DESC:FIELD
The present disclosure relates to pharmaceuticals. Particularly, the present disclosure relates to Lumateperone intermediate salts, processes for their preparation and Lumateperone intermediate obtained therefrom.
BACKGROUND
The background information herein below relates to the present disclosure but is not necessarily prior art.
Lumateperone (CAS No. 313368-91-1) is an antipsychotic drug, indicated for the treatment of schizophrenia. It is also used in the treatment of depressive episodes associated with bipolar disorder. Lumateperone provides selective and simultaneous modulation of neurotransmitters such as serotonin, dopamine, and glutamate and the like. These neurotransmitter levels play a vital role in the treatment and management of schizophrenia. Lumateperone can alleviate both positive and negative symptoms of schizophrenia. The structure of lumateperone is represented by structure (I) below:

Structure (I)
Ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (CAS No. 313369-26-5) is a key intermediate for the synthesis of Lumateperone. The structure of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo [1,2,3-de]quinoxaline-8(7H)-carboxylate is represented by structure (II) below:

Structure (II)
The conventional methods for the preparation of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate intermediate are associated with drawbacks such as low yield/purity. These conventional methods require further purification which is not economical. The impurities in the intermediates may affect the efficacy, safety and stability of the final product.
Therefore, there is felt a need to provide a process for the preparation of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate with a high purity and high yield that mitigates the aforestated drawbacks or at least provide an alternative solution.
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 background or to at least provide a useful alternative.
Another object of the present disclosure is to provide Lumateperone intermediates.
Yet another object of the present disclosure is to provide ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate salts as Lumateperone intermediates.
Still another object of the present disclosure is to provide ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate tosylate as Lumateperone intermediate.
Yet another object of the present disclosure is to provide ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate hydrochloride as Lumateperone intermediate.
Still another object of the present disclosure is to provide ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate oxalate as Lumateperone intermediate.
Yet another object of the present disclosure is to provide ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate phosphate as Lumateperone intermediate.
Still another object of the present disclosure is to provide a process for the preparation of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5] pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate salts.
Yet another object of the present disclosure is to provide a simple and cost-effective process for the preparation of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate salts.
Still another object of the present disclosure is to provide an environment-friendly and commercially scalable process for the preparation of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate salts.
Yet another object of the present disclosure is to provide a process for the preparation of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (free base) with high purity.
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 ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate salts (Lumateperone intermediates) and a process for their preparation.
The present disclosure provides ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate salts selected from the group consisting of:

Formula (I),
. HCl;
Formula (II),
. H2C2O4; and
Formula (III),
.
Ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5] pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate salts have a purity in the range of 98.5 % to 99.99 %.
Further, the present disclosure provides a process for the preparation of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo [1,2,3-de]quinoxaline-8(7H)-carboxylate salts (Lumateperone intermediate salts). The process comprises the following steps:
i. cyclizing ethyl(4aS,9bR)-6-bromo-5-(2-(methylamino)-2-oxoethyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate by using a first base and a chelating agent, in the presence of a first catalyst in a first fluid medium at a first predetermined temperature for a first predetermined time period in an inert atmosphere to obtain ethyl (6bR,10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate;
ii. reducing ethyl(6bR,10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate by using a reducing agent in the presence of a second catalyst in a second fluid medium at a second predetermined temperature for a second predetermined time period to obtain ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate; and
iii. reacting ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate with an acid in a third fluid medium at a third predetermined temperature for a third predetermined time period to obtain ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate salt as the Lumateperone intermediate salts.
The first base is selected from an organic base and an inorganic base.
The organic base is selected from the group consisting of triethylamine, trimethylamine, N,N-dimethyl ethylene diamine, N,N’-diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,4-diazabicyclo[2.2.2]octane (DABCO), sodium t-butoxide and potassium t-butoxide.
The inorganic base is selected from the group consisting of a metal hydride, a metal carbonate, a metal bicarbonate and a metal phosphate.
The metal hydride is selected from the group consisting of sodium hydride, lithium hydride and potassium hydride.
The metal carbonate is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate and barium carbonate.
The metal bicarbonate is selected from the group consisting of sodium bicarbonate, potassium bicarbonate, cesium bicarbonate and barium bicarbonate.
The metal phosphate is potassium phosphate.
