1-(4-butoxyphenyl)-3-hydroxypropyl-1-ketone as well as preparation method and application thereof
By providing a preparation method for 1-(4-butoxyphenyl)-3-hydroxypropyl-1-one, the problem of impurities generated by the degradation of dyclonine hydrochloride is solved, and the preparation of high-purity products and medicines are realized Improvements in quality control.
Patent Information
- Application Number
- CN202411485277.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-23
- Publication Date
- 2025-01-24
AI Technical Summary
Dacronin hydrochloride will degrade during long-term storage or high-temperature conditions, resulting in impurity 1-(4-butoxyphenyl)-3-hydroxypropyl-1-one, which affects the quality and safety of the drug, and lacks effectiveness. synthesis method.
Provided is a preparation method of 1-(4-butoxyphenyl)-3-hydroxypropyl-1-one, which includes reacting 4-butoxyphenylpropenone and benzyl alcohol under the action of a catalyst under nitrogen protection, After multi-step catalysis and column chromatography, high-purity target compounds were obtained.
Realized the preparation of high-purity 1- (4-but butyoxyzhenyl) -3-hydroxyl propyl-1-ketone, which is used for the qualitative and quantitative analysis of the impurity hydrochloride hydrochloride. Essence
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Figure CN119350149A_ABST
Abstract
Description
Technical Field
[0001] The present application relates to the field of biomedicine technology, and specifically to 1-(4-butoxyphenyl)-3-hydroxypropyl-1-ketone and a preparation method and application thereof. Background Art
[0002] Dyclonine is a local anesthetic with rapid onset, long duration of action, few adverse reactions and high safety. The dosage forms of dyclonine hydrochloride that have been marketed or reported in China mainly include ointments, creams, liniments, solutions, gels and emulsion-type slurries. The main component of dyclonine is dyclonine hydrochloride, with the chemical name of 1-(4-butoxyphenyl)-3-(1-piperidinyl)-1-propanone hydrochloride, which is white or almost white crystals or crystalline powder, with the CAS number of 536-43-6 and the molecular formula as follows:
[0003] Studies have found that dyclonine hydrochloride will degrade during long-term storage, especially under high temperature conditions, to produce the impurity 1-(4-butoxyphenyl)-3-hydroxypropyl-1-one. This impurity will affect the quality of dyclonine hydrochloride and produce side effects, thereby affecting the safety of drug use. Therefore, the study of the impurity content is the key to the quality evaluation and control of dyclonine hydrochloride.
[0004] However, there is no report on the synthesis of 1-(4-butoxyphenyl)-3-hydroxypropyl-1-one, so there is an urgent need to provide a simple and efficient synthesis method of 1-(4-butoxyphenyl)-3-hydroxypropyl-1-one, so as to obtain high-purity 1-(4-butoxyphenyl)-3-hydroxypropyl-1-one, so as to prepare impurity reference substances for qualitative and quantitative analysis of impurities in the production of dyclonine hydrochloride and its preparations, and realize the quality evaluation and control of dyclonine hydrochloride drugs. Summary of the invention
[0005] In order to achieve qualitative and quantitative analysis of the impurity 1-(4-butoxyphenyl)-3-hydroxypropyl-1-one in the drug dyclonine hydrochloride, the present application provides a 1-(4-butoxyphenyl)-3-hydroxypropyl-1-one and a preparation method and application thereof.
[0006] In the first aspect, the present application provides a 1-(4-butoxyphenyl)-3-hydroxypropyl-1-ketone, using the following technical solution: A 1-(4-butoxyphenyl)-3-hydroxypropyl-1-one, the structural formula of which is shown in Formula I:
[0007] In a second aspect, the present application provides a method for preparing 1-(4-butoxyphenyl)-3-hydroxypropyl-1-one.
[0008] A method for preparing 1-(4-butoxyphenyl)-3-hydroxypropyl-1-ketone comprises the following steps: (1) Under nitrogen protection, 4-butoxyphenylpropenone and benzyl alcohol in a molar ratio of 1:(1-5) are dissolved in solvent A, reacted under the action of catalyst A, and monitored by TLC, vacuum distilled, and column chromatography to obtain intermediate 1; (2) The intermediate 1 is dissolved in solvent B, and hydrogen is introduced in the presence of catalyst B. The reaction is kept warm, and 1-(4-butoxyphenyl)-3-hydroxypropyl-1-one is obtained by TLC monitoring, filtration, vacuum distillation, and column chromatography.
