Preparation of quetiapine intermediate

Abstract

The present invention relates to a process for the preparation of 10,11-dihydro-11- oxodibenzo[b,f][1,4]thiazepine of formula (1), a synthetic intermediate for preparation of Quetiapine.

Description

[0001] PREPARATION OF QUETIAPINE INTERMEDIATE

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a process for the preparation of 10,11-dihydro-l 1- oxodibenzo[b,f][l,4]thiazepine of formula (1), a synthetic intermediate for preparation of Quetiapine.

[0004] BACKGROUND OF THE INVENTION

[0005] The following discussion of the prior art is intended to present the invention in an appropriate technical context and allows its significance to be properly appreciated. Unless clearly indicated to the contrary, reference to any prior art in this specification should not be construed as an expressed or implied admission that such art is widely known or forms part of common general knowledge in the field.

[0006] Quetiapine, sold under the brand name Seroquel and it is an atypical antipsychotic medication used for the treatment of schizophrenia, bipolar disorder, and major depressive disorder. Quetiapine was developed in 1985 and approved for medical use in the United States in 1997. It is available as a generic medication.

[0007] Quetiapine was first described in a patent publication US 4879288. It is prepared starting from 10,11-dihydro-l l-oxodibenzo[b,f][l,4]thiazepine of formula (1), which is first halogenated with phosphorous oxychloride, then isolated and condensed with 1 -(2-hydroxyethoxy) ethyl piperazine to obtain quetiapine. After purification by flash chromatography the yield was 77.7%.

[0008] The prior art processes for the preparation of quetiapine intermediate are not suitable for the large scale commercial production.

[0009] Therefore, inventors of the present invention have developed a process which is a simple, efficient and cost-effective process and provides the desired intermediate in improved yield and purity and 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 toxic and / or costly solvents, also does not involve use of costlier reagents. Accordingly, the present invention provides a process for the preparation of intermediate of formula (1), which is simple, efficient, cost effective, environmentally friendly and commercially scalable for large scale operations.

[0010] SUMMARY OF THE INVENTION

[0011] The present invention provides a process for the preparation of 10,11-dihydro-l l- oxodibenzo[b,f][l,4]thiazepine of formula (1), a synthetic intermediate for preparation of Quetiapine.

[0012] DETAILED DESCRIPTION OF THE INVENTION

[0013] Before the present invention is described, it is to be understood that this invention is not limited to particular methodologies and materials described, as these may vary as per the person skilled in the art. It is also to be understood that the terminology used in the description is for the purpose of describing the particular embodiments only and is not intended to limit the scope of the present invention.

[0014] Before the present invention is described, it is to be understood that unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Further, it is to be understood that the present invention is not limited to the methodologies and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described, as these may vary within the specification indicated. Unless stated to the contrary, any use of the words such as "including," "containing," "comprising," "having" and the like, means "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims. Further the terms disclosed embodiments are merely exemplary methods of the invention, which may be embodied in various forms.

[0015] The term “about,” as used herein, is intended to qualify the numerical values, which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term “about” should be understood to mean that range which would encompass the recited value and the range which would be included by rounding up or down to that figure as well, taking into account significant figures.

[0016] The term “heating”, as used herein, is heating the solution gradually to a temperature in the range of 50-150°C.

[0017] Accordingly, the present invention relates to a process for the preparation of 10, 11 -dihydro- 11- oxodibenzo[b,f][l,4]thiazepine having the formula (1), comprising the steps of: a) condensing 2-aminothiophenol (2) with 2-chlorobenzonitrile (3) in a solvent, in presence of a base and optionally in presence of a catalyst to give 2-[(2-aminophenyl)- sulfanyl]benzonitrile (4), which may or may not be isolated; and b) hydrolyzing the compound (4) obtained in step (a) in presence of sulphuric acid to give 2-

[0018] [(2-aminophenyl)sulfanyl]benzoic acid sulphate salt (5);

