WO2022195500A1

WO2022195500A1 - A process for the preparation of lumateperone tosylate intermediate

Info

Publication number: WO2022195500A1
Application number: PCT/IB2022/052370
Authority: WO
Inventors: Savankumar Dahyabhai PATEL; Anandkumar Balchand JAIN; Jignasu Thakorbhai DESAI; Rajeev Ramchandra DUBEY; Ajit Kumar CHOUBEY
Original assignee: Ami Organics Ltd.
Priority date: 2021-03-16
Filing date: 2022-03-16
Publication date: 2022-09-22

Abstract

The present disclosure relates to a process for the preparation of lumateperone tosylate intermediate. The process comprises the conversion of benzyl 6-bromo-5-(2-(methylamino)-2-oxoethyl)-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate to lumateperone tosylate intermediate in a comparatively high yield and high purity. The process of the present disclosure is simple, employs inexpensive reagents and is environment friendly.

Description

A PROCESS FOR THE PREPARATION OF LUMATEPERONE TOSYLATE INTERMEDIATE

FIELD

The present disclosure relates to a process for the preparation of lumateperone tosylate intermediate.

BACKGROUND

The background information herein below relates to the present disclosure but is not necessarily prior art.

Benzyl,3-methyl-2-oxo-2,3,9,10-tetrahydro-lH-pyrido[3',4’:4,5]pyrrolo[l,2,3-de] quinoxaline-8(7H) carboxylate (lumateperone tosylate intermediate) represented as Formula (I) is the key raw material for the preparation of lumateperone tosylate drug which is used for the treatment of schizophrenia.

Formula (I)

The conventional route for preparing lumateperone tosylate intermediate includes the use of high-cost reagents such as tris(dibenzylideneacetone)dipalladium (Pd (dba) ) as a metal catalyst and Xantphos that produces hazardous waste, Hence, such conventional processes are not economic and not environment friendly.

Therefore, there is felt a need to provide a process for the preparation of lumateperone tosylate intermediate that mitigates the drawbacks mentioned hereinabove or at least provide a useful alternative. OBJECTS

Some of the objects of the present disclosure, which at least one embodiment herein satisfies, are as follows: It is an object of the present disclosure to ameliorate one or more problems of the prior art or to at least provide a useful alternative.

An object of the present disclosure is to provide a process for the preparation of benzyl, 3- methyl-2-oxo-2,3,9,10-tetrahydro-lH-pyrido[3',4':4,5]pyrrolo[l,2,3-de] quinoxaline-8(7H) carboxylate (I) (lumateperone tosylate intermediate). Another object of the present disclosure is to provide a process for the preparation of benzyl,3-methyl-2-oxo-2,3,9,10-tetrahydro-lH-pyrido[3',4':4,5]pyrrolo[l,2,3-de] quinoxaline-8(7H) carboxylate (I) with a comparatively high yield and high purity.

Still another object of the present disclosure is to provide a simple, economical and eco- friendly process for preparation of benzyl 3-methyl-2-oxo-2,3,9,10-tetrahydro-lH- pyrido[3',4':4,5]pyrrolo[l,2,3-de]quinoxaline-8(7H) carboxylate.

Other objects and advantages of the present disclosure will be more apparent from the following description, which is not intended to limit the scope of the present disclosure.

SUMMARY:

The present disclosure relates to a process for the preparation of lumateperone tosylate intermediate. The process comprises mixing benzyl 6-bromo-5-(2-(methylamino)-2- oxoethyl)-l,3,4,5-tetrahydro-2H-pyrido[4,3-b] indole-2-carboxylate with predetermined amounts of a base, a metal halide, and a catalyst in a predetermined amount of a fluid medium under stirring to obtain a reaction mixture. The mixture is heated to a first predetermined temperature for a first predetermined time period to obtain a product mixture comprising a crude benzyl,3-methyl-2-oxo-2,3,9,10-tetrahydro- lHpyrido[3',4':4,5]pyrrolo[l,2,3-de]quinoxaline-8(7H) carboxylate (lumateperone tosylate intermediate). The crude lumateperone tosylate intermediate is isolated and purified to obtain a pure lumateperone tosylate intermediate. DETAILED DESCRIPTION

The present disclosure relates to a process for the preparation of lumateperone tosylate intermediate. Embodiments are provided so as to thoroughly and fully convey the scope of the present disclosure to the person skilled in the art. Numerous details are set forth, relating to specific components, and methods, to provide a complete understanding of embodiments of the present disclosure. It will be apparent to the person skilled in the art that the details provided in the embodiments should not be construed to limit the scope of the present disclosure. In some embodiments, well-known processes, well-known apparatus structures, and well-known techniques are not described in detail.