[0009] The present application provides a method for preparing 1-(4-butoxyphenyl)-3-hydroxypropyl-1-one. The above-mentioned preparation method has the advantages of simple operation, high yield and purity of 1-(4-butoxyphenyl)-3-hydroxypropyl-1-one, and the 1-(4-butoxyphenyl)-3-hydroxypropyl-1-one prepared by the method can be used for the qualitative and quantitative analysis of impurities in dyclonine hydrochloride raw materials and related preparations, so as to strengthen the quality control of dyclonine hydrochloride and related preparations, thereby improving the product quality of dyclonine hydrochloride and related preparations.
[0010] In the present application, by controlling the molar ratio of 4-butoxyphenylpropenone to benzyl alcohol in step (1) within the range of 1:(1-5), and the molar ratio of 4-butoxyphenylpropenone to catalyst A within the range of 1:(0.1-0.5), the yield of the obtained 1-(4-butoxyphenyl)-3-benzyloxypropyl-1-one intermediate can reach more than 83%, and the purity can reach more than 98%.
[0011] In the preparation method of 1-(4-butoxyphenyl)-3-hydroxypropyl-1-one provided in the present application, 4-butoxyphenylpropenone is first used as a starting material, and under the action of a catalyst, it is reacted with benzyl alcohol to generate a 1-(4-butoxyphenyl)-3-benzyloxypropyl-1-one intermediate, and then the intermediate is catalytically hydrogenated to remove the benzyl group, and finally 1-(4-butoxyphenyl)-3-hydroxypropyl-1-one is generated. The synthetic route of the above reaction is as follows: In some embodiments, the molar ratio of 4-butoxyphenylpropenone to benzyl alcohol can be 1:(1-2), 1:(1-3), 1:(1-4), 1:(1-5), 1:(2-3), 1:(2-4), 1:(2-5), 1:(3-4), 1:(3-5) or 1:(4-5).
[0012] In a specific embodiment, the molar ratio of 4-butoxyphenylpropenone to benzyl alcohol can also be 1:1, 1:2, 1:3, 1:4 or 1:5.
[0013] Optionally, the molar ratio of 4-butoxyphenylpropenone to benzyl alcohol is 1:(3-5).
[0014] Through experimental research, the present application found that by further controlling the molar ratio of 4-butoxyphenylpropenone to benzyl alcohol within the above range, the yield of the obtained 1-(4-butoxyphenyl)-3-benzyloxypropyl-1-one intermediate can reach more than 86.0% and the purity can reach more than 99.00%.
[0015] Optionally, the molar ratio of the 4-butoxyphenylpropenone to the catalyst A is 1:(0.1-0.5).
[0016] In some embodiments, the molar ratio of 4-butoxyphenylpropenone to catalyst A can be 1: (0.1-0.2), 1: (0.1-0.3), 1: (0.1-0.4), 1: (0.1-0.5), 1: (0.2-0.3), 1: (0.2-0.4), 1: (0.2-0.5), (0.3-0.4), (0.3-0.5) or (0.4-0.5).
[0017] In a specific embodiment, the molar ratio of the 4-butoxyphenylpropenone to the catalyst A can also be 1:0.1, 1:0.2, 1:0.3, 1:0.4 or 1:0.5.
[0018] Optionally, the molar ratio of the 4-butoxyphenylpropenone to the catalyst A is 1:(0.2-0.4).
[0019] Through experimental research, the present application found that by further controlling the molar ratio of 4-butoxyphenylpropenone to catalyst A within the above range, the yield of the obtained 1-(4-butoxyphenyl)-3-benzyloxypropyl-1-one intermediate can reach more than 87.0% and the purity can reach more than 99.00%.
[0020] Optionally, the catalyst B is selected from palladium carbon, palladium hydroxide carbon and Raney nickel; the weight ratio of the catalyst B to the intermediate 1 is (0.1-0.12):1.
[0021] In a specific embodiment, the catalyst B is 10% palladium hydroxide / carbon, and the weight ratio of the 10% palladium hydroxide / carbon to the intermediate 1 is 0.1:1.
