrahydrofuran, and acetone. The following examples use dichloromethane as an example.
[0024] The paraformaldehyde and hydrochloric acid are added in one or more batches, either all at once or in two, three, or four batches.
[0025] This application also provides a 4-butoxy-3-piperidinylphenylacetone hydrochloride, prepared using the above method. The 4-butoxy-3-piperidinylphenylacetone hydrochloride prepared by this invention has higher yield and purity.
[0026] The following description, in conjunction with specific embodiments and comparative examples, further illustrates the point:
[0027] Sources of raw and auxiliary materials:
[0028] Raw material names source Specification 4-(n-Butoxy)acetophenone Jinan Liheng Biotechnology Co., Ltd. 98% purity Piperidine hydrochloride Shanghai McLean Biochemical Technology Co., Ltd. 98% purity Anhydrous ethanol Shanghai Aladdin Biochemical Technology Co., Ltd. Anhydrous grade, ≤0.003% water Paraformaldehyde Jinan Hongli Chemical Co., Ltd. Purity ≥ 99% hydrochloric acid Huanghua Xinsheng Chemical Co., Ltd. Concentration 36% dichloromethane Shanghai Aladdin Biochemical Technology Co., Ltd. 99% purity Acetyl chloride Nanjing Weiao Chemical Co., Ltd. 99% purity Acetic anhydride Sigma Aldrich (Shanghai) Trading Co., Ltd. 99% purity
[0029] Example 1
[0030] 400 g (2.08 mol) of 4-(n-butoxy)acetophenone and 304.8 g (2.50 mol) piperidine hydrochloride were added to 500 ml of anhydrous ethanol and stirred. Then, 120 g of paraformaldehyde and 4 ml of hydrochloric acid solution were added, and the mixture was reacted at 70 °C for 30 minutes. After cooling to 60 °C, 40 g of paraformaldehyde and 1.33 ml of hydrochloric acid were added, and the mixture was reacted at 70 °C for 4 hours. After cooling and crystallization, the mixture was filtered to obtain crude 4-butoxy-3-piperidinyl acetone hydrochloride.
[0031] Take the above crude 4-butoxy-3-piperidinyl phenylacetone hydrochloride, add 400 ml of dichloromethane and 59.41 ml of acetyl chloride, and stir for 30 min. Add hydrochloric acid dropwise to the reaction to adjust the pH to 3, and stir for 1 h. Cool to 8℃ and stir for 2 h. Filter and dry to obtain an off-white solid, denoted as 4-butoxy-3-piperidinyl phenylacetone hydrochloride 1.
[0032] Example 2
[0033] 400 g (2.08 mol) of 4-(n-butoxy)acetophenone and 304.8 g (2.50 mol) piperidine hydrochloride were added to 500 ml of anhydrous ethanol and stirred. Then, 120 g of paraformaldehyde and 4 ml of hydrochloric acid solution were added, and the mixture was reacted at 70 °C for 30 minutes. After cooling to 60 °C, 40 g of paraformaldehyde and 1.33 ml of hydrochloric acid were added, and the mixture was reacted at 70 °C for 4 hours. After cooling and crystallization, the mixture was filtered to obtain crude 4-butoxy-3-piperidinyl acetone hydrochloride.
[0034] Take the above crude 4-butoxy-3-piperidinyl phenylacetone hydrochloride, add 400 ml of dichloromethane and 74.26 ml of acetyl chloride, and stir for 30 min. Add hydrochloric acid dropwise to the reaction to adjust the pH to 3, and stir for 1 h. Cool to 8℃ and stir for 2 h. Filter and dry to obtain a white solid, denoted as 4-butoxy-3-piperidinyl phenylacetone hydrochloride 2.
[0035] Example 3
[0036] 400 g (2.08 mol) of 4-(n-butoxy)acetophenone and 304.8 g (2.50 mol) piperidine hydrochloride were added to 500 ml of anhydrous ethanol and stirred. Then, 120 g of paraformaldehyde and 4 ml of hydrochloric acid solution were added, and the mixture was reacted at 70 °C for 30 minutes. After cooling to 60 °C, 40 g of paraformaldehyde and 1.33 ml of hydrochloric acid were added, and the mixture was reacted at 70 °C for 4 hours. After cooling and crystallization, the mixture was filtered to obtain crude 4-butoxy-3-piperidinyl acetone hydrochloride.
