WO2015110883A1 - An improved process for the preparation of trazodone and hydrochloride salt thereof - Google Patents

An improved process for the preparation of trazodone and hydrochloride salt thereof Download PDF

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Publication number
WO2015110883A1
WO2015110883A1 PCT/IB2014/066841 IB2014066841W WO2015110883A1 WO 2015110883 A1 WO2015110883 A1 WO 2015110883A1 IB 2014066841 W IB2014066841 W IB 2014066841W WO 2015110883 A1 WO2015110883 A1 WO 2015110883A1
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Prior art keywords
compound
trazodone
free base
tetra
hydrochloride salt
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PCT/IB2014/066841
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English (en)
French (fr)
Inventor
Shashikant KADAM
Narender Rao SOMISETTI
Srinivas ASHILI
Narsimulu RAIGONI
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Piramal Enterprises Limited
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Application filed by Piramal Enterprises Limited filed Critical Piramal Enterprises Limited
Priority to EP14879353.2A priority Critical patent/EP3097099A4/en
Priority to JP2016547540A priority patent/JP2017505302A/ja
Priority to CA2937417A priority patent/CA2937417C/en
Publication of WO2015110883A1 publication Critical patent/WO2015110883A1/en
Priority to IL246835A priority patent/IL246835A0/en

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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 present invention relates to an improved process for the preparation of 2- ⁇ 3-[4-(3- chlorophenyl)piperazin-l-yl]propyl ⁇ [l,2,4]triazolo[4,3- ]pyridin-3(2H)-one, generically known as Trazodone, and its hydrochloride salt.
  • Trazodone 2- ⁇ 3-[4-(3- chlorophenyl)piperazin-l-yl]propyl ⁇ [l,2,4]triazolo[4,3- ]pyridin-3(2H)-one, generically known as Trazodone, and its hydrochloride salt.
  • Trazodone hydrochloride referred to as the compound- I.
  • Trazodone is a serotonin-2 receptor antagonist/reuptake inhibitor that decreases extracellular gamma-amino-butyric acid (GABA) levels in the cerebral cortex through the blockade of 5- hydroxytryptamine 2A (5-HT 2 A) receptors. This decrease is accompanied by an increase in 5- HTrelease. At higher doses, trazodone inhibits 5-HT transport and this inhibition of 5-HT uptake results in further increase in 5-HT levels. It is contemplated that this dual mechanism may be responsible for the anti-depressant properties of Trazodone. Moreover, the interaction between the GABAergic and serotoninergic systems may explain its sedative/anxiolytic properties.
  • GABA gamma-amino-butyric acid
  • Trazodone is therefore a psychoactive compound with sedative and anti-depressant properties. It is rapidly absorbed from the upper gastro-intestinal tract and is extensively metabolized after oral administration. It is normally used to relieve symptoms of depression such as feelings of sadness, worthlessness, or guilt; loss of interest in daily activities; changes in appetite; tiredness; thoughts of death or suicide; and insomnia. Trazodone in its salt form, particularly as hydrochloride salt, is represented by the following structural formula;
  • the US'009 Patent also describes an alternative process for the synthesis of trazodone which comprises condensation of 2-(3-chloropropyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one with l-(3- chlorophenyl)piperazine in the presence of triethyl amine and the solvent, dioxane.
  • the US'009 Patent further describes two more alternative processes for the preparation of trazodone, wherein one process comprises reaction of 2-(3-morpholinopropyl)- [l,2,4]triazolo[4,3-a]pyridin-3(2H)-one with 3-chloroaniline; and the other comprises reaction of 2-(3-aminopropyl)-[l,2,4]triazolo[4,3-a]pyridin-3(2H)-one with 3-chloro-N,N-bis(2- chloroethyl)aniline.
  • European Patent EP1108722B1 describes a process for preparation of Trazodone hydrochloride (compound-I) comprising treatment of Trazodone base with aqueous solution of hydrochloric acid.
