Method for preparing dapoxetine hydrochloride intermediate

Abstract

The invention provides a preparation method of a dapoxetine hydrochloride intermediate (R)-3-chlorophenylpropanol. The preparation method is good in safety, convenient to operate, low in cost, good in product quality, high in yield and easier to industrialize. According to the method, the N, N-diethyl aniline hydrochloride is subjected to post-treatment in a vacuum concentration manner, so that the water content in the N, N-diethyl aniline hydrochloride can be remarkably reduced, and further, the hydration loss of (R)-3-chlorophenylpropanol caused by the water content in the N, N-diethyl aniline hydrochloride is avoided; the vacuum concentration mode is simple and convenient to operate, and the product is high in yield and quality.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to a method for preparing an intermediate of Dapoxetine hydrochloride. BACKGROUND

[0002] Dapoxetine hydrochloride is a selective serotonin reuptake inhibitor (SSRIs) for the on-demand treatment of premature ejaculation in adult men, and is the first oral drug approved for the treatment of premature ejaculation in the world. Compared with traditional SSRIs, Dapoxetine hydrochloride has a short half-life, small side effects, better safety and tolerability, and a broad market. Its chemical formula is as follows:

[0003]

[0004] An important intermediate compound (R)-3-chlorobenzene propyl alcohol is involved in the preparation process of Dapoxetine hydrochloride, and the purity and chiral purity of the intermediate compound are directly related to the quality of the subsequent intermediate and Dapoxetine hydrochloride. Therefore, developing a simple and safe (R)-3-chlorobenzene propyl alcohol preparation process with quality, efficiency and cost advantages is of great significance for the efficient preparation of the raw drug Dapoxetine hydrochloride. SUMMARY

[0005] In order to improve the above technical problems, the present application provides a method for preparing an intermediate of Dapoxetine hydrochloride (R)-3-chlorobenzene propyl alcohol, which comprises the following steps:

[0006] (i) Preparation of N,N-diethyl aniline hydrochloride: N,N-diethyl aniline is dissolved in dichloromethane, and hydrogen chloride gas is introduced. After the reaction is completed, the reaction system is concentrated to obtain N,N-diethyl aniline hydrochloride;

[0007] (ii) Adding ethylene glycol dimethyl ether and dichloromethane to N,N-diethyl aniline hydrochloride, then adding sodium borohydride and (S)-(α,α)-diphenyl proline alcohol, stirring and reacting, then adding a dichloromethane solution of 3-chlorobenzene propyl ketone, and obtaining the intermediate of Dapoxetine hydrochloride (R)-3-chlorobenzene propyl alcohol after the reaction is completed.

[0008] According to the embodiment of the present application, in step (i), the concentration of the reaction system is reduced pressure concentration; preferably, the temperature of the reduced pressure concentration is 50-65℃, for example 60±2℃.

[0009] According to an embodiment of the present application, in step (i), the concentration operation is specifically as follows: the reaction system is concentrated at 50-65°C (for example, 60±2°C) under reduced pressure until the distillate distillation speed is obviously slowed down, then dichloromethane (the mass-volume ratio of N,N-diethylaniline to dichloromethane is 1g:1-5mL, for example, 1g:2mL, 1g:2.25mL, 1g:2.5mL, 1g:3mL) is added, stirred and dissolved, then the system is concentrated again at 50-65°C (for example, 60±2°C) under reduced pressure until the distillate distillation speed is obviously slowed down, and the system is maintained for 0.5-2 hours (for example, 1 hour) during the concentration.

[0010] According to an embodiment of the present application, in step (i), the reaction temperature is 0-30°C, for example, 10-15°C.

[0011] According to an embodiment of the present application, in step (i), the reaction time is 0.5-5 hours, for example, 2 hours.

[0012] According to an embodiment of the present application, in step (i), the mass-volume ratio of N,N-diethylaniline to dichloromethane is 1g:3-10mL, for example, 1g:5mL, 1g:5.6mL, 1g:6mL.

[0013] According to an embodiment of the present application, in step (i), hydrogen chloride gas is slowly introduced until the pH of the system is ≤2.

[0014] According to an embodiment of the present application, in step (ii), (S)-(α,α)-diphenylprolinol is added in solid form.

