WO2017166050A1 - Procédé de préparation de chlorhydrate de trazodone - Google Patents

Procédé de préparation de chlorhydrate de trazodone Download PDF

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Publication number
WO2017166050A1
WO2017166050A1 PCT/CN2016/077666 CN2016077666W WO2017166050A1 WO 2017166050 A1 WO2017166050 A1 WO 2017166050A1 CN 2016077666 W CN2016077666 W CN 2016077666W WO 2017166050 A1 WO2017166050 A1 WO 2017166050A1
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WO
WIPO (PCT)
Prior art keywords
chloro
trazodone
chloropropyl
phenyl
hydrochloride
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2016/077666
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English (en)
Chinese (zh)
Inventor
彭锦安
王秋成
闫鹏
朱杭杭
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Shenthen Foncoo Pharmaceutical Co Ltd
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Shenthen Foncoo Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Priority to PCT/CN2016/077666 priority Critical patent/WO2017166050A1/fr
Publication of WO2017166050A1 publication Critical patent/WO2017166050A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of chemistry and chemical industry, and in particular relates to a preparation method of trazodone hydrochloride.
  • Trazodone hydrochloride Hydrochloride is a derivative of triazopyridine, which is mainly used for the treatment of depression and anxiety disorders accompanied by depressive symptoms and mood disorders after drug withdrawal.
  • the product has low side effects and strong tolerance. Its mechanism of action is: inhibiting the uptake of 5-HT by synaptic neurons, thereby increasing the concentration of 5-HT in the synaptic cleft to transmit information and achieve antidepressant purposes.
  • trazodone hydrochloride has a significant effect on improving sleep disorders.
  • trazodone hydrochloride is accompanied by a variety of impurities, wherein the impurity alkyl compound N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine is identified as a suspected gene.
  • Toxic impurities which are listed as key impurities in USP 38, are considered to be no more than 2.5 ppm, considering that the maximum daily dose of trazodone hydrochloride is 600 mg.
  • the impurity is one of the reactants for the synthesis of trazodone, according to the principle of chemical reaction equilibrium, it cannot be completely converted into trazodone, so controlling the residue becomes a difficult point and a key process for preparing trazodone hydrochloride, how to koji Controlling the yield of the impurity N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine during the synthesis of oxazolone, providing a method for preparing a rarer to produce less trazodone hydrochloride. It has become a technical problem to be solved in the field.
  • the present invention provides a preparation method of trazodone hydrochloride, which aims to reduce the impurity N-(3-chloro-phenyl)-N'-(3-chlorochloride) in the preparation product of trazodone hydrochloride.
  • the content of propyl)-piperazine is not limited to butyl-piperazine.
  • the present invention is achieved by a method for preparing trazodone hydrochloride comprising the following steps:
  • N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine hydrochloride is mixed with pyridine triazolone in a solvent, a base is added, and the mixture is heated to reflux;
  • reaction system is sequentially subjected to hot filtration, lye is added, and the temperature is raised again by reflux;
  • the resulting trazodone is reacted with hydrochloric acid.
  • the ratio of the amount of the pyridine triazolone to the N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine hydrochloride is from 1 to 1.5: 1.
  • the base is one of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, pyridine; the base and the N-(3- The ratio of the amount of the substance of chloro-phenyl)-N'-(3-chloropropyl)-piperazine hydrochloride is from 2 to 3:1.
  • the solvent is n-butanol, isobutanol, n-propanol, isopropanol, ethanol, methanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide or N, One of N-dimethylacetamide; the volume-to-mass ratio of the solvent to the N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine hydrochloride is 10 to 30 mL: 1 g.
  • the product of the temperature rise and reflux includes N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine, and the end point of the temperature rise reflux is the N-( The content of 3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine is less than 0.05%.
  • the temperature of the hot filtration is 50 to 75 °C.
  • the concentration of the alkali liquid is 5% to 20% by weight; the solute of the alkali liquid is sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, One of pyridine.
  • volume ratio of the lye to the solvent is from 1% to 15%:1.
  • the temperature of the temperature rise and reflux is 80 to 85 °C.
  • the temperature for re-heating and refluxing is 82 to 87 ° C, and the time is 6 to 8 hours.
  • the temperature of the crystallization is -5 to 15 ° C, and the time is 1 to 4 hours.
  • preparation method further comprises: filtering and drying after crystallization.
  • the concentration of the hydrochloric acid is 12 mol/L, and the condition that the trazodone is reacted with hydrochloric acid is to adjust the reaction system to a pH of 1 to 5.
  • the invention also provides a method for reducing the content of the impurity N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine in the preparation of trazodone hydrochloride, which adopts the preparation method described above Carry out the reaction.
  • the invention has the beneficial effects that: the invention improves the preparation process of the trazodone hydrochloride, adjusts the reaction parameters in the reaction process, and further increases the reaction after adding the alkali aqueous solution after the completion of the synthesis reaction, and performs the temperature rising reflux. And cooling and crystallization, etc., to make the impurity N-(3-chloro-benzene Base
  • the residual amount of -N'-(3-chloropropyl)-piperazine is within 2.5 ppm, reaching industry-standard standards.
  • the preparation method of the trazodone hydrochloride of the invention improves the total yield of the product; the process streamlining step reduces the production cost; and the process is stable and can be industrially produced.
  • Figure 1 is a chemical structural formula of trazodone hydrochloride prepared by the present invention.
  • FIG. 3 is a detection device according to an embodiment of the present invention.
  • FIG. 4 is an MS/MS method parameter provided by an embodiment of the present invention.
  • FIG. 5 is a detection result provided by an embodiment of the present invention.