[0037] Take the above crude 4-butoxy-3-piperidinyl phenylacetone hydrochloride, add 400 ml of dichloromethane and 89.11 ml of acetyl chloride, and stir for 30 min. Add hydrochloric acid dropwise to the reaction to adjust the pH to 3, and stir for 1 h. Cool to 8℃ and stir for 2 h. Filter and dry to obtain an off-white solid, denoted as 4-butoxy-3-piperidinyl phenylacetone hydrochloride 3.
[0038] Example 4
[0039] 400 g (2.08 mol) of 4-(n-butoxy)acetophenone and 304.8 g (2.50 mol) piperidine hydrochloride were added to 500 ml of anhydrous ethanol and stirred. Then, 120 g of paraformaldehyde and 4 ml of hydrochloric acid solution were added, and the mixture was reacted at 70 °C for 30 minutes. After cooling to 60 °C, 40 g of paraformaldehyde and 1.33 ml of hydrochloric acid were added, and the mixture was reacted at 70 °C for 4 hours. After cooling and crystallization, the mixture was filtered to obtain crude 4-butoxy-3-piperidinyl acetone hydrochloride.
[0040] Take the above crude 4-butoxy-3-piperidinyl phenylacetone hydrochloride, add 400 ml of dichloromethane and 44.55 ml of acetyl chloride, and stir for 30 min. Add hydrochloric acid dropwise to the reaction to adjust the pH to 3, and stir for 1 h. Cool to 8℃ and stir for 2 h. Filter and dry to obtain a white solid, denoted as 4-butoxy-3-piperidinyl phenylacetone hydrochloride 4.
[0041] Example 5
[0042] 400 g (2.08 mol) of 4-(n-butoxy)acetophenone and 304.8 g (2.50 mol) of piperidine hydrochloride were added to 500 ml of anhydrous ethanol and stirred. Then, 120 g of paraformaldehyde and 40 ml of hydrochloric acid solution were added. The mixture was reacted at 70 °C for 30 minutes, cooled to 60 °C, and then 40 g of paraformaldehyde and 14 ml of hydrochloric acid were added. The mixture was reacted at 70 °C for 4 hours, cooled to crystallize, and filtered to obtain crude 4-butoxy-3-piperidinyl acetone hydrochloride.
[0043] Take the above crude 4-butoxy-3-piperidinyl phenylacetone hydrochloride, add 400 ml of dichloromethane and 79.40 ml of acetic anhydride, and stir for 30 min. Add hydrochloric acid dropwise to the reaction to adjust the pH to 3, and stir for 1 h. Cool to 8℃ and stir for 2 h. Filter and dry to obtain a white solid, denoted as 4-butoxy-3-piperidinyl phenylacetone hydrochloride 5.
[0044] Example 6
[0045] 400 g (2.08 mol) of 4-(n-butoxy)acetophenone and 304.8 g (2.50 mol) of piperidine hydrochloride were added to 500 ml of anhydrous ethanol and stirred. Then, 120 g of paraformaldehyde and 40 ml of hydrochloric acid solution were added. The mixture was reacted at 70 °C for 30 minutes, cooled to 60 °C, and then 40 g of paraformaldehyde and 14 ml of hydrochloric acid were added. The mixture was reacted at 70 °C for 4 hours, cooled to crystallize, and filtered to obtain crude 4-butoxy-3-piperidinyl acetone hydrochloride.
[0046] Take the above crude 4-butoxy-3-piperidinyl phenylacetone hydrochloride, add 400 ml of dichloromethane and 59.41 ml of acetyl chloride, and stir for 30 min. Add hydrochloric acid dropwise to the reaction to adjust the pH to 2, and stir for 1 h. Cool to 8 °C and stir for 2 h. Filter and dry to obtain a white solid, denoted as 4-butoxy-3-piperidinyl phenylacetone hydrochloride 6.
