Synthetic method of dapoxetine and intermediate thereof

A synthesis method and compound technology, applied in chemical instruments and methods, preparation of organic compounds, preparation of amino hydroxyl compounds, etc., can solve problems such as expensive catalysts, and achieve green and environmentally friendly synthesis processes, low production costs, and cheap and easy-to-obtain raw materials Effect

Active Publication Date: 2020-02-28
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0029] The above three routes have all adopted the chiral catalytic synthesis method, route 1 has used more expensive chiral catalyst, the chiral catalyst used in route 2 is cheaper,

Method used

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  • Synthetic method of dapoxetine and intermediate thereof
  • Synthetic method of dapoxetine and intermediate thereof
  • Synthetic method of dapoxetine and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0089] Add 200mL of water and 100mL of methanol into a single-mouth 500mL round-bottom flask, add 0.2mol / 32.83g of sodium benzenesulfinate, 0.1mol / 11.72g of tert-butyl carbamate, 0.12mol / 12.72g of benzaldehyde, 70mL of formic acid, Stir well at room temperature 25°C for 3 days to form an emulsion. Use a sand core funnel to filter under reduced pressure, fully stir and wash with 30 mL of distilled water for 3 times, fully stir and wash with 30 mL of diethyl ether for 2 times, fully stir and wash with 30 mL of n-hexane once, and dry naturally to obtain 32.3 g of white powdery solid compound 2 with a yield of 93%. .

[0090] The reaction formula is as follows:

[0091]

Embodiment 2

[0093] Add 20mmol / 6.95g of the product of Example 1 into a 500mL round-bottomed flask, stir and dissolve with 160mL of dichloromethane, weigh 62g of potassium carbonate and dissolve it in 160mL of water and stir until it becomes clear, then pour the potassium carbonate aqueous solution into the round-bottomed flask , fully stirred at room temperature for 5 hours, extracted with a 500mL separatory funnel to obtain the organic phase, then extracted twice with 80mL dichloromethane, combined the organic phases, dried with anhydrous sodium sulfate, and obtained 3.78g colorless oil Liquid compound 3, yield 92%.

[0094] The reaction formula is as follows:

[0095]

Embodiment 3

[0097] Preparation of acetaldehyde: Add paraldehyde into the flask, add concentrated sulfuric acid dropwise, distill at normal pressure, control the temperature at 55-60°C, connect the condensing pipe to a low-temperature constant temperature reaction bath, and lower the temperature of the cooling system to -10-0°C , and the receiving bottle was cooled in an ice-water bath. The collected acetaldehyde was stored at low temperature. Concentrated sulfuric acid is used as a catalyst, and the catalyst consumption is 0.5% of the mass of paraldehyde.

[0098] Add 4mmol / 0.46g of L-proline and 12mmol / 12g of PEG1000 into a 250mL round-bottomed flask, add 30mL of redistilled acetonitrile, stir at room temperature for 15min, and then transfer to 20mmol / 4. In 10g of acetonitrile (50mL) solution, stir at 0°C, then dissolve redistilled acetaldehyde in 70mL of acetonitrile to form a solution and drop it into the reaction flask, after 3.5h, analyze by high-performance liquid chromatography w...

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PUM

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Abstract

The invention discloses a synthetic method of dapoxetine and its intermediate, i.e., (S)-3-(tert-butyloxycarbonyl)amino-3-phenylpropanol as shown in a formula 5 which is described in the specification. The synthetic method of (S)-3-(tert-butyloxycarbonyl)amino-3-phenylpropanol is as shown in a synthesis route which is described in the specification, wherein a compound 3 and acetaldehyde are subjected to a Mannich reaction in an organic solvent under the action of a supramolecular catalyst constructed by a chiral catalyst and a polymer so as to obtain a compound 4, and the polymer is at least one selected from of the group consisting of PEG 200, PEG 400, PEG 600, MeOPEG 750, PEG 800, PEG 1000, PPG 800 and PPG 1000. The dapoxetine is synthesized from the (S)-3-(tert-butyloxycarbonyl)amino-3-phenylpropanol prepared by using the above method according to steps as shown in the synthesis route. The synthetic method of dapoxetine and the intermediate thereof has the characteristics of usage of cheap and easily available raw materials, high yield and low cost, and is more beneficial to industrial production.

Description

[0001] (1) Technical field [0002] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a synthesis method of dapoxetine and its intermediate—(S)-3-(tert-butoxycarbonyl)amino-3-phenylpropanol. [0003] (2) Background technology [0004] Dapoxetine, compound 8, English name Dapoxetine, chemical name (S)-N,N-dimethyl-3-(naphthalen-1-yloxy)-1-phenylpropan-1-amine【(S)-(N,N -Dimethyl)-3-(naphthyl-1-oxy)amphetamine], originally a selective light tryptamine reuptake inhibitor used to treat depression, but relevant medical clinical trial data show that its treatment Male premature ejaculation has a remarkable curative effect and has a very broad market prospect, and its hydrochloride is used clinically. It was first launched in Finland and Sweden in Europe in February 2009. It is used for the on-demand treatment of premature ejaculation in adult men and has become a new drug for improving premature ejaculation in men. The clinical researc...

Claims

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Application Information

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IPC IPC(8): C07C269/06C07C271/12C07C271/18C07C271/16C07C315/00C07C317/28C07C213/08C07C215/28C07C213/06C07C217/48
CPCC07C269/06C07C315/00C07C213/08C07C213/06C07C317/28C07C271/12C07C271/18C07C271/16C07C215/28C07C217/48
Inventor 许丹倩夏爱宝白亮盘龚健
Owner ZHEJIANG UNIV OF TECH
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