[0022] Optionally, the solvent A is selected from acetonitrile, dioxane and N,N-dimethylformamide, or no solvent is added; and the solvent B is selected from tetrahydrofuran, ethyl acetate, methanol and ethanol.
[0023] Optionally, the eluent used in the column chromatography is n-hexane / ethyl acetate (30 / 1-5 / 1).
[0024] In a specific embodiment, the eluent used in the column chromatography is n-hexane / ethyl acetate in a volume ratio of 10 / 1.
[0025] Optionally, the reaction temperature of step (1) is 30-130°C; the reaction temperature of step (2) is 25-65°C, and the pressure is 1.0atm-6.0atm.
[0026] In some embodiments, the reaction temperature of step (1) can be 30-50°C, 30-85°C, 30-100°C, 30-130°C, 50-85°C, 50-100°C, 50-130°C, 85-100°C, 85-130°C or 100-130°C.
[0027] In some specific embodiments, the reaction temperature of step (1) can also be 30°C, 50°C, 85°C, 100°C or 130°C.
[0028] In some embodiments, the reaction temperature of step (2) can be 25-30°C, 25-45°C, 25-65°C, 30-45°C, 30-65°C or 45-65°C.
[0029] In some specific embodiments, the reaction temperature of step (2) can also be 25°C, 30°C, 45°C, or 65°C.
[0030] In some embodiments, the pressure of step (2) can be 1.0-2.0 atm, 1.0-4.0 atm, 1.0-6.0 atm, 2.0-4.0 atm, 2.0-6.0 atm or 4.0-6.0 atm.
[0031] In some specific embodiments, the pressure of step (2) can also be 1.0 atm, 2.0 atm, 4.0 atm or 6.0 atm.
[0032] Optionally, the reaction temperature of step (1) is 50-100°C; the reaction temperature of step (2) is 25-45°C, and the pressure is 1.0atm-4.0atm.
[0033] In the third aspect, the present application provides the application of 1-(4-butoxyphenyl)-3-hydroxypropyl-1-one in the quality control of dyclonine hydrochloride and related preparations.
[0034] The 1-(4-butoxyphenyl)-3-hydroxypropyl-1-ketone prepared in the present application can be used as an impurity standard for the qualitative and quantitative analysis of impurities in dyclonine hydrochloride, and for scientifically evaluating the quality of dyclonine hydrochloride and related preparations, thereby improving the safety of dyclonine hydrochloride and related preparations.
[0035] In summary, this application has the following beneficial effects: 1. The preparation method of 1-(4-butoxyphenyl)-3-hydroxypropyl-1-one provided in the present application has the advantages of simple operation, high yield and purity of 1-(4-butoxyphenyl)-3-hydroxypropyl-1-one, and the 1-(4-butoxyphenyl)-3-hydroxypropyl-1-one prepared by the method can be used as an impurity standard for qualitative and quantitative analysis of impurities, and scientifically evaluate the quality of dyclonine hydrochloride and related preparations, thereby improving the safety of dyclonine hydrochloride and related preparations.
[0036] 2. In step (1) of the preparation method of 1-(4-butoxyphenyl)-3-hydroxypropyl-1-one provided in the present application, by further controlling the molar ratio of 4-butoxyphenylpropenone to benzyl alcohol within the range of 1:(3-5), the molar ratio of 4-butoxyphenylpropenone to catalyst A within the range of 1:(0.2-0.4), and the reaction temperature within the range of 50-100°C, the yield of the obtained 1-(4-butoxyphenyl)-3-benzyloxypropyl-1-one intermediate can reach more than 86.0%, and the purity can reach more than 99.00%.