  • US Patent No.5,256,664 describes a process for the preparation of trazodone which comprises treatment of l-(3-chlorophenyl)-4-(3-chloropropyl)piperazine hydrochloride with an aqueous solution of sodium hydroxide (NaOH) and extraction with methylene chloride. The organic layer was concentrated to produce an oily intermediate compound, l-(3-chlorophenyl)-4-(3- chloropropyl)piperazine (free base) which is further reacted with [l,2,4]triazolo[4,3-a]pyridin- 3(2H)-one in the presence of sodium hydroxide and in isopropyl alcohol as the solvent under reflux conditions.
  • the crude oily trazodone was purified using flash chromatography on silica gel.
  • the purified trazodone in isopropyl alcohol was further treated with 2N HCL (hydrochloric acid) to produce trazodone hydrochloride with 47% of yield.
  • Hungarian patent application No. 201324 describes a process for the preparation of Trazodone comprising reaction of l,2,4-triazolo-(4,3-a)-pyridine -3(2H)-one with l-(3'-chloro-propyl)-4- (m-chlorophenyl)-piperazine -hydrochloride in the presence of an alkali-carbonate or powdered sodium-hydroxide wherein the reaction is carried out specifically in a polar aprotic solvent.
  • US Patent No. 8,133, 893(the US'893 Patent) and US Patent No. 8,314,236 describe a process for the purification of trazodone and further conversion of the purified trazodone to its hydrochloride salt.
  • the process described in the US'893 Patent essentially comprises ;(a) preparing an organic phase comprising trazodone in at least one organic solvent; (b) preparing an aqueous phase comprising at least one basic compound and optionally, contains a phase transfer catalyst ; (c) mixing said aqueous phase with said organic phase to obtain a mixture; (d) heating said mixture at a temperature of at least 40° C for at least 30 minutes; (e) recovering said trazodone; and, (f) optionally, treating said trazodone with hydrochloric acid to obtain trazodone hydrochloride.
  • the said trazodone hydrochloride is obtained by the treatment with 12N HC1 aqueous solution.
  • the process of US'893 require azeotropic distillation of crude trazodone solution to remove residual water that was incurred from the aqueous phase. It is evident from the above discussion of the processes for the synthesis of trazodone described in afore cited patent documents that the reported processes primarily requires longer reaction time. Further, the prior art processes involve additional purification methods such as column chromatography, or taking the compound in an organic solvent and washing it with basic aqueous solution; which render the process costlier. Also, these processes involve tedious workup procedures.
  • trazodone and/or its salt such as Trazodone hydrochloride (the compound I) with improved yield and purity in shorter time duration.
  • Inventors of the present invention have developed an improved process that addresses the problems associated with the processes reported in the prior art.
  • the process of the present invention does not involve use of any additional costly reagents.
  • the process does not require additional purification steps and critical workup procedure such as azeotropic distillation.
  • the present invention provides a process for the preparation of trazodone or its salt, which is cost effective, environmentally friendly and commercially scalable for large scale operations.
  • the present invention relates to an improved process for the preparation of trazodone or its hydrochloride salt (the compound I), comprising reacting the compound-II (as described herein) with the compound-Ill (as described herein) optionally in the presence of an inorganic base, and a catalyst.
  • the present invention relates to an improved process for the preparation of trazodone or its hydrochloride salt (the compound I), comprising reacting the compound-II (as described herein) with the compound-Ill (as described herein) optionally in the presence of an inorganic base, and a catalyst; wherein in the said process the trazodone free base and/or its hydrochloride salt are isolated by precipitation at lower temperature.
  • the present invention relates to an improved process for the preparation of trazodone or its hydrochloride salt (the compound I), comprising reacting the compound-II (as described herein) with the compound-Ill (as described herein) in the presence of an inorganic base and a phase transfer catalyst.
  • the present invention relates to an improved process for the preparation of trazodone or its hydrochloride salt (the compound I), comprising reacting the compound-II (as described herein) with the compound-Ill (as described herein) in the presence of an antioxidant as the catalyst.
  • the present invention relates to an improved process for the preparation of trazodone hydrochloride (compound I), comprising reacting the compound-II with the compound-Ill in the presence of an inorganic base and a phase transfer catalyst followed by treatment with an alcoholic solution of hydrogen chloride.