[0015] According to an embodiment of the present application, in step (ii), the volume ratio of ethylene glycol dimethyl ether to dichloromethane is 0.5-2.0:0.5-2.0, for example, 1:1.

[0016] According to an embodiment of the present application, in step (ii), the volume-mass ratio of ethylene glycol dimethyl ether to N,N-diethylaniline is 3-10mL:1g, for example, 5mL:1g, 5.6mL:1g, 6mL:1g.

[0017] According to an embodiment of the present application, the mass ratio of N,N-diethylaniline to sodium borohydride is 0.5-2:0.2-1.0, for example, 1:0.5.

[0018] According to an embodiment of the present application, the mass ratio of N,N-diethylaniline to (S)-(α,α)-diphenylprolinol is 0.5-2:0.001-0.1, preferably 1:0.01, 1:0.017, 1:0.02, 1:0.022, 1:0.03.

[0019] According to an embodiment of the present application, the mass ratio of N,N-diethyl aniline to 3-chloropropiophenone is 0.5-2:1.0-2.0, preferably 1:1.1, 1:1.12, 1:1.13, 1:1.2.

[0020] According to an embodiment of the present application, the mass ratio of N,N-diethyl aniline, sodium borohydride, (S)-(α,α) diphenyl prolinol, 3-chloropropiophenone is 0.5-2:0.2-1.0:0.001-0.1:1.0-2.0, preferably 1:0.5:0.017:1.13.

[0021] According to an embodiment of the present application, the reaction temperature in step (ii) is 0-30℃, for example 10-15℃.

[0022] According to an embodiment of the present application, in step (ii), the concentration of 3-chloropropiophenone in dichloromethane solution is 0.5-2.0 g / mL, for example 1 g / mL, 1.25 g / mL.

[0023] According to an embodiment of the present application, step (ii) is specifically as follows:

[0024] To N,N-diethyl aniline hydrochloride, add ethylene glycol dimethyl ether and dichloromethane, stir to dissolve, cool the system to 0-10℃, add sodium borohydride in batches, stir the system at 0-30℃ (for example 10-15℃) for 0.2-1 hour (for example 0.5 hour); add (S)-(α,α)-diphenyl prolinol, after addition, stir the system at 0-30℃ (for example 10-15℃) for 0.5-2 hours (for example 1 hour); drop 3-chloropropiophenone in dichloromethane solution, control the temperature of the system to 0-30℃ (for example 10-15℃) during the dropping process, stir for 0.5-2 hours (for example 1 hour), to obtain the hydrochloride dapoxetine intermediate (R)-3-chloropropyl alcohol.

[0025] According to an embodiment of the present application, after the reaction in step (ii) is completed, add 2-butanone (or acetone) to the system, stir at room temperature (for example 20-30℃) for 0.5-2 hours (for example 1 hour); then, add toluene, water, concentrated hydrochloric acid to the system, stir at room temperature (for example 20-30℃) for 0.2-1 hour (for example 0.5 hour) to obtain toluene extraction layer; concentrate the toluene extraction layer under reduced pressure, to obtain the hydrochloride dapoxetine intermediate (R)-3-chloropropyl alcohol;

[0026] Preferably, after obtaining the toluene extraction layer, the toluene extraction layer can be extracted again, and the toluene extraction layers are combined.

[0027] Preferably, after obtaining the toluene extraction layer, the toluene extraction layer is washed with hydrochloric acid solution and 100 mL purified water in sequence;

[0028] Preferably, after concentrating the toluene extraction layer under reduced pressure, the concentrate is further purified; for example, the concentrate is further purified by recrystallization.

[0029] According to an embodiment of the present application, the volume ratio of toluene, water and concentrated hydrochloric acid is 1:1.3-2.0:0.05-0.2, for example, 1:1.67:0.1, 1:1.67:0.13.

[0030] According to an embodiment of the present application, the solvent used in the recrystallization step is a mixed solvent of ethyl acetate and n-hexane or n-hexane; preferably, the volume ratio of ethyl acetate and n-hexane is 1:10.

