JP2017505302A - Improved process for producing trazodone and its hydrochloride - Google Patents

Abstract

The present invention provides an improved process for producing substantially pure trazodone and its hydrochloride salt. The method comprises reacting compound-II (described) with compound-III (described), optionally in the presence of an inorganic base and a catalyst, wherein in the method, trazodone free base and / or Or its hydrochloride is isolated by precipitation at low temperature. An improved method for producing trazodone hydrochloride (Compound I) provides a product that contains less than 10 ppm total alkylated material (described herein) as an impurity. An improved process for preparing trazodone hydrochloride (Compound I) provides a product comprising 1- (3-chlorophenyl) -4- (3-chloropropyl) piperazine as impurities in a total amount of less than 2.5 ppm.

Description

  The present invention relates to 2- {3- [4- (3-chlorophenyl) piperazin-1-yl] propyl} [1,2,4] triazolo [4,3-a] pyridine-3, commonly known as trazodone. It relates to an improved process for preparing (2H) -one and its hydrochloride. In particular, the present invention provides an improved process for preparing trazodone hydrochloride (referred to as Compound-I).

  The following discussion of the prior art is intended to present the invention in an appropriate technical context, allowing its significance to be properly understood. Unless expressly indicated otherwise, any prior art reference in this specification is an explicit indication that such techniques are well known or form part of the common general knowledge in the art. Or should be understood as implied self-approval.

Trazodone is a serotonin-2 receptor antagonist / reuptake inhibitor that decreases extracellular gamma aminobutyric acid (GABA) levels in the cerebral cortex by blocking the 5-hydroxytryptamine _2A (5-HT _2A ) receptor. is there. This decrease is accompanied by an increase in 5-HT release. At high doses, trazodone inhibits 5-HT transport, and this inhibition of 5-HT uptake further results in increased 5-HT levels. It is believed that this bilateral mechanism may be involved in trazodone's antidepressant properties. Furthermore, the interaction between GABAergic and serotonergic systems can explain its sedative / anti-anxiety properties. Trazodone is therefore a psychoactive compound with sedative and antidepressant properties. Trazodone is rapidly absorbed from the upper gastrointestinal tract and is extensively metabolized after oral administration. Trazodone is usually used to relieve symptoms of depression, such as sadness, lethargy or guilt; indifference to daily activities; changes in appetite; fatigue; thoughts about death or suicide; and insomnia It is done.

（Ｉ） The salt form of trazodone, in particular the hydrochloride, is represented by the following structural formula;

(I)

  U.S. Pat. No. 3,381,009 ('009 U.S. Patent) describes [1,2,4] triazolo [4,3-a] pyridine-3 (2H in the presence of sodium hydride and dioxane solvent. ) -One and 1- (3-chlorophenyl) -4- (3-chloropropyl) piperazine are described for the synthesis of trazodone. This process requires about 20 hours of stirring under reflux conditions.

  The '009 US patent also describes 2- (3-chloropropyl)-[1,2,4] triazolo [4,3-a] pyridin-3 (2H) -one in the presence of triethylamine and dioxane solvents. An alternative method for synthesizing trazodone is also described, including the condensation of 1- (3-chlorophenyl) piperazine with 1- (3-chlorophenyl) piperazine.

  The '009 U.S. patent further describes two additional alternative methods for producing trazodone, one of which is 2- (3-morpholinopropyl)-[1,2,4] triazolo [4, Comprising reacting 3-a] pyridin-3 (2H) -one with 3-chloroaniline, the other being 2- (3-aminopropyl)-[1,2,4] triazolo [4, 3-a] reacting 3-pyridin-3 (2H) -one with 3-chloro-N, N-bis (2-chloroethyl) aniline.

  European Patent No. EP 1108722 B1 describes a process for the preparation of trazodone hydrochloride (compound-I) comprising treating a trazodone base with an aqueous solution of hydrochloric acid.

  U.S. Published Patent Application No. 2009/209550 includes deuterated 3- (4- (3- Synthesis of deuterated compounds in which chlorophenyl) piperazin-1-yl) propan-1-ol is treated with [1,2,4] triazolo [4,3-a] pyridin-3 (2H) -one It is disclosed.

  In US Pat. No. 5,256,664, 1- (3-chlorophenyl) -4- (3-chloropropyl) piperazine hydrochloride is treated with an aqueous solution of sodium hydroxide (NaOH) and extracted with methylene chloride. A process for the preparation of trazodone is described. The organic layer is concentrated to give an oily intermediate compound, ie 1- (3-chlorophenyl) -4- (3-chloropropyl) piperazine (free base), and isopropyl alcohol as solvent in the presence of sodium hydroxide. In addition, it is further reacted with [1,2,4] triazolo [4,3-a] pyridin-3 (2H) -one under reflux conditions. Crude oily trazodone is purified using flash chromatography on silica gel. The purified isopropyl alcohol containing trazodone is further treated with 2N HCL (hydrochloric acid) to obtain trazodone hydrochloride in a yield of 47%.

  In Hungarian patent application No. 201324, the reaction is carried out specifically in an aprotic polar solvent in the presence of alkali carbonate or powdered sodium hydroxide, 1,2,4-triazolo- (4, A process for producing trazodone comprising reacting 3-a) -pyridin-3 (2H) -one with 1- (3′-chloro-propyl) -4- (m-chlorophenyl) -piperazine-hydrochloride Have been described.