The chelating agent is selected from the group consisting of N, N-dimethyl ethylene diamine 1,2-diamine, l,2-aminoalcohol, l,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,2- (aminomethyl)pyridine, 4,7-diphenyl-1,10-phenanthroline, 4,7-dimethyl-1,10-phenanthroline, 5-methyl- 1,10-phenanthroline, 5-chloro-l,10-phenanthroline, and 5-nitro-l,10-phenanthroline.
The first catalyst is selected from the group consisting of copper iodide (CuI), copper bromide (CuBr), copper chloride (CuCl), copper (II) acetate (Cu(OAc)2), copper (I) benzoate (CuBn), copper sulphate (CuSO4), copper (I) oxide (Cu2O), potassium iodide (KI) and lithium iodide (LiI).
The mole ratio of ethyl(4aS,9bR)-6-bromo-5-(2-(methylamino)-2-oxoethyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate to the first base is in the range of 1:3 to 1:5.
The mole ratio of ethyl(4aS,9bR)-6-bromo-5-(2-(methylamino)-2-oxoethyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate to the chelating agent is in the range of 1:0.2 to 1:0.5.
The mole ratio of ethyl(4aS,9bR)-6-bromo-5-(2-(methylamino)-2-oxoethyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate to the first catalyst is in the range of 1:0.1 to 1:0.3.

The inert atmosphere is selected from nitrogen and argon.
The reducing agent is selected from the group consisting of sodium borohydride (NaBH4), lithium aluminum hydride (LiAlH4), sodium cyanoborohydride (NaBH3CN), hydrogen in presence of nickel (H2/Ni), hydrogen in presence of palladium on charcoal (H2/Pd/C), hydrogen in presence of nickel boride (H2/NiB), hydrogen in presence of platinum (H2/Pt), hydrogen in presence of platinum oxide (H2/PtO), hydrogen in presence of rhodium (H2/Rh), hydrogen in presence of ruthenium (H2/Ru), hydrogen in presence of zinc oxide (H2/ZnO) and hydrogen in presence of pentacyanocobaltate(II) (H2/[Co(CN)5]3?).
The second catalyst is selected from the group consisting of
• a metal hydride selected from diisobutyl aluminum hydride (DIBAL), sodium bis(2-methoxyethoxy) aluminum hydride and sodium cyanoborohydride;
• a borane selected from boron trifluoride etherate, borane tetrahydrofuran complex (borane-THF), borane-dimethylsulfide complex, diborane and borane-ammonia;
• an organoborane selected from bis(benzyloxy)borane, 9-borabicyclo[3.3. 1]nonane (BBN) and trialkylboranes; and
• a transition metal catalyst selected from nickel catalyst, platinum catalyst, palladium catalyst, rhodium catalyst and ruthenium catalyst.
The acid is selected from the group consisting of p-toluene sulfonic acid, hydrochloric acid, oxalic acid and phosphoric acid.
The ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate salts are selected from the group consisting of:
• ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate tosylate;
• ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido [3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate hydrochloride;
• ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de]quinoxaline-8(7H)-carboxylate oxalate; and
• ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido [3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate phosphate.

The first fluid medium is selected from the group consisting of 1,4-dioxane, dimethoxyethane (DME), toluene, xylene and chlorobenzene.
The second fluid medium is selected from the group consisting of tetrahydrofuran (THF), methanol, dioxane and diethyl ether.
The third fluid medium is selected from the group consisting of ethyl acetate, butyl acetate, isobutyl acetate, isopropyl acetate, propyl acetate, methyl acetate, acetonitrile, acetone, methanol, ethanol, butanol, isopropyl alcohol, pentanol, sulfolane, dichloromethane, toluene, m-xylene and 1, 4-dioxane.
The first predetermined temperature is in the range of 75 °C to 150 °C.
The second predetermined temperature is in the range of 0 °C to 15 °C.
The third predetermined temperature is in the range of 15 °C to 40 °C.
The first predetermined time period is in the range of 20 hours to 30 hours.
The second predetermined time period is in the range of 5 hours to 15 hours.
The third predetermined time period is in the range of 5 hours to 15 hours.
The yield of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate salt obtained is in the range of 85% to 95%.
The purity of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5] pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate salt obtained is in the range of 98.5% to 99.99%.
Still further, a process for the preparation of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate, comprises the following steps:
i. cyclizing ethyl(4aS,9bR)-6-bromo-5-(2-(methylamino)-2-oxoethyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate by using a first base and a chelating agent, in the presence of a first catalyst in a first fluid medium at a first predetermined temperature for a first predetermined time period in an inert atmosphere to obtain ethyl (6bR,10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate;
ii. reducing ethyl(6bR,10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate by using a reducing agent in the presence of a second catalyst in a second fluid medium at a second predetermined temperature for a second predetermined time period to obtain ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate;
iii. reacting ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate with an acid in a third fluid medium at a third predetermined temperature for a third predetermined time period to obtain ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate salts; and
iv. reacting ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate salts with a second base followed by extracting using a fourth fluid medium to obtain ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline -8(7H)-carboxylate.