  • Step 1 Mixing N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine hydrochloride with pyridine triazolone, adding a base, and heating to reflux;
  • Step 2 sequentially heat-filtering the reaction system, adding an alkali solution, and heating the reflux again;
  • Step three crystallization, filtration, and drying to obtain trazodone
  • Step 4 The obtained trazodone is reacted with hydrochloric acid to obtain trazodone hydrochloride.
  • the specific process is: sequentially adding N-(3-chloro-phenyl group) to the reaction flask at room temperature. )-N'-(3-chloropropyl)-piperazine hydrochloride, pyridine triazolone, reaction solvent, mechanical stirring, addition of alkali, nitrogen protection, heating to reflux, after the reaction reaches the end point, control temperature is hot Filtration, the filtrate was added with an aqueous alkali solution, and the temperature was refluxed to continue the reaction. The filtrate was cooled and crystallized, kept warm, filtered, and dried under vacuum at 50 ° C to give a pale yellow solid.
  • the ratio of the amount of the pyridine triazolone to the N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine hydrochloride is 1 to 1.5:1, preferably 1.1 to 1.3:1.
  • the base is one of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, pyridine; wherein the base and the N-(3-chloro-phenyl)
  • the ratio of the amount of the substance of -N'-(3-chloropropyl)-piperazine hydrochloride is from 2.0 to 3.0:1, preferably from 2.1 to 2.4:1.
  • the solvent is n-butanol, isobutanol, n-propanol, isopropanol, ethanol, methanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide or N,N-dimethyl
  • the volume-to-mass ratio of the solvent to N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine hydrochloride is 10 to 30 mL: 1 g, preferably 15 ⁇ 20mL: 1g.
  • the reaction product includes N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine, and the temperature at reflux is 80-85 ° C.
  • the content of N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine is detected by HPLC to be less than 0.05%, preferably less than 0.02%, and the time is generally 24 to 28 hours, preferably 26 hours.
  • the temperature of the hot filtration is 50 to 75 ° C, preferably 60 to 70 ° C.
  • the concentration of the added alkali solution is 5% ⁇ 20%wt, preferably 10% ⁇ 15%wt; the solute of the alkali solution is sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, three One of ethylamine and pyridine is preferably sodium hydroxide or potassium hydroxide.
  • the volume ratio of the lye to the solvent is from 1% to 15%:1, preferably from 5% to 10%:1.
  • the temperature at which the temperature is again refluxed is 82 to 87 ° C, and the time is 6 to 8 hours, preferably 8 hours.
  • the temperature of the crystallization is -5 to 15 ° C, preferably 0 to 5 ° C; and the time is 1 to 4 hours, preferably 2 to 3 hours.
  • the filtration was carried out at room temperature, and the drying was naturally air-dried.
  • the concentration of hydrochloric acid used is 12 mol/L, and the reaction between the trazodone and hydrochloric acid is such that the reaction system is adjusted to have a pH of 1 to 5, preferably 2.5 to 3.5.
  • the key impurity of the obtained trazodone hydrochloride is N-(3-chloro-phenyl)-N'-(3-chloro
  • the propyl)-piperazine residue is 100 ppm or more, and if the impurity is not separately purified, the trazodone hydrochloride is directly obtained, and even if it is purified a plurality of times, it is difficult to achieve the requirement of 2.5 ppm or less.
  • Patent CN 101772490 The method of B requires an increase in the step of separately purifying the impurity by trazodone or trazodone hydrochloride.
  • the patent reports a yield higher than 85%, the method is cumbersome, uses a high boiling point and is not commonly used as a solvent; Large; when using a solvent that is miscible with water, it is difficult to recover trazodone, and it is used in azeotropic distillation to consume energy during production.
  • the preparation method of the invention has low solvent and small water ratio; on the basis of the conventional preparation method of trazodone, the hot filtration, the addition of alkaline water and the reheating and refluxing operation are carried out, and the improved operation is compared with the original process. Combine, reduce energy consumption and save time.
  • the preparation method of the present invention solves the problems existing in the prior art, and the effect is remarkable.
  • N-(3-chloro-phenyl group) 100 g (0.323 mol) of N-(3-chloro-phenyl group) was sequentially added to a 2 L three-necked flask at room temperature.
  • -N'-(3-chloropropyl)-piperazine hydrochloride 52.4 g (0.388 mol) of pyridine triazolone, 1500 mL of isopropanol, mechanical stirring, 29.7 g (0.743) Mol) sodium hydroxide, nitrogen protection, warming to reflux, reaction for 26 hours
  • HPLC detection of N-(3-chloro-phenyl The content of -N'-(3-chloropropyl)-piperazine was 0.02%.
  • Diluent acetonitrile, water and formic acid (100:900:1, v/v/v)).
  • the preparation method of trazodone hydrochloride provided by the invention can achieve the key impurity N-(3-chloro-phenyl)-N'-(3-chloropropene) which is produced during the preparation process.
  • the residual amount of the base)-piperazine is controlled within 2.5 ppm, which is significantly lower than the content of the impurity N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine in the prior preparation process. Therefore, it can directly meet the limit requirement of the impurity in the industry.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention est appliquée au domaine de la chimie et de l'ingénierie chimique, et concerne un procédé de préparation de chlorhydrate de trazodone, comprenant les étapes suivantes : le mélange de chlorhydrate de N-(3-chloro-phényl))-N'-(3-chloropropyl)-pipérazine avec de la 1,2,4-triazolo[4,3-a] pyridin-3 (2H)-one dans un solvant, l'ajout d'alcali au mélange, et la refusion pendant le chauffage ; la réalisation d'une filtration à chaud dans un système de réaction, l'ajout d'un liquide alcalin, et la refusion tout en chauffant à nouveau en séquence ; l'obtention de trazodone par cristallisation ; et la réaction du trazodone obtenu avec de l'acide chlorhydrique pour obtenir du chlorhydrate de trazodone. Le procédé de préparation du chlorhydrate de trazodone, selon la présente invention, améliore le rendement total du produit et réduit significativement la teneur en impureté, N-(3-chloro-phényl))-N'-(3-chloropropyl)-pipérazine, et peut donc répondre directement aux exigences liées à l'industrie. Le procédé simplifie les étapes du procédé, réduit les coûts de production, présente une bonne stabilité de procédé et est applicable à la production industrielle.
PCT/CN2016/077666 2016-03-29 2016-03-29 Procédé de préparation de chlorhydrate de trazodone Ceased WO2017166050A1 (fr)