  • the present invention relates to an improved process for the preparation of trazodone hydrochloride (compound I), comprising isolation of pure trazodone free base or its hydrochloride salt in the absence of water.
  • an improved process for the preparation of trazodone hydrochloride (the compound I) wherein the product contains total amount of alkylating substances (as described herein) as impurities in less than 10 ppm.
  • an improved process for the preparation of trazodone hydrochloride (the compound I) wherein the product contains total amount of l-(3-chlorophenyl)-4-(3-chloropropyl) piperazine as an impurity in less than 2.5 ppm.
  • the present invention relates to an improved process for the preparation of trazodone hydrochloride (the compound I) represented by the following formula;
  • step (b) treating the compound I as free base obtained in the above step (a) with an alcoholic solution of hydrogen chloride to obtain the corresponding hydrochloride salt (the compound I); wherein, in the said process compound I as a free base and/or its hydrochloride salt (compound I) are isolated by precipitation at a lower temperature.
  • the step (a) is carried out in the presence of an inorganic base; and the said inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, calcium carbonate, sodium hydroxide and potassium hydroxide.
  • the catalyst used in the process step (a) is a phase transfer catalyst or an antioxidant.
  • the catalyst used in the process step (a) is a phase transfer catalyst.
  • the present invention relates to a process for the preparation of trazodone or its hydrochloride salt (compound I) of the following formula,
  • the phase transfer catalyst is a quaternary ammonium salt selected from the group consisting of tricaprylyl methyl ammonium chloride (Aliquat 336), tetra-n-butyl ammonium bromide, triethylbenzylammonium chloride (TEBAC), cetyltrimethylammonium bromide (CTAB), cetylpyridiniumbromide, N-benzylquininiumchloride, tetra-n-butyl ammonium chloride, tetra-n-butyl ammonium hydroxide, tetra-n-butyl ammonium iodide, tetra- ethyl ammonium chloride, benzyltributyl ammonium chloride, benzyltriethylammoniumbromide, hexadecyltriethylammoniumchloride, tetramethylammonium chloride, hexadecyl,
  • the phase transfer catalyst is tetra-n-butyl ammonium bromideor triethylbenzyl Ammonium Chloride (TEBAC).
  • the catalyst used in the process step (a) is an antioxidant.
  • the present invention relates to a process for the preparation of trazodone or its hydrochloride salt (compound I) of the following formula,
  • the antioxidant is selected from the group consisting of butylatedhydroxytoluene (BHT), butylatedhydroxyanisole (BHA), tertiary butylhydroquinone (TBHQ), propylgallate (PG), and hydroquinone monomethylether (MEHQ).
  • BHT butylatedhydroxytoluene
  • BHA butylatedhydroxyanisole
  • TBHQ tertiary butylhydroquinone
  • PG propylgallate
  • MEHQ hydroquinone monomethylether
  • the antioxidant used in step (a) is butylatedhydroxytoluene (BHT).
  • the solvent used in step (a) of the process is selected from an alcohol such as ethyl alcohol, n-propyl alcohol, isopropyl alcohol, isobutyl alcohol and methanol; an ether such as ethyl ether or propylether; aromatic hydrocarbon solvents such as toluene, benzene or xylene; and other solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, dioxane, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide or dimethylacetamide.
  • the solvent used in step (a) of the process is isopropyl alcohol (IPA).
  • the alcoholic solution of hydrogen chloride used in step (b) of the process is selected from the group consisting of isopropyl alcohol hydrochloride (IPA.HCl), ethanolic HCl and methanolic HCl.
  • the alcoholic solution of hydrogen chloride used in step (b) of the process is isopropyl alcohol hydrochloride (IPA.HCl).
  • trazodone free base as obtained in step (a) of the process is isolated by precipitation at lower temperature.
  • trazodone hydrochloride (compound I) as obtained in step (b) of the process is isolated by precipitation at lower temperature.
  • trazodone free base in step (a); and/or trazodone hydrochloride in step (b) of the process is isolated by precipitation at lower temperature of about 5 °C.
  • the term 'lower temperature" referred to in the step (a)and step (b) of the above process can range from 0 °C to 10°C.In the context of the present invention the term "lower temperature” can be used interchangeably with the term "lower temperature of about 5°C".