The first base is selected from an organic base and an inorganic base.
The organic base is selected from the group consisting of triethylamine, trimethylamine, N, N-dimethyl ethylene diamine, N, N’-diisopropylethylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), l,4-diazabicyclo [2.2.2] octane (DABCO), sodium t-butoxide and potassium t-butoxide.
The inorganic base is selected from the group consisting of a metal hydride, a metal carbonate, a metal bicarbonate and a metal phosphate.
The metal hydride is selected from the group consisting of sodium hydride, lithium hydride and potassium hydride.
The metal carbonate is selected from the group consisting of sodium carbonate, potassium carbonate, caesium carbonate and barium carbonate.
The metal bicarbonate is selected from the group consisting of sodium bicarbonate, potassium bicarbonate, caesium bicarbonate and barium bicarbonate.
The metal phosphate is potassium phosphate.
The chelating agent is selected from the group consisting of N, N-dimethyl ethylene diamine 1,2-diamine, l,2-aminoalcohol, l,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, 2-(aminomethyl)pyridine, 4,7-diphenyl-1,10-phenanthroline, 4,7-dimethyl-1,10-phenanthroline, 5-methyl-1,10-phenanthroline, 5-chloro-l,10-phenanthroline, and 5-nitro-l,10-phenanthroline.
The first catalyst is selected from the group consisting of copper iodide (CuI), copper bromide (CuBr), copper chloride (CuCl), copper (II) acetate (Cu(OAc)2), copper (I) benzoate (CuBn), copper sulphate (CuSO4), copper (I) oxide (Cu2O), potassium iodide (KI) and lithium iodide (LiI).
The mole ratio of ethyl (4aS,9bR)-6-bromo-5-(2-(methylamino)-2-oxoethyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate to the first base is in the range of 1:3 to 1:5.
The mole ratio of ethyl(4aS,9bR)-6-bromo-5-(2-(methylamino)-2-oxoethyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate to the chelating agent is in the range of 1:0.2 to 1:0.5.
The mole ratio of ethyl(4aS,9bR)-6-bromo-5-(2-(methylamino)-2-oxoethyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate to the first catalyst is in the range of 1:0.1 to 1:0.3.

The inert atmosphere is selected from nitrogen and argon.
The reducing agent is selected from the group consisting of sodium borohydride (NaBH4), lithium aluminum hydride (LiAlH4), sodium cyanoborohydride (NaBH3CN), hydrogen in presence of nickel (H2/Ni), hydrogen in presence of palladium on charcoal (H2/Pd/C), hydrogen in presence of nickel boride (H2/NiB), hydrogen in presence of platinum (H2/Pt), hydrogen in presence of platinum oxide (H2/PtO), hydrogen in presence of rhodium (H2/Rh), hydrogen in presence of ruthenium (H2/Ru), hydrogen in presence of zinc oxide (H2/ZnO) and hydrogen in presence of pentacyanocobaltate(II) (H2/[Co(CN)5]3?).
The second catalyst is selected from the group consisting of
• a metal hydride selected from diisobutyl aluminum hydride (DIBAL), sodium bis(2-methoxyethoxy) aluminum hydride and sodium cyanoborohydride;
• a borane selected from boron trifluoride etherate, borane tetrahydrofuran complex (borane-THF), borane-dimethylsulfide complex, diborane and borane-ammonia;
• an organoborane selected from the group consisting of bis(benzyloxy)borane, 9-borabicyclo[3.3.1] nonane(BBN) and trialkylboranes; and
• a transition metal catalyst selected from nickel catalyst, platinum catalyst, palladium catalyst, rhodium catalyst and ruthenium catalyst.
The acid is selected from the group consisting of p-toluene sulfonic acid, hydrochloric acid, oxalic acid and phosphoric acid.
The ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate salts are selected from the group consisting of:
• ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate tosylate;
• ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido [3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate hydrochloride;
• ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de]quinoxaline-8(7H)-carboxylate oxalate; and
• ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido [3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate phosphate.

The first fluid medium is selected from the group consisting of 1,4-dioxane, dimethoxyethane (DME), toluene, xylene and chlorobenzene.
