Method for preparing dapoxetine hydrochloride process impurities
The keto and hydroxy impurities of dapoxetine hydrochloride were successfully prepared by reacting 1-naphthol with 3-chloropropiophenone in dimethyl sulfoxide and granular potassium carbonate, followed by reduction with sodium borohydride. This solves the preparation difficulties in the existing technology and achieves efficient and easy-to-scalable impurity preparation.
Patent Information
- Application Number
- CN202410423598.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-04-09
- Publication Date
- 2025-10-14
AI Technical Summary
It is difficult to efficiently prepare keto impurities and hydroxyl impurities of dapoxetine hydrochloride in the existing technology. In particular, the preparation method of the hydroxyl impurity of formula (II) is complicated and has a low yield, making it difficult to produce on a large scale.
1-naphthol and 3-chloropropiophenone are reacted with granular potassium carbonate in dimethyl sulfoxide, and then reduced with sodium borohydride in an alcohol solvent to prepare a keto impurity, which is further reduced to obtain a hydroxy impurity.
The method achieves high-purity and high-yield preparation of keto impurities and hydroxyl impurities, is simple to operate, and is suitable for large-scale production.
Smart Images
Figure CN120774783A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to a method for preparing process impurities of dapoxetine hydrochloride, a drug for treating male premature ejaculation. Background Art
[0002] Dapoxetine hydrochloride, chemically known as (S)-(+)-(N,N-dimethylamino)-3-(naphthyl-1-oxy)-1-phenylpropane hydrochloride, is a selective serotonin reuptake inhibitor (SSRI). It was launched in Europe in 2009 and subsequently in several other countries and regions. It entered the Chinese market in 2013 (trade name: Priligy). It is used for the on-demand treatment of premature ejaculation in adult men and is the world's first oral medication approved for the treatment of premature ejaculation. Compared to traditional SSRIs, dapoxetine hydrochloride has a shorter half-life, fewer side effects, better safety and tolerability, and a broad market. Its chemical formula is shown below:
[0003]
[0004] The preparation process of dapoxetine hydrochloride may produce a keto impurity represented by formula (I) and a hydroxy impurity represented by formula (II). Therefore, reference standards for these two impurities are necessary to develop feasible detection methods for controlling the quality of dapoxetine hydrochloride. However, there are few reports in the literature on the preparation of these two impurities, especially the hydroxy impurity represented by formula (II).
[0005]
[0006] Among them, Zhou Weicheng et al. published an article titled "A novel Friedel–Crafts alkylation of naphthols without Lewis acid" in Tetrahedron Letters (2015). The article mentioned a method for preparing a keto impurity of formula (I), which involves using 1-naphthol and 3-chloropropiophenone in a mixed solvent of tetrahydrofuran and water, with sodium hydroxide as an acid-binding agent. However, experiments have shown that this method is relatively cumbersome to operate and is a laboratory milligram-scale reaction. The yield of the target product is not high, making it difficult to prepare on a large scale.
[0007] Moreover, during the exploration of impurity preparation, it was found that the reaction of 1-naphthol with 3-chlorophenylpropiotone is a Friedel-Crafts reaction without Lewis acid catalysis. The solvent, base, reaction temperature, feed ratio, etc. all have an impact on the reaction. When the reaction conditions are not suitable, it is difficult to obtain the target product.
[0008] Therefore, in order to facilitate the quality research of dapoxetine hydrochloride, it is necessary to obtain relevant impurity reference substances, and then it is necessary to prepare the process impurities of dapoxetine hydrochloride, so as to better control the quality of dapoxetine hydrochloride and provide the society with safe, effective and quality-controlled drugs. Summary of the Invention
[0009] To improve the above technical problems, the present invention provides a method for preparing the compounds represented by formula (I) and formula (II), comprising the following steps:
[0010]
[0011] (1) 1-naphthol is dissolved in dimethyl sulfoxide (DMSO) solvent, granular potassium carbonate is used as an acid binding agent, and the mixture is stirred and reacted with 3-chloropropiophenone to obtain a compound represented by formula (I);
[0012] (2) The compound represented by formula (I) is dissolved in an alcohol solvent and subjected to a reduction reaction to obtain the compound represented by formula (II).