[0019] (4) (5) c) cyclizing the compound (5) obtained in step (b) in an aromatic solvent and in presence of a catalyst to give 10,11-dihydro-l l-oxodibenzo[b,f][l,4]thiazepine of formula (1); and d) optionally purifying 10,11-dihydro-l l-oxodibenzo[b,f][l,4]thiazepine of formula (1). The present invention also relates to the process, wherein step (a) can be carried out without isolating the compound of formula (4). The solvent used in step (a) is an ether solvent selected from tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether, dioxane, 1,4-dioxane, 1,2-dioxane or 1,3-dioxane; an alcoholic solvent selected from methanol, ethanol, isopropanol, t-amyl alcohol, t-butyl alcohol or hexanol; a halogenated solvent selected from dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene or chloroform; a ketone solvent selected form acetone, propanone, methyl ethyl ketone or methyl isobutyl ketone; an aprotic solvent selected from acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) or N-methylpyrrolidone (NMP); an aromatic solvent selected from toluene, xylene or benzene; water or a mixture thereof.

[0020] The base used in step (a) is an alkali metal hydroxide selected from lithium hydroxide, sodium hydroxide or potassium hydroxide; an alkali metal carbonate selected from lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate; an alkali metal bicarbonate selected from sodium bicarbonate or potassium bicarbonate; an alkali metal alkoxides selected from sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or potassium tert- butoxide, or an organic amines selected from triethylamine, diisopropylethylamine, pyridine, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) or l,5-diazabicyclo[4.3.0]non-5-ene (DBN).

[0021] The catalyst used in step (a) is a “phase transfer catalyst” and is selected from the tetra butyl ammonium chloride (TBAC), tetra butyl ammonium bromide (TBAB) , tetra propyl ammonium bromide, tributyl benzyl ammonium bromide, tetra octyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate or ethyl triphenyl phosphonium bromide.

[0022] The hydrolysis of compound of formula (4) in step (b) is carried out by using sulphuric acid in water at temperature ranging from 80°C to 100°C.

[0023] The aromatic solvent used in step (c) is selected from ethylbenzene, o-xylene, m-xylene, p-xylene, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole or mesitylene.

[0024] The catalyst used in step (c) is selected from boric acid, methane sulphonic acid, sulphuric acid, p-toluene sulphonic acid or phosphorous pentoxide. The solvent used for purification in step (d) is an ether solvent selected from tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether, dioxane, 1,4-dioxane, 1,2- dioxane or 1,3-dioxane; an alcoholic solvent selected from methanol, ethanol, isopropanol, t-amyl alcohol, t-butyl alcohol or hexanol; a halogenated solvent selected from dichloromethane, 4- bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene or chloroform; a ketone solvent selected form acetone, propanone, methyl ethyl ketone or methyl isobutyl ketone; an aprotic solvent selected from acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) or N-methylpyrrolidone (NMP); an aromatic solvent selected from toluene, xylene or benzene; water or a mixture thereof. The complete synthetic scheme of preparation of 10, 11 -dihydro- 11- oxodibenzo[b,f][l,4]thiazepine of formula (1) according to the present invention can be represented as below: According to another specific aspect of the present invention relates to a process for the preparation of 10,l l-dihydro-l l-oxodibenzo[b,f][l,4]thiazepine having the formula (1), comprising the steps of: a) condensing 2-aminothiophenol (2) with 2-chlorobenzonitrile (3) in DMF, in presence of potassium carbonate and tetra butyl ammonium chloride (TBAC) to give 2-[(2- aminophenyl)- sulfanyl]benzonitrile (4), which may or may not be isolated; and b) hydrolyzing the compound (4) obtained in step (a) in presence of aqueous sulphuric acid to give 2-[(2-aminophenyl)sulfanyl]benzoic acid sulphate salt (5); c) cyclizing the compound (5) obtained in step (b) in o-xylene and in presence of boric acid to give 10,l l-dihydro-l l-oxodibenzo[b,f][l,4]thiazepine of formula (1); and d) optionally purifying 10,11-dihydro-l l-oxodibenzo[b,f][l,4]thiazepine of formula (1).

[0025] The present invention also relates to the process, wherein step (a) can be carried out without isolating the compound of formula (4).

[0026] The term “about,” as used herein, is intended to qualify the numerical values, which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term “about” should be understood to mean that range which would encompass the recited value and the range which would be included by rounding up or down to that figure as well, taking into account significant figures.

[0027] According to the invention, the overall yield of compound of formula (1) as obtained by using the process of the present invention is with purity of at least about 99.9% by HPLC.