[0031] According to an embodiment of the present application, step (ii) is specifically as follows: ethylene glycol dimethyl ether and dichloromethane are added to N,N-diethyl aniline hydrochloride, and the system is stirred and dissolved; the system is cooled to 0-10°C, and sodium borohydride is added in batches; the system is stirred at 0-30°C (for example, 10-15°C) for 0.2-1 hour (for example, 0.5 hour); (S)-(α,α)-diphenyl prolinol is added, and after the addition is completed, the system is stirred at 0-30°C (for example, 10-15°C) for 0.5-2 hours (for example, 1 hour); a dichloromethane solution of 3-chloropropiophenone is added dropwise, and the temperature of the system is controlled to 0-30°C (for example, 10-15°C) during the dropwise addition; and the system is stirred for 0.5-2 hours (for example, 1 hour).

[0032] After the reaction is completed, 2-butanone is added to the system, and the system is stirred at room temperature (for example, 20-30°C) for 0.5-2 hours (for example, 1 hour); then, toluene, water and concentrated hydrochloric acid are added to the system, and the system is stirred at room temperature (for example, 20-30°C) for 0.2-1 hour (for example, 0.5 hour) to obtain a toluene extraction layer; the toluene extraction layer is washed with hydrochloric acid solution and 100 mL purified water in sequence; and then the washed toluene extraction layer is concentrated under reduced pressure, and recrystallization is performed, to obtain the hydrochloric acid dapoxytine intermediate (R)-3-chloropropyl alcohol.

[0033] Advantages:

[0034] The present application provides a preparation method of the hydrochloric acid dapoxytine intermediate (R)-3-chloropropyl alcohol, which has good safety, is convenient to operate, has low cost, good product quality and high yield, and is more suitable for industrialization.

[0035] The present application can significantly reduce the water content of N,N-diethyl aniline hydrochloride by using the method of vacuum concentration for post-treatment of N,N-diethyl aniline hydrochloride, thereby avoiding the hydration loss of (R)-3-chloropropyl phenol caused by the moisture in N,N-diethyl aniline hydrochloride; and the method of vacuum concentration is simple to operate, and the product has high yield and high quality. BRIEF DESCRIPTION OF DRAWINGS

[0036] Figure 1 (R)-3-chloropropyl phenol HPLC spectrum.

[0037] Figure 2 (R)-3-chloropropyl phenol isomer spectrum.

[0038] Figure 3 (R)-3-chloropropyl phenol nuclear magnetic resonance hydrogen spectrum. DETAILED DESCRIPTION

[0039] The technical solutions of the present application will be further described in detail below in combination with specific examples. It should be understood that the following examples are only illustratively described and explained, and should not be interpreted as limiting the scope of protection of the present application. Any technology realized based on the above description of the present application is covered within the scope of protection intended by the present application.

[0040] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0041] Example 1

[0042] 250 milliliters of dichloromethane were added to the system, then 44.37 grams of N,N-diethyl aniline were added, and the system was stirred and controlled to 10-15°C; HCl(g) was slowly introduced until the pH of the system was ≤2, and the introduction of HCl(g) was stopped, and the system was stirred at 10-15°C for 2 hours; the system was concentrated under reduced pressure at 60±2°C until the distillate distillation rate significantly slowed down, 100 milliliters of dichloromethane were added and stirred to dissolve, then concentrated under reduced pressure at 60±2°C again until the distillate distillation rate significantly slowed down, and the system was maintained for 1 hour, to obtain N,N-diethyl aniline hydrochloride (55.50 grams, yield 100.5%, HPLC purity 99.399% based on 100% yield, titration content 99.9%, moisture content: 0.05%).