[0013] According to an embodiment of the present invention, the particle size of the granular potassium carbonate is ≥150 microns, and can be 150-2000 microns, for example, 150-900 microns, such as 200 microns, 400 microns, 600 microns, 800 microns, 1000 microns, 1200 microns, 1400 microns.
[0014] According to an embodiment of the present invention, in step (1), the molar ratio of the 3-chloropropiophenone, 1-naphthol and granular potassium carbonate is (1-2): (1-2): (0.5-2); preferably 1:1:1.
[0015] According to an embodiment of the present invention, in step (1), the mass volume ratio of 3-chloropropiophenone to dimethyl sulfoxide is (1-10) g / mL, for example (2-8) g / mL, such as 3 g / mL.
[0016] According to an embodiment of the present invention, in step (1), the reaction temperature is 20-100°C, such as 60-75°C, preferably 70-75°C.
[0017] According to an embodiment of the present invention, step (1) comprises adding 1-naphthol, granular potassium carbonate and dimethyl sulfoxide into a reaction flask and stirring, then adding 3-chloropropiophenone, stirring the system and heating it to 70-75° C., and reacting for 1 hour to obtain a compound represented by formula (I).
[0018] According to an embodiment of the present invention, in step (2), the reaction can be carried out in the presence of a reducing agent, and the reducing agent is selected from metal reducing agents, sulfides, metal complex hydrides, alkoxyaluminum, formic acid and its derivatives, hydrazine hydrate, heterogeneous catalytic hydrogenation, etc.; preferably, catalysts such as sodium borohydride, potassium borohydride, borane and borane complexes are used, and more preferably, sodium borohydride.
[0019] According to an embodiment of the present invention, step (2) can be carried out in the presence of a solvent, and the solvent is selected from an alcohol solvent, and the alcohol solvent is a fatty alcohol solvent, preferably methanol, ethanol, and more preferably methanol.
[0020] According to an embodiment of the present invention, step (2) comprises dissolving the compound of formula (I) in methanol solvent and reducing it with sodium borohydride to obtain the compound of formula (II).
[0021] Beneficial effects
[0022] The present invention uses two commercially available materials, 1-naphthol and 3-chloropropiophenone, in the presence of granular potassium carbonate (particle size ≥150 microns) and dimethyl sulfoxide to prepare a keto impurity represented by formula (I) of dapoxetine hydrochloride, and then obtains a hydroxy impurity represented by formula (II) through a reduction reaction. The process is simple to operate, the product has high purity, good and stable yield, and is easy to prepare on a large scale. BRIEF DESCRIPTION OF THE DRAWINGS
[0023] Figure 1 The compound represented by formula (I) 1 H NMR (the solvent is deuterated DMSO). DETAILED DESCRIPTION
[0024] The technical solutions of the present disclosure will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present disclosure and should not be construed as limiting the scope of protection of the present disclosure. All technologies implemented based on the above content of the present disclosure are included within the scope of protection intended by the present disclosure.
[0025] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.
[0026] Example 1
[0027] Preparation of 3-(4-hydroxynaphthalen-1-yl)-1-phenylpropyl-1-one (keto impurity of formula (I)):
[0028] Add 15 ml of dimethyl sulfoxide, 4.09 g of granular potassium carbonate (150 μm ≤ ≤ 900 μm), 5.00 g of 3-chloropropiophenone, and 4.27 g of 1-naphthol to a 100 ml three-necked flask. Heat to an internal temperature of 65-70°C while stirring and keep the reaction warm for 1 hour. The temperature was lowered to 15-25°C, the system was diluted with 10 ml of ethyl acetate and 5 ml of n-hexane, filtered, the filter cake was washed with 10 ml of ethyl acetate, the filtrate was combined and washed with 25 ml of purified water, and then washed twice with 10 ml of saturated brine, 1.50 g of anhydrous sodium sulfate was added to the organic layer, and the mixture was stirred and dehydrated at 15-25°C for 0.5 hour, filtered, washed with 5 ml of ethyl acetate, and the organic layer was concentrated under reduced pressure at 60±5°C. The concentrate was chromatographed on an ethyl acetate / n-hexane column, then slurried with ethyl acetate / n-hexane = 1 / 3, filtered, washed, and dried to give a light green powder (2.60 g, yield 31.7%, HPLC purity 95%).
