Midbody for preparing dapoxetine and preparation method for dapoxetine

A technology of dapoxetine and intermediates, applied in the field of organic synthesis of medicines, can solve the problems of highly toxic solvents, difficult to remove impurities, difficult to control optical purity, etc., and achieves simple operation, difficult to remove impurities, and mild reaction conditions. Effect

CN107473977AInactive Publication Date: 2017-12-15成都海杰亚医药科技有限公司
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Patent Information

Authority / Receiving Office
CN · China
Patent Type
Applications(China)
Current Assignee / Owner
Publication Date
2017-12-15
Estimated Expiration
Not applicable · inactive patent

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Abstract

The invention relates to a midbody for preparing dapoxetine and a preparation method for dapoxetine. The dapoxetine hydrochloride with high optical purity can be acquired through a preparation path provided by the invention according to the steps of performing sulfonylation reaction, performing substitution reaction with 1-kaempferol, removing Boc protecting group from acid system and then converting into the compound dapoxetine shown as formula II in formalin under the effect of reducing agent. The preparation method provided by the invention is mild in reaction condition, simple in operation, high in optical purity and chemical purity and suitable for industrial large-scale production.
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Description

technical field

[0001] The invention relates to the technical field of organic synthesis of medicines, in particular to a preparation method of dapoxetine. Background technique

[0002] Dapoxetine, its cultural name: (+)-(S)-N,N-dimethyl-(α)-[2-(1-naphthyloxy)ethyl]-benzylamine .

[0003] Cas. No. 119356-11-3, its structural formula:

[0004]

[0005] Dapoxetine (dapoxetine) is a chemical drug, as a new rapid SSRI, with a short half-life, belonging to the selective serotonin reuptake inhibitor (SSRI), used for the treatment of male premature ejaculation and erectile dysfunction, the effective rate It is 98%. The drug was developed by Eli Lilly and was first launched in Sweden and Finland in 2009. The trade name is Priligy. Xetine is absorbed quickly and can quickly reach the effective blood concentration; the tissue distribution is wide, and the drug concentration in nerve tissue is close to the blood concentration. This drug is the first oral prescription drug approve...

Examples

Embodiment 1

[0051] Adopt the following route to synthesize dapoxetine:

[0052]

[0053]Concretely comprise following reaction steps:

[0054] a) performing a sulfonylation reaction on the hydroxyl group of the compound represented by the formula VI with a suitable sulfonylation reagent to obtain the compound of the formula V;

[0055] The preparation method described in step a, its sulfonylation reagent refers to methanesulfonyl chloride, phenylsulfonyl chloride, p-toluenesulfonyl chloride, 2-nitrobenzenesulfonyl chloride, 3-nitrobenzenesulfonyl chloride, 4- Nitrobenzenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride, etc., preferably methanesulfonyl chloride and 3-nitrobenzenesulfonyl chloride.

[0056] The base used in the sulfonylation reaction is selected from triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, cesium carbonate, etc., preferably Triethylamine and...

Embodiment 2

[0064] Example 2 Preparation experiment of dapoxetine hydrochloride

[0065] The S-1-N-Boc-3-aminophenylpropanol used in the experiment was produced by the company itself.

[0066] Step 1: Sulfonylation reaction

[0067] Dissolve S-1-N-Boc-3-aminophenylpropanol VI (2.51 kg, 10.0 mole) in 25kg of dichloromethane, control the temperature in the kettle to less than 10 degrees, add triethylamine (1.51kg, 15.0 mole ), add methanesulfonyl chloride (1.35kg, 12.0 mole) dropwise to the reaction system, stir for 1 hour after the dropwise addition, TLC monitors that the reaction is complete, add dilute hydrochloric acid to the reaction system to make the reaction system nearly neutral, let stand , liquid separation, the aqueous layer was extracted twice with dichloromethane, the organic phase was combined, the organic phase was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated to dryness to obtain intermediate Va (3.12 kg, yield 95% ...