The second fluid medium is selected from the group consisting of tetrahydrofuran (THF), methanol, dioxane and diethyl ether.
The third fluid medium is selected from the group consisting of ethyl acetate, butyl acetate, isobutyl acetate, isopropyl acetate, propyl acetate, methyl acetate, acetonitrile, acetone, methanol, ethanol, butanol, isopropyl alcohol, pentanol, sulfolane, dichloromethane, toluene, m-xylene and 1, 4-dioxane.
The first predetermined temperature is in the range of 75 °C to 150 °C.
The second predetermined temperature is in the range of 0 °C to 15 °C.
The third predetermined temperature is in the range of 15 °C to 40 °C.
The first predetermined time period is in the range of 20 hours to 30 hours.
The second predetermined time period is in the range of 5 hours to 15 hours.
The third predetermined time period is in the range of 5 hours to 15 hours.
The second base is selected from an organic base and an inorganic base.
The organic base is selected from the group consisting of triethylamine, trimethylamine, N,N’-diisopropylethylamine, 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) and l,4-diazabicyclo[2.2.2]octane (DABCO).
The inorganic base is selected from the group consisting of sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, and ammonia.
The fourth fluid medium is selected from the group consisting of ethyl acetate, butyl acetate, isobutyl acetate, isopropyl acetate, propyl acetate, methyl acetate, acetonitrile, acetone, methanol, ethanol, butanol, isopropyl alcohol, pentanol, sulfolane and 1,4-Dioxane.
The yield of ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate obtained is in the range of 93% to 99%.
The purity of ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate obtained is in the range of 98% to 99.99%.
DETAILED DESCRIPTION
The present disclosure relates to pharmaceuticals. Particularly, the present disclosure relates to Lumateperone intermediate salts, processes for their preparation and Lumateperone intermediate obtained therefrom.
Embodiments, of the present disclosure, will now be described herein. 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.
The terms first, second, third, etc., should not be construed to limit the scope of the present disclosure as the aforementioned terms may be only used to distinguish one element, component, region, layer or section from another component, region, layer or section. Terms such as first, second, third etc., when used herein do not imply a specific sequence or order unless clearly suggested by the present disclosure.
The conventional methods for the preparation of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate intermediate are associated with drawbacks such as low yield/purity. These conventional methods require further purification which is not economical. The impurities in the intermediates may affect the efficacy, safety and stability of the final product.
The present disclosure provides a process for the preparation of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate with high stability and a process for its preparation with high purity and high yield.
The present disclosure provides ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate salts and a process for their preparation.
In a first aspect, the present disclosure provides ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8 (7H)-carboxylate salts selected from the group consisting of:

Formula (I),


and
.
In an embodiment of the present disclosure, ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate salts have a purity in the range of 98.5 % to 99.99 %. In an exemplary embodiment of the present disclosure, the HPLC purity of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5] pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate tosylate is 99.95%.
In a second aspect, the present disclosure provides a process for the preparation of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo [1,2,3-de]quinoxaline-8(7H)-carboxylate salts (Lumateperone intermediate salts). The process comprises the following steps:
i. cyclizing ethyl(4aS,9bR)-6-bromo-5-(2-(methylamino)-2-oxoethyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate by using a first base and a chelating agent, in the presence of a first catalyst in a first fluid medium at a first predetermined temperature for a first predetermined time period in an inert atmosphere to obtain ethyl (6bR,10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate;
ii. reducing ethyl(6bR,10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate by using a reducing agent, in the presence of a second catalyst in a second fluid medium at a second predetermined temperature for a second predetermined time period to obtain ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate; and
iii. reacting ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate with an acid in a third fluid medium at a third predetermined temperature for a third predetermined time period to obtain ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate salt as Lumateperone intermediate salts.

The process is described in detail below.
Step I: Preparation of ethyl(6bR,10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3’4’4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate
In this step, a predetermined amount of ethyl(4aS, 9bR)-6-bromo-5-(2-(methylamino)-2-oxoethyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate is cyclized by using a first base and a chelating agent in the presence of a first catalyst in a first fluid medium at a first predetermined temperature for a first predetermined time period in an inert atmosphere to obtain ethyl(6bR, 10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3’4’:4,5] pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate.