[0029] Example 2
[0030] Preparation of 3-(4-hydroxynaphthalen-1-yl)-1-phenylpropyl-1-one (keto impurity of formula (I)):
[0031] Add 15 ml of dimethyl sulfoxide, 2.05 g of granular potassium carbonate (150 μm ≤ ≤ 900 μm), 2.05 g of powdered potassium carbonate (particle size < 100 μm), 5.00 g of 3-chloropropiophenone, and 4.27 g of 1-naphthol to a 100 ml three-necked flask. Heat to an internal temperature of 65-70°C while stirring and maintain for 1 hour. The temperature was lowered to 15-25°C, the system was diluted with 10 ml of ethyl acetate and 5 ml of n-hexane, filtered, the filter cake was washed with 10 ml of ethyl acetate, the filtrate was combined and washed with 25 ml of purified water, and then washed twice with 10 ml of saturated brine, 1.50 g of anhydrous sodium sulfate was added to the organic layer, and the mixture was stirred and dehydrated at 15-25°C for 0.5 hour, filtered, washed with 5 ml of ethyl acetate, and the organic layer was concentrated under reduced pressure at 60±5°C. The concentrate was chromatographed on an ethyl acetate / n-hexane column, then slurried with ethyl acetate / n-hexane = 1 / 3, filtered, washed, and dried to give a light green powder (1.64 g, yield 20.0%, HPLC purity 94%).
[0032] Example 3
[0033] Preparation of 3-(4-hydroxynaphthalen-1-yl)-1-phenylpropyl-1-one (keto impurity of formula (I)):
[0034] Add 15 ml of dimethyl sulfoxide, 5 ml of purified water, 4.09 g of granular potassium carbonate (150 μm ≤ ≤ 900 μm), 5.00 g of 3-chloropropiophenone, and 4.27 g of 1-naphthol to a 100 ml three-necked flask. Heat to an internal temperature of 65-70°C while stirring and maintain for 1 hour. The temperature was lowered to 15-25°C, the system was diluted with 10 ml of ethyl acetate and 5 ml of n-hexane, filtered, the filter cake was washed with 10 ml of ethyl acetate, the filtrate was combined and washed with 25 ml of purified water, and then washed twice with 10 ml of saturated brine, 1.50 g of anhydrous sodium sulfate was added to the organic layer, and the mixture was stirred and dehydrated at 15-25°C for 0.5 hour, filtered, washed with 5 ml of ethyl acetate, and the organic layer was concentrated under reduced pressure at 60±5°C. The concentrate was chromatographed on an ethyl acetate / n-hexane column, then slurried with ethyl acetate / n-hexane = 1 / 3, filtered, washed, and dried to give a light green powder (1.52 g, yield 18.6%, HPLC purity 93%).
[0035] Example 4
[0036] Preparation of 3-(4-hydroxynaphthalen-1-yl)-1-phenylpropyl-1-one (keto impurity of formula (I)):
[0037] Add 15 ml of dimethyl sulfoxide, 4.09 g of granular potassium carbonate (150 μm ≤ ≤ 900 μm), 5.00 g of 3-chloropropiophenone, and 4.27 g of 1-naphthol to a 100 ml three-necked flask. Heat to an internal temperature of 75-80°C while stirring and keep the reaction warm for 1 hour. The temperature was lowered to 15-25°C, the system was diluted with 10 ml of ethyl acetate and 5 ml of n-hexane, filtered, the filter cake was washed with 10 ml of ethyl acetate, the filtrate was combined and washed with 25 ml of purified water, and then washed twice with 10 ml of saturated brine, 1.50 g of anhydrous sodium sulfate was added to the organic layer, and the mixture was stirred and dehydrated at 15-25°C for 0.5 hour, filtered, washed with 5 ml of ethyl acetate, and the organic layer was concentrated under reduced pressure at 60±5°C. The concentrate was chromatographed on an ethyl acetate / n-hexane column, then slurried with ethyl acetate / n-hexane = 1 / 3, filtered, washed, and dried to give a light green powder (2.55 g, yield 31.1%, HPLC purity 94%).