[0043] To the N,N-diethylaniline hydrochloride system, 250 ml of ethylene glycol dimethyl ether and 250 ml of dichloromethane were added and stirred to dissolve, the system was cooled to 0-10°C, 22.62 g of sodium borohydride was added in batches, the system was stirred at 10-15°C for 0.5 h; 0.75 g of (S)-(a,a)-diphenylprolinol was added, after addition, the system was stirred at 10-15°C for 1 h; a solution of 3-chloropropiophenone in dichloromethane (50.00 g of 3-chloropropiophenone was dissolved in 50 ml of dichloromethane) was added dropwise, the system was controlled to 10-15°C during the dropwise addition, after dropwise addition, the system was stirred at the temperature for 1 h, and TLC monitoring was performed (developing agent: ethyl acetate / n-hexane = 1 / 9), if the reaction was not completed, TLC monitoring was performed every 1 h until the reaction was completed (3-chloropropiophenone raw material was ≤0.5%). After the reaction was completed, 50 ml of 2-butanone was added dropwise to the system, after dropwise addition, the system was stirred at 20-30°C for 1 h; 150 ml of toluene, 250 ml of purified water and 15 ml of concentrated hydrochloric acid were sequentially added to the system, the system was stirred at 20-30°C for 0.5 h; the system was allowed to stand to separate into layers, the toluene layer was retained, and the water layer was extracted with 100 ml of toluene again; the toluene layers obtained were combined and sequentially washed with a hydrochloric acid solution (15 ml of hydrochloric acid was added to 100 ml of purified water) and 100 ml of purified water; the system was allowed to stand to separate into layers, and the toluene layer was separated; the toluene layer was concentrated to dryness under reduced pressure at 60±5°C, and recrystallized with ethyl acetate / n-hexane = 1 / 10 to obtain white fluffy solid (R)-3-chloropropyl alcohol (43.01 g, yield 85.0%, HPLC purity 99.302%, isomer ee value 99.201%).

[0044] The reaction formula is as follows:

[0045]

[0046] Example 2

[0047] To the system, 600 ml of dichloromethane was added, then 88.74 g of N,N-diethylaniline was added, the system was stirred and controlled to 5-10°C; HCl(g) was slowly introduced until the pH of the system was ≤2, and the introduction of HCl(g) was stopped, the system was stirred at 5-10°C for 2 h; the system was concentrated under reduced pressure at 60±2°C until the distillation rate of the distillate was significantly reduced, 200 ml of dichloromethane was added and stirred to dissolve, then the system was concentrated under reduced pressure at 60±2°C until the distillation rate of the distillate was significantly reduced, and the system was maintained for 1 h, to obtain N,N-diethylaniline hydrochloride (111.85 g, yield 101.3%, HPLC purity 99.421% based on 100% yield, titration content 99.9%, moisture content: 0.07%).

[0048] To the N,N-diethylaniline hydrochloride system, 600 ml of ethylene glycol dimethyl ether and 600 ml of dichloromethane were added, stirred and dissolved, the system was cooled to 0-5°C, 44.00 g of sodium borohydride was added in batches, the system was stirred at 5-10°C for 0.5 hours; 2.00 g of (S)-(α,α) diphenyl prolinol was added, after the addition was completed, the system was stirred at 10-15°C for 1 hour; a solution of 3-chloropropiophenone in dichloromethane (100.00 g of 3-chloropropiophenone was dissolved in 80 ml of dichloromethane) was added dropwise, the temperature of the system was controlled at 10-15°C during the dropwise addition, after the dropwise addition was completed, the system was stirred at the temperature for 1 hour, and TLC monitoring was performed (developing agent: ethyl acetate / n-hexane = 1 / 9); if the reaction was not completed, TLC monitoring was performed every 1 hour until the reaction was completed (3-chloropropiophenone raw material was ≤0.5%). After the reaction was completed, 100 ml of acetone was added dropwise to the system, after the dropwise addition was completed, the system was stirred at 20-30°C for 1 hour; 300 ml of toluene, 500 ml of purified water, and 30 ml of concentrated hydrochloric acid were sequentially added to the system, the system was stirred at 20-30°C for 0.5 hours; the system was allowed to stand and separate into layers, the toluene layer was retained, and the water layer was extracted with 200 ml of toluene again; the toluene layers obtained were combined and sequentially washed with a hydrochloric acid solution (30 ml of hydrochloric acid was added to 200 ml of purified water) and 200 ml of purified water; the system was allowed to stand and separate into layers, the toluene layer was separated, the toluene layer was concentrated to dryness under reduced pressure at 60±5°C, recrystallized with ethyl acetate / n-hexane = 1 / 10, filtered, washed, and vacuum dried at 40±2°C until the weight was constant to obtain white fluffy solid (R)-3-chloropropyl alcohol (84.00 g, yield 83.0%, HPLC purity 98.578%, isomer ee value 99.076%).