The terminology used, in the present disclosure, is only for the purpose of explaining a particular embodiment and such terminology shall not be considered to limit the scope of the present disclosure. As used in the present disclosure, the forms "a,” "an," and "the" may be intended to include the plural forms as well, unless the context clearly suggests otherwise. The terms "comprises," "comprising," “including,” and “having,” are open-ended transitional phrases and therefore specify the presence of stated features, integers, steps, operations, elements, modules, units and/or components, but do not forbid the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. The particular order of steps disclosed in the method and process of the present disclosure is not to be construed as necessarily requiring their performance as described or illustrated. It is also to be understood that additional or alternative steps may be employed.

As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed elements. Benzyl,3-methyl-2-oxo-2,3,9,10-tetrahydro-lH-pyrido[3',4':4,5]pyrrolo[l,2,3-de] quinoxaline-8(7H) carboxylate represented as Formula (I) is used as an intermediate in the preparation of lumateperone tosylate drug which is used for the treatment of schizophrenia.

Benzyl 3-methyl-2-oxo-2,3,9,10-tetrahydro-1 H-pyrido[3',4':4,5] pyrrolo[1 ,2,3-de]quinoxaline-8(7H)-carboxylate Chemical Formula: C H N O Exact Mass: 375.16

Formula (I)

The present disclosure provides a process for the preparation of lumateperone tosylate intermediate.

Particularly, the present disclosure relates to a process for the preparation of benzyl, 3- methyl-2-oxo-2,3,9,10-tetrahydro-lH-pyrido[3’,4’:4,5]pyrrolo[l,2,3-de]quinoxaline-

8(7H)carboxylate(I) (lumateperone tosylate intermediate). The process of the present disclosure is simple, economical and eco-friendly and provides a comparatively high yield of lumateperone tosylate intermediate.

The process for the preparation of lumateperone tosylate intermediate comprises the following steps: i. mixing benzyl 6-bromo-5-(2-(methylamino)-2-oxoethyl)-l,3,4,5-tetrahydro-2H- pyrido[4,3-b]indole-2-carboxylate with predetermined amounts of a base, a metal halide, and a catalyst in a predetermined amount of a fluid medium under stirring to obtain a reaction mixture; ii. heating the reaction mixture to a first predetermined temperature for a first predetermined time period to obtain a product mixture comprising a crude benzyl 3- methyl-2-oxo-2,3,9,10-tetrahydro-lH pyrido[3’,4’:4,5]pyrrolo [1,2,3-de] quinoxaline- 8(7H)-carboxylate (crude lumateperone tosylate intermediate); and iii. isolating and purifying the crude lumateperone tosylate intermediate to obtain a pure lumateperone tosylate intermediate.

In an embodiment of the present disclosure, the schematic representation of the synthetic route for preparing lumateperone tosylate intermediate is given below as scheme I.

Scheme I

The process for the preparation of lumateperone tosylate intermediate in accordance with the present disclosure is described in detail herein below:

In a first step, benzyl 6-bromo-5-(2-(methylamino)-2-oxoethyl)-l, 3, 4, 5-tetrahydro-2H- pyrido [4, 3-b] indole-2-carboxylate is mixed with predetermined amounts of a base, a metal halide, and a catalyst in a predetermined amount of a fluid medium under stirring to obtain a reaction mixture.

The base is selected from the group consisting of potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide. In an exemplary embodiment, the base is potassium carbonate.