In an embodiment of the present disclosure, a predetermined amount of ethyl(4aS,9bR)-6-bromo-5-(2-(methylamino)-2-oxoethyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate is mixed with a predetermined amount of first base, a predetermined amount of first catalyst and a predetermined amount of chelating agent in a predetermined amount of first fluid medium to obtain a first mixture. The first mixture is refluxed at a first predetermined temperature for a first predetermined time period in an inert atmosphere to obtain a first reaction mass comprising ethyl(6bR,10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3’4’4,5] pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate.
The first reaction mass is cooled to a temperature in the range of 20 °C to 35 °C and filtered to obtain a wet cake and a filtrate. The wet cake was separated followed by addition of an equivalent amount of toluene and water to the wet cake and stirred for a time period in the range of 15 minutes to 60 minutes to obtain a first biphasic mixture comprising a first organic layer (toluene layer) and a first aqueous layer. The first organic layer (toluene layer) and the first aqueous layer were separated to obtain a separated first organic layer and a separated first aqueous layer. The separated first aqueous layer was extracted predetermined number of times by using a predetermined amount of toluene to obtain a second biphasic mixture comprising a second organic layer (toluene layer) and a second aqueous layer. The second organic layer (toluene layer) was separated from the second biphasic mixture and combined with the first separated organic layer (toluene layer) followed by distillation at a pressure of 700 mmHg to obtain ethyl(6bR,10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3’4’:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate.
In an embodiment of the present disclosure, the first base is selected from an organic base and an inorganic base. In an exemplary embodiment of the present disclosure, the first base is inorganic base.
In an embodiment of the present disclosure, the organic base is selected from the group consisting of triethylamine, trimethylamine, N, N-dimethyl ethylene diamine, N, N’-diisopropylethylamine (Hünig's base), pyridine, 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU), l,4-diazabicyclo[2.2.2]octane (DABCO), sodium t-butoxide and potassium t-butoxide.
In an embodiment of the present disclosure, the inorganic base is selected from the group consisting of a metal hydride, a metal carbonate, metal bicarbonate and a metal phosphate.
In an embodiment of the present disclosure, the metal hydride is selected from the group consisting of sodium hydride, lithium hydride and potassium hydride; the metal carbonate is selected from the group consisting of sodium carbonate, potassium carbonate, caesium carbonate and barium carbonate; the metal bicarbonate is sodium bicarbonate, and the metal phosphate is potassium phosphate. In an exemplary embodiment of the present disclosure, the inorganic base is potassium carbonate.
In an embodiment of the present disclosure, a mole ratio of ethyl(4aS, 9bR)-6-bromo-5-(2-(methylamino)-2-oxoethyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate to the first base is in the range of 1:3 to 1:5. In an exemplary embodiment of the present disclosure, the mole ratio of ethyl(4aS, 9bR)-6-bromo-5-(2-(methylamino)-2-oxoethyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b] indole-2-carboxylate to the first base is 1:4.3.
In an embodiment of the present disclosure, the chelating agent is selected from the group consisting of N, N-dimethyl ethylene diamine, 1,2-diamine, l,2-aminoalcohol, l,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, 2-(aminomethyl)pyridine, 4,7-diphenyl-1,10-phenanthroline, 4,7-dimethyl-1,10-phenanthroline, 5-methyl- 1,10-phenanthroline, 5-chloro-l,10-phenanthroline, and 5-nitro-l,10-phenanthroline. In an exemplary embodiment of the present disclosure, the chelating agent is N, N-dimethyl ethylene diamine.
In an embodiment of the present disclosure, a mole ratio of ethyl(4aS, 9bR)-6-bromo-5-(2-(methylamino)-2-oxoethyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido [4,3-b]indole-2-carboxylate to the chelating agent is in the range of 1:0.2 to 1:0.5. In an exemplary embodiment of the present disclosure, the mole ratio of ethyl(4aS, 9bR)-6-bromo-5-(2-(methylamino)-2-oxoethyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate to the chelating agent is 1:0.36.
In an embodiment of the present disclosure, the first catalyst is selected from the group consisting of copper iodide (CuI), copper bromide (CuBr), copper chloride (CuCl), copper (II) acetate (Cu(OAc)2), copper (I) benzoate (CuBn), copper sulphate (CuSO4), copper (I) oxide (Cu2O), potassium iodide (KI) and lithium iodide (LiI). In an exemplary embodiment of the present disclosure, the first catalyst is copper iodide (CuI).