[0028] The invention is further illustrated by the following examples which are provided to be exemplary of the invention, and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. EXAMPLES

[0029] Example 1

[0030] Preparation of 2-(2-aminophenylthio) benzoic acid sulphate of formula (5)

[0031] In to a cleaned and dried flask under nitrogen atmosphere was charged 2-chloro benzonitrile (2) (1 mol) followed by DMF, potassium carbonate (1 mol) and tetra butyl ammonium chloride (10 mmol). The reaction mixture was heated slowly to 90°C and 2-amino thiophenol (3) (1 mol) was added. Reaction mass was maintained for 3-4 hr at same temperature till process analysis showed completion of reaction, distillation of DMF was started. After complete removal of DMF, reaction mass was cooled to 25-30°C. A 30% aqueous solution of sulphuric acid was added while maintaining reaction temperature between 25-30°C. Reaction temperature was raised to 90-95 °C after complete addition of sulphuric acid solution and maintained for 10-12 hr till complete conversion of nitrile to carboxylic acid. Reaction progress was monitored by TLC (Thin-layer chromatography). Reaction mass was cooled to 25-30°C and filtered the product. The obtained wet cake was washed with water. Unloaded and dried in oven between 60-65 °C till water content was below 1 %. The obtained crude product was washed with Toluene to obtain final product having 99.5 % purity by HPLC.

[0032] Yield: 80%

[0033] Example 2

[0034] Preparation of 2-(2-aminophenylthio) benzoic acid sulphate of formula (5)

[0035] In to a cleaned and dried flask under nitrogen atmosphere was charged 2-chloro benzonitrile (2) ( 1 mol) followed by DMF, Sodium carbonate ( 1 mol) and tetra butyl ammonium hydrogen sulfate (10 mmol). The reaction mixture was heated slowly to 90°C and 2-amino thiophenol (3) (1 mol) was added. Reaction mass was maintained for 3-4 hr at same temperature till process analysis showed completion of reaction, distillation of DMF was started. After complete removal of DMF, reaction mass was cooled to 25-30°C. A 30% aqueous solution of sulphuric acid was added while maintaining reaction temperature between 25-30°C. Reaction temperature was raised to 90-95 °C after complete addition of sulphuric acid solution and maintained for 10-12 hr till complete conversion of nitrile to carboxylic acid. Reaction progress was monitored by TLC (Thin-layer chromatography). Reaction mass was cooled to 25-30°C and filtered the product. The obtained wet cake was washed with water. Unloaded and dried in oven between 60-65 °C till water content was below 1 %. The obtained crude product was washed with Toluene to obtain final product having 99.5 % purity by HPLC.

[0036] Yield: 73%

[0037] Example 3

[0038] Preparation of 2-(2-aminophenylthio) benzoic acid sulphate of formula (5)

[0039] In to a cleaned and dried flask under nitrogen atmosphere was charged 2-chloro benzonitrile (2) (1 mol) followed by DMF, Cesium carbonate (1 mol) and tetra butyl ammonium chloride (10 mmol). The reaction mixture was heated slowly to 90°C and 2-amino thiophenol (3) (1 mol) was added. Reaction mass was maintained for 3-4 hr at same temperature till process analysis showed completion of reaction, distillation of DMF was started. After complete removal of DMF, reaction mass was cooled to 25-30°C. A 30% aqueous solution of sulphuric acid was added while maintaining reaction temperature between 25-30°C. Reaction temperature was raised to 90-95 °C after complete addition of sulphuric acid solution and maintained for 10-12 hr till complete conversion of nitrile to carboxylic acid. Reaction progress was monitored by TLC (Thin-layer chromatography). Reaction mass was cooled to 25-30°C and filtered the product. The obtained wet cake was washed with water. Unloaded and dried in oven between 60-65 °C till water content was below 1 %. The obtained crude product was washed with Toluene to obtain final product having 99.5 % purity by HPLC.