[0037] 3. In step (2) of the method for preparing 1-(4-butoxyphenyl)-3-hydroxypropyl-1-one provided in the present application, the reaction temperature is further controlled within the range of 25-45°C, and the pressure is controlled within the range of 1.0atm-4.0atm. The yield and purity of the obtained 1-(4-butoxyphenyl)-3-hydroxypropyl-1-one are higher, with the yield reaching more than 95.0% and the purity reaching more than 98.00%. BRIEF DESCRIPTION OF THE DRAWINGS
[0038] Figure 1 is the nuclear magnetic resonance spectrum of 1-(4-butoxyphenyl)-3-hydroxypropyl-1-ketone obtained in Example 1; Figure 2 This is the HPLC chromatogram of 1-(4-butoxyphenyl)-3-hydroxypropyl-1-one obtained in Example 1. DETAILED DESCRIPTION
[0039] The present application provides 1-(4-butoxyphenyl)-3-hydroxypropyl-1-ketone, and the preparation method thereof comprises the following steps: (1) Under nitrogen protection, 4-butoxyphenylpropenone and benzyl alcohol are dissolved in solvent A, and catalyst A is added; then the temperature is raised to 30-130° C., and the mixture is stirred and reacted for 8-12 h. The reaction progress is monitored by TLC (petroleum ether / ethyl acetate 3 / 1). After the reaction is completed, the filtrate is subjected to vacuum distillation and column chromatography to obtain intermediate 1.
[0040] The molar ratio of 4-butoxyphenylpropenone to benzyl alcohol is 1:(1-5); the catalyst A is selected from chromium chloride, bismuth chloride and indium trifluoromethanesulfonate; the molar ratio of 4-butoxyphenylpropenone to catalyst A is 1:(0.1-0.5); the solvent A is selected from acetonitrile, dioxane and N,N-dimethylformamide, or no solvent is added; the eluent used in the column chromatography is n-hexane / ethyl acetate (30 / 1-5 / 1).
[0041] (2) The intermediate 1 was dissolved in solvent B, and catalyst B was added. Hydrogen was introduced for replacement three times, and hydrogen was continued to be introduced until the pressure was 1.0 atm-6.0 atm. The mixture was stirred and kept warm at 25-65° C. for 10-15 h. The reaction progress was monitored by TLC (petroleum ether / ethyl acetate 3 / 1). After the reaction was completed, the mixture was filtered and the filtrate was distilled under reduced pressure and subjected to column chromatography to obtain 1-(4-butoxyphenyl)-3-hydroxypropyl-1-one.
[0042] Wherein, the catalyst B is selected from palladium / carbon, palladium hydroxide / carbon and Raney nickel; the solvent B is selected from tetrahydrofuran, ethyl acetate, methanol and ethanol; and the eluent used in the column chromatography is n-hexane / ethyl acetate (30 / 1-5 / 1).
[0043] In the examples of the present application, 4-butoxyphenylpropenone was prepared by the company; bismuth chloride was purchased from Shanghai Titan Technology; 10% palladium hydroxide on carbon was purchased from Anhui Zesheng Technology Co., Ltd.; the remaining raw materials, reagents, solvents, etc. of the present application can also be obtained through commercial purchase.
[0044] The present application is further described in detail below in combination with preparation examples, embodiments and detection experiments.
[0045] Preparation Example 1-9 Preparation Examples 1-9 respectively synthesize a 1-(4-butoxyphenyl)-3-benzyloxypropyl-1-one.
[0046] The difference between the above preparation examples lies in the molar ratio of 4-butoxyphenylpropenone to benzyl alcohol, as shown in Table 1 below.
[0047] The preparation method of 1-(4-butoxyphenyl)-3-benzyloxypropyl-1-one synthesized in Preparation Example 1-9 comprises the following steps: under nitrogen protection, 4-butoxyphenylpropenone (5.00 g, 24.48 mmol) and benzyl alcohol (the amount added is calculated according to the molar ratio shown in Table 1) are dissolved in N,N-dimethylformamide (25 mL), and bismuth chloride (the amount added is calculated according to the molar ratio shown in Table 1) is added; then the temperature is raised to 85° C., the mixture is stirred and kept warm for 9 hours, and the reaction progress is monitored by TLC (petroleum ether / ethyl acetate: 3 / 1). After the reaction is completed, the filtrate is subjected to reduced pressure distillation to remove N,N-dimethylformamide, and column chromatography (n-hexane / ethyl acetate: 10 / 1) is performed to obtain 1-(4-butoxyphenyl)-3-benzyloxypropyl-1-one.
