Dapoxetine intermediate and preparation method thereof

A volume and protective gas technology, applied in chemical instruments and methods, preparation of organic compounds, preparation of carbonyl compounds by hydrolysis, etc., can solve the problems of high price, high production cost, unsuitable for industrial production, etc.

Active Publication Date: 2016-07-06
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The technical problem to be solved by the present invention is to overcome the high cost of raw materials, harsh reaction conditions, low conversion rate, low yield and production cost of the preparation method of 3-(1-naphthyloxy)-1-phenylacetone in the prior art. high, not suitable for industrial production and other defects and provide a dapoxetine intermediate and its preparation method

Method used

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  • Dapoxetine intermediate and preparation method thereof
  • Dapoxetine intermediate and preparation method thereof
  • Dapoxetine intermediate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] Example 1: Preparation of 2-(2-chloroethyl)-2-phenyl-1,3-dioxolane (compound shown in formula 3)

[0079] Compound 4 (100g, 0.6mol, 1eq) was dissolved in 500mL of dichloromethane (DCM), followed by adding ethylene glycol (133mL, 4eq), trimethyl orthoformate (126.3g about 130mL, 1.19mol, 2eq), mass Concentrated sulfuric acid with a percentage content of 98% (the mass percentage refers to the percentage of the mass of sulfuric acid in the total mass of the concentrated sulfuric acid reagent) (5.8g, 0.1eq). The reaction solution was heated to reflux (45° C.), and after stirring for 6 h, TLC detected that compound 4 disappeared, and the temperature was lowered to cool. Add 20gNaHCO 3 The pH of the solid was adjusted to about 7, and stirred for 10 minutes. After suction filtration, the organic layer was washed with brine (100 mL), dried and concentrated to obtain about 152 g of an oily substance. Add 100mL of isopropanol to the residue, cool overnight to crystallize, and ...

Embodiment 2

[0080] Embodiment 2: Preparation of (3-chloro-1,1-dimethoxypropyl)benzene (compound shown in formula 3)

[0081] Compound 4 (5g, 0.03mol, 1eq) was dissolved in 25mL of dichloromethane (DCM), followed by adding methanol (4.8mL, 4eq), trimethyl orthoformate (6.3g about 6.5mL, 0.06mol, 2eq), mass Concentrated sulfuric acid with a percentage content of 98% (the mass percentage refers to the percentage of the mass of sulfuric acid in the total mass of the concentrated sulfuric acid reagent) (0.29g, 0.1eq). The reaction solution was heated to reflux (42° C.), and after stirring for 6 h, compound 4 disappeared as detected by TLC, and the temperature was lowered to cool. Add 1.5gNaHCO 3 The pH of the solid was adjusted to about 7, and stirred for 10 minutes. After suction filtration, the organic layer was washed with brine (10 mL), dried and concentrated to obtain about 7.2 g of an oily substance. Column chromatography (PE:EA=50:1) of the residue gave about 4.5 g of colorless oil (...

Embodiment 3

[0082] Embodiment 3: Preparation of (3-chloro-1,1-dimethoxypropyl)benzene (compound shown in formula 3)

[0083]Compound 4 (5g, 0.03mol, 1eq) was dissolved in 25mL of dichloromethane (DCM), followed by adding methanol (4.8mL, 4eq), trimethyl orthoformate (6.3g about 6.5mL, 0.06mol, 2eq), mass Concentrated sulfuric acid with a percentage content of 98% (the mass percentage refers to the percentage of the mass of sulfuric acid in the total mass of the concentrated sulfuric acid reagent) (0.29g, 0.1eq). The reaction solution was heated to reflux (about 42° C.), and after stirring for 6 h, compound 4 disappeared as detected by TLC, and the temperature was lowered to cool. Add 1.5gNaHCO 3 The pH of the solid was adjusted to about 7, and stirred for 10 minutes. After suction filtration, the organic layer was washed with brine (10 mL), dried and concentrated to obtain about 7.2 g of an oily substance. Add 30mL of isopropanol to the residue, cool overnight to crystallize, and sucti...

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Abstract

The invention discloses a dapoxetine intermediate and a preparation method thereof and provides a preparation method for the compound represented in the formula (2). The preparation method includes a step of performing a nucleophilic substitution reaction to the compound represented in the formula (3) with 1-naphthol in a solvent in the presence of alkali to prepare the compound represented in the formula (2). The R1 and the R2 are independently C1-C4 alkyl groups, or that the R1, the R2, oxygen atoms connected thereto respectively and carbon atoms connected to the oxygen atoms form a five-membered saturated ring structure or six-membered saturated ring structure, wherein X is Cl, Br or I. The raw materials are low in cost and easy to obtain. The preparation method is mild in reaction conditions, is high in conversion rate, is high in yield, is simple in after treatment, is low in production cost, is high in chemical purity of product, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a dapoxetine intermediate and a preparation method thereof. Background technique [0002] 3-(1-naphthyloxy)-1-phenylacetone is an important intermediate in the synthetic process of the drug dapoxetine hydrochloride (dapoxetinehydrochloride) for the treatment of male premature ejaculation and sexual dysfunction, and its structural formula is as follows: [0003] [0004] The following three methods are currently reported in the literature. [0005] Route 1: (Jiang Junrong, CN101367739) [0006] [0007] Route 2: (Wen Ao, Liu Zijun, etc., CN102442891) [0008] [0009] Route 3: (Zhou Tao, Zeng Fanzhi, CN102229538) [0010] [0011] According to route 1 or 2, the by-product obtained by the Friedel-Crafts alkylation of 1-naphthol in the ortho and para positions has a structure as shown in formula A Rather than the important intermediate 3-(1-naphthyloxy)-1-phenylacetone in the synthetic process of dapoxetine hydroc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C43/315C07C41/50C07D317/22C07C49/84C07C45/42
Inventor 朱怡君李鸿雁周伟澄
Owner SHANGHAI INST OF PHARMA IND CO LTD
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