In an embodiment of the present disclosure, a molar ratio of benzyl 6-bromo-5-(2- (methylamino)-2-oxoethyl)-l,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate to the base is in the range of 1:2 to 1:3. In an exemplary embodiment, the molar ratio of benzyl 6- bromo-5-(2-(methylamino)-2-oxoethyl)-l,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2- carboxylate to the base is 1:2.3. The metal halide is selected from the group consisting of copper iodide, copper bromide (CuBr), copper chloride (CuCl), copper acetate (Cu(OAc)₂), copper sulphate (CuSCb) and copper oxide (CuO). In an exemplary embodiment, the metal halide is copper iodide.

In an embodiment of the present disclosure, a molar ratio of benzyl 6-bromo-5-(2- (methyIamino)-2-oxoethyI)-l,3,4,5-tetrahydro-2H-pyrido[4,3-b]indoIe-2-carboxyIate to the metal halide is in the range of 1:0.1 to 1:0.3. In an exemplary embodiment, the molar ratio of benzyl 6-bromo-5-(2-(methyIamino)-2-oxoethyI)-l,3,4,5-tetrahydro-2H-pyrido[4,3-b]indoIe- 2-carboxylate to the metal halide is 1:0.24.

The catalyst is selected from the group consisting of N,N’-dimethyIethyIenediamine (DMEDA), l,8-DiazabicycIo(5.4.0)undec-7-ene (DBU), l,5-DiazabicycIo(4.3.0)non-5-ene (DBN), I,4-diazabicycIo[2.2.2]octane (DABCO), imidazolium carbene, 4- (dimethylamino)pyridine, TMEDA 1,2-diamine and 1,2-aminoaIcohoI. In an exemplary embodiment, the catalyst is N,N’-dimethyIethyIenediamine (DMEDA). In another exemplary embodiment, the catalyst is l,8-DiazabicycIo(5.4. 0)undec-7-ene (DBU).

In an embodiment of the present disclosure, a molar ratio of benzyl 6-bromo-5-(2- (methyIamino)-2-oxoethyI)-l,3,4,5-tetrahydro-2H-pyrido[4,3-b]indoIe-2-carboxyIate to the catalyst is in the range of 1:0.5 to 1:1.5. In an exemplary embodiment, the molar ratio of benzyl 6-bromo-5-(2-(methyIamino)-2-oxoethyI)-l,3,4,5-tetrahydro-2H-pyrido[4,3-b]indoIe- 2-carboxylate to DMEDA is 1:0.73. In another exemplary embodiment, the molar ratio of benzyl 6-bromo-5-(2-(methyIamino)-2-oxoethyI)-l,3,4,5-tetrahydro-2H-pyrido[4,3-b]indoIe- 2-carboxylate to DBU is 1:0.9. In yet another exemplary embodiment, the molar ratio of benzyl 6-bromo-5-(2-(methyIamino)-2-oxoethyI)-l,3,4,5-tetrahydro-2H-pyrido[4,3-b]indoIe- 2-carboxylate to DMDEA is 1:1.14.

The fluid medium is selected from the group consisting of dimethyl sulfoxide (DMSO), dimethyl form amide (DMF) and toluene. In an exemplary embodiment, the fluid medium is DMSO. In another exemplary embodiment, the fluid medium is DMF. In still another exemplary embodiment, the fluid medium is toluene.

The amount of fluid medium is in the range of 1 litre to 5 litres per mole of benzyl 6-bromo- 5-(2-(methylamino)-2-oxoethyl)-l,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate. In an exemplary embodiment of the present disclosure, the amount of fluid medium is 2.3 litres per mole of benzyl 6-bromo-5-(2-(methylamino)-2-oxoethyl)-l,3,4,5-tetrahydro-2H- pyrido[4,3-b]indole-2-carboxylate.

In a second step, the reaction mixture is heated to a first predetermined temperature for a first predetermined time period to obtain a product mixture comprising a crude benzyI-3-methyI- 2-oxo-2,3,9,10-tetrahydro-lH pyrido[3',4':4,5]pyrroIo [1,2,3-de] quinoxaIine-8(7H)- carboxylate (crude lumateperone tosylate intermediate).