[0049] Example 3

[0050] 1000 ml of dichloromethane was added to the system, then 177.48 g of N,N-diethylaniline was added, the system was stirred and the temperature was controlled at 10-15°C; HCl(g) was slowly introduced until the pH of the system was ≤2, the introduction of HCl(g) was stopped, and the system was stirred at 10-15°C for 2 hours; the system was concentrated under reduced pressure at 60±2°C until the distillation rate of the distillate significantly slowed down, 500 ml of dichloromethane was added after stirring and dissolving, then the system was concentrated under reduced pressure at 60±2°C again until the distillation rate of the distillate significantly slowed down, and the system was maintained for 1 hour to obtain N,N-diethylaniline hydrochloride (221.90 g, yield 100.5%, HPLC purity 99.431% based on 100% yield, titration content 99.9%, moisture content: 0.06%).

[0051] N,N-diethylaniline hydrochloride system was added 1000 ml of ethylene glycol dimethyl ether and 1000 ml of dichloromethane, stirred and dissolved, the system was cooled to 0-10°C, 90.48 g of sodium borohydride was added in batches, the system was stirred at 10-15°C for 0.5 hours; 3.00 g of (S)-(a,a)-diphenylprolinol was added, after addition, the system was stirred at 10-15°C for 1 hour; a solution of 3-chloropropiophenone in dichloromethane (200.00 g of 3-chloropropiophenone was dissolved in 200 ml of dichloromethane) was added dropwise, the temperature of the system was controlled at 10-15°C during the dropwise addition, after the dropwise addition was completed, the system was stirred at the temperature for 1 hour, and TLC monitoring was performed (developing agent: ethyl acetate / n-hexane = 1 / 9), if the reaction did not reach the end point, TLC monitoring was performed every 1 hour until the reaction reached the end point (3-chloropropiophenone raw material was ≤0.5%).

[0052] After the reaction was completed, 200 ml of 2-butanone was added dropwise to the system, after the dropwise addition was completed, the system was stirred at 20-30°C for 1 hour; 600 ml of toluene, 1000 ml of purified water, and 80 ml of concentrated hydrochloric acid were sequentially added to the system, the system was stirred at 20-30°C for 0.5 hours; the system was allowed to stand and separate into layers, the toluene layer was retained, and the water layer was extracted with 500 ml of toluene; the obtained toluene layers were combined and sequentially washed with a hydrochloric acid solution (60 ml of hydrochloric acid was added to 500 ml of purified water) and 500 ml of purified water; the system was allowed to stand and separate into layers, and the toluene layer was separated; the toluene layer was concentrated to dryness under reduced pressure at 60±5°C, and recrystallized with n-hexane to obtain white fluffy solid (R)-3-chloropropyl alcohol (184.30 g, yield 91.1%, HPLC purity 99.691%, isomer ee value 99.194%, melting point: 55-56°C).

[0053] Characterization data of (R)-3-chloropropyl alcohol: 1 H-NMR (600MHz, CDCl3) δ 7.368-7.370 (m, 4H, ArH), 7.302 (m, 1H, ArH), 4.945-4.967 (m, 1H, CH), 3.727-3.750 (m, 1H, CH2), 3.561-3.579 (m, 1H, CH2), 2.243 (m, 1H, CH2), 2.098-2.106 (m, 1H, CH2); ES-MS M / Z = 170.1 (M + HPLC spectrum of (R)-3-chloropropyl alcohol is shown in the attached Figure 1 isomer spectrum is shown in the attached Figure 2 nuclear magnetic resonance hydrogen spectrum is shown in the attached Figure 3 .

[0054] The above describes the embodiments of the present application. However, the present application is not limited to the above-described embodiments. Any modification, equivalent replacement, improvement, and the like made within the spirit and principle of the present application should be included in the scope of protection of the present application.

