| 87.53% |
With hydrogenchloride In ethyl acetate; isopropanol at 0 - 20℃; |
26
Example-26: Preparation of Dapoxetine hydrochloride; Taken 50gr. of dapoxetine, 250ml. of ethyl acetate at ambient temperature and heated to 45-50°C.Added 5gr. of special carbon and stirred for lOmin. at 45-50°C and the reaction mass was filtered through carbon bed. The carbon bed was washed with 50ml. of hot ethylacetate.The ethyl acetate layer was cooled to ambient temperature. Then added 50ml. of 18% Isopropyl alcohol hydrochloric acid mixture drop-wise within 45-60min.Then the reaction mass was stirred for 30min. at ambient temperature and cooled to 0-5°C.The reaction mass was filtered and the cake was washed with 50ml. of chilled ethyl acetate and dried at 90-95°C for 4hrs. to furnish 49gr. of the title compound.Wt: 49 g. (%Yield: 87.53%); Purity by HPLC: 99.98%; Chiral purity: 99.98% and R-isomer: 0.012% ; SOR: (+) 130.72° (C=l% in CH3OH) ; Assay: 100.51%; M.P: 180-182°C. |
| 86% |
With hydrogenchloride In ethyl acetate for 1h; Cooling with ice; |
8
The above oil (103 g) was dissolved in ethyl acetate (400 ml)A dry hydrogen chloride gas was introduced into the reaction solution under an ice bath,Stirring lh,To the reaction solution p Η = 1.0 stop ventilation, stirring at room temperature lh.Filtration to obtain a white solid, that was 99.1g dapoxetine hydrochloride, the yield of 86%, the product of mp 178-180 ° C, [a] 23D = +129 ~ 130, c = l, Me0H. |
| 85% |
With hydrogenchloride In 2-methoxy-2-methylpropane; lithium hydroxide monohydrate |
3 Example 3
Compound 6 (1.0 g, 0.015 mol) was dissolved in 10 ml anhydrous methyl tert-butyl ether,A solution of hydrogen chloride in methyl tert-butyl ether was added dropwise to the solution until no more white solids were produced.1.10 g (yield 97.7%) of pale white powder was filtered.The resulting compound was used as a 22-fold amount of isopropanol:Recrystallization from n-hexane (1:1) gave 0.85 g of white powder 1 (yield 85%).[α]25 D = +130.9° (c = 1%, methanol), mp 179.1-180.2°C. |
| 85% |
With hydrogenchloride In Isopropyl acetate Large scale; |
2.4; 2.5 Step 4: Dimethylation
Dichloromethane (25.0 kg) was added sequentially to a 50-L reactor.The intermediate II obtained in the above step (2.50 kg 9.98 mol)Stir and maintain the temperature at 1025°C.Add 5% sodium hydroxide solution dropwise, 0.5 ~ 1.0h drop is completed,After stirring until the solution is completely clarified, the solution is separated and the dichloromethane layer is separated.Dichloromethane (5.0 kg) was added to the aqueous layer, stirred, and the solution was separated.The methylene chloride phases were combined, washed with purified water (5.0 kg), and partitioned to give a dichloromethane solution.The methylene chloride solution was transferred to a 50 L reactor and methanol (0.38 kg, 12.0 mol) was added.Formaldehyde aqueous solution (9.70kg), open nitrogen protection, at 20 ~ 30 °C,Sodium triacetoxyborohydride (12.0 kg, 56.50 mol) was added slowly and the addition was completed between 2.0 and 3.0 h.After the addition is completed, the reaction is carried out at 20 to 30°C for 1.5 to 3.0 hours. Add purified water (30.0kg)Keep the temperature at 5-20°C, add 20% sodium hydroxide solution to the system.When the pH of the system is between 9.0 and 11.0, stop dropping and stir for 20-30 minutes.The reaction mixture was separated, and the dichloromethane layer was separated. Dichloromethane (10.0 kg) was added to the aqueous layer and stirred.Stationary liquid. Combine the methylene chloride layer and transfer it to a 100-liter reactor.Add purified water (30.0 kg) and stir. The methylene chloride layer was separated and repeatedly washed with purified water (150.0 kg). The dichloromethane layer was combined.Anhydrous magnesium sulfate (2.0 kg) was added to the dichloromethane layer and dried for 3.0-5.0 h. filter,The solid was washed twice with methylene chloride and 2.0 kg each time. The diamino compound in dichloromethane was collected. The solvent was concentrated under reduced pressure to give the crude free base.Soluble in 10kg isopropyl acetate, pass hydrogen chloride gas (1.6~2.0kg),After the feed was stopped, the system gradually precipitated solids and stirred for 3.0-4.0 h. filter,Dapoxicillin hydrochloride 2.8 kg was obtained in a yield of 85%. Step 5: Refinement of the crude productTo a 20-L reactor, isopropanol (15.0 kg) was added in sequence.Dapoxetine hydrochloride crude product 2.8kg, stirring, heated to 60 ~ 70 °C, after all the system dissolved and clarified,The hot filter was used to remove mechanical impurities, and the temperature was controlled at 35-45°C and stirred for 1.0-2.0h.Then cool down to 20 ~ 30 °C, stirring and devitrification 3.0 ~ 4.0h. 2.38 kg of pure product was obtained by filtration, yield 85%. |
| 78.5% |
With hydrogenchloride In methanol; lithium hydroxide monohydrate at 0 - 30℃; Large scale; |
1.S4; 3 Step S4, salt formation reaction.