[0040] Yield: 76%

[0041] Example 4

[0042] Preparation of Dibenzorb,firi,41thiazepin-ll(10H)-one of formula (1)

[0043] In to a cleaned and dried flask under nitrogen atmosphere was charged o-xylene followed by 2-(2- aminophenylthio) benzoic acid sulphate (4) (1 (mol) and boric acid (10 mmol) as catalyst. The reaction mixture was heated slowly to 135-140°C. Water was removed azeotropically from the reaction mixture. The reaction was maintained further for 15 hr till process analysis showed completion of reaction, temperature of the reaction was cooled down to 25-30°C. Maintained for 1 hr at same temperature. Filtered the reaction mass. Unloaded wet cake and leached into purified water. Filtered again and finally leached into methanol. Filtered the product. Unloaded and weighed the wet cake. Dried in oven for 6 Hrs at 60°C to obtain compound of formula (1). (HPLC Purity is greater than 99.9 %) Yield: 83%. Example 5

[0044] Preparation of Dibenzorb,firi,41thiazepin-ll(10H)-one of formula (1)

[0045] In to a cleaned and dried flask under nitrogen atmosphere was charged o-xylene followed by 2-(2- aminophenylthio) benzoic acid sulphate (4) (1 mol) and sulphuric acid (10 mmol) as catalyst. The reaction mixture was heated slowly to 135-140°C. Water was removed azeotropically from the reaction mixture. The reaction was maintained further for 18 hr till process analysis showed completion of reaction, temperature of the reaction was cooled down to 25-30°C. Maintained for 1 hr at same temperature. Filtered the reaction mass. Unloaded wet cake and leached into purified water. Filtered again and finally leached into methanol. Filtered the product. Unloaded and weighed the wet cake. Dried in oven for 6 Hrs at 60°C to obtain compound of formula (1).

[0046] (HPLC Purity is greater than 99.9 %)

[0047] Yield: 81%.

[0048] Example 6

[0049] Preparation of Dibenzorb,firi,4]thiazepin-ll(10H)-one of formula (1)

[0050] In to a cleaned and dried flask under nitrogen atmosphere was charged o-xylene followed by 2-(2- aminophenylthio) benzoic acid sulphate (4) (1 mol) and p-toluene sulphonic acid (10 mmol) as catalyst. The reaction mixture was heated slowly to 135-140°C. Water was removed azeotropically from the reaction mixture. The reaction was maintained further for 18 hr till process analysis showed completion of reaction, temperature of the reaction was cooled down to 25-30°C. Maintained for 1 hr at same temperature. Filtered the reaction mass. Unloaded wet cake and leached into purified water. Filtered again and finally leached into methanol. Filtered the product. Unloaded and weighed the wet cake. Dried in oven for 6 Hrs at 60°C to obtain compound of formula (1).

[0051] (HPLC Purity is greater than 99.9 %)

[0052] Yield: 77%. Example 7

[0053] Preparation of Dibenzorb,firi,41thiazepin-ll(10H)-one of formula (1)

[0054] In to a cleaned and dried flask under nitrogen atmosphere was charged o-xylene followed by 2-(2- aminophenylthio) benzoic acid sulphate (4) (1 mol) and phosphorous pentoxide (10 mmol) as catalyst. The reaction mixture was heated slowly to 135-140°C. Water was removed azeotropically from the reaction mixture. The reaction was maintained further for 18 hr till process analysis showed completion of reaction, temperature of the reaction was cooled down to 25-30°C. Maintained for 1 hr at same temperature. Filtered the reaction mass. Unloaded wet cake and leached into purified water. Filtered again and finally leached into methanol. Filtered the product. Unloaded and weighed the wet cake. Dried in oven for 6 Hrs at 60°C to obtain compound of formula (1).

[0055] (HPLC Purity is greater than 99.9 %)

[0056] Yield: 79%.

Claims

We Claim:

1. A process for the preparation of 10,l l-dihydro-l l-oxodibenzo[b,f][l,4]thiazepine having formula (1),comprising the steps of, a) condensing 2-aminothiophenol (2) with 2-chlorobenzonitrile (3) in a solvent, in presence of a base and optionally in presence of a catalyst to give 2-[(2-aminophenyl)- sulfanyl]benzonitrile (4), which may or may not be isolated; andb) hydrolyzing the compound (4) obtained in step (a) in presence of sulphuric acid to give 2-[(2-aminophenyl)sulfanyl]benzoic acid sulphate salt (5);c) cyclizing the compound (5) obtained in step (b) in an aromatic solvent and in presence of a catalyst to give 10,11-dihydro-l l-oxodibenzo[b,f][l,4]thiazepine of formula (1); andd) optionally purifying 10,11-dihydro-l l-oxodibenzo[b,f][l,4]thiazepine of formula (1). wherein - the process, wherein step (a) can be carried out without isolating the compound of formula (4).

