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A kind of biosynthesis method of dapoxetine intermediate and intermediate thereof

A technology for biosynthesis and dapoxetine, applied in chemical instruments and methods, preparation of carbon-based compounds, preparation of organic compounds, etc., can solve the problems of being unable to be suitable for large-scale industrial production, low product yield, and high cost, and achieve synthesis The effect of novel route, good product purity and low cost

Active Publication Date: 2022-02-11
HUAIYIN INSTITUTE OF TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] Existing patent literature: US19925135947; Non-patent literature: 1: Tetrahedron Letters 53 (2012) 3680-3682; 2: Synthetic Communications, 42: 3061-3067, 2012; all introduce the synthesis process of dapoxetine intermediate, but now In the existing technology, the synthesis process of dapoxetine intermediates is often complicated, the cost is high, and there are also defects of low product yield and poor quality, which cannot be suitable for industrialized large-scale production

Method used

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  • A kind of biosynthesis method of dapoxetine intermediate and intermediate thereof
  • A kind of biosynthesis method of dapoxetine intermediate and intermediate thereof

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Embodiment 1

[0033] Preparation of compound (4)

[0034] Under room temperature conditions, add compound (2) 1.69kg (10mol) and compound (3) 1.59kg (11mol) in 7L dichloromethane and 5L water in 20L reactor, add catalyst tetrabutylammonium bromide 16g (0.05 mol) and benzyltriethylammonium chloride 12g (0.05mol), after the TLC monitoring reaction was completed (42 hours), the reaction liquid was separated, and the organic phase was washed with 5% aqueous sodium bicarbonate solution 5L, and the organic phase was Concentration under pressure (0.02 mmHg) gave 2.68 kg (9.7 mol) of compound (4), with a molar yield of 97%, and a purity of 98.6% by HPLC.

[0035] 1 H NMR (400MHz, DMSO-d 6 )δ8.14–7.94(m,2H),7.71–7.24(m,9H),7.01–6.59(m,1H),4.13(t,J=7.8Hz,2H),2.97(t,J=7.8Hz ,2H).

[0036] ESI+[M+H] + =277.

[0037] Preparation of compound (1)

[0038] At 25°C, add the reaction solvent to the reaction kettle, then add the ammonia source, adjust the pH to 8.0 with hydrochloric acid, then add PLP ...

Embodiment 2

[0047] According to the synthetic method of embodiment 1, difference is: in the preparation of compound (4), the mol ratio of compound (2) and compound (3) is 1:1.2, and reaction temperature is 50 ℃, and reaction solvent is toluene and water ( Volume ratio 1:1), the molar ratio of compound (2) and catalyst tetrabutyl ammonium chloride is 200:20; Molar yield is 95.2%. Purity by HPLC: 97.2%.

[0048] In the preparation of compound (1), the reaction solvent is water / ethanol, the ammonia source is butylamine, and the concentration is 1.25M; the mass concentration of compound (4) is 150g / L; the compound (4) and biological enzyme (S152E, L161V) The mass concentration ratio is 75:1; the mass yield is 95.5%, and the HPLC detection purity is 97.8%.

Embodiment 3

[0050] According to the synthetic method of Example 1, the difference is that in the preparation of compound (4), the molar ratio of compound (2) and compound (3) is 1:1, the reaction temperature is 0 ° C, the reaction solvent is tetrahydrofuran, compound ( 2) The molar ratio to the catalyst benzyltriethylammonium chloride is 200:1; the molar yield is 92.1%. Purity by HPLC: 95.6%.

[0051] In the preparation of compound (1), the reaction solvent is water / methanol, the ammonia source is propylamine, and the concentration is 0.25M; the mass concentration of compound (4) is 2g / L; the mass concentration ratio of compound (4) and biological enzyme (ABJ05767) The ratio is 1:1; the mass yield is 90.5%, and the HPLC detection purity is 94.8%.

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Abstract

The invention discloses a biosynthesis method of a dapoxetine intermediate and an intermediate thereof. The method uses compound (2) and compound (3) as starting materials, and prepares compound (4) through a phase transfer catalytic substitution reaction , the compound (4) finally obtains the dapoxetine intermediate compound (1) through a biological enzyme conversion reaction, and its reaction formula is as follows: The biosynthesis method of the dapoxetine intermediate of the present invention has a novel synthetic route, Simple and easy to implement, low cost, high synthetic yield, high yield, good product purity, good product quality, cheap and easy-to-get raw materials, and suitable for industrial production. The preparation of poxetine provides a new intermediate raw material.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a biosynthesis method of a dapoxetine intermediate and an intermediate thereof. Background technique [0002] Dapoxetine (common name: (S)-Dapoxetine, trade name: Priligy), chemical name: S-(+)-N,N-dimethyl-a-[2-(naphthyloxy)ethyl base] benzylamine. The molecular weight of dapoxetine: 305.413; CAS registration number: 119356-77-3; the structural formula is shown in formula 1: [0003] [0004] Dapoxetine is currently the only drug developed for premature ejaculation (PE), and it is also the only treatment drug approved by CFDA for premature ejaculation (PE) indications. [0005] Dapoxetine is now approved for the treatment of premature ejaculation (PE) in nearly 60 countries around the world. Based on clinical trials involving more than 16,000 men worldwide, it has been proven that dapoxetine can significantly improve all indicators of premature ejaculati...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C217/48C07C49/84C07C45/64C12P13/00
CPCC07C217/48C07C45/64C12P13/001C07C49/84
Inventor 黄燕鸽游庆红袁君张世忠许莹李进徐纬川
Owner HUAIYIN INSTITUTE OF TECHNOLOGY
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