  U.S. Pat. No. 8,133,893 (the '893 U.S. Patent) and U.S. Pat. No. 8,314,236 disclose a process for purifying trazodone and a process for further converting the purified trazodone to its hydrochloride salt. Have been described. The process described in the '893 US patent essentially comprises: (a) preparing an organic phase comprising trazodone in at least one organic solvent; (b) at least one basic compound. An aqueous phase containing a phase transfer catalyst is prepared as appropriate; (c) mixing the aqueous phase and the organic phase to obtain a mixture; (d) heating the mixture at a temperature of at least 40 ° C. for at least 30 minutes. (E) recovering the trazodone; and (f) treating the trazodone with hydrochloric acid as appropriate to obtain trazodone hydrochloride. The trazodone hydrochloride is obtained by treatment with 12N aqueous HCl. In addition, the US 893 process requires azeotropic distillation of the crude trazodone solution to remove residual water brought in from the aqueous phase.

  From the above discussion on the method of synthesizing trazodone described in the above patent literature, it is clear that firstly, the reported method requires a long reaction time. In addition, prior art methods include additional purification methods such as column chromatography, or the method is more expensive because it involves dissolving the compound in an organic solvent and washing with a basic aqueous solution. . These methods also include tedious post-processing procedures. In view of these drawbacks, a simple, commercially advantageous and improved yield and purity for producing salts such as trazodone and / or trazodone hydrochloride (compound I) in a shorter time and There is a need to develop industrially feasible methods.

  The inventors of the present invention have developed improved methods that address the problems associated with methods reported in the prior art. The method of the present invention does not involve the use of any additional expensive reagents. Furthermore, the process does not require additional purification steps and essential work-up procedures such as azeotropic distillation.

  Thus, the present invention provides a process for producing trazodone or a salt thereof that is cost effective, environmentally friendly and commercially expandable for large scale operations.

  In certain aspects, the present invention reacts compound-II (described herein) with compound-III (described herein), optionally in the presence of an inorganic base and a catalyst. To an improved process for preparing trazodone or its hydrochloride (compound I).

  In certain aspects, the present invention reacts compound-II (described herein) with compound-III (described herein), optionally in the presence of an inorganic base and a catalyst. In which the trazodone free base and / or its hydrochloride is isolated by precipitation at low temperature.

  In certain aspects, the present invention reacts Compound-II (described herein) with Compound-III (described herein) in the presence of an inorganic base and a phase transfer catalyst. And relates to an improved process for preparing trazodone or its hydrochloride (compound I).

  In certain aspects, the present invention reacts Compound-II (described herein) with Compound-III (described herein) in the presence of an antioxidant as a catalyst. And relates to an improved process for preparing trazodone or its hydrochloride (compound I).

  In another aspect, the present invention provides a reaction between compound-II and compound-III in the presence of an inorganic base and a phase transfer catalyst followed by treatment with an alcohol solution of hydrogen chloride (trazodone hydrochloride ( It relates to an improved process for preparing compounds I).

  In another aspect, the present invention relates to an improved process for producing trazodone hydrochloride (Compound I) comprising isolating pure trazodone free base or its hydrochloride salt in the absence of water.

  According to another aspect of the present invention, there is provided an improved method for producing trazodone hydrochloride (Compound I), wherein the product contains less than 10 ppm total alkylated material (described herein) as an impurity. provide.

  According to another aspect of the present invention, the preparation of trazodone hydrochloride (compound I) comprising 1- (3-chlorophenyl) -4- (3-chloropropyl) piperazine as a product with a total amount of less than 2.5 ppm as impurities. Provide an improved method for doing this.

（化合物Ｉ）
を製造するための、以下の工程；
（ａ）適宜無機塩基および触媒の存在下、溶媒中で、以下の式で示される化合物−ＩＩまたはその塩酸塩；

化合物−ＩＩ
と以下の式を有する化合物−ＩＩＩ；

化合物−ＩＩＩ
とを反応させて遊離塩基として化合物Ｉを得る；
（ｂ）上記の工程（ａ）で得た遊離塩基としての化合物Ｉを塩化水素のアルコール溶液で処理して対応する塩酸塩（化合物Ｉ）を得る；
を含む改良法に関し、上記方法において、遊離塩基および／またはその塩酸塩（化合物Ｉ）としての化合物Ｉは低温で沈殿により単離する。 DETAILED DESCRIPTION OF THE INVENTION Accordingly, the present invention relates to trazodone hydrochloride represented by the following formula (compound I);

(Compound I)
The following steps to produce:
(A) Compound-II or a hydrochloride thereof represented by the following formula in a solvent, optionally in the presence of an inorganic base and a catalyst;

Compound-II
And compound-III having the formula:

Compound-III
To give compound I as the free base;
(B) treating the compound I as the free base obtained in the above step (a) with an alcohol solution of hydrogen chloride to obtain the corresponding hydrochloride (compound I);
In the above process, compound I as the free base and / or its hydrochloride salt (compound I) is isolated by precipitation at low temperature.

  In the context of the present invention, when the term “as appropriate” is used with respect to any element, eg, an inorganic base, the term is intended to mean that the element of interest is present or absent. Both options are intended to be within the scope of the present invention.

スキームＩ The above inventive method is illustrated in Scheme I below:

Scheme I

  In certain embodiments, step (a) is performed in the presence of an inorganic base, wherein the inorganic base is from the group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, calcium carbonate, sodium hydroxide and potassium hydroxide. To be elected.

  In certain embodiments, the catalyst used in step (a) of the method is a phase transfer catalyst or an antioxidant.