[0038] Example 5
[0039] Preparation of 3-(4-hydroxynaphthalen-1-yl)-1-phenylpropyl-1-one (keto impurity of formula (I)):
[0040] Add 15 ml of dimethyl sulfoxide, 4.91 g of granular potassium carbonate (150 μm ≤ ≤ 900 μm), 5.00 g of 3-chloropropiophenone, and 4.27 g of 1-naphthol to a 100 ml three-necked flask. Heat to an internal temperature of 75-80°C while stirring and keep the reaction warm for 1 hour. The temperature was lowered to 15-25°C, the system was diluted with 10 ml of ethyl acetate and 5 ml of n-hexane, filtered, the filter cake was washed with 10 ml of ethyl acetate, the filtrate was combined and washed with 25 ml of purified water, and then washed twice with 10 ml of saturated brine, 1.50 g of anhydrous sodium sulfate was added to the organic layer, and the mixture was stirred and dehydrated at 15-25°C for 0.5 hour, filtered, washed with 5 ml of ethyl acetate, and the organic layer was concentrated under reduced pressure at 60±5°C. The concentrate was chromatographed on an ethyl acetate / n-hexane column, then slurried with ethyl acetate / n-hexane = 1 / 3, filtered, washed, and dried to give a light green powder (2.46 g, yield 30.0%, HPLC purity 93%).
[0041] Example 6
[0042] Preparation of 3-(4-hydroxynaphthalen-1-yl)-1-phenylpropyl-1-one (keto impurity of formula (I)):
[0043] Add 15 ml of dimethyl sulfoxide, 4.09 g of granular potassium carbonate (150 μm ≤ ≤ 900 μm), 5.00 g of 3-chloropropiophenone, and 3.00 g of 1-naphthol to a 100 ml three-necked flask. Heat to an internal temperature of 75-80°C while stirring and keep the reaction warm for 1 hour. The temperature was lowered to 15-25°C, the system was diluted with 10 ml of ethyl acetate and 5 ml of n-hexane, filtered, the filter cake was washed with 10 ml of ethyl acetate, the filtrate was combined and washed with 25 ml of purified water, and then washed twice with 10 ml of saturated brine, 1.50 g of anhydrous sodium sulfate was added to the organic layer, and the mixture was stirred and dehydrated at 15-25°C for 0.5 hour, filtered, washed with 5 ml of ethyl acetate, and the organic layer was concentrated under reduced pressure at 60±5°C. The concentrate was chromatographed on an ethyl acetate / n-hexane column, then slurried with ethyl acetate / n-hexane = 1 / 3, filtered, washed, and dried to give a light green powder (1.47 g, yield 17.9%, HPLC purity 94%).
[0044] Example 7
[0045] Preparation of 3-(4-hydroxynaphthalen-1-yl)-1-phenylpropyl-1-one (keto impurity of formula (I)):
[0046] Add 60 ml of dimethyl sulfoxide, 16.36 g of granular potassium carbonate (150 μm ≤ ≤ 900 μm), 20.00 g of 3-chloropropiophenone, and 17.08 g of 1-naphthol to a 250 ml three-necked flask. Heat to an internal temperature of 70-75°C with stirring and maintain for 1 hour. The temperature was lowered to 15-25°C, the system was diluted with 40 ml of ethyl acetate and 20 ml of n-hexane, filtered, the filter cake was washed with 40 ml of ethyl acetate, the filtrate was combined and washed with 100 ml of purified water, and then washed twice with 40 ml of saturated brine, 6.00 g of anhydrous sodium sulfate was added to the organic layer, and the mixture was stirred and dehydrated at 15-25°C for 0.5 hour, filtered, washed with 20 ml of ethyl acetate, and the organic layer was concentrated under reduced pressure at 60±5°C. The concentrate was chromatographed on an ethyl acetate / n-hexane column, then slurried with ethyl acetate / n-hexane = 1 / 3, filtered, washed, and dried to give a light green powder (11.47 g, yield 35.0%, HPLC purity 96%).