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PCT/CN2016/077666 WO2017166050A1 (fr) 2016-03-29 2016-03-29 Procédé de préparation de chlorhydrate de trazodone

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Application Number Priority Date Filing Date Title
PCT/CN2016/077666 WO2017166050A1 (fr) 2016-03-29 2016-03-29 Procédé de préparation de chlorhydrate de trazodone

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210032243A1 (en) * 2018-02-07 2021-02-04 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. Continuous process for the preparation of trazodone
CN117517545A (zh) * 2023-12-08 2024-02-06 重庆锐恩医药有限公司 一种盐酸曲唑酮有关物质检测方法
WO2025220036A1 (fr) * 2024-04-16 2025-10-23 Medilux Laboratories Pvt. Ltd. Nouveau procédé de préparation de chlorhydrate de trazodone

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
XUE, XUMING ET AL.: "Synthesis of Trazodone Hydrochloride", CHINESE JOURNAL OF PHARMACEUTICALS, vol. 39, no. 11, 31 December 2008 (2008-12-31), pages 808 - 810, XP008183924, ISSN: 1001-8255 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210032243A1 (en) * 2018-02-07 2021-02-04 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. Continuous process for the preparation of trazodone
US12221438B2 (en) * 2018-02-07 2025-02-11 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. Continuous process for the preparation of trazodone
CN117517545A (zh) * 2023-12-08 2024-02-06 重庆锐恩医药有限公司 一种盐酸曲唑酮有关物质检测方法
WO2025220036A1 (fr) * 2024-04-16 2025-10-23 Medilux Laboratories Pvt. Ltd. Nouveau procédé de préparation de chlorhydrate de trazodone

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