  In one embodiment, the catalyst used in step (a) of the method is a phase transfer catalyst.

（化合物Ｉ）
を製造するための、以下の工程；
（ａ）無機塩基および相間移動触媒の存在下、溶媒中で、以下の式で示される化合物−ＩＩ塩酸塩；

化合物−ＩＩ塩
と以下の式を有する化合物−ＩＩＩ；

化合物−ＩＩＩ
とを反応させて遊離塩基として化合物Ｉを得る；
（ｂ）上記の工程（ａ）で得た遊離塩基としての化合物Ｉを塩化水素のアルコール溶液で処理して対応する塩酸塩を得る；
を含む方法に関し、上記方法において、遊離塩基および／またはその塩酸塩（化合物Ｉ）としての化合物Ｉは低温で沈殿により単離する。 Accordingly, in certain embodiments, the present invention provides a trazodone of formula or a hydrochloride salt thereof (Compound I):

(Compound I)
The following steps to produce:
(A) Compound-II hydrochloride represented by the following formula in a solvent in the presence of an inorganic base and a phase transfer catalyst;

Compound-II salt and Compound-III having the formula:

Compound-III
To give compound I as the free base;
(B) treating the compound I as the free base obtained in step (a) above with an alcohol solution of hydrogen chloride to obtain the corresponding hydrochloride;
In the above method, compound I as the free base and / or its hydrochloride salt (compound I) is isolated by precipitation at low temperature.

  In some embodiments, the phase transfer catalyst is tricaprylmethylammonium chloride (Aliquat 336), tetra-n-butylammonium bromide, triethylbenzylammonium chloride (TEBAC), cetyltrimethylammonium bromide (CTAB), cetylpyridinium bromide, N-benzyl Quininium chloride, tetra-n-butylammonium chloride, tetra-n-butylammonium hydroxide, tetra-n-butylammonium iodide, tetraethylammonium chloride, benzyltributylammonium chloride, benzyltriethylammonium bromide, hexadecyltriethylammonium chloride, Tetramethylammonium chloride, hexadecyl trimer Quaternary ammonium salt selected from the group consisting of Le ammonium chloride and octyl trimethyl ammonium chloride or a mixture thereof.

  In some embodiments, the phase transfer catalyst is tetra-n-butylammonium bromide or triethylbenzylammonium chloride (TEBAC).

  In certain embodiments, the catalyst used in step (a) of the method is an antioxidant.

を製造するための、以下の工程；
（ａ）抗酸化剤の存在下、溶媒中で、以下の式で示される遊離塩基としての化合物−ＩＩ；

化合物−ＩＩ
と以下の式を有する化合物−ＩＩＩ；

化合物−ＩＩＩ
とを反応させて遊離塩基として化合物Ｉを得る；
（ｂ）上記の工程（ａ）で得た遊離塩基としての化合物Ｉを塩化水素のアルコール溶液で処理して対応する塩酸塩を得る；
を含む方法に関し、上記方法において、遊離塩基および／またはその塩酸塩（化合物Ｉ）としての化合物Ｉは低温で沈殿により単離する。 Accordingly, in certain embodiments, the present invention provides a trazodone of formula or a hydrochloride salt thereof (Compound I):

The following steps to produce:
(A) Compound-II as a free base represented by the following formula in a solvent in the presence of an antioxidant;

Compound-II
And compound-III having the formula:

Compound-III
To give compound I as the free base;
(B) treating the compound I as the free base obtained in step (a) above with an alcohol solution of hydrogen chloride to obtain the corresponding hydrochloride;
In the above method, compound I as the free base and / or its hydrochloride salt (compound I) is isolated by precipitation at low temperature.

  In some embodiments, the antioxidant is selected from the group consisting of butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), tertiary butylhydroquinone (TBHQ), propyl gallate (PG) and hydroquinone monomethyl ether (MEHQ). It is.

  In certain embodiments, the antioxidant used in step (a) is butylhydroxytoluene (BHT).

  In some embodiments, the solvent used in step (a) of the method is an alcohol such as ethyl alcohol, n-propyl alcohol, isopropyl alcohol, isobutyl alcohol and methanol; an ether such as ethyl ether or propyl ether; toluene, benzene Or an aromatic hydrocarbon solvent such as xylene; and other solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, dioxane, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide or dimethylacetamide.

  In one embodiment, the solvent used in step (a) of the method is isopropyl alcohol (IPA).

  In certain embodiments, the alcohol solution of hydrogen chloride used in step (b) of the method is selected from the group consisting of isopropyl alcohol hydrochloride (IPA.HCl), ethanolic HCl, and methanolic HCl.

  In one embodiment, the alcohol solution of hydrogen chloride used in step (b) of the method is isopropyl alcohol hydrochloride (IPA.HCl).

  In certain embodiments, the trazodone free base obtained in step (a) of the method is isolated by precipitation at low temperature.

  In certain embodiments, the trazodone hydrochloride (compound I) obtained in step (b) of the method is isolated by precipitation at low temperature.

  In certain embodiments, the trazodone free base of step (a) and / or trazodone hydrochloride of step (b) of the method is isolated by precipitation at a low temperature of about 5 ° C.

  The term “low temperature” mentioned in step (a) and step (b) of the above method can range from 0 ° C. to 10 ° C. In the context of the present invention, the term “low temperature” may be used interchangeably with the term “low temperature of about 5 ° C.”.