  • process for the preparation of trazodone hydrochloride comprises the steps of, (1) dissolving the compound II (as its hydrochloride salt)in a solvent, in the presence of an
  • step (2) adding the compound III and a phase transfer catalyst to the reaction mixture of step (1);
  • step (6) isolating the precipitated product obtained in the step (5) and treating it with an alcoholic solution of hydrogen chloride at a temperature of about 60 °C; (7) cooling the reaction mixture of step (6) to a lower temperature of about 5 °C to obtain a
  • the solvent used in the step-(l) of the above process is selected from an alcohol such as ethyl alcohol, n-propyl alcohol, isopropyl alcohol, isobutyl alcohol and methanol; an ether such as ethyl ether or propylether; aromatic hydrocarbon solvents such as toluene, benzene or xylene; and other solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, dioxane, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide or dimethylacetamide.
  • an alcohol such as ethyl alcohol, n-propyl alcohol, isopropyl alcohol, isobutyl alcohol and methanol
  • an ether such as ethyl ether or propylether
  • aromatic hydrocarbon solvents such as toluene, benzene or xylene
  • other solvents
  • the solvent used in step-( 1 ) of the above process is selected from the group consisting of ethyl alcohol, n-propyl alcohol, isopropyl alcohol, isobutyl alcohol and methanol.
  • the solvent used in step-( 1 ) of the above process is isopropyl alcohol (IPA).
  • the inorganic base used in the step-(l) of the above process is selected from the group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, calcium carbonate, sodium hydroxide and potassium hydroxide.
  • the inorganic base is used in an amount ranging from 1.5 to 2.5 equivalents with reference to the compound II.
  • the phase transfer catalyst used in the step-(2) of the above process is a quaternary ammonium salt selected from the group consisting of tricaprylyl methyl ammonium chloride (Aliquat 336), tetra-n-butyl ammonium bromide, triethylbenzylammonium chloride (TEBAC), cetyltrimethyl- ammonium bromide (CTAB), cetylpyridiniumbromide,N- benzylquininiumchloride, tetra-n-butyl ammonium chloride, tetra-n-butyl ammonium hydroxide, tetra-n-butyl ammonium iodide, tetra-ethyl ammonium chloride, benzyltributylammonium chloride, benzyltriethylammoniumbromide, hexadecyltriethylammoniumchloride,
  • phase transfer catalyst used in the step-(l) of the process is selected from tetra-n-butyl ammonium bromideor triethylbenzylammonium chloride (TEBAC).
  • TEBAC triethylbenzylammonium chloride
  • the phase transfer catalyst (PTC) is used in an amount ranging from 1 % to 5% with reference to the compound-II.
  • the term 'temperature of about 85°C referred to in the step (3) of the above process can range from 80 °C to 90°C.
  • step (5), step (7) and step (10) of the above process can range from 0°C to 10°C.
  • step (6) The term 'isolating the precipitated product' referred to in the step (6), step (8) and step (10) corresponds to the steps involving filtration, washing and drying.
  • the 'alcoholic solution of hydrogen chloride' used in the step (6) of the above process is selected from the group consisting of isopropyl alcohol hydrochloride (IPA.HC1), ethanolic HCl and methanolic HCl.
  • the alcoholic solution of hydrogen chloride used in the process is isopropyl alcohol hydrochloride (IPA.HC1).
  • the 'alcoholic solvent' used in the steps (6) and (8) of the process(as depicted in the Scheme II) is an alcohol selected from the group consisting of methanol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol and isobutyl alcohol.
  • the alcohol used in step-(8) of the process is methanol.
  • the process of the present invention as illustrated in the above Scheme-II comprises reaction of the compound II (as its HCl salt) and compound III in the presence of an inorganic base selected from sodium carbonate or potassium carbonate, and a phase transfer catalyst (PTC) catalyst selected from tetra-n-butyl ammonium bromide or triethylbenzylammonium chloride (TEBAC) in isopropyl alcohol as the solvent.