The first predetermined temperature is in the range of 80 °C to 120 °C. In an exemplary embodiment, the first predetermined temperature is 85 °C. In another exemplary embodiment, the first predetermined temperature is 120 °C. The first predetermined time period is in the range of 10 hours to 25 hours. In an exemplary embodiment, the first predetermined time period is 16 hours. In another exemplary embodiment, the first predetermined time period is 12 hours. In yet another exemplary embodiment, the first predetermined time period is 24 hours.

In a third step, the crude lumateperone tosylate intermediate is isolated and purified to obtain a pure lumateperone tosylate intermediate.

The step of isolation of crude lumateperone tosylate intermediate comprises the following sub-steps:

(i) cooling the so obtained product mixture to a second predetermined temperature to obtain a cooled mass; (ii) filtering the cooled mass to obtain a wet cake followed by washing the wet cake with the fluid medium to obtain a washed wet cake; and

(iii) drying the washed wet cake at a third predetermined temperature to obtain a pure lumateperone tosylate intermediate having a moisture content in the range of 0.1 % to 1 %. In an embodiment of the present disclosure, the so obtained lumateperone tosylate intermediate is subjected to further purification step when toluene is used as a fluid medium. In another embodiment of the present disclosure, the purification of the so obtained lumateperone tosylate intermediate is not required when DMSO/DMF is used as a fluid medium.

The further purification step when toluene is used as the fluid medium, comprises the following sub-steps: a. dissolving the washed wet cake obtained in the isolation sub-step (ii) in water to obtain a slurry; b. heating the slurry to a fourth predetermined temperature for a second predetermined time period to obtain a heated slurry; c. cooling the heated slurry to a fifth predetermined temperature followed by filtration to obtain a residue mass and a filtrate; and d. drying the residue mass at the third predetermined temperature to obtain a pure lumateperone tosylate intermediate having a moisture content in the range of 0.1 % to 1 %. The second predetermined temperature is in the range of 15 °C to 80 °C. In an exemplary embodiment, the second predetermined temperature is 25 °C. In another exemplary embodiment, the second predetermined temperature is 70 °C.

The fluid medium is selected from the group consisting of toluene, DMSO, DMF. In an exemplary embodiment, the fluid medium is toluene. In another exemplary embodiment, the fluid medium is DMSO. In still another exemplary embodiment, the fluid medium is DMF.

The third predetermined temperature is in the range of 50 °C to 70 °C. In an exemplary embodiment, the third predetermined temperature is 60 °C.

The fourth predetermined temperature is in the range of 70 °C to 90 °C. In an exemplary embodiment, the fourth predetermined temperature is 80 °C. The second predetermined time period is in the range of 0.5 hour to 1.5 hours. In an exemplary embodiment, the second predetermined time period is 1 hour. The fifth predetermined temperature is in the range of 50 °C to 70 °C. In an exemplary embodiment, the fifth predetermined temperature is 60 °C.

The moisture content of the so obtained pure lumateperone tosylate intermediate is in the range of 0.1 % to 1%. The lumateperone tosylate intermediate having less moisture content results in the desired quality product in next stage by using the reduction stage.

The process of the present disclosure provides lumateperone tosylate intermediate with a yield in the range of 45 % to 60 % and a purity in the range of 93 % to 98 %.

In an embodiment of the present disclosure, water is added to the filtrate obtained in sub-step (v) in a drop wise manner to obtain a precipitate of lumateperone tosylate intermediate. The so obtained precipitated lumateperone tosylate intermediate is filtered to obtain a third wet cake. The second wet cake and third wet cake so obtained are mixed together and dried at 60°C till the moisture content is 0.1 % to 1 % to obtain the pure lumateperone tosylate intermediate.

The present disclosure provides an alternative process for the preparation of lumateperone tosylate intermediate by using non-toxic and cheap reagents. As a result of using non-toxic, inexpensive and easily available reagents, the process of the present disclosure is cost efficient, economic and environmental friendly.

The process for the preparation of lumateperone tosylate intermediate of the present disclosure has the following advantages:

• the process is carried out under mild reaction conditions;

• involve convenient operations;

• easy purification of the product;

• low production costs;

• improved yield of the product;

• environment friendly; and

• suitable for industrial applications/scale-up.