In a specific embodiment, the method for producing trazodone hydrochloride (Compound I) comprises the following steps;
(1) Dissolving compound II (as its hydrochloride salt) in a solvent in the presence of an inorganic base;
(2) adding compound III and phase transfer catalyst to the reaction mixture of step (1);
(3) stirring the reaction mixture of step (2) above at a temperature of about 85 ° C;
(4) filtering the hot reaction mixture from step (3) above and stirring the reaction mixture at a temperature of about 70 ° C;
(5) filtering the reaction mixture of step (4) and cooling the filtrate to a low temperature of about 5 ° C. to obtain a precipitated product;
(6) The precipitated product obtained in step (5) is isolated and treated with an alcohol solution of hydrogen chloride at a temperature of about 60 ° C .;
(7) cooling the reaction mixture of step (6) to a low temperature of about 5 ° C. to obtain a precipitated product;
(8) The precipitated product obtained in the above step (7) is isolated and dissolved in an alcohol solvent;
(9) treating the reaction mixture of step (8) above with charcoal powder and stirring at reflux temperature; and (10) cooling the reaction mixture of step (9) above to a low temperature of about 5 ° C. and precipitation. Isolated trazodone hydrochloride (Compound I) is isolated.

スキーム−ＩＩ As a specific embodiment, the method of the present invention is illustrated in Scheme-II below.

Scheme-II

  Solvents used in step-(1) of the above method (illustrated in Scheme II) are alcohols such as ethyl alcohol, n-propyl alcohol, isopropyl alcohol, isobutyl alcohol and methanol; ethyl ether or propyl ether Selected from: ethers such as; 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 .

  In certain embodiments, the solvent used in step- (1) of the above method (illustrated in Scheme II) is selected from the group consisting of ethyl alcohol, n-propyl alcohol, isopropyl alcohol, isobutyl alcohol, and methanol.

  In certain embodiments, the solvent used in step-(1) of the above method (illustrated in Scheme II) is isopropyl alcohol (IPA).

  The inorganic base used in step-(1) of the above method (illustrated in Scheme II) consists of sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, calcium carbonate, sodium hydroxide and potassium hydroxide. Selected from the group.

  In certain embodiments, in the method of the present invention (illustrated in Scheme II), the inorganic base is used in an amount of 1.5 to 2.5 equivalents based on Compound II.

  The phase transfer catalyst used in step- (2) of the above method (illustrated in Scheme II) is tricaprylmethylammonium chloride (Aliquat 336), tetra-n-butylammonium bromide, triethylbenzylammonium chloride (TEBAC). ), Cetyltrimethylammonium bromide (CTAB), cetylpyridinium bromide, N-benzylquininium chloride, tetra-n-butylammonium chloride, tetra-n-butylammonium hydroxide, tetra-n-butylammonium iodide, tetraethylammonium chloride , Benzyltributylammonium chloride, benzyltriethylammonium bromide, hexadecyltriethylammonium chloride, tet Methyl ammonium chloride, a quaternary ammonium salt selected from the group consisting of hexadecyltrimethylammonium chloride and octyl trimethyl ammonium chloride or a mixture thereof.

  In certain embodiments, the phase transfer catalyst used in step- (1) of the method (illustrated in Scheme II) is selected from tetra-n-butylammonium bromide or triethylbenzylammonium chloride (TEBAC).

  In certain embodiments, in the method of the present invention (illustrated in Scheme II), a phase transfer catalyst (PTC) is used in an amount of 1% to 5% based on Compound-II.

  The term “temperature of about 85 ° C.” referred to in step (3) of the above method (illustrated in Scheme II) can range from 80 ° C. to 90 ° C.

  The term “low temperature of about 5 ° C.” referred to in step (5), step (7) and step (10) of the above method (illustrated in Scheme II) ranges from 0 ° C. to 10 ° C. obtain.

  The term “isolating the precipitated product” mentioned in step (6), step (8) and step (10) corresponds to a step comprising filtration, washing and drying.

  The “hydrogen chloride alcohol solution” used in step (6) of the above method (illustrated in Scheme II) is selected from the group consisting of isopropyl alcohol hydrochloride (IPA.HCl), ethanolic HCl and methanolic HCl. .

  In one embodiment, the alcohol solution of hydrogen chloride used in the method is isopropyl alcohol hydrochloride (IPA.HCl).

  The “alcohol solvent” used in steps (6) and (8) of the process (illustrated in Scheme II) is selected from the group consisting of methanol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol and isobutyl alcohol. It is alcohol.

  In certain embodiments, the alcohol used in step-(8) of the method (illustrated in Scheme II) is methanol.

  As illustrated in Scheme-II above, the process of the present invention comprises an inorganic base selected from sodium carbonate or potassium carbonate and a phase selected from tetra-n-butylammonium bromide or triethylbenzylammonium chloride (TEBAC). Reacting compound II (as its HCl salt) with compound III in isopropyl alcohol as solvent in the presence of a transfer catalyst (PTC) catalyst. The reaction mixture was heated at a temperature of 80-85 ° C. for 8-12 hours and filtered. The filtrate was distilled off 4.75 times under reduced pressure, cooled to a low temperature of about 0-5 ° C. and kept for 2 hours. The precipitated product was isolated by filtration and the wet cake was dissolved in 3 volumes of IPA (isopropyl alcohol) and acidified with IPA HCl at a temperature of about 50-60 ° C. The reaction mixture was cooled to 0-5 ° C. and the precipitated product was isolated by filtration. Six times the amount of methanol was added to the dried product, heated to reflux until the product was dissolved, and further treated with charcoal 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 obtained in a yield of about 85% and a purity of about ≧ 99.9% (HPLC).