[0048] Table 1 Molar ratio of 4-butoxyphenylpropenone to benzyl alcohol in the preparation method of Preparation Examples 1-9 Preparation Example 10-13 Preparation Examples 10-13 respectively synthesize 1-(4-butoxyphenyl)-3-benzyloxypropyl-1-one.
[0049] The difference between the above preparation example and preparation example 4 is: reaction temperature, as shown in Table 2 below.
[0050] Table 2 Reaction temperature in the preparation method of Preparation Example 4 and Preparation Examples 10-13 Preparation Example Reaction temperature (℃) 4 85 10 30 11 50 12 100 13 130 The performance test was conducted to test the yield and purity of 1-(4-butoxyphenyl)-3-benzyloxypropyl-1-one obtained in Preparation Example 1-13. The results are shown in Table 3 below.
[0051] Table 3 Yield and purity test results of intermediates obtained in Preparation Examples 1-13 From the test results in Table 3, it can be seen that Preparation Example 1-13 uses 4-butoxyphenylpropenone and benzyl alcohol as raw materials, and the molar ratio of 4-butoxyphenylpropenone to benzyl alcohol is controlled in the range of 1:(1-5), and a high-purity and high-yield 1-(4-butoxyphenyl)-3-benzyloxypropyl-1-one intermediate can be obtained, and the yield is 83.25-89.02% and the purity is 98.19-99.21%.
[0052] From the test results of Preparation Examples 1-5, it can be seen that the yield of 1-(4-butoxyphenyl)-3-benzyloxypropyl-1-one obtained in Preparation Example 1-2 is only 83.25-84.77%, and the purity is 98.79-98.88%; while the yield of 1-(4-butoxyphenyl)-3-benzyloxypropyl-1-one obtained in Preparation Example 3-5 is 86.43-89.02% (≥86.00%), and the purity is 99.06-99.21% (≥99.00%). Therefore, it is explained that the present application further controls the molar ratio of 4-butoxyphenylpropenone to benzyl alcohol within the range of 1:(3-5), and the yield and purity of the obtained 1-(4-butoxyphenyl)-3-benzyloxypropyl-1-one are higher.
[0053] From the test results of Preparation Example 4 and Preparation Examples 6-9, it can be seen that the yield of 1-(4-butoxyphenyl)-3-benzyloxypropyl-1-one obtained in Preparation Example 6 is only 84.27%, and the purity is 98.55%; the yield of 1-(4-butoxyphenyl)-3-benzyloxypropyl-1-one obtained in Preparation Example 9 is 87.25%, and the purity is only 98.63%; and the yield of 1-(4-butoxyphenyl)-3-benzyloxypropyl-1-one obtained in Preparation Example 4 and Preparation Examples 7-8 is 87.38-89.02% (≥87.00%), and the purity is 99.06-99.21% (≥99.00%). Therefore, considering the comprehensive cost, it is shown that the present application further controls the molar ratio of 4-butoxyphenylpropenone to catalyst A within the range of 1:(0.2-0.4), and the yield and purity of the obtained 1-(4-butoxyphenyl)-3-benzyloxypropyl-1-one are higher.
[0054] From the test results of Preparation Examples 4 and 10-13, it can be seen that the yield of 1-(4-butoxyphenyl)-3-benzyloxypropyl-1-one obtained in Preparation Example 10 is only 87.82%, and the purity is 98.37%; the yield of 1-(4-butoxyphenyl)-3-benzyloxypropyl-1-one obtained in Preparation Example 13 is 86.03%, and the purity is 98.19%; and the yield of 1-(4-butoxyphenyl)-3-benzyloxypropyl-1-one obtained in Preparation Examples 4 and 11-12 is 88.46-89.02% (≥88.00%), and the purity is 99.08-99.21% (≥99.00%). Therefore, it is explained that the present application further controls the reaction temperature in the preparation method within the range of 50-100°C, and the yield and purity of 1-(4-butoxyphenyl)-3-benzyloxypropyl-1-one obtained are higher.
[0055] Example 1 Example 1 Synthesis of 1-(4-butoxyphenyl)-3-hydroxypropyl-1-ketone.
[0056] The preparation method of the above 1-(4-butoxyphenyl)-3-hydroxypropyl-1-ketone is: (1) According to the method provided in Preparation Example 4, a scaled-up test was carried out to prepare 1-(4-butoxyphenyl)-3-benzyloxypropyl-1-one.
