Method for removing dapoxetine hydrochloride polymerization impurities

Abstract

The invention discloses a method for removing polymerization impurities of dapoxetine hydrochloride, which comprises the following operation steps of: (1) adding a dapoxetine hydrochloride crude product containing the polymerization impurities into a good solvent of dapoxetine hydrochloride, heating, stirring and dissolving; (2) adding an adsorbent into the clear solution obtained in the step (1), stirring for a certain time, and filtering; (3) dropwise adding a poor solvent of dapoxetine hydrochloride into the filtrate obtained in the step (2) while keeping the temperature; and (4) cooling and crystallizing the mixed system obtained in the step (3), and carrying out suction filtration to obtain a refined dapoxetine hydrochloride product. According to the dapoxetine hydrochloride obtained through the refining method of the dapoxetine hydrochloride polymeric impurities, the recovery rate can reach 90% or above, and the purity of the dapoxetine hydrochloride can reach 99.93% or above. The method has the characteristics of high yield, simple operation, mild conditions, less discharge of three wastes and the like, is suitable for industrial production, and has high practical value.

Description

Technical Field

[0001] The present invention relates to a method for removing polymeric impurities of dapoxetine hydrochloride to obtain high-purity dapoxetine hydrochloride. Background Art

[0002] Dapoxetine hydrochloride has the chemical name of (S)-N,N-dimethyl-3-(naphthalen-1-yloxy)-benzenepropanamine hydrochloride, and the molecular formula: C 21 H 23 NO·HCl. It is a selective serotonin reuptake inhibitor (SSRI), developed by Eli Lilly and Company in the United States, and was launched in Europe in 2009 under the trade name Priligy for the treatment of premature ejaculation (PE) in men. This drug has a short half-life, small adverse reactions, and remarkable effects, and is the world's first approved prescription drug for oral administration for the treatment of PE. Its structural formula is shown as follows:

[0003]

[0004] Using (R)-1-phenyl-3-(naphthalen-1-yloxy)propan-1-ol as the starting material, it reacts with methanesulfonyl chloride to generate a sulfonate active intermediate. The active intermediate undergoes a nucleophilic substitution reaction with dimethylamine to generate dapoxetine, and then reacts with hydrochloric acid to form dapoxetine hydrochloride. After concentration and purification with isopropanol, the finished product of dapoxetine hydrochloride is obtained. An unknown impurity with a peak area of more than 0.1% appears at the position of RRT 1.88 - 1.89 after detecting the API. By comparison, the content of this impurity in the previous pilot batches was 0.06%. Therefore, this impurity is a process impurity. After enrichment and liquid-phase preparation, it is identified by HNMR as the following possible structure.

[0005]

[0006] Through experimental analysis, this impurity is generated from the unreacted methanesulfonate intermediate state during the reaction and the API during the post-treatment process. High temperature and acidic conditions can significantly promote the increase in its content. Since the post-treatment process for preparing the API involves long-term high temperature and strong acid conditions, the probability of generating this impurity is relatively high. Therefore, in addition to strictly controlling process parameters, it is very necessary to find a suitable method for removing this polymeric impurity for the smooth production of the API and the safety of drug use.

[0007] Currently, there are relatively few literature reports and patents on this polymeric impurity, and there is no specific research on the generation mechanism and purification method of this impurity. Although some literature has certain reference significance, either the yield is relatively low or the purity is not ideal after purification.

[0008] Therefore, there is still no method that is simple to operate and can obtain highly pure refined nicorandil. There is still a need to develop a refining method for crude dapoxetine hydrochloride containing specific polymeric impurities that is suitable for industrial production and can meet clinical requirements. Summary of the Invention

[0009] To solve the above technical problems, the present invention provides a method for removing polymeric impurities of dapoxetine hydrochloride. The crude dapoxetine hydrochloride containing the specific polymeric impurities is dissolved in acetonitrile and adsorbed with a cation exchange resin, then filtered. The filtrate is kept warm and water is added dropwise, followed by cooling crystallization, filtration, and drying to obtain refined dapoxetine hydrochloride. This method effectively reduces the content of the specific polymeric impurities. The preparation process has mild conditions, no toxic and harmful substances, and the obtained dapoxetine hydrochloride has high purity and high yield, with high economic benefits.

[0010] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0011] (1) Add the crude dapoxetine hydrochloride containing polymeric impurities to a good solvent of dapoxetine hydrochloride, heat and stir to dissolve.

[0012] (2) Add the adsorbent to the clarified solution obtained in step (1), stir for a certain time and then filter.

[0013] (3) Dropwise add a poor solvent of dapoxetine hydrochloride to the filtrate obtained in step (2) while keeping it warm.