In another embodiment, the method for producing trazodone hydrochloride (Compound I) comprises the following steps;
(I) dissolving compound II (free base) in a solvent;
(Ii) adding compound III and an antioxidant to the reaction mixture of step (i);
(Iii) stirring the reaction mixture of step (ii) above at a temperature of about 85 ° C;
(Iv) filtering the hot reaction mixture and stirring the reaction mixture at a temperature of about 70 ° C .;
(V) filtering the reaction mixture of step (iv) and cooling the filtrate to a low temperature of about 5 ° C. to obtain a precipitated product;
(Vi) isolating the precipitated product obtained in step (v) and treating with an alcohol solution of hydrogen chloride at a temperature of about 60 ° C .;
(Vii) cooling the reaction mixture of step (vi) to a low temperature of about 5 ° C. to obtain a precipitated product;
(Viii) isolating the precipitated product obtained in step (vii) above and dissolving in an alcohol solvent;
(Ix) treating the reaction mixture of step (viii) above with charcoal powder and stirring at reflux temperature; and (x) cooling the reaction mixture of step (ix) above to a low temperature of about 5 ° C and precipitation. Isolated trazodone hydrochloride (Compound I) is isolated.

スキーム−ＩＩＩ As with the specific embodiments described above, the method of the present invention is illustrated in Scheme-III below.

Scheme-III

  Solvents used in step-(i) of the above method (illustrated in Scheme III) are those described for step (1) of the method for preparing trazodone hydrochloride illustrated in Scheme III above. Is the same.

  In certain embodiments, the solvent used in step-(i) of the above method (illustrated in Scheme III) is isopropyl alcohol (IPA).

  Antioxidants used in step-(ii) of the above method (illustrated in Scheme III) are butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), tertiary butylhydroquinone (TBHQ), gallic It is selected from the group consisting of propyl acid (PG) and hydroquinone monomethyl ether (MEHQ).

  In certain embodiments, the antioxidant used in step- (ii) of the method (illustrated in Scheme III) is butylhydroxytoluene (BHT).

  In certain embodiments, in the method of the present invention (illustrated in Scheme III), the antioxidant is used in an amount of 0.01 to 0.1 molar equivalents based on Compound-II.

  In certain embodiments, in the method of the present invention (illustrated in Scheme III), the antioxidant is used in an amount of 0.02 molar equivalent based on Compound-II.

  The term “temperature above about 85 ° C.” referred to in step (iii) of the above method (illustrated in Scheme III) can range from 80 ° C. to 90 ° C.

  The term “low temperature of about 5 ° C.” referred to in steps (v), (vii) and (x) (illustrated in Scheme III) of the above method ranges from 0 ° C. to 10 ° C. obtain.

  The term “isolating the precipitation product” referred to in step (vi), step (viii) and step (x) of the method (illustrated in Scheme III) includes filtration, washing and drying. It corresponds to.

  The term “alcohol solution of hydrogen chloride” referred to in step (vi) of the above method (illustrated in Scheme III) is from the group consisting of isopropyl alcohol hydrochloride (IPA.HCl), ethanolic HCl and methanolic HCl. To be elected.

  In some embodiments, the alcohol solution of hydrogen chloride used in the method (illustrated in Scheme III) is isopropyl alcohol hydrochloride (IPA.HCl).

  The “alcohol solvent” used in steps (vi) and (viii) of the process (illustrated in Scheme III) is an alcohol such as methanol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol and isobutyl alcohol. .

  In certain embodiments, the alcohol used in step- (viii) of the method (illustrated in Scheme III) is methanol.

  The method of the present invention described in Scheme-III above includes butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), tertiary butylhydroquinone (TBHQ), propyl gallate (PG) and hydroquinone monomethyl ether ( Reacting compound II (free base) with compound III in isopropyl alcohol as solvent in the presence of an antioxidant as catalyst selected from the group consisting of MEHQ). The reaction mixture was heated at a temperature of 80-85 ° C. for 8-12 hours and filtered. The filtrate was distilled off 4.75 times under reduced pressure, cooled to a low temperature of about 0-5 ° C. and kept for 2 hours. The precipitated product was isolated by filtration and the wet cake was dissolved in 3 volumes of methanol and acidified with IPA HCl at a temperature of about 50-60 ° C. The reaction mixture was cooled to 0-5 ° C. and the precipitated product was isolated by filtration. Six times the amount of methanol was added to the dried product, heated to reflux until the product was dissolved, and further treated with charcoal 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 obtained in a yield of about 76% and a purity of about ≧ 99.9% (HPLC).

  Compound II and Compound III used in the methods of the present invention can be prepared by any method reported in the prior art, for example, Compounds II and III are each U.S. Pat. No. 4,252,806. ('806 US patent) and US 4,465,683 (' 683 US patent). The process for preparing Compound-II described in the '806 US patent includes condensing 1- (3-chlorophenyl) piperazine and 1-bromo-3-chloropropane, and is described in the' 683 US patent. The process for preparing compound III comprises condensing 2-chloropyridine and semicarbazide hydrochloride.

  From the method for synthesizing trazodone or trazodone hydrochloride reported in the prior art, it is clear that the yield of trazodone hydrochloride obtained by the method is around 75% and the purity is 99%. Provides the desired compound, ie trazodone hydrochloride (Compound I), in a yield of about 85% and a purity of about ≧ 99.9%.