Claims

1. A method for preparing a dapoxetine hydrochloride intermediate (R)-3-chlorobenzene propanol, the method comprising the following steps: (i) preparation of N,N-diethyl aniline hydrochloride: dissolving N,N-diethyl aniline in dichloromethane, slowly bubbling hydrogen chloride gas into the reaction system, and after the reaction is complete, concentrating the reaction system to obtain N,N-diethyl aniline hydrochloride; (ii) adding ethylene glycol dimethyl ether and dichloromethane to the N,N-diethyl aniline hydrochloride, then adding sodium borohydride, adding (S)-(α,α)-diphenyl prolinol, stirring and reacting, then adding a dichloromethane solution of 3-chlorobenzene propanone, and after the reaction is complete, obtaining the dapoxetine hydrochloride intermediate (R)-3-chlorobenzene propanol. In step (i), the reaction system is concentrated under reduced pressure; preferably, the temperature of the reduced pressure concentration is 50-65°C, for example 60±2°C. In step (i), the reaction temperature is 0-30°C.

2. The method of claim 1, wherein, In step (i), the reaction time is preferably 0.5-5 hours. In step (i), the mass / volume ratio of N,N-diethyl aniline to dichloromethane is preferably 1g:3-10mL.

3. The method according to claim 1 or 2, characterized in that, In step (i), the hydrogen chloride gas is slowly bubbled in until the pH of the system is ≤2. In step (ii), the (S)-(α,α)-diphenyl prolinol is added in solid form. In step (ii), the volume ratio of ethylene glycol dimethyl ether to dichloromethane is preferably 0.5-2.0:0.5-2.

0. In step (ii), the volume / mass ratio of ethylene glycol dimethyl ether to N,N-diethyl aniline is preferably 3-10mL:1g.

4. The method according to any one of claims 1 to 3, characterized in that, In step (ii), the mass ratio of N,N-diethyl aniline to sodium borohydride is preferably 0.5-2:0.2-1.

0. In step (ii), the mass ratio of N,N-diethyl aniline to (S)-(α,α)-diphenyl prolinol is preferably 0.5-2:0.001-0.

1. In step (ii), the mass ratio of N,N-diethyl aniline to 3-chlorobenzene propanone is preferably 0.5-2:1.0-2.

0. In step (ii), the reaction temperature is preferably 0-30°C. In step (ii), the concentration of the dichloromethane solution of 3-chlorobenzene propanone is preferably 0.5-2.0g / mL. Step (ii) is specifically: ​ ​ 5. The method according to any one of claims 1 to 4, characterized in that, ​ To N,N-diethyl aniline hydrochloride, add ethylene glycol dimethyl ether and dichloromethane, stir and dissolve, cool the system to 0-10°C, add sodium borohydride in batches, stir the system at 0-30°C for 0.2-1 hour; add (S)-(α,α)-diphenyl prolinol, after addition, stir the system at 0-30°C for 0.5-2 hours; drop 3-chloropropiophenone in dichloromethane, control the temperature of the system to 0-30°C during drop, stir and react for 0.5-2 hours, to obtain the hydrochloride dapoxetine intermediate (R)-3-chloropropyl alcohol.

6. The method according to any one of claims 1 to 5, characterized in that, After the reaction in step (ii) is completed, add 2-butanone or acetone to the system, stir and react at room temperature for 0.5-2 hours; then, add toluene, water, and concentrated hydrochloric acid to the system, stir and react at room temperature for 0.2-1 hour, to obtain a toluene extraction layer; reduce the pressure and concentrate the toluene extraction layer, to obtain the hydrochloride dapoxetine intermediate (R)-3-chloropropyl alcohol.

7. The method according to any one of claims 1 to 6, characterized in that, After the toluene extraction layer is obtained, the residual layer can be extracted again with toluene, and the toluene extraction layers are combined. Preferably, after the toluene extraction layer is obtained, the toluene extraction layer can be washed with hydrochloric acid solution and 100 ml of purified water in sequence. Preferably, after the toluene extraction layer is reduced in pressure and concentrated, the concentrate can be further purified; for example, the concentrate can be further purified by recrystallization. Preferably, the volume ratio of toluene, water, and concentrated hydrochloric acid is 1:1.3-2.0:0.05-0.2, for example, 1:1.67:0.1, 1:1.67:0.

13.

8. The method of claim 7, wherein, The solvent used in the recrystallization step is a mixed solvent of ethyl acetate and n-hexane or n-hexane; preferably, the volume ratio of ethyl acetate and n-hexane is 1:10.

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