At 0~30°C, 14.4kg of methanol was added to the 100L reaction kettle, 9.6kg of dapoxetine prepared in step S3 was added, stirred, 4.8kg of hydrochloric acid gas was introduced, and the detected pH was about 1.0, and the solution was clear. Cool down to 0±5°C, add 120kg of methyl tert-butyl ether dropwise, finish adding in 2h, keep stirring at 0±5°C for 2-4h after dripping, and centrifuge to obtain dapoxetine hydrochloride as a white solid. It was placed in a vacuum drying oven, and the temperature was controlled at 45-55° C., and dried to obtain 8.42 kg of white solids, and the calculated yield was 78.5%.The obtained dapoxetine hydrochloride white solid was detected and analyzed by HPLC. |
| 40% |
With hydrogenchloride In lithium hydroxide monohydrate for 2h; |
1
In a 2 L three-mouth bottle by adding 500 ml tetrahydrofuran, lowering the temperature to 0 °C, adding 23.0 g (0.606 µM) NaBH4, Added under mixing 50 g (S)-3 - amino -3 - phenyl propionic acid dap - 1 (303 µM). The 77 g iodine (0.303 µM) dissolved in 250 ml of tetrahydrofuran, is added to the reaction solution under stirring in the drop. Then completing, heating reflux for 20 hours, stopping the reaction, cooling, dropping 50 ml methanol quenching reaction. The organic solvent and steaming and remove, dropping 20% NaOH solution, to PH is 8 - 10, the stirring 2 h. Ethyl acetate is divided into 3 time extraction, the combined organic phase. The addition of about 10% formic acid solution stirring, liquid. In the aqueous phase by adding 70 ml 85% formic acid and 140 ml 37% formaldehyde, 90 °C lower reaction 8 hours. The cooling, for 20% NaOH to adjust the PH to 8 - 10, ethyl acetate extraction three times, the combined organic phase, turns on lathe does (S)-3 - dimethyl amino -3 - phenyl propanol dap - 3 crude product. The dap - 3 crude and 37.0g1 - [...] adding 2 L three-opening in the bottle, at room temperature by adding 380 mLN, N - dimethyl formamide and 47.3 g tert-butanolate, the temperature is raised to 70 °C stirring 5 h. The reaction liquid to room temperature, hexane and water added, stirring 15 minutes, standing liquid. The upper layer is cetane collected, washed with water once. Hexane phase and steaming and to remove the solvent, adding tetrahydrofuran is dissolved. Stirring next adds by drops 26.2 ml concentrated hydrochloric acid. Reaction 2 hours, steaming and remove the tetrahydrofuran and water, to the solvent-free steam, adding isopropanol, steaming and to the solvent-free steam. In the resultant product added to isopropanol, heating under stirring to make it dissolve completely. Stop heating, dropping ethyl acetate, during the dropping out of the crystal. After dropping cooling to room temperature, continuing to stir overnight, filtered, the filter cake is washed with ethyl acetate, and a ground line, N2 dry, product west reaches anchors the sandbank hydrochloride 41 g, yield 40%. |
|
With hydrogenchloride In ethyl acetate at 0 - 5℃; for 1h; |
7
Example-7 Preparation of (+)-Dapoxetine Hydrochloride:The solution of 60 g of Dapoxetine base is prepared in 480 mL of ethyl acetate at 25° to 350C and is stirred for 15 minutes. The reaction is filtered through fine filter hyflosupercel bed at 250C t0 35°C and the bed is washed with 2 x 60 mL of ethyl acetate. The reaction mixture is taken into the flask and cooled to 00C to 50C. The HCl gas is purged at O0C to 5°C till the pH is acidic between 1- 2. The solid material is precipitated. The purging is stopped and the reaction mixture was stirred for 1 hour at O0C to' 50C. The product is filtered at 0° to 50C and washed with 2 x 60 mL of ethyl acetate (chilled). Purification: The solution of 125.6 g of (+)-Dapoxetine Hydrochloride is prepared in 377 mL of fine