[0014] (4) Cool the mixed system obtained in step (3) for crystallization, and filter by suction to obtain refined dapoxetine hydrochloride.

[0015] Further, in step (1), the good solvent of dapoxetine hydrochloride is at least one of DMF, DMSO, and acetonitrile, preferably acetonitrile; the mass ratio of the crude dapoxetine hydrochloride to the solvent is 1:(3 - 5), more preferably 1:4, and the dissolution temperature is 50 - 60°C.

[0016] Further, in step (2), the weight ratio of the crude dapoxetine hydrochloride to the adsorbent is 1:(0.5 - 1.5), more preferably 1:1. The adsorbent is a weakly acidic cation exchange resin (manufacturer: Tianjin Yunkai Resin Technology Co., Ltd.; model: YKWD151), and keep warm and stir for 0.5 - 2 h.

[0017] Further, in step (3), the poor solvent is water; the mass ratio of the crude dapoxetine hydrochloride to water is 1:(4 - 8), more preferably 1:6; the dropping and keeping warm temperature is 50 - 60°C.

[0018] Further, in step (4), the temperature for cooling crystallization is 0 - 10°C; the crystallization time is 1 - 3 h.

[0019] The present invention uses common acetonitrile and water as the refining solvents, and all operations are conventional operations. Each operation is carried out at non-ultra-high and ultra-low temperatures (-5 to 40 °C). By adding an acidic cation exchange resin as an adsorbent during refining, the content of degradation impurities is effectively reduced. Further, the nicorandil prepared by the present invention has a high yield and high product purity. The reaction conditions during the preparation process are relatively mild, the cycle is short, and it is actually a process method suitable for production. Description of the Drawings

[0020] Figure 1 It is the HPLC chromatogram of the crude dapoxetine hydrochloride in Example 1;

[0021] Figure 2 It is the HPLC chromatogram of the refined dapoxetine hydrochloride in Example 3;

[0022] Figure 3 For the 1 HNMR chromatogram. Detailed Description of the Invention

[0023] The technical solutions of the present invention will be further described in detail below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto.

[0024] Example 1

[0025]

[0026] Add 15.9 kg of triethylamine, 153 kg of toluene and 29.4 kg of intermediate 2 (V9069-6) into a 500 L reaction tank, cool down to -15 to 0 °C, and dropwise add 14.7 kg of methanesulfonyl chloride under nitrogen protection, control the temperature at -15 to 0 °C and react for 2 h to generate the intermediate sulfonate. Control the temperature at 15 to 0 °C, slowly introduce dimethylamine gas (the gas flow rate is about 6 kg / h, and the tank is in a emptied state), and after adding, keep stirring at -15 to 0 °C for 2 h. Heat up to 20 to 30 °C and react for 6 h, remove the excess dimethylamine under reduced pressure, wash with water and concentrate. Add 84 kg of isopropanol and 14 kg of hydrochloric acid with a concentration of 10 mol / L, stir for 0.5 h to form the hydrochloride, concentrate to dryness, then crystallize with isopropanol, centrifuge and dry at 40 to 50 °C to obtain the crude dapoxetine hydrochloride, batch number 21041801X. An unknown impurity appears at about 46 min in the liquid phase of this batch. The HPLC chromatogram is as Figure 1 shown. The 4th peak corresponds to dapoxetine hydrochloride, and the 13th peak corresponds to the polymeric impurity. After enrichment, liquid phase and nuclear magnetic resonance (as Figure 3As shown: The two characteristic peaks at 4.7 - 4.8 ppm (1H) and 5.1 - 5.2 ppm (1H) are the chemical shifts of the two benzyl groups PhCH in the molecular structure, and the chemical shifts of the two methyl groups CH3 on nitrogen are at 2.8 - 3.0 ppm (3H) and 2.5 - 2.6 ppm (3H).) It was identified as a polymeric impurity, and the structure is as follows:

[0027]

[0028] This impurity is relatively large and contains the same active groups as the finished product, which may affect the efficacy and drug safety of the finished product. However, its structure is highly similar to that of the finished product, and it is difficult to remove by conventional purification methods. In Example 2, this application conducted detailed research to reduce the content of this impurity.

[0029] Example 2

[0030] Based on the principle of low cost and simple operation, the present invention preferentially considered conventional solvent pulping or recrystallization methods to remove impurities, and selected isopropanol, ethanol, DMF, dichloromethane, methyl tert - butyl ether, acetonitrile, etc. to purify the crude dapoxetine hydrochloride. The specific results are as follows:

[0031]

[0032]

[0033] It can be seen from the table that isopropanol and acetonitrile solvents have a certain impurity - removing effect, but the effect is not obvious, and the polymeric impurity has not decreased significantly.