[0047] Example 7
[0048] 400 g (2.08 mol) of 4-(n-butoxy)acetophenone and 304.8 g (2.50 mol) of piperidine hydrochloride were added to 500 ml of anhydrous ethanol and stirred. Then, 120 g of paraformaldehyde and 40 ml of hydrochloric acid solution were added. The mixture was reacted at 70 °C for 30 minutes, cooled to 60 °C, and then 40 g of paraformaldehyde and 14 ml of hydrochloric acid were added. The mixture was reacted at 70 °C for 4 hours, cooled to crystallize, and filtered to obtain crude 4-butoxy-3-piperidinyl acetone hydrochloride.
[0049] Take the above crude 4-butoxy-3-piperidinylphenylacetone hydrochloride, add 400 ml of dichloromethane and 59.41 ml of acetyl chloride, and stir for 30 min. Add hydrochloric acid dropwise to the reaction to adjust the pH to 4, and stir for 1 h. Cool to 8℃ and stir for 2 h. Filter and dry to obtain a white solid, denoted as 4-butoxy-3-piperidinylphenylacetone hydrochloride 7.
[0050] Comparative Example 1
[0051] 400 g (2.08 mol) of 4-(n-butoxy)acetophenone and 304.8 g (2.50 mol) of piperidine hydrochloride were added to 500 ml of anhydrous ethanol and stirred. Then, 120 g of paraformaldehyde and 40 ml of hydrochloric acid solution were added. The mixture was reacted at 70 °C for 30 minutes, cooled to 60 °C, and then 40 g of paraformaldehyde and 14 ml of hydrochloric acid were added. The mixture was reacted at 70 °C for 4 hours, cooled to crystallize, and filtered to obtain crude 4-butoxy-3-piperidinyl acetone hydrochloride.
[0052] Take the above crude 4-butoxy-3-piperidinyl phenylacetone hydrochloride, add 400 ml of dichloromethane and 29.70 ml of acetyl chloride, and stir for 30 min. Add hydrochloric acid dropwise to the reaction to adjust the pH to 3, and stir for 1 h. Cool to 8℃ and stir for 2 h. Filter and dry to obtain a white solid, denoted as 4-butoxy-3-piperidinyl phenylacetone hydrochloride 8.
[0053] Comparative Example 2
[0054] 400 g (2.08 mol) of 4-(n-butoxy)acetophenone and 304.8 g (2.50 mol) of piperidine hydrochloride were added to 500 ml of anhydrous ethanol and stirred. Then, 120 g of paraformaldehyde and 40 ml of hydrochloric acid solution were added. The mixture was reacted at 70 °C for 30 minutes, cooled to 60 °C, and then 40 g of paraformaldehyde and 14 ml of hydrochloric acid were added. The mixture was reacted at 70 °C for 4 hours, cooled to crystallize, and filtered to obtain crude 4-butoxy-3-piperidinyl acetone hydrochloride.
[0055] Take the above crude 4-butoxy-3-piperidinyl phenylacetone hydrochloride, add 400 ml of dichloromethane and 118.81 ml of acetyl chloride, and stir for 30 min. Add hydrochloric acid dropwise to the reaction to adjust the pH to 3, and stir for 1 h. Cool to 8℃ and stir for 2 h. Filter and dry to obtain an off-white solid, denoted as 4-butoxy-3-piperidinyl phenylacetone hydrochloride 9.
[0056] Comparative Example 3
[0057] 400 g (2.08 mol) of 4-(n-butoxy)acetophenone and 304.8 g (2.50 mol) of piperidine hydrochloride were added to 500 ml of anhydrous ethanol and stirred. Then, 120 g of paraformaldehyde and 40 ml of hydrochloric acid solution were added. The mixture was reacted at 70 °C for 30 minutes, cooled to 60 °C, and then 40 g of paraformaldehyde and 14 ml of hydrochloric acid were added. The mixture was reacted at 70 °C for 4 hours, cooled to crystallize, and filtered to obtain crude 4-butoxy-3-piperidinyl acetone hydrochloride.
[0058] Take the above crude 4-butoxy-3-piperidinyl phenylacetone hydrochloride, add 400 ml of dichloromethane and 59.41 ml of acetyl chloride, and stir for 30 min. Add hydrochloric acid dropwise to the reaction to adjust the pH to 1, and stir for 1 h. Cool to 8 °C and stir for 2 h. Filter and dry to obtain a white solid, denoted as 4-butoxy-3-piperidinyl phenylacetone hydrochloride 10.