The foregoing description of the embodiments has been provided for purposes of illustration and is not intended to limit the scope of the present disclosure. Individual components of a particular embodiment are generally not limited to that particular embodiment but are interchangeable. Such variations are not to be regarded as a departure from the present disclosure, and all such modifications are considered to be within the scope of the present disclosure.

The present disclosure is further described in light of the following experiments which are set forth for illustration purpose only and not to be construed for limiting the scope of the disclosure. The following experiments can be scaled up to industrial/commercial scale and the results obtained can be extrapolated to the industrial scale.

EXPERIMENTAL DETAILS:

Preparation of benzyl 3-methyl-2-oxo-2,3,9,10-tetrahydro-lH-pyrido [3',4’:4,5] pyrrolo [1, 2, 3-de]quinoxaline-8(7H)-carboxylate (I) (lumateperone tosylate intermediate) in accordance with the present disclosure:

Example 1: Preparation of lumateperone tosylate intermediate by using N.N’- dimethylethylenediamine (DMEDA) as a catalyst and DMSO as a fluid medium

In a reactor, 450 ml of DMSO, 100 g of benzyl 6-bromo-5-(2-(methylamino)-2-oxoethyl)- l,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate, 71 g of potassium carbonate, 10.5 g of copper iodide, 22 g of N,N’-diemethylethylenediamine (DMEDA) were charged under stirring to obtain a reaction mixture. The reaction mixture was flushed with 50 ml DMSO in the reactor under stirring to obtain a resultant mixture. The resultant mixture was heated by slowly raising the temperature to 80 °C and further maintained at 120°C for 16 hours to obtain a product mixture comprising a crude lumateperone tosylate intermediate. The reaction was monitored by checking the thin layer chromatography (TLC) of the product mixture against the starting material.

The so obtained product mixture was cooled to 65 °C to obtain a cooled mass. The cooled mass was filtered to obtain a wet cake followed by washing with 100 ml DMSO to obtain a washed wet cake and a filtrate. 1500 ml of water was added to the so obtained filtrate in a dropwise manner to obtain a precipitate of lumateperone tosylate intermediate. The so obtained precipitated lumateperone tosylate intermediate was filtered to obtain a residue mass. The wet cake and the residue mass were mixed together and dried at 60°C till the moisture content was 1 % to obtain the pure lumateperone tosylate intermediate. The yield of pure lumateperone tosylate intermediate was 42 g (51.05 %) and the purity was

96.5 %.

Example 2: Preparation of lumateperone tosylate intermediate by using 1,8- Diazabicvclo(5.9.0)undec-7-ene (DBU)as a catalyst and DMSO as a fluid medium

In a reactor, 450 ml of DMSO, 100 g of benzyl 6-bromo-5-(2-(methylamino)-2-oxoethyl)-

1.3.4.5 -tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate, 71 g of potassium carbonate, 10.5 g of copper iodide, 30 g of l,8-Diazabicyclo(5.4.0)undec-7-ene (DBU) were charged under stirring to obtain a reaction mixture. The reaction mixture was flushed with 50 ml DMSO in the reactor under stirring to obtain a resultant mixture. The resultant mixture was heated by slowly raising the temperature to 85 °C and further maintained at 85 °C for 12 hours to obtain a product mixture comprising a crude lumateperone tosylate intermediate. The reaction was monitored by checking the thin layer chromatography (TLC) of the product mixture against the starting material.

The so obtained product mixture was cooled to 65°C to obtain a cooled mass. The cooled mass was filtered to obtain a wet cake followed by washing with 100 ml DMSO to obtain a washed wet cake and a filtrate. 1500 ml of water was added to the so obtained filtrate in a dropwise manner to obtain a precipitate of lumateperone tosylate intermediate. The so obtained precipitated lumateperone tosylate intermediate was filtered to obtain a residue mass. The wet cake and the residue mass were mixed together and dried at 60°C till the moisture content was 1 % to obtain the pure lumateperone tosylate intermediate.

The yield of pure lumateperone tosylate intermediate was 47.5 g (57.74 %) and the purity was 97.93 %.