[0057] (2) The 1-(4-butoxyphenyl)-3-benzyloxypropyl-1-one intermediate was dissolved in ethanol (20 mL), and 10% palladium hydroxide / carbon (0.20 g) was added. The mixture was replaced with hydrogen three times, and hydrogen was continuously introduced until the pressure reached 2.0 atm. The mixture was stirred and kept warm at 30° C. for 12 h. The reaction progress was monitored by TLC (petroleum ether / ethyl acetate 3 / 1). After the reaction was completed, the palladium hydroxide / carbon was removed by filtration, and the filtrate was concentrated to dryness by distillation under reduced pressure. The mixture was subjected to column chromatography (n-hexane / ethyl acetate: 10 / 1) to obtain 1-(4-butoxyphenyl)-3-hydroxypropyl-1-one.
[0058] Example 2 Example 2 Synthesis of 1-(4-butoxyphenyl)-3-hydroxypropyl-1-ketone.
[0059] The difference between the above embodiment and embodiment 1 is that 10% palladium hydroxide / carbon is replaced by 10% palladium / carbon.
[0060] Embodiment 3-8 Examples 3-8 respectively synthesized a 1-(4-butoxyphenyl)-3-hydroxypropyl-1-one.
[0061] The above embodiment differs from embodiment 1 in that the reaction temperature and pressure are specifically shown in Table 4 below.
[0062] Table 4 Reaction temperature and pressure in Example 1, Example 3-8 Performance testing (1) The nuclear magnetic resonance (NMR) spectrum of 1-(4-butoxyphenyl)-3-hydroxypropyl-1-ketone obtained in Example 1 was measured using a 400 MHz nuclear magnetic resonance spectrometer. The spectrum is shown in FIG. Figure 1 The specific results are as follows: MS (ESI) [M + H] + =223; HNMR (400MHz, CD3Cl, ppm) δ7.94 (dd, J=9.70, 2.65, 2H), 6.95 (t, J=2.70, 2H), 4.03 (dd, J=13.05, 6 .55, 4H), 3.19 (t, J=5.35, 2H), 2.90 (s, 1H), 1.78-1.83 (m, 2H), 1.48-1.55 (m, 2H), 0.99 (t, J=7.40, 3H).
[0063] (2) According to the methods of Examples 1-8, 1-(4-butoxyphenyl)-3-hydroxypropyl-1-one was prepared respectively, the single-step yield of step (2) was calculated, and the purity of 1-(4-butoxyphenyl)-3-hydroxypropyl-1-one was tested. The results are shown in Table 5 below.
[0064] Table 5 Yield and purity test results of 1-(4-butoxyphenyl)-3-hydroxypropyl-1-ketone obtained in Examples 1-8 According to the test results of Table 5, the yield of 1-(4-butoxyphenyl)-3-hydroxypropyl-1-ketone obtained in Examples 1-8 is 91.24-97.89%, and the purity is 97.47-99.04%. Therefore, it is explained that the preparation method of 1-(4-butoxyphenyl)-3-hydroxypropyl-1-ketone provided by the present application can obtain 1-(4-butoxyphenyl)-3-hydroxypropyl-1-ketone with a yield of >90.0% and a purity of >97.00%.
[0065] The test results of Examples 1-5 show that the yield of 1-(4-butoxyphenyl)-3-hydroxypropyl-1-ketone obtained in Examples 1 and 3-4 is 95.28-97.89% (≥95.00%), and the purity is 98.74-99.04% (≥98.00%). However, the yield of 1-(4-butoxyphenyl)-3-hydroxypropyl-1-ketone obtained in Examples 2 and 5 is only 91.24-93.35% (<95.00%), and the purity is 97.83-97.89% (<98.00%). Therefore, it is explained that the present application further controls the reaction temperature of step (2) in the preparation method of 1-(4-butoxyphenyl)-3-hydroxypropyl-1-ketone within the range of 25-45°C, and the yield and purity of the obtained 1-(4-butoxyphenyl)-3-hydroxypropyl-1-ketone are higher.