  • PTC phase transfer catalyst
  • TEBAC triethylbenzylammonium chloride
  • the precipitated product was isolated by filtration and the wet cake was dissolved in 3 volume of IPA (isopropyl alcohol) and acidified with IPA HC1 at a temperature about 50-60 °C.
  • the reaction mixture was cooled to 0-5 °C and the precipitated product was isolated by filtration.
  • To the dry product added 6 volume of methanol, heated to reflux until dissolution of product and further treated with carbon powder.
  • the reaction mixture was filtered and the filtrate was cooled to 0-5 °C.
  • the precipitated product, trazodone hydrochloride (compound I) was isolated and the said compound was obtained in a yield of about 85% and purity of about > 99.9% (HPLC).
  • process for the preparation of trazodone hydrochloride comprises the steps of,
  • step (ii) adding the compound III and an antioxidant to the reaction mixture of step (i);
  • step (vii) cooling the reaction mixture of step (vi) to a lower temperature of about 5 °C to
  • step (viii) isolating the precipitated product obtained in the above step (vii), and dissolving it in an alcoholic solvent; treating the reaction mixture of the above step (viii) with carbon powder and stirring it at reflux temperature; and
  • step-(i) of the above process is the same as that described in respect of step (1) of the process for the preparation of trazodone hydrochloride as depicted in the above Scheme III.
  • the solvent used in step-(i) of the above process is isopropyl alcohol (IPA).
  • the antioxidant used in the step-(ii) of the above process is selected from the group consisting of butylatedhydroxytoluene (BHT), butylatedhydroxyanisole (BHA), tertiary butylhydroquinone (TBHQ), propyl Gallate (PG), hydroquinone monomethylether (MEHQ).
  • BHT butylatedhydroxytoluene
  • BHA butylatedhydroxyanisole
  • TBHQ tertiary butylhydroquinone
  • PG propyl Gallate
  • MEHQ hydroquinone monomethylether
  • the antioxidant used in the step-(ii) of the process is butylatedhydroxytoluene (BHT).
  • BHT butylatedhydroxytoluene
  • the antioxidant is used in an amount ranging from 0.01 to 0.1 mole equivalent with reference to the compound-II.
  • the antioxidant in an embodiment, in the process (as depicted in the Scheme III) of the present invention, is used in an amount of 0.02 mole equivalent with reference to the compound-II.
  • the term 'higher temperature of about 85 °C referred to in the step (iii) of the above process (as depicted in the Scheme III) can range from 80 °C to 90 °C.
  • step (v), step (vii) and step (x) of the above process can range from 0°C to 10°C.
  • the term 'isolating the precipitated product' referred to in the step (vi), step (viii) and step (x) of the process (as depicted in the Scheme III) corresponds to the steps involving filtration, washing and drying.
  • 'alcoholic solution of hydrogen chloride' referred to in the step (vi) of the above process (as depicted in the Scheme III) is selected from the group consisting of isopropyl alcohol hydrochloride (IPA.HC1), ethanolic HC1 and methanolic HC1.
  • IPA.HC1 isopropyl alcohol hydrochloride
  • ethanolic HC1 isopropyl alcohol hydrochloride
  • methanolic HC1 methanolic HC1.
  • the alcoholic solution of hydrogen chloride used in the process is isopropyl alcohol hydrochloride (IPA.HC1).
  • the 'alcoholic solvent' used in the steps (vi) and (viii) of the process(as depicted in the Scheme III) is an alcohol such as methanol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol and isobutyl alcohol.
  • the alcohol used in step-(viii) of the process is methanol.
  • the process of the present invention as illustrated in the above Scheme-Ill comprises reaction of the compound II (free base) and the compound III in the presence of an antioxidant as the catalyst selected from the group consisting of butylatedhydroxytoluene (BHT), butylatedhydroxyanisole (BHA), tertiary butylhydroquinone (TBHQ), propyl Gallate (PG) and hydroquinone monomethylether (MEHQ);in isopropyl alcohol as the solvent.