[0047] Example 8
[0048] Preparation of 3-(4-hydroxynaphthalen-1-yl)-1-phenylpropyl-1-one (keto impurity of formula (I)):
[0049] Add 150 ml of dimethyl sulfoxide, 40.90 g of granular potassium carbonate (150 μm ≤ ≤ 900 μm), 50.00 g of 3-chloropropiophenone, and 42.70 g of 1-naphthol to a 500 ml three-necked flask. Heat to an internal temperature of 70-75°C while stirring and keep the reaction warm for 1 hour. The temperature was lowered to 15-25°C, the system was diluted with 100 ml of ethyl acetate and 50 ml of n-hexane, filtered, the filter cake was washed with 100 ml of ethyl acetate, the filtrate was combined and washed with 250 ml of purified water, and then washed twice with 100 ml of saturated brine, 15.00 g of anhydrous sodium sulfate was added to the organic layer, and the mixture was stirred and dehydrated at 15-25°C for 0.5 hour, filtered, washed with 50 ml of ethyl acetate, and the organic layer was concentrated under reduced pressure at 60±5°C. The concentrate was chromatographed on an ethyl acetate / n-hexane column (n-hexane → ethyl acetate / n-hexane = 1 / 10 → ethyl acetate / n-hexane = 1 / 5), then slurried with 60 ml of ethyl acetate / n-hexane = 1 / 3, filtered, washed, and dried in vacuo at 40±2°C to constant weight to give a light green powder (25.51 g, yield 31.2%, HPLC purity 95%).
[0050] 1H-NMR (600MHz, DMSO) δ9.921(s,1H),8.165-8.178(m,1H),7.964-7.990(m,3H),7.619(m,1H),7.490-7.523(m,3H),7.448-7.461(m,1H),7.190-7.203(m,1H),6.768-6.781(m,1H),3.385-3.398(m,2H),3.287-3.300(m,2H). See the attached NMR spectrum. Figure 1 ES-MS M / Z=276 (M+).
[0051] Example 9
[0052] Preparation of 4-(3-hydroxy-3-phenylpropyl)naphthol-1-ol (hydroxy impurity of formula (II)):
[0053] 1.00 g of 3-(4-hydroxynaphthalen-1-yl)-1-phenylpropyl-1-one (keto impurity of formula (I)) and 10 ml of methanol were added to a 50 ml three-necked flask, the temperature was controlled to 5-10° C., 0.14 g of sodium borohydride was added in batches, and after the addition was completed, the system was heated to 20-25° C. The system released heat and quickly changed from a suspension to a brown-red clear solution. The system was stirred and reacted at 20-25° C. for 1 hour, monitored by TLC (developing solvent: ethyl acetate / n-hexane = 1 / 5). When the raw material reaction was complete, the mixture was stopped. The reaction was stopped, 2 ml of purified water was added to the system, and the system was concentrated under reduced pressure at 50±5°C until no obvious distillate was distilled out. 5 ml of ethyl acetate was added to dissolve the concentrate, and the mixture was washed with 2 ml of purified water and 2 ml of saturated brine. 0.50 g of anhydrous sodium sulfate was added to the organic layer, and the mixture was stirred and dehydrated at 15-25°C for 0.5 hour. The mixture was filtered, washed, concentrated under reduced pressure, and recrystallized from ethyl acetate / n-hexane to obtain a light brown solid (0.75 g, yield 74.9%, HPLC purity 95%, ES-MS M / Z=278 (M+)).
[0054] Example 10
[0055] Preparation of 3-(4-hydroxynaphthalen-1-yl)-1-phenylpropyl-1-one (keto impurity of formula (I)):
[0056] 15 ml of dimethyl sulfoxide, 4.10 g of powdered potassium carbonate (particle size <100 μm), 5.00 g of 3-chloropropiophenone, and 4.27 g of 1-naphthol were added to a 100 ml three-necked flask. The mixture was heated to an internal temperature of 65-70°C with stirring and kept for 1 hour. The mixture was cooled to 15-25°C, diluted with 15 ml of ethyl acetate and 5 ml of n-hexane, filtered, and the filter cake was washed with 15 ml of ethyl acetate. The combined filtrates were washed with 25 ml of purified water and then washed twice with 10 ml of saturated brine. 1.50 g of anhydrous sodium sulfate was added to the organic layer, and the mixture was stirred and dehydrated at 15-25°C for 0.5 hour. The mixture was filtered and washed with 10 ml of ethyl acetate. The organic layer was concentrated under reduced pressure at 60±5°C. The concentrate was chromatographed on an ethyl acetate / n-hexane column, then slurried with ethyl acetate / n-hexane = 1 / 3, filtered, washed, and dried to obtain a light green powder (1.54 g, yield 18.8%, HPLC purity 93%).