[0034] Furthermore, on this basis, to ensure the refining yield and refining purity, 4 times the mass of acetonitrile of the crude dapoxetine hydrochloride was used as the solvent, and different adsorbents accounting for 20% of the mass of the crude dapoxetine hydrochloride were added to remove the excessive polymeric impurity. The specific screening results are as follows:

[0035]

[0036] Note: The weakly acidic cation - exchange resin was purchased from Tianjin Yunkai Resin Technology Co., Ltd.; model: YKWD151; the basic anion - exchange resin was purchased from Tianjin Yunkai Resin Technology Co., Ltd., model YKW204.

[0037] The experimental results show that when a cation - exchange resin is added to the acetonitrile refining system, the impurity - removing effect is relatively prominent, and it can effectively remove various impurities in the system. In particular, the cation - exchange resin has a strong adsorption capacity for polymeric impurities. Therefore, the scheme of using acetonitrile as the solvent and the cation - exchange resin as the adsorbent was selected as the preferred scheme. To improve the yield, the scheme was optimized and implemented in Example 3.

[0038] Example 3

[0039] 20 g of crude dapoxetine hydrochloride (batch number 21041801X) and 80 g of acetonitrile were added to a three-necked flask, and the temperature was raised to 50 - 60 °C until clear. 20 g of cation exchange resin (manufacturer: Tianjin Yunkai Resin Technology Co., Ltd.; model: YKWD151) was added to the system, and the mixture was stirred at a constant temperature for 1 h, then filtered. 120 g of water was added dropwise to the filtrate at 50 - 60 °C, and the temperature was lowered for crystallization. The temperature for crystallization was 0 - 10 °C; the crystallization time was 2 h. After filtration and drying at 40 - 50 °C, 18.8 g of refined dapoxetine hydrochloride was obtained, with a yield of 94%, a purity of 99.93%, a polymer impurity content of 0.033%. The HPLC chromatogram is as Figure 2 shown. The peak corresponding to No. 2 is dapoxetine hydrochloride, and the peak corresponding to No. 5 is the polymer impurity.

[0040] It should be noted that the above examples are only used to illustrate the present invention and not to limit it. The present invention is not limited to the above examples. All technical solutions and their improvements that do not depart from the spirit and scope of the present invention shall be covered by the scope of the claims of the present invention.

Claims

1. A method for removing polymeric impurities of dapoxetine hydrochloride, characterized in that, The process is as follows: (1) Add the crude dapoxetine hydrochloride containing polymerization impurities to a good solvent of dapoxetine hydrochloride, heat up and stir to dissolve; (2) Add an adsorbent to the clarified solution obtained in step (1), stir for a certain time and then filter; (3) Dropwise add a poor solvent of dapoxetine hydrochloride to the filtrate obtained in step (2) under heat preservation; (4) Cool down the mixed system obtained in step (3) for crystallization, and filter by suction to obtain the refined dapoxetine hydrochloride.

2. The method for removing the polymeric impurities of dapoxetine hydrochloride according to claim 1, wherein: In step (1), the good solvent of dapoxetine hydrochloride is at least one of DMF, DMSO and acetonitrile; the mass ratio of the crude dapoxetine hydrochloride to the solvent is 1:(3 - 5); the dissolution temperature is 50 - 60°C.

3. The method for removing the polymeric impurities of dapoxetine hydrochloride according to claim 1, wherein: In step (2), the weight ratio of the crude dapoxetine hydrochloride to the adsorbent is 1:(0.5 - 1.5), the adsorbent is a weakly acidic cation exchange resin, and stir under heat preservation for 0.5 - 2 h.

4. The method for removing polymeric impurities of dapoxetine hydrochloride according to claim 1, characterized in that: In step (3), the poor solvent is water; the mass ratio of the crude dapoxetine hydrochloride to water is 1:(4 - 8), and the heat preservation temperature is 50 - 60°C.

5. The method for removing the polymeric impurities of dapoxetine hydrochloride according to claim 1, wherein: In step (4), the temperature for cooling crystallization is 0 - 10°C; the crystallization time is 1 - 3 h.

6. The method for removing polymeric impurities of dapoxetine hydrochloride according to claim 2, wherein: The good solvent of dapoxetine hydrochloride is acetonitrile, and the mass ratio of the crude dapoxetine hydrochloride to the solvent is 1:

4.

7. The method for removing the polymeric impurities of dapoxetine hydrochloride according to claim 3, wherein: The weight ratio of the crude dapoxetine hydrochloride to the adsorbent is 1:1, and the weakly acidic cation exchange resin is purchased from Tianjin Yunkai Resin Technology Co., Ltd.; model: YKWD151.

8. The method for removing the polymeric impurities of dapoxetine hydrochloride according to claim 4, wherein: The mass ratio of the crude dapoxetine hydrochloride to water is 1:6.

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