Example 3: Preparation of lumateperone tosylate intermediate by using N.N’- dimethylethylenediamine (DMEDA)as a catalyst and DMF as a fluid medium

In a reactor, 450 ml of DMF, 100 g of benzyl 6-bromo-5-(2-(methylamino)-2-oxoethyl)- l,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate, 71 g of potassium carbonate, 10.5 g of copper iodide, 30 g of l,8-Diazabicyclo(5.4.0)undec-7-ene (DBU) were charged under stirring to obtain a reaction mixture. The reaction mixture was flushed with 50 ml DMF in the reactor under stirring to obtain a resultant mixture. The resultant mixture was heated by slowly raising the temperature to 85 °C and further maintained at 120 °C for 24 hours to obtain a product mixture comprising a crude lumateperone tosylate intermediate. The reaction was monitored by checking the thin layer chromatography (TLC) of the product mi ture against the starting material.

The so obtained product mixture was cooled to 65°C to obtain a cooled mass. The cooled mass was filtered to obtain a wet cake followed by washing with 100 ml DMF to obtain a washed wet cake and a filtrate. 1500 ml of water was added to the so obtained filtrate in a dropwise manner to obtain a precipitate of lumateperone tosylate intermediate. The so obtained precipitated lumateperone tosylate intermediate was filtered to obtain a residue mass. The wet cake and the residue mass were mixed together and dried at 60°C till the moisture content was 1 % to obtain the pure lumateperone tosylate intermediate.

The yield of pure lumateperone tosylate intermediate was 38 g (46.19 %) and the purity was 93.5 %.

Example 4: Preparation of lumateperone tosylate intermediate by using Diazabicvclol5.4.01undec-7-ene (DBU ) as a catalyst and DMF as a fluid medium

In a reactor, 450 ml of DMF, 100 g of benzyl 6-bromo-5-(2-(methyIamino)-2-oxoethyI)- l,3,4,5-tetrahydro-2Fi-pyrido[4,3-b]indole-2-carboxylate, 71 g of potassium carbonate, 10.5 g of copper iodide, 30 g of l,8-DiazabicycIo(5.4.0)undec-7-ene (DBU) were charged stirring to obtain a reaction mixture. The reaction mixture was flushed with 50 ml DMF in the reactor under stirring to obtain a resultant mixture. The resultant mixture was heated by slowly raising the temperature to 85 °C and further maintained at 120 °C for 24 hours to obtain a product mixture comprising a crude lumateperone tosylate intermediate. The reaction was monitored by checking the thin layer chromatography (TLC) of the product mixture against the starting material.

The yield of pure lumateperone tosylate intermediate was 41 g (49.84 %) and the purity was 94.2 %.

Example 5: Preparation of lumateperone tosylate intermediate by using N.N’- dimethylethylenediamine (DM EDA ) as a catalyst and toluene as a fluid medium

In a reactor, 700 ml of toluene, 155 g of benzyl 6-bromo-5-(2-(methylamino)-2-oxoethyl)- l,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate, 110 g of potassium carbonate, 16 g of copper iodide and 22 g of N,N’-dimethylethylenediamine were charged under stirring to obtain a reaction mixture. The reaction mixture was flushed with 75 ml of toluene in the reactor under stirring to obtain a resultant mixture. The resultant mixture was heated by slowly raising the temperature to 110 °C and further maintained at 110 °C for 20 hours to obtain a product mixture comprising a crude benzyl 3-methyl-2-oxo-2, 3, 9, 10-tetrahydro- lH-pyrido[3',4':4,5] pyrrolo [l,2,3-de]quinoxaline-8(7H)-carboxylate (I) (crude lumateperone tosylate intermediate). The reaction was monitored by checking the thin layer chromatography (TLC) of the product mixture against the starting material.

The so obtained product mixture was cooled to 25 °C to obtain a cooled mass. The cooled mass was filtered to obtain a wet cake followed by washing with 155 ml toluene to obtain a washed wet cake and a filtrate. The so obtained washed wet cake was dissolved in 1000 ml water to obtain a slurry. The slurry was heated to 80 °C and the temperature was maintained at 80 °C for 1 hour to obtain a heated slurry. The heated slurry was cooled to 60 °C followed by hot filtration to obtain a residue mass and a filtrate. The residue mass was further washed with 250 ml of hot water followed by drying at 60 °C till the moisture content of the residue mass was 1 % to obtain the pure lumateperone tosylate intermediate.