  In addition, US Pat. No. 8,133,893 (the '893 US patent) describes genetics of alkylating substances such as 2,2-dichloroethylamine and 1-bromo-3-chloropropane used in the synthesis of trazodone. Toxic has been reported. The '893 U.S. patent also describes other potentially harmful alkylating substances that may be present as impurities in trazodone or trazodone hydrochloride, i.e., N- (3-chlorophenyl) -N'-(3-chloro Propyl) -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- [1,2,4] -triazolo [4,3-a] pyridin-3-one, 2,2-dibromoethylamine, 1,3 -Dichloropropane, and mixtures thereof have also been identified. The '893 US patent describes a process for purifying trazodone to reduce the content of these alkylated materials in the final product to less than 15 ppm. The '893 US patent describes that trazodone was prepared by a method such as that disclosed in US 3,381,009. The purification method described in the '893 U.S. patent essentially prepares an organic phase containing trazodone and an aqueous phase containing a basic compound, and the aqueous phase is added to the organic phase for specific alkylation. Including mixing the two phases by reducing the content of the substance to less than 15 ppm.

  Thus, in another aspect, the present invention provides an improved process for producing trazodone hydrochloride (Compound I), wherein the product comprises less than 10 ppm total alkylated material (described herein) as an impurity. About.

  In certain embodiments, the product obtained by the method of the present invention contains less than 5 ppm total alkylated material (described herein) as an impurity.

  Alkylating substances, referred to herein as impurities, may be present in the product, and trazodone or trazodone hydrochloride may be 1-3 (chlorophenyl) -4- (3-chloropropyl) piperazine, 2,2-dichloro Including ethylamine and 1-bromo-3-chloropropane.

  In certain embodiments, the methods of the present invention control the level of certain alkylating substances as impurities during the reaction itself. The method of the present invention does not require any additional purification method, such as a method involving washing the organic phase containing trazodone with a basic aqueous solution. The product, ie, trazodone hydrochloride, which contains less than 5 ppm total alkylated material (as described herein) as an impurity, reduces the temperature of the reaction mixture containing the product to about 5 ° C. and reduces the precipitated product It is obtained by the present method by isolation by filtration. Since the process does not include any additional purification steps, the overall yield of the process increases to around 85%.

  The trazodone hydrochloride obtained by the method of the present invention is substantially pure, especially with regard to the presence of certain alkylating substances as impurities, eg 1-3 (chlorophenyl), which is a known genotoxic substance, as determined by LCMS, for example. ) -4- (3-chloropropyl) piperazine is present in less than 2.5 ppm, whereas other undesired alkylating substances, namely 2,2-dichloroethylamine and 1-bromo-3-chloropropane, It is shown that it is not detected in the final product.

  According to another aspect of the present invention, the preparation of trazodone hydrochloride (compound I) comprising 1- (3-chlorophenyl) -4- (3-chloropropyl) piperazine as a product with a total amount of less than 2.5 ppm as impurities. Provide an improved method for doing this.

  In certain embodiments, the product obtained by the process of the present invention comprises 1- (3-chlorophenyl) -4- (3-chloropropyl) piperazine as impurities in a total amount of less than 2.5 ppm.

  The invention is further illustrated by the following examples, which are provided as typical examples of the invention and are not intended to limit the scope of the invention. Although the invention has been described with reference to specific embodiments thereof, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.

Example-1
A round bottom flask was charged with Compound II (HCl salt) (100 gm, 0.323 M), sodium carbonate (65 g, 0.613 mol) and 600 mL of isopropyl alcohol (IPA). To this reaction mixture, compound III (50.8 g, 0.337 mol) and tetra-n-butylammonium bromide (5 g, 5% w / w) were added. The reaction mixture was stirred at a temperature around 80-85 ° C. for 12 hours. The hot reaction mixture was filtered and the cake was washed with IPA (0.5 volumes). The filtrate was distilled off 4.75 times, cooled to a low temperature around 0-5 ° C. and kept for 2 hours. The precipitated product was filtered and washed with cooled IPA (0.5 volumes). The resulting crude product was dissolved in 3 times the amount of IPA and the reaction was heated to 55-60 ° C. to obtain a clear solution. To this clear solution, IPA HCl was added at 55-60 ° C. to adjust the pH within the range of 2.0-2.5. The reaction was cooled to a temperature around 0 ° C. and kept at 0-5 ° C. for 2 hours. The precipitated product was filtered, the wet cake was washed with 0.5 volumes of chilled IPA and the product was sucked dry under vacuum. Methanol (575 mL) was added to the dried compound and heated to reflux until the reaction became a clear solution. 6 g of carbon was added to the methanol solution and stirred at reflux temperature for 30 minutes. The solution was filtered through a bed of celite and washed with 60 mL of hot methanol. The collected filtrate was distilled off to 2 to 3 times the amount under vacuum. The solution was cooled to a low temperature of about 0-5 ° C. and held for 2 hours. The precipitated product was filtered and washed with 30 mL of cooled methanol. The product was dried to give trazodone hydrochloride in 83% yield and 99.98% purity (HPLC).