[0057] Example 11
[0058] Preparation of 3-(4-hydroxynaphthalen-1-yl)-1-phenylpropyl-1-one (keto impurity of formula (I)):
[0059] 865 mg of 2-naphthol was dissolved in 3 ml of tetrahydrofuran and added dropwise to a solution of 0.3 g of sodium hydroxide and 1.5 ml of water at room temperature. After stirring at room temperature for 15 minutes, 843.1 mg of 3-chloropropiophenone dissolved in 3 ml of tetrahydrofuran was added dropwise over approximately 10 minutes. After the addition was complete, the reaction was continued at room temperature for 2 hours. TLC monitoring (developing solvent: ethyl acetate / n-hexane = 1 / 5) indicated a chaotic reaction with a low content of the desired product. The reaction was discarded without further post-processing.
[0060] The above is an exemplary description of the implementation methods of the technical solutions disclosed herein. It should be understood that the scope of protection of the present disclosure is not limited to the above-mentioned implementation methods. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the spirit and principles of the present disclosure shall be included in the scope of protection of the claims of this application.
Claims
1. A method for preparing the compound represented by formula (I) and formula (II), comprising the following steps: (1) 1-naphthol is dissolved in dimethyl sulfoxide solvent, granular potassium carbonate is used as an acid binding agent, and the mixture is stirred and reacted with 3-chloropropiophenone to obtain a compound represented by formula (I); (2) The compound represented by formula (I) is dissolved in an alcohol solvent and subjected to a reduction reaction to obtain the compound represented by formula (II).
2. The preparation method according to claim 1, characterized in that In step (1), the particle size of the granular potassium carbonate is ≥150 μm, and can be 150-2000 μm, for example, 150-900 μm.
3. The preparation method according to claim 1 or 2, characterized in that In step (1), the molar ratio of 3-chloropropiophenone, 1-naphthol and granular potassium carbonate is (1-2): (1-2): (0.5-2).
4. The preparation method according to any one of claims 1 to 3, characterized in that In step (1), the mass volume ratio of the 3-chloropropiophenone to dimethyl sulfoxide is (1-10) g / mL, for example (2-8) g / mL.
5. The preparation method according to any one of claims 1 to 4, characterized in that In step (1), the reaction temperature is 20-100°C, for example 60-75°C.
6. The preparation method according to any one of claims 1 to 5, characterized in that Step (1) comprises adding 1-naphthol, granular potassium carbonate and dimethyl sulfoxide into a reaction flask and stirring, then adding 3-chloropropiophenone, stirring the system and heating it to 70-75° C., and reacting for 1 hour to obtain the compound represented by formula (I).
7. The preparation method according to any one of claims 1 to 6, characterized in that In step (2), the reaction can be carried out in the presence of a reducing agent, and the reducing agent is selected from metal reducing agents, sulfides, metal complex hydrides, alkoxyaluminum, formic acid and its derivatives, hydrazine hydrate, and heterogeneous catalytic hydrogenation; preferably, catalysts such as sodium borohydride, potassium borohydride, borane and borane complexes are used, and more preferably, sodium borohydride.
8. The preparation method according to any one of claims 1 to 7, characterized in that Step (2) can be carried out in the presence of a solvent, wherein the solvent is selected from an alcohol solvent, wherein the alcohol solvent is a fatty alcohol solvent, preferably methanol, ethanol, and more preferably methanol.
9. The preparation method according to any one of claims 1 to 8, characterized in that Step (2) comprises dissolving the compound of formula (I) in methanol solvent and reducing it with sodium borohydride to obtain the compound of formula (II).