2. The process as claimed in claim 1, wherein the solvent used in step (a) is an ether solvent selected from tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether, dioxane, 1,4-dioxane, 1,2-dioxane or 1,3-dioxane; an alcoholic solvent selected from methanol, ethanol, isopropanol, t-amyl alcohol, t-butyl alcohol or hexanol; a halogenated solvent selected from dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene or chloroform; a ketone solvent selected form acetone, propanone, methyl ethylketone or methyl isobutyl ketone; an aprotic solvent selected from acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) or N- methylpyrrolidone (NMP); an aromatic solvent selected from toluene, xylene or benzene; water or a mixture thereof.

3. The process as claimed in claim 1 , wherein the base used in step (a) is an alkali metal hydroxide selected from lithium hydroxide, sodium hydroxide or potassium hydroxide; an alkali metal carbonate selected from lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate; an alkali metal bicarbonate selected from sodium bicarbonate or potassium bicarbonate; an alkali metal alkoxides selected from sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or potassium tert-butoxide, or an organic amines selected from triethylamine, diisopropylethylamine, pyridine, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) or l,5-diazabicyclo[4.3.0]non-5-ene (DBN).

4. The process as claimed in claim 1, wherein the catalyst used in step (a) is a “phase transfer catalyst” and is selected from the tetra butyl ammonium chloride (TBAC), tetra butyl ammonium bromide (TBAB) , tetra propyl ammonium bromide, tributyl benzyl ammonium bromide, tetra octyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate or ethyl triphenyl phosphonium bromide.

5. The process as claimed in claim 1, wherein the hydrolysis of compound of formula (4) in step (b) is carried out by using sulphuric acid in water.

6. The process as claimed in claim 1 , wherein the hydrolysis of compound of formula (4) in step (b) is carried out at temperature ranging from 80°C to 100°C.

7. The process as claimed in claim 1, wherein the aromatic solvent used in step (c) is selected from ethylbenzene, o-xylene, m-xylene, p-xylene, chlorobenzene, o-dichlorobenzene, fluorobenzene, anisole or mesitylene.

8. The process as claimed in claim 1, wherein the catalyst used in step (c) is selected from boric acid, methane sulphonic acid, sulphuric acid, p-toluene sulphonic acid or phosphorous pentoxide.

9. The process as claimed in claim 1, wherein the solvent used for purification in step (d) is an ether solvent selected from tetrahydrofuran, cyclopentyl methyl ether, 2- methyltetrahydrofuran, diethyl ether, dioxane, 1,4-dioxane, 1,2-dioxane or 1,3-dioxane; an alcoholic solvent selected from methanol, ethanol, isopropanol, t-amyl alcohol, t-butyl alcohol or hexanol; a halogenated solvent selected from dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene or chloroform; a ketone solvent selected form acetone, propanone, methyl ethyl ketone or methyl isobutyl ketone; an aprotic solvent selected from acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) or N-methylpyrrolidone (NMP); an aromatic solvent selected from toluene, xylene or benzene; water or a mixture thereof.

10. A process for the preparation of 10,l l-dihydro-l l-oxodibenzo[b,f][l,4]thiazepine (1), having a purity of about 99.9% or more by area percentage of HPLC,comprising the steps of: a) condensing 2-aminothiophenol (2) with 2-chlorobenzonitrile (3) in DMF, in presence of potassium carbonate and tetra butyl ammonium chloride (TBAC) to give 2-[(2- aminophenyl)- sulfanyl]benzonitrile (4), which may or may not be isolated; andb) hydrolyzing the compound (4) obtained in step (a) in presence of aqueous sulphuric acid to give 2-[(2-aminophenyl)sulfanyl]benzoic acid sulphate salt (5);(4) (5) c) cyclizing the compound (5) obtained in step (b) in o-xylene and in presence of boric acid to give 10,l l-dihydro-l l-oxodibenzo[b,f][l,4]thiazepine of formula (1); andd) optionally purifying 10,11-dihydro-l l-oxodibenzo[b,f][l,4]thiazepine of formula (1). wherein -the process, wherein step (a) can be carried out without isolating the compound of formula (4).

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