  • BHT butylatedhydroxytoluene
  • BHA butylatedhydroxyanisole
  • TBHQ tertiary butylhydroquinone
  • PG propyl Gallate
  • MEHQ hydroquinone monomethylether
  • the filtrate was distilled out under reduced pressure up to 4.75 volumes, and cooled to a lower temperature of about 0-5 °C and maintained for 2h.
  • the precipitated product was isolated by filtration and the wet cake was dissolved in 3 volume of methanol and acidified with IPA HC1 at a temperature about 50-60 °C.
  • the reaction mixture was cooled to 0-5 °C and the precipitated product was isolated by filtration.
  • the reaction mixture was filtered, and the filtrate was cooled to 0-5 °C.
  • the precipitated product, trazodone hydrochloride (compound I) was isolated and the said compound was obtained in a yield of about 76% and purity of about > 99.9% (HPLC).
  • the compound II and the compound III used in the process of the present invention can be prepared by any method reported in the prior art; for instance, the said compounds II and III can be prepared by the process described in US Patent No 4,252,806 (US'806 Patent) and US 4,465,683 (US'683 Patent) respectively.
  • the process for the preparation of compound-II as described in the patent US'806 comprises condensation of l-(3-chlrophenyl) piperazine with 1- bromo-3-chloropropane;and the process for the preparation of compound III as described in the US'683 Patent comprises condensation of 2-chloropyridine with semicarbazide hydrochloride.
  • the US'893Patent also identifies other potential hazardous alkylating substances namely N-(3-chlorophenyl)-N'-(3-chloropropyl)-piperazine, 2-(3-chloropropyl)-s- triazolo-[4,3-a]-pyridin-3-one, 3-chloro-N,N'-dichloroethyl-aniline, 2- ⁇ 3-[bis-(2-chloroethyl)- amino]-propyl ⁇ -2H-[l,2,4]-triazolo[4,3-a]pyridin-3-one, 2,2-dibromoethylamine, 1,3- dichloropropane, and a mixture thereof, that may be present as impurities in trazodone or trazodone hydrochloride.
  • the US '893 patent describes a process for the purification of trazodone in order to lower the content of these alkylating substances in the final product to below 15 ppm. It is described in the US '893 patent that trazodone was prepared by the process as per disclosed in US 3,381,009.
  • the purification process described in the US'893 Patent essentially comprises preparation of an organic phase containing trazodone, and of an aqueous phase containing a basic compound; and further mixing the two phases by which the said aqueous phase is added to the said organic phase resulting in lowering the content of the specified alkylating substances to below 15 ppm.
  • the present invention relates to an improved process for the preparation of trazodone hydrochloride (compound I) wherein the product contains total amount of alkylating substances (as described herein) as impurity below 10 ppm.
  • the product obtained by process of the present invention contains total amount of alkylating substances (as described herein) as impurity below 5 ppm.
  • alkylating substances referred to herein as impurities that can be present in the product, trazodone or trazodone hydrochloride include l-3(chlorophenyl)-4-(3- chloropropyl) piperazine, 2,2-dichloroethylamine and l-bromo-3-chloro propane.
  • the process of the present invention controls the level of the specified alkylating substances as impurity during the reaction itself.
  • the process of the present invention does not require any additional purification methods such as a method involving giving basic aqueous solution wash to the organic phase containing trazodone.
  • the product i.e. trazodone hydrochloride containing total amount of alkylating substances (as described herein)as impurity below 5 ppm, is obtained by the process of the present by reducing the temperature to about 5 °C of the reaction mixture containing the product, and isolating the precipitated product by filtration. Since the instant process does not involve any additional purification step, the overall yield of the process increased to around 85%.
  • the trazodone hydrochloride obtained by the process of the present invention is substantially pure, particularly in terms of the presence of certain alkylating substances as impurities, for instance the quantification by LCMS method indicates the content of l-3(chloro phenyl)-4-(3- chloro propyl) piperazine, which is a known genotoxic substance, is present below 2.5 ppm, whereas as the other undesired alkylating substances namely 2,2-dichloroethylamine and 1- bromo-3-chloro propane are not detected in the final product.
  • an improved process for the preparation of trazodone hydrochloride (the compound I) wherein the product contains total amount of l-(3-chlorophenyl)-4-(3-chloropropyl) piperazine as impurity below 2.5 ppm.