filtered isopropyl alcohol at 250C to 35°C. The reaction mixture is heated at reflux temperature to obtain the clear solution. The reaction mixture is maintained at reflux temperature for 15 minutes. The reaction mixture is cooled down to 25°C to 350C within 1 hour. The product starts precipitating at 450C to 55°C. The reaction mixture is stirred at 250C to 350C for 1 hour. The reaction mass is further cooled to 1O0C to 150C and was allowed to stirred at 1O0C to 150C. The reaction mixture is washed with fine filtered isopropyl alcohol (2 x 62.5 mL) and the product is dried at 5O0C to 550C. Chiral purity = (-) Dapoxetine : Below Detection Limit MD25 [C = 1% methanol] = + 131.7° M.P. : 18O0C-1840C. |
| 10 g |
With hydrogenchloride In ethyl acetate; isopropanol at 25 - 30℃; for 2h; |
6
ExampIe-6 The solid, (5^-(+)-N,N-Dimethyl-3-(Naphthalen-l-yloxy)-l-phenylpropan-l -amine Tartrate (12.0 g) is added into a mixture of dichloromethane (75ml) and water (75 ml). The organic layer separated after adjusting pH to 8-10. The organic layer is distilled completely to dryness to obtain a thick mass of solid. [a] D 25 (C=l, MeOH) = (+ ) 104° HPLC; Chiral (S-Isomer; 95%; R-Isomer-5%) To the above thick mass IPA-HCl (3 ml) is added in presence of ethyl acetate (30 ml). It is stirred for 2 hr at 25-30°C. The solid is filtered at 0-5°C.Yield is 10 gm. [a] D 25 (C=l, MeOH) = (+ ) 128° HPLC Chiral (S-Isomer 99.80, R-Isomer 0.08) HPLC Purity; 99.81% MR; 182-183°C |
|
With hydrogenchloride In propan-2-one |
4 A method for the synthesis of dapoxetine hydrochloride
The present embodiment relates to a process for the preparation of dapoxetine hydrochloride, which comprises the steps of:(1) Preparation of S-dapoxetine according to the method described in Example 1;(2) A solution of (S) -N, N-dimethyl-1-phenyl-3- (naphthyl-1-oxo)(3.1 g, 0.01 mol) was dissolved in anhydrous acetone (20 mL)Ice bath slowly drip concentrated hydrochloric acid (0.45mL) to no white precipitate, filter, recovery of mother liquor, cake drying,The solid was recrystallized from isopropanol to give 2.9 g of dapoxetine hydrochloride (HPLC: 99.85%, . : 99.91%). |
|
With hydrogenchloride In ethyl acetate at -5 - 20℃; |
6; 7 Step 7: Preparation of finished product of dapoxetine hydrochloride
4g,24ml of ethyl acetate was added into a three-necked flask and dissolved with stirring at room temperature. The temperature was controlled to -5 DEG C to 0 DEG C and hydrogen chloride gas was introduced into the solution to adjust the pH of the solution to 2,The temperature was controlled at 0-5 ° C, and the mixture was filtered with suction after stirring for 1 hour. The filter cake was washed with ethyl acetate and dried at 40 ° C to obtain 4.27 g of crude dapoxetine hydrochloride.Yield 95%;_the crude product dapoxetine hydrochloride 4g,Isopropanol 20ml added to the three-necked flask, heated to reflux, clear,Slowly cooled to -5 ~ -10 stirring crystallization 1h after filtration,The filter cake was washed with a small amount of ethyl acetate and dried under reduced pressure at 40 ° C.Dapoxetine hydrochloride product 3.79g, 94.8% yield. |
| 324 g |
With hydrogenchloride In lithium hydroxide monohydrate; ethyl acetate at 0 - 20℃; |
1.3 Step 3:
480 g of (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy) amphetamine was dissolved in 1.5 L of ethyl acetate.After cooling to 0-5 ° C, dry hydrogen chloride gas was introduced into the solution until the pH of the solution was 1-2, and the mixture was stirred at room temperature for 4-5 h. Filtration gave a white solid,Dry at 45-50 ° C for 20-24 h,(S)-N,N-Dimethyl-(α)-[2-(1-naphthalenyloxy)ethyl]benzylamine hydrochloride 324 g was obtained. |
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