Example-2:
A round bottom flask was charged with Compound II (HCl salt) (100 gm, 0.323 M), potassium carbonate (84.24 g, 0.613 mol) and 600 mL of isopropyl alcohol (IPA). To this reaction mixture, Compound III (50.8 g, 0.337 mol) and tetra-n-butylammonium bromide (5 g, 5% w / w) were added with stirring. The reaction mixture was stirred at a temperature around 80-85 ° C. for 12 hours. The hot reaction mixture was filtered and the cake was washed with IPA (0.5 volumes). The filtrate was distilled off 4.75 times, cooled to a low temperature around 0-5 ° C. and kept for 2 hours. The precipitated product was filtered and washed with cooled IPA (0.5 volumes). The resulting crude product was dissolved in 3 times the amount of IPA and the reaction was heated to 55-60 ° C. to obtain a clear solution. To this clear solution, IPA HCl was added at 55-60 ° C. to adjust the pH within the range of 2.0-2.5. The reaction was cooled to a temperature around 0 ° C. and kept at 0-5 ° C. for 2 hours. The precipitated product was filtered, the wet cake was washed with 0.5 volumes of chilled IPA and the product was sucked dry under vacuum. Methanol (575 mL) was added to the dried compound and heated to reflux until the reaction became a clear solution. 6 g of carbon was added to the methanol solution and stirred at reflux temperature for 30 minutes. The solution was filtered through a bed of celite and washed with 60 mL of hot methanol. The collected filtrate was distilled off to 2 to 3 times the amount under vacuum. The solution was cooled to a low temperature of about 0-5 ° C. and held for 2 hours. The precipitated product was filtered and washed with 30 mL of cooled methanol. The product was dried to give trazodone hydrochloride in 83% yield and 99.98% purity (HPLC).

Example-3
A round bottom flask was charged with Compound II (100 gm, 0.323 M), sodium carbonate (65 g, 0.613 mol) and 600 mL of isopropyl alcohol (IPA). To this reaction mixture, Compound III (50.8 g, 0.337 mol) and triethylbenzylammonium chloride (TEBAC) (5 g, 5% w / w) were added with stirring. The reaction mixture was stirred at a temperature around 80-85 ° C. for 12 hours. The hot reaction mixture was filtered and the cake was washed with IPA (0.5 volumes). The filtrate was distilled off 4.75 times, cooled to a low temperature around 0-5 ° C. and kept for 2 hours. The precipitated product was filtered and washed with cooled IPA (0.5 volumes). The resulting crude product was dissolved in 3 times the amount of IPA and the reaction was heated to 55-60 ° C. to obtain a clear solution. To this clear solution, IPA HCl was added at 55-60 ° C. to adjust the pH within the range of 2.0-2.5. The reaction was cooled to a temperature around 0 ° C. and kept at 0-5 ° C. for 2 hours. The precipitated product was filtered, the wet cake was washed with 0.5 volumes of chilled IPA and the product was sucked dry under vacuum. Methanol (575 mL) was added to the dried compound and heated to reflux until the reaction became a clear solution. 6 g of carbon was added to the methanol solution and stirred at reflux temperature for 30 minutes. The solution was filtered through a bed of celite and washed with 60 mL of hot methanol. The collected filtrate was distilled off to 2 to 3 times the amount under vacuum. The solution was cooled to a low temperature of about 0-5 ° C. and held for 2 hours. The precipitated product was filtered and washed with 30 mL of cooled methanol. The product was dried to give trazodone hydrochloride in 83% yield and 99.98% purity (HPLC).

Example-4
A round bottom flask was charged with Compound II (HCl salt) (100 g), 628 mL DM water, 152 mL toluene, and aqueous sodium hydroxide (23 g sodium hydroxide dissolved in 76 mL DM water). The reaction mixture was stirred and the organic layer was separated.
The collected organic layer (toluene layer) was washed with DM water. The solvent is completely distilled off under vacuum at temperatures below 70-75 ° C. to give compound II (free base), ie 1- (3-chlorophenyl) -4- (3-chloropropyl) piperazine (free base). It was.

Example-5
A round bottom flask was charged with 800 mL of isopropyl alcohol (IPA) containing Compound II (free base) obtained in (Example-4) and Compound-III (53.3 gm). To this reaction mixture was added BHT (1.55 g) at 30-35 ° C. The reaction mixture was stirred at reflux temperature for 14-16 hours. The hot reaction mixture was filtered and the cake was washed with IPA. The filtrate was distilled off 4.7 times, cooled to a low temperature around 0-5 ° C. and kept for 2 hours. The precipitated product (trazodone free base) was filtered and washed with chilled IPA (500 mL). The resulting crude product was dissolved in 300 mL of methanol and the reaction was heated to 55-60 ° C. to obtain a clear solution. To this clear solution, IPA HCl was added at 55-60 ° C. to adjust the pH within the range of 2.0-2.5. The reaction was cooled to a temperature around 0 ° C. and kept at 0-5 ° C. for 2 hours. The precipitated product was filtered, the wet cake was washed with 50 mL of chilled methanol, and the product was sucked dry under vacuum. Methanol (600 mL) was added to the dried compound and heated to reflux until the reaction became a clear solution. 5 g of carbon was added to this methanol solution and stirred at reflux temperature for 30 minutes. The solution was filtered through a bed of celite and washed with 50 mL of hot methanol. The collected filtrate was distilled off to 2 to 3 times the amount under vacuum. The solution was cooled to a low temperature of about 0-5 ° C. and held for 2 hours. The precipitated product was filtered and washed with 100 mL of chilled methanol. The product was dried to give trazodone hydrochloride in 76% yield and 99.98% purity (HPLC).