  • the product obtained by process of the present invention contains total amount of l-(3-chlorophenyl)-4-(3-chloropropyl) piperazine as impurity below 2.5 ppm.
  • the filtrate was distilled off up to 4.75 volume and cooled to lower temperature around 0-5 °C and maintained for 2hours.
  • the precipitated product was filtered and washed with (0.5 volume) of chilled IPA.
  • the obtained crude product was dissolved in 3 volume of IPA and heated the mass to 55-60°C to get clear solution.
  • IPA HC1 To this clear solution was added IPA HC1 to adjust pH in the range of 2.0 to 2.5 at 55-60°C.
  • the reaction mass was cooled to temperature of around 0°C and maintained for 2 hours at 0-5°C.
  • the precipitated product was filtered and the wet cake was washed with 0.5 volume of chilled IPA, suck dried the product using vacuum.
  • To this dried compound was added methanol (575 mL) and heated to reflux until mass becomes clear solution.
  • the precipitated product was filtered and washed with (0.5 volume) of chilled IPA.
  • the obtained crude product was dissolved in 3 volume of IPA and heated the mass to 55-60°C to get clear solution.
  • IPA HC1 To this clear solution was added IPA HC1 to adjust pH in the range of 2.0 to 2.5 at 55-60°C.
  • the reaction mass was cooled to temperature around 0°C and maintained for 2 hours at 0-5 °C.
  • the precipitated product was filtered and the wet cake was washed with 0.5 volume of chilled IPA, suck dried the product using vacuum.
  • To this dried compound was added methanol (575 mL) and heated to reflux until the mass becomes clear solution. Added 6 g of carbon to this methanol solution and stirred for 30 min at reflux temperature.
  • the precipitated product was filtered and washed with chilled IPA (0.5 volumes).
  • the obtained crude product was dissolved in 3 volume of IPA and heated the mass to 55-60°C to get clear solution.
  • IPA HC1 To this clear solution was added IPA HC1 to adjust pH in the range of 2.0 to 2.5 at 55-60°C.
  • the reaction mass was cooled to temperature of around 0°C and maintained for 2 hours at 0-5 °C.
  • the precipitated product was filtered and the wet cake was washed with 0.5 volume of chilled IPA, suck dried the product using vacuum.
  • To this dried compound was added methanol (575 mL) and heated to reflux until the mass becomes clear solution. Added 6 g of carbon to this methanol solution and stirred for 30 min at reflux temperature.
  • the obtained crude product was dissolved in 300 ml of methanol and heated the mass to 55-60°C to get clear solution.
  • IPA HC1 to adjust pH in the range of 2.0 to 2.5 at 55-60°C.
  • the reaction mass was cooled to temperature of around 0°C and maintained for 2 hours at 0-5°C.
  • the precipitated product was filtered and the wet cake was washed with 50 ml of chilled methanol, suck dried the product using vacuum.
  • To this dried compound was added methanol (600 ml) and heated to reflux until mass becomes clear solution. Added 5 g of carbon to this methanol solution and stirred for 30 min at reflux temperature.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
PCT/IB2014/066841 2014-01-21 2014-12-12 An improved process for the preparation of trazodone and hydrochloride salt thereof WO2015110883A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP14879353.2A EP3097099A4 (en) 2014-01-21 2014-12-12 An improved process for the preparation of trazodone and hydrochloride salt thereof
JP2016547540A JP2017505302A (ja) 2014-01-21 2014-12-12 トラゾドンおよびその塩酸塩を製造するための改良法
CA2937417A CA2937417C (en) 2014-01-21 2014-12-12 An improved process for the preparation of trazodone and hydrochloride salt thereof
IL246835A IL246835A0 (en) 2014-01-21 2016-07-19 Improved process for the preparation of trazodone and its hydrochloride salt

Applications Claiming Priority (2)

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Publication number Priority date Publication date Assignee Title
WO2018169420A1 (en) 2017-03-14 2018-09-20 Politechnika Krakowska im. Tadeusza Kościuszki Method 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

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IL246835A0 (en) 2016-08-31
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