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Preparation method of key intermediate of paroxetine hydrochloride

A technology of paroxetine hydrochloride and intermediates, which is applied in the field of drug synthesis, can solve problems such as environmental pollution and waste, and achieve the effects of improving enterprise benefits and reducing input costs.

Active Publication Date: 2018-12-18
ZHEJIANG HUABANG MEDICAL & CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there is a key intermediate (±)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine racemate in the process of synthesizing paroxetine hydrochloride, but the synthesis Paroxetine hydrochloride only needs (-) trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine, because only this spatial configuration is effective, if (+)- If trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine cannot be utilized, it will cause a lot of waste and cause environmental pollution

Method used

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  • Preparation method of key intermediate of paroxetine hydrochloride
  • Preparation method of key intermediate of paroxetine hydrochloride
  • Preparation method of key intermediate of paroxetine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Add (+)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine (15.00g, 0.0672mol) and BPO (0.488g, 0.0020mol) into a 250ml three-necked flask ), add 80ml of dichloromethane to dissolve compound I, add NBS (17.94g, 0.1008mol) dichloromethane solution (concentration: 0.5mol / L) dropwise at room temperature, continue to stir for 6 hours after the addition is completed, and the HPLC central control shows the reaction End, then dropwise add 30ml of water to quench the reaction, separate the layers, extract the aqueous layer three times with dichloromethane (40ml×3 times), combine the organic layer, wash the organic layer three times with water (30ml×3 times), dry over anhydrous sodium sulfate, iso Compound II (16.84 g, 0.05575 mol) was obtained by beating with propanol, and the molar yield was 82.96%.

[0022] Add compound II (X=Br, 15.00g, 0.0496mol) and 90ml 1,2-dichloroethane into a 250ml three-necked flask, raise the temperature, and add 60ml N,N-diisopropylethylami...

Embodiment 2

[0025] Add (+)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine (15.00g, 0.0672mol) and azobisisobutyronitrile ( 0.328g, 0.0020mol), add 80ml tetrahydrofuran to dissolve compound Ⅰ, add NCS (17.95g, 0.1344mol) tetrahydrofuran solution (concentration: 0.7mol / L) dropwise at room temperature, continue stirring for 6 hours after the addition is completed, and the HPLC central control displays After the reaction was completed, 30ml of water was added dropwise to quench the reaction, concentrated to dry tetrahydrofuran, and separated, the aqueous layer was extracted three times with dichloromethane (40ml×3 times), the organic layer was combined, and the organic layer was washed three times with water (30ml×3 times). Drying over sodium sulfate and beating with isopropanol gave Compound II (13.07 g, 0.0507 mol), with a molar yield of 75.50%.

[0026] Add compound II (X=Cl, 12.78g, 0.0496mol) and 90ml toluene to a 250ml three-necked flask, raise the temperature, and add 60ml...

Embodiment 3

[0029]Add (+)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine (15.00g, 0.0672mol) and BPO (0.488g, 0.0020mol) into a 250ml three-necked flask ), add 80ml DMF to dissolve compound I, add NIS (27.22g, 0.121mol) DMF solution (concentration: 0.8mol / L) dropwise at room temperature, continue to stir for 6 hours after the addition is completed, the HPLC central control shows that the reaction is over, and then drop Add 30ml of water to quench the reaction, separate the layers, extract the aqueous layer three times with ethyl acetate (40ml×3 times), combine the organic layer, wash the organic layer three times with water (30ml×3 times), dry over anhydrous sodium sulfate, and beat with MTBE to obtain compound II (18.61g, 0.05329mol), molar yield 79.30%.

[0030] Add compound II (X=I, 17.32g, 0.0496mol) and 90ml chloroform into a 250ml three-necked flask, heat up, and add 60ml N,N-diisopropylethylamine (16.03g, 0.124mol) dropwise in chloroform at 60°C (Concentration is 1mol...

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Abstract

The invention discloses a preparation method of a key intermediate of paroxetine hydrochloride. The preparation method comprises: carrying out benzyl site halogenation on (+)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine as a starting material through a halogenation reagent to obtain a compound II, carrying out an elimination reaction process on the compound II to obtain a compound III, and carrying out catalytic hydrogenation reduction on the compound III to obtain (+)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine. The preparation method can convert a by-product (+)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine, which cannot be directly utilized, into (+ / -)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine. The product can be directly used as an intermediate for synthesizing paroxetine hydrochloride, change wastes into valuables, improve the benefits of enterprises and reduce the input cost of the enterprise.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a key intermediate of paroxetine hydrochloride (+)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine through a chemical method A synthetic method for conversion to (±)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine. . Background technique [0002] Paroxetine hydrochloride is a drug developed by GlaxoSmithKline to treat various types of depression, including depression accompanied by anxiety and reactive depression. It was first launched in 1992. At present, there is a key intermediate (±)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine racemate in the process of synthesizing paroxetine hydrochloride, but the synthesis Paroxetine hydrochloride only needs (-) trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine, because only this spatial configuration is effective, if (+)- If trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpipe...

Claims

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Application Information

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IPC IPC(8): C07D211/22
CPCC07D211/22
Inventor 万风云汤玉涛郑裕义
Owner ZHEJIANG HUABANG MEDICAL & CHEM
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