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Preparation method of dapoxetine hydrochloride related substance I

A technology of dapoxetine hydrochloride and related substances, which is applied in the field of drug synthesis, can solve the problems of long synthetic routes, ineffective separation of configurations, expensive raw materials, etc., and achieve low cost, high product configuration selectivity, and synthetic Effects in simple steps

Inactive Publication Date: 2019-06-28
WEIFANG UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The main disadvantage of this method is that the synthetic route is long (6 steps), the raw material is expensive, and the obtained product is a racemate, and the configuration cannot be effectively separated.

Method used

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  • Preparation method of dapoxetine hydrochloride related substance I
  • Preparation method of dapoxetine hydrochloride related substance I
  • Preparation method of dapoxetine hydrochloride related substance I

Examples

Experimental program
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Effect test

preparation example Construction

[0033] The preparation of dapoxetine hydrochloride related substance I of the present invention comprises steps 1 to 3:

[0034] Step 1: 1-naphthol undergoes Friedel-Crafts alkylation reaction with 3-chloropropiophenone under alkaline conditions to generate compound 1.

[0035] Step 2: Compound 1 reacts with (R)-3-chloro-1-phenyl-1-propanol under basic conditions to generate compound 2 through a substitution reaction.

[0036] Step 3: Compound 2 finally generates dapoxetine related substance I through a one-pot multi-step method. The specific method is that compound 2 is first reacted with methanesulfonyl chloride, and then dimethylamine gas is introduced into the reaction. After the reaction is completed, hydrogen chloride gas is introduced to form a salt.

[0037] Its synthetic route is as follows:

[0038]

[0039] In the process of preparing dapoxetine hydrochloride related substance I, the present invention realizes the generation of compound 1 under alkaline conditi...

Embodiment 1

[0044]

[0045] Dissolve 10 g of 1-naphthol in acetonitrile (20 mL), add Na 2 CO 3 (20g), heated to reflux for 1h. 10 g of 3-chloropropiophenone was dissolved in acetonitrile (20 mL), and added dropwise to the reaction solution under a water bath, and the reaction was refluxed for 3 hours. TLC detection showed that the reaction of 3-chloropropiophenone was complete. Cool to room temperature, add 100 ml of ethyl acetate to separate layers, wash the organic phase twice with water and once with saturated brine, combine the organic phases and evaporate to dryness under reduced pressure to obtain a crude product. Purified by silica gel column chromatography, an off-white solid (compound 1) was obtained with a yield of 93%.

[0046] 1 H NMR (400MHz, CDCl3) δ8.26 (d, J = 8.0Hz, 1H), 8.03-7.97 (m, 1H), 7.96 (d, J = 7.6Hz, 2H), 7.59-7.48 (m, 3H) ,7.44(t,J=7.3Hz,2H),7.22(d,J=7.5Hz,1H),6.76(d,J=7.5Hz,1H),5.40(s,1H),3.43(dd,J= 18.1, 6.2Hz, 4H).

Embodiment 2

[0048]

[0049] Add 7g of compound 1 to DMF (50ml), add 5g (R)-3-chloro-1-phenyl-1-propanol (CAS No. 100306-33-0), add DBU (6g), and heat up to 70 The reaction was carried out at ℃ for 5 h, and the raw materials were detected by TLC to be completely reacted. Cool to room temperature, add ethanol (EA) (100ml) to separate the layers, wash three times with water, once with saturated brine, dry, and concentrate to dryness under reduced pressure. Purified by silica gel column chromatography, a light yellow solid (compound 2) was obtained with a yield of 87%.

[0050] 1H NMR (400MHz, CDCl 3)δ8.25(d,J=8.1Hz,1H),7.93(d,J=8.1,1H),7.89(d,J=7.8Hz,2H),7.55-7.41(m,3H),7.41-7.35 (m,4H),7.31(m,2H),7.21(m,2H),6.67(d,J=7.8Hz,1H),5.09(s,1H),4.34-4.02(m,2H),3.36( m, 4H), 2.41-2.21 (m, 3H).

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Abstract

The invention discloses a preparation method of a dapoxetine hydrochloride related substance I. The method comprises the following steps that 1, 1-naphthol is dissolved into a first solvent, an alkaline substance is added to form the alkaline environment, 3-Chloropropiophenone is added for a reaction, and a compound shown in the formula I is generated; 2, the compound shown in the formula I is dissolved into a second solvent, under the alkali condition, the compound reacts with (R)-3-choro-1-phenyl-1-propyl alcohol, and a compound shown in a formula II is generated; 3, the compound shown in the formula II is dissolved into a third solvent, triethylamine and methylsulfonyl chloride are added for a stirring reaction, after the reaction is completed, dimethylamine gas is introduced, after thereaction is performed, hydrogen chloride gas is introduced, and the dapoxetine hydrochloride related substance I is obtained; the preparation method is simple in synthesis steps, mild in reaction condition, high in product yield and high in product structure selectivity, and the sample with high purity can be obtained as a reference substance for inspecting the dapoxetine hydrochloride related substance.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of related substance I of dapoxetine hydrochloride. Background technique [0002] Dapoxetine Hydrochloride, the chemical name is (S)-N,N-dimethyl-3-(naphthyl-1-oxyl)-1-phenylpropan-1-amine hydrochloride , is a new type of serotonin reuptake inhibitor, which has the characteristics of fast absorption and clearance in the body. It is the first oral drug approved for the treatment of premature ejaculation in men. So far, it has been approved for marketing in more than 50 countries in the world. Its structural formula is as follows: [0003] [0004] Dapoxetine related substance I is an impurity produced in the production process of dapoxetine hydrochloride. Its structural formula is as follows: [0005] [0006] Dapoxetine related substance I has a crucial impact on the safety and effectiveness of the final drug. Therefore, determine the prepara...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/02C07C217/48
Inventor 潘斌
Owner WEIFANG UNIV OF SCI & TECH
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