[0059] Comparative Example 4
[0060] 400 g (2.08 mol) of 4-(n-butoxy)acetophenone and 304.8 g (2.50 mol) of piperidine hydrochloride were added to 500 ml of anhydrous ethanol and stirred. Then, 120 g of paraformaldehyde and 40 ml of hydrochloric acid solution were added. The mixture was reacted at 70 °C for 30 minutes, cooled to 60 °C, and then 40 g of paraformaldehyde and 14 ml of hydrochloric acid were added. The mixture was reacted at 70 °C for 4 hours, cooled to crystallize, and filtered to obtain crude 4-butoxy-3-piperidinyl acetone hydrochloride.
[0061] Take the above crude 4-butoxy-3-piperidinyl phenylacetone hydrochloride, add 400 ml of dichloromethane and 59.41 ml of acetyl chloride, and stir for 30 min. Add hydrochloric acid dropwise to the reaction to adjust the pH to 5, and stir for 1 h. Cool to 8 °C and stir for 2 h. Filter and dry to obtain an off-white solid, denoted as 4-butoxy-3-piperidinyl phenylacetone hydrochloride 11.
[0062] The experimental variables for Examples 1-7 and Comparative Examples 1-4 are shown in Table 2.
[0063] Table 2. Experimental variable settings for Examples 1-7 and Comparative Examples 1-4
[0064]
[0065]
[0066] Note: In Table 2, ΔX = molar amount of 4-(n-butoxy)acetophenone - molar amount of piperidine hydrochloride.
[0067] The 4-butoxy-3-piperidinylphenylacetone hydrochloride 1-11 prepared in Examples 1-7 and Comparative Examples 1-4 were weighed, the purity of 4-butoxy-3-piperidinylphenylacetone hydrochloride was measured, and the yield of 4-butoxy-3-piperidinylphenylacetone hydrochloride was calculated.
[0068] The actual yield of 4-butoxy-3-piperidinyl phenylacetone hydrochloride was calculated as follows:
[0069] Actual yield of 4-butoxy-3-piperidinyl phenylacetone hydrochloride = Actual yield of 4-butoxy-3-piperidinyl phenylacetone hydrochloride / Theoretical yield of 4-butoxy-3-piperidinyl phenylacetone hydrochloride x 100%
[0070] Theoretical yield of 4-butoxy-3-piperidinyl acetone hydrochloride = number of moles of 4-(n-butoxy)acetophenone x 325.86 g / mol
[0071] The purity of 4-butoxy-3-piperidinyl phenylacetone hydrochloride 1-11 was determined by high performance liquid chromatography (HPLC) as published in Chinese Pharmacist, Vol. 16, No. 8, 2013. The measurement results are shown in Table 3.
[0072] Table 3 shows the actual yield, purity, and actual recovery rate of 4-butoxy-3-piperidinyl phenylacetone hydrochloride in white solids 1-11.
[0073]
[0074]
[0075] The following conclusions can be drawn from observing Table 3:
[0076] Comparing 4-butoxy-3-piperidinyl phenylacetone hydrochloride 1–5 with 4-butoxy-3-piperidinyl phenylacetone hydrochloride 8–9, it can be seen that the purity of 4-butoxy-3-piperidinyl phenylacetone hydrochloride 1–5 reaches over 99.5%, and the actual yield of 4-butoxy-3-piperidinyl phenylacetone hydrochloride reaches over 90%, with 4-butoxy-3-piperidinyl phenylacetone hydrochloride 1 having the highest purity and actual yield; the purity and actual yield of 4-butoxy-3-piperidinyl phenylacetone hydrochloride 8–9 are lower. Therefore, it is evident that… Under the same conditions, when the molar ratio of the acylation reagent to the molar difference between 4-(n-butoxy)acetophenone and piperidine hydrochloride is 1.5 to 3:1, the yield and purity of the prepared 4-butoxy-3-piperidinyl phenylacetone hydrochloride are higher, with the yield increasing to over 90% and the purity exceeding 99.5%. In particular, when the molar ratio of the acylation reagent to the molar difference between 4-(n-butoxy)acetophenone and piperidine hydrochloride is 2:1, the yield and purity of the prepared 4-butoxy-3-piperidinyl phenylacetone hydrochloride are the highest.