The yield of pure lumateperone tosylate intermediate was 60 g (47.05 %) and the purity was 94.6 %.

Example 6: Preparation of lumateperone tosylate intermediate by using DiazabicycloI5.4.01undec-7-ene (DBU) as a catalyst and toluene as a fluid medium In a reactor, 450 ml of toluene, 100 g of benzyl 6-bromo-5-(2-(methylamino)-2-oxoethyl)- l,3,4,5-tetrahydro-2H-pyrido[4,3-b]indoIe-2-carboxyIate, 71 g of potassium carbonate, 10.5 g of copper iodide, 30 g of l,8-Diazabicyclo(5.4. 0)undec-7-ene (DBU) were charged under stirring to obtain a reaction mixture. The reaction mixture was flushed with 50 ml toluene in the reactor under stirring to obtain a resultant mixture. The resultant mixture was heated by slowly raising the temperature to 110 °C and further maintained at 110 °C for 18 hours to obtain a product mixture comprising a crude lumateperone tosylate intermediate. The reaction was monitored by checking the thin layer chromatography (TLC) of the product mixture against the starting material.

The so obtained product mixture was cooled to 25°C to obtain a cooled mass. The cooled mass was filtered to obtain a wet cake followed by washing with 155 ml toluene to obtain a washed wet cake and a filtrate. The so obtained washed wet cake was dissolved in 1000 ml water to obtain a slurry. The slurry was heated to 80°C and the temperature was maintained at 80°C for 1 hour to obtain a heated slurry. The heated slurry was cooled to 60°C followed by hot filtration to obtain a residue mass and a filtrate. The residue mass was further washed with 200 ml of hot water followed by drying at 60°C till the moisture content of the residue mass was 1 % to obtain the pure lumateperone tosylate intermediate.

The yield of pure lumateperone tosylate intermediate was 40 g (48.62 %) and the purity was 94.9 %.

From the Examples 1 to 4, it was observed that when DMSO was used as the fluid medium (in examples 1 to 2), the time required for completion of the reaction was 12 hours to 16 hours which was less as compared to examples 3 to 4, wherein DMF was used as the fluid medium. Further, the yield (51 % and 57.74 % respectively) and purity (96.5 % and 97.93 % respectively) of lumateperone tosylate intermediate obtained in examples 1 to 2 was higher than the yield and purity of the Examples 5 to 6, wherein toluene was used as the fluid medium.

The objective of the present disclosure, i.e. to provide a simple, economical and eco-friendly process that requires minimum time period for the preparation of lumateperone tosylate intermediate with a comparatively high yield and high purity was achieved. The reason for achieving high yield and high purity of the product (lumateperone tosylate intermediate) in comparatively less time period was that the reaction was carried out in nitrogen atmosphere by using the appropriate fluid medium (DMSO/DMF) and the catalyst (DMEDA/DBU).

TECHNICAL ADVANCEMENTS

The present disclosure described hereinabove has several technical advantages including, but not limited to, the realization of a process for preparing lumateperone tosylate intermediate that: provides a comparatively high purity and high yield of the product (lumateperone tosylate intermediate); employs inexpensive reagents and is industrially feasible; and is simple and environment friendly.

Throughout this specification the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

The use of the expression “at least” or “at least one” suggests the use of one or more elements or ingredients or quantities, as the use may be in the embodiment of the invention to achieve one or more of the desired objects or results. While certain embodiments of the inventions have been described, these embodiments have been presented by way of example only, and are not intended to limit the scope of the inventions. Variations or modifications to the formulation of this invention, within the scope of the invention, may occur to those skilled in the art upon reviewing the disclosure herein. Such variations or modifications are well within the spirit of this invention.

The numerical values given for various physical parameters, dimensions and quantities are only approximate values and it is envisaged that the values higher than the numerical value assigned to the physical parameters, dimensions and quantities fall within the scope of the invention unless there is a statement in the specification to the contrary.

While considerable emphasis has been placed herein on the specific features of the preferred embodiment, it will be appreciated that many additional features can be added and that many changes can be made in the preferred embodiment without departing from the principles of the disclosure. These and other changes in the preferred embodiment of the disclosure will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the disclosure and not as a limitation.