[0066] The test results of Example 1 and Examples 6-8 show that the yield of 1-(4-butoxyphenyl)-3-hydroxypropyl-1-ketone obtained in Examples 1 and 6-7 is 95.04-97.89% (≥95.00%), and the purity is 98.51-99.04% (≥98.00%). The yield of 1-(4-butoxyphenyl)-3-hydroxypropyl-1-ketone obtained in Example 8 is only 94.26% (<95.00%), and the purity is 97.47% (<98.00%). Therefore, it is explained that the pressure of step (2) in the preparation method of 1-(4-butoxyphenyl)-3-hydroxypropyl-1-ketone is further controlled within the range of 1.0atm-4.0atm in the present application, and the yield and purity of 1-(4-butoxyphenyl)-3-hydroxypropyl-1-ketone are higher.
[0067] Although the present invention has been described in detail above with general descriptions and specific embodiments, it is obvious to those skilled in the art that some modifications or improvements may be made thereto based on the present invention. Therefore, these modifications or improvements made without departing from the spirit of the present invention all fall within the scope of protection claimed by the present invention.
Claims
1. A 1-(4-butoxyphenyl)-3-hydroxypropyl-1-one, characterized in that: The structural formula of the 1-(4-butoxyphenyl)-3-hydroxypropyl-1-one is shown in Formula I:
2. The method for preparing 1-(4-butoxyphenyl)-3-hydroxypropyl-1-ketone according to claim 1, characterized in that: The following steps are involved: (1) Under nitrogen protection, 4-butoxyphenylpropenone and benzyl alcohol in a molar ratio of 1:(1-5) are dissolved in solvent A, reacted under the action of catalyst A, and monitored by TLC, vacuum distilled, and column chromatography to obtain intermediate 1; (2) The intermediate 1 is dissolved in solvent B, and hydrogen is introduced in the presence of catalyst B. The reaction is kept warm, and 1-(4-butoxyphenyl)-3-hydroxypropyl-1-one is obtained by TLC monitoring, filtration, vacuum distillation, and column chromatography.
3. The method for preparing 1-(4-butoxyphenyl)-3-hydroxypropyl-1-ketone according to claim 2, characterized in that: The molar ratio of the 4-butoxyphenylpropenone to the benzyl alcohol is 1:(3-5).
4. The method for preparing 1-(4-butoxyphenyl)-3-hydroxypropyl-1-ketone according to claim 2, characterized in that: The catalyst A is selected from chromium chloride, bismuth chloride and indium trifluoromethanesulfonate; the molar ratio of the 4-butoxyphenylpropenone to the catalyst A is 1:(0.1-0.5).
5. The method for preparing 1-(4-butoxyphenyl)-3-hydroxypropyl-1-ketone according to claim 2, characterized in that: The catalyst B is selected from palladium carbon, palladium hydroxide carbon and Raney nickel; the weight ratio of the catalyst B to the intermediate 1 is (0.1-0.12):
1.
6. The method for preparing 1-(4-butoxyphenyl)-3-hydroxypropyl-1-ketone according to claim 2, characterized in that: The solvent A is selected from acetonitrile, dioxane and N,N-dimethylformamide, or no solvent is added; the solvent B is selected from tetrahydrofuran, ethyl acetate, methanol and ethanol.
7. The method for preparing 1-(4-butoxyphenyl)-3-hydroxypropyl-1-ketone according to claim 2, characterized in that: The eluent used in the column chromatography is n-hexane / ethyl acetate (30 / 1-5 / 1).
8. The method for preparing 1-(4-butoxyphenyl)-3-hydroxypropyl-1-ketone according to claim 2, characterized in that: The reaction temperature of step (1) is 30-130°C; the reaction temperature of step (2) is 25-65°C, and the pressure is 1.0 atm-6.0 atm.
9. The method for preparing 1-(4-butoxyphenyl)-3-hydroxypropyl-1-ketone according to claim 8, characterized in that: The reaction temperature of step (1) is 50-100°C; the reaction temperature of step (2) is 25-45°C, and the pressure is 1.0atm-4.0atm.
10. Use of 1-(4-butoxyphenyl)-3-hydroxypropyl-1-one obtained by the preparation method of 1-(4-butoxyphenyl)-3-hydroxypropyl-1-one according to claim 1 or claims 2 to 9 in the quality control of dyclonine hydrochloride and related preparations.