[0077] Comparing 4-butoxy-3-piperidinyl phenylacetone hydrochloride 1, 6–7 with 4-butoxy-3-piperidinyl phenylacetone hydrochloride 10–11, it can be seen that the purity of 4-butoxy-3-piperidinyl phenylacetone hydrochloride 1, 6–7 reaches over 99.5%, and the actual yield of 4-butoxy-3-piperidinyl phenylacetone hydrochloride reaches over 90%, with 4-butoxy-3-piperidinyl phenylacetone hydrochloride 1 having the highest purity and actual yield; the purity and actual yield of 4-butoxy-3-piperidinyl phenylacetone hydrochloride 10–11 are also higher. The yield was low, indicating that, under the same conditions, the yield and purity of 4-butoxy-3-piperidinylphenylacetone hydrochloride were higher when the pH range was 2–4 during the purification process. The yield could be increased to over 90%, and the purity was greater than 99.5%. In particular, the yield and purity of 4-butoxy-3-piperidinylphenylacetone hydrochloride were highest when the pH range was 2–4 during the purification process.
[0078] It is understood that the above embodiments are merely exemplary implementations used to illustrate the principles of this application, and this application is not limited thereto. For those skilled in the art, various modifications and improvements can be made without departing from the spirit and substance of this application, and these modifications and improvements are also considered to be within the scope of protection of this invention.
Claims
1. A method for preparing 4-butoxy-3-piperidinyl phenylacetone hydrochloride, characterized in that, include: 4-(n-Butoxy)acetophenone was dissolved in anhydrous ethanol, and piperidine hydrochloride, paraformaldehyde, and hydrochloric acid were added to generate crude 4-butoxy-3-piperidinylphenylacetone hydrochloride. The crude 4-butoxy-3-piperidinylphenylacetone hydrochloride was placed in an organic solvent, and an acylation reagent was added to adjust the pH to 2-4. After filtration and drying, 4-butoxy-3-piperidinylphenylacetone hydrochloride was obtained. The molar ratio of the acylation reagent to the molar difference between 4-(n-Butoxy)acetophenone and piperidine hydrochloride was 1.5-3:1, the molar difference between 4-(n-Butoxy)acetophenone and piperidine hydrochloride was greater than zero, and the 4-butoxy-3-piperidinylphenylacetone hydrochloride was insoluble in organic solvents.
2. The method for preparing 4-butoxy-3-piperidinyl phenylacetone hydrochloride according to claim 1, characterized in that, The molar ratio of 4-(n-butoxy)acetophenone to piperidine hydrochloride is 1.5 to 4:
1.
3. The method for preparing 4-butoxy-3-piperidinyl phenylacetone hydrochloride according to claim 1, characterized in that, The molar ratio of the acylation reagent to the molar difference between 4-(n-butoxy)acetophenone and piperidine hydrochloride is 1.8 to 2.5:
1.
4. The method for preparing 4-butoxy-3-piperidinyl phenylacetone hydrochloride according to claim 1, characterized in that, The molar ratio of the acylation reagent to the molar difference between 4-(n-butoxy)acetophenone and piperidine hydrochloride is 2:
1.
5. The method for preparing 4-butoxy-3-piperidinyl phenylacetone hydrochloride according to claim 1, characterized in that, The pH value is 2.5 to 3.
5.
6. The method for preparing 4-butoxy-3-piperidinyl phenylacetone hydrochloride according to claim 5, characterized in that, The pH value is 3.
7. The method for preparing 4-butoxy-3-piperidinyl phenylacetone hydrochloride according to claim 1, characterized in that, The acylation reagent is one or both of acetyl chloride and acetic anhydride.
8. The method for preparing 4-butoxy-3-piperidinyl phenylacetone hydrochloride according to claim 1, characterized in that, The organic solvent is one or more of dichloromethane, ethyl acetate, tetrahydrofuran, and acetone.
9. The method for preparing 4-butoxy-3-piperidinyl phenylacetone hydrochloride according to claim 1, characterized in that, The paraformaldehyde and hydrochloric acid are added in one or more batches.
10. A 4-butoxy-3-piperidinyl phenylacetone hydrochloride is prepared by the method according to any one of claims 1 to 9.