Claims

CLAIMS:

1. A process for the preparation of lumateperone tosylate intermediate, said process comprising the following steps: a. mixing benzyl 6-bromo-5-(2-(methylamino)-2-oxoethyl)-l,3,4,5-tetrahydro- 2H-pyrido[4,3-b]indole-2-carboxylate with predetermined amounts of a base, a metal halide, and a catalyst in a predetermined amount of a fluid medium under stirring to obtain a reaction mixture; b. heating said reaction mixture to a first predetermined temperature for a first predetermined time period to obtain a product mixture comprising a crude benzyl-3-methyl-2-oxo-2,3,9,10-tetrahydro-lH pyrido[3',4':4,5]pyrrolo[l,2,3- de]quinoxaline-8(7H)-carboxylate (crude lumateperone tosylate intermediate); and c. isolating said crude lumateperone tosylate intermediate to obtain a pure lumateperone tosylate intermediate.

2. The process as claimed in claim 1, wherein said base is selected from the group consisting of potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide; and wherein a molar ratio of benzyl 6-bromo-5-(2-(methylamino)-2-oxoethyl)-l,3,4,5-tetrahydro-2H-pyrido[4,3- b]indole-2-carboxylate to said base is in the range of 1:1 to 1:3.

3. The process as claimed in claim 1, wherein said metal halide is selected from the group consisting of copper iodide (Cul), copper bromide (CuBr), copper chloride (CuCl), copper acetate (Cu(OAc)2), copper sulphate (CuSCL) and copper oxide (CuO); and wherein a molar ratio of benzyl 6-bromo-5-(2-(methylamino)-2- oxoethyl)-l,3,4,5-tetrahydro-2H-pyrido [4, 3-b] indole-2-carboxylate to said metal halide is in the range of 1:0.1 to 1:0.3.

4. The process as claimed in claim 1, wherein said catalyst is selected from the group consisting of N,N’-diemethylethylenediamine (DMEDA), 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-Diazabicyclo(4.3.0)non-5-ene (DBN), l,4-diazabicyclo[2.2.2]octane (DABCO), imidazolium carbene, 4- (dimethylamino)pyridine, TMEDA 1,2-diamine and 1,2-aminoalcohol and wherein a molar ratio of benzyl 6-bromo-5-(2-(mcthylamino)-2-oxocthyl)- 1 ,3,4,5-tctrahydro- 2H-pyrido[4,3-b]indole-2-carboxylate to said catalyst is in the range of 1:0.5 to 1:1.5.

5. The process as claimed in claim 1, wherein said fluid medium is selected from the group consisting of dimethyl sulfoxide (DMSO), dimethyl formamide (DMF) and toluene; and wherein said predetermined amount of said fluid medium is in the range of 1 litre to 5 litres per mole of benzyl 6-bromo-5-(2-(methylamino)-2-oxoethyl)- l,3,4,5-tetrahydro-2Fl-pyrido[4,3-b]indole-2-carboxylate.

6. The process as claimed in claim 1, wherein said first predetermined temperature is in the range of 80 °C to 200 °C and said first predetermined time period is in the range of 10 hours to 25 hours.

7. The process as claimed in claim 1, wherein said step of isolating said crude lumateperone tosylate intermediate comprises the following sub-steps:

(i) cooling said product mixture obtained in step-b of claim 1 to a second predetermined temperature to obtain a cooled mass; (ii) filtering said cooled mass to obtain a wet cake followed by washing said wet cake with said fluid medium to obtain a washed wet cake; and

(iii) drying said washed wet cake at a third predetermined temperature to obtain a pure lumateperone tosylate intermediate having a moisture content in the range of 0.1 % to 1.0 %.

8. The process as claimed in claim 7, wherein said second predetermined temperature is in the range of 15 °C to 80 °C; and said third predetermined temperature is in the range of 50 °C to 70 °C .

9. The process as claimed in claim 7, wherein said fluid medium is selected from the group consisting of dimethyl sulfoxide (DMSO), dimethyl formamide (DMF) and toluene.