Claims (22)

Trazodone or its hydrochloride salt (compound I)

(Compound I)
The manufacturing method of the following, Comprising:
(A) Compound-II or a hydrochloride thereof represented by the following formula in a solvent, optionally in the presence of an inorganic base and a catalyst;

Compound-II
And compound-III having the formula:

Compound-III
To give compound I as the free base;
(B) treating the compound I as the free base obtained in the above step (a) with an alcohol solution of hydrogen chloride to obtain the corresponding hydrochloride (compound I);
Wherein the free base and / or Compound I as Compound I is isolated by precipitation at low temperature in the above method.   The method of claim 1, wherein the catalyst is a phase transfer catalyst or an antioxidant.   The process according to claim 1 or claim 2, wherein the catalyst is a phase transfer catalyst.   Phase transfer catalysts are tetra-n-butylammonium bromide, triethylbenzylammonium chloride (TEBAC), cetyltrimethylammonium bromide (CTAB), cetylpyridinium bromide, tricaprylmethylammonium chloride, N-benzylquininium chloride, tetra-n- Butylammonium chloride, tetra-n-butylammonium hydroxide, tetra-n-butylammonium iodide, tetraethylammonium chloride, benzyltributylammonium chloride, benzyltriethylammonium bromide, hexadecyltriethylammonium chloride, tetramethylammonium chloride, hexadecyltrimethyl Ammonium chloride and octyltri Chill chloride, or selected from the group consisting of mixtures thereof, The method according to claim 2 or claim 3.   The process according to claim 4, wherein the phase transfer catalyst is tetra-n-butylammonium bromide or triethylbenzylammonium chloride (TEBAC).   The method according to any one of claims 1 to 5, wherein step (a) of the method is carried out in the presence of an inorganic base.   The method according to any one of claims 1 to 6, wherein the 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 process according to claim 1 or claim 2, wherein the catalyst is an antioxidant.   The antioxidant is selected from the group consisting of butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), tertiary butylhydroquinone (TBHQ), propyl gallate (PG) and hydroquinone monomethyl ether (MEHQ). 9. A method according to claim 2 or claim 8.   The method of claim 9, wherein the antioxidant is butylhydroxytoluene (BHT).   Solvent is ethyl alcohol, n-propyl alcohol, isopropyl alcohol, isobutyl alcohol, methanol; ethyl ether, propyl ether, toluene, benzene, xylene, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, dioxane, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide 11. A process according to any one of claims 1 to 10 selected from the group consisting of and dimethylacetamide.   12. A process according to claim 11 wherein the solvent is selected from the group consisting of ethyl alcohol, n-propyl alcohol, isopropyl alcohol, isobutyl alcohol and methanol.   The process according to claim 1, wherein the precipitation of Compound I as the free base or its hydrochloride is carried out at a low temperature of 0 ° C to 10 ° C.   13. The method according to any one of claims 1 to 12, wherein the compound I or its free base contains an alkylating substance with a total amount of less than 10 ppm as an impurity.   15. The method of claim 14, wherein the alkylating material is 1- (3-chlorophenyl) -4- (3-chloropropyl) piperazine present as less than 2.5 ppm as an impurity. Trazodone or its hydrochloride salt (compound I)

(Compound I)
The manufacturing method of the following, Comprising:
(B) a salt of compound-II represented by the following formula in a solvent in the presence of an inorganic base and a phase transfer catalyst;

A salt of Compound-II and Compound-III having the formula:

Compound-III
To give compound I as the free base;
(C) treating the compound I as the free base obtained in step (c) above with an alcohol solution of hydrogen chloride to obtain the corresponding hydrochloride;
And isolating trazodone free base and / or its hydrochloride salt by precipitation at low temperature in the above process.   The process according to claim 16, wherein the inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, calcium carbonate, sodium hydroxide or potassium hydroxide.   Phase transfer catalysts are tetra-n-butylammonium bromide, triethylbenzylammonium chloride (TEBAC), cetyltrimethylammonium bromide (CTAB), cetylpyridinium bromide, tricaprylmethylammonium chloride (Aliquat 336), N-benzylquininium chloride, Tetra-n-butylammonium chloride, tetra-n-butylammonium hydroxide, tetra-n-butylammonium iodide, tetraethylammonium chloride, benzyltributylammonium chloride, benzyltriethylammonium bromide, hexadecyltriethylammonium chloride, tetramethylammonium chloride , Hexadecyltrimethylammonium chloride Chloride, octyl trimethyl ammonium chloride, or selected from the group consisting of mixtures thereof, The method according to claim 16 or 17. Trazodone or its hydrochloride salt (compound I)

(Compound I)
The manufacturing method of the following, Comprising:
(D) a free base of compound-II represented by the following formula in a solvent in the presence of an antioxidant;

Compound-III having the free base of Compound-II and the following formula:

Compound-III
To give compound I as the free base;
(E) treating the compound I as the free base obtained in step (e) above with an alcohol solution of hydrogen chloride to give the corresponding hydrochloride;
And isolating trazodone free base and / or its hydrochloride salt by precipitation at low temperature in the above process.   The antioxidant is selected from the group consisting of butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), tertiary butylhydroquinone (TBHQ), propyl gallate (PG), hydroquinone monomethyl ether (MEHQ). 19. The method according to 19.   Solvents such as ethyl alcohol, n-propyl alcohol, isopropyl alcohol, isobutyl alcohol and methanol; ethers such as ethyl ether and propyl ether; or toluene, benzene, xylene, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, 21. Process according to claims 19 and 20 selected from other hydrocarbon solvents such as dioxane, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide and dimethylacetamide.   The process according to claims 19 and 21, wherein the precipitation of the product trazodone free base and trazodone hydrochloride is carried out at a low temperature of 0 ° C to 10 ° C.