In an embodiment of the present disclosure, a mole ratio of ethyl(4aS, 9bR)-6-bromo-5-(2-(methylamino)-2-oxoethyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido [4,3-b]indole-2-carboxylate to the first catalyst is in the range of 1:0.1 to 1:0.3. In an exemplary embodiment of the present disclosure, the mole ratio of ethyl(4aS, 9bR)-6-bromo-5-(2-(methylamino)-2-oxoethyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate to the first catalyst is 1:0.2.
In an embodiment of the present disclosure, the first fluid medium is selected from the group consisting of 1,4-dioxane, dimethoxyethane, toluene, xylene and chlorobenzene. In an exemplary embodiment of the present disclosure, the first fluid medium is 1,4-dioxane.
In an embodiment of the present disclosure, the first predetermined temperature is in the range of 15 °C to 200 °C. In an exemplary embodiment of the present disclosure, the first predetermined temperature is in the range of 100 °C to 110 °C.
In an embodiment of the present disclosure, the first predetermined time period is in the range of 20 hours to 30 hours. In an exemplary embodiment of the present disclosure, the first predetermined time period is 24 hours.
In an embodiment of the present disclosure, the inert atmosphere is selected from nitrogen and argon. In an exemplary embodiment of the present disclosure, the inert atmosphere is nitrogen.
STEP II: Preparation of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate
In this step, a predetermined amount of ethyl (6bR,10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate is reduced by using a reducing agent in the presence of a second catalyst in a second fluid medium at a second predetermined temperature for a second predetermined time period to obtain ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate.
In an embodiment of the present disclosure, a predetermined amount of ethyl (6bR,10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline 8(7H)-carboxylate obtained in step I is mixed with a predetermined amount of second fluid medium and cooled to a second predetermined temperature to obtain a second mixture. The second mixture is maintained at the second predetermined temperature and a predetermined amount of a reducing agent is added to the second mixture followed by adding a predetermined amount of a second catalyst to obtain a third mixture. The third mixture is maintained at the second predetermined temperature for a second predetermined time period to obtain a resultant comprising ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3’4’4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate.
A predetermined amount of water was slowly added in the resultant at second predetermined temperature followed by adding an alkali solution to adjust the pH to 7 to obtain a second reaction mass. The second reaction mass is extracted for predetermined times using predetermined amount of ethyl acetate to obtain ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3’4’4,5]pyrrolo [1,2,3-de] quinoxaline-8(7H)-carboxylate.
In an embodiment of the present disclosure, the reducing agent is selected from the group consisting of sodium borohydride (NaBH4), lithium aluminum hydride, sodium cyanoborohydride (NaBH3CN), hydrogen in presence of nickel (H2/Ni), hydrogen in presence of palladium on charcoal (H2/Pd/C), hydrogen in presence of nickel boride (H2/NiB), hydrogen in presence of platinum (H2/Pt), hydrogen in presence of platinum oxide (H2/PtO), hydrogen in presence of rhodium (H2/Rh), hydrogen in presence of ruthenium (H2/Ru), hydrogen in presence of zinc oxide (H2/ZnO) and hydrogen in presence of pentacyanocobaltate(II) (H2/[Co(CN)5]3?).
In an embodiment of the present disclosure, the second catalyst is selected from the group consisting of a metal hydride selected from diisobutyl aluminum hydride (DIBAL), sodium bis(2-methoxyethoxy) aluminum hydride (Red-Al) and sodium cyanoborohydride; a borane selected from the group consisting of boron trifluoride etherate, borane tetrahydrofuran complex (borane-THF), borane-dimethylsulfide complex, diborane and borane-ammonia; an organoborane selected from bis(benzyloxy)borane, 9-borabicyclo[3.3.1]nonane (BBN) and trialkylboranes; and a transition metal catalyst selected from nickel catalyst, platinum catalyst, palladium catalyst, rhodium catalyst and ruthenium catalyst. In an exemplary embodiment of the present disclosure, the second catalyst is boron trifluoride etherate.
In an embodiment of the present disclosure, the second fluid medium is selected from the group consisting of tetrahydrofuran (THF), methanol, dioxane, diethyl ether. In an exemplary embodiment of the present disclosure, the second fluid medium is tetrahydrofuran (THF).
In an embodiment of the present disclosure, the second predetermined temperature is in the range of 0 °C to 15 °C. In an exemplary embodiment of the present disclosure, the second predetermined temperature is 5 °C.
In an embodiment of the present disclosure, the second predetermined time period is in the range of 5 hours to 15 hours. In an exemplary embodiment of the present disclosure, the second predetermined time period is 7 hours.
In an embodiment of the present disclosure, the alkali solution is selected from the group consisting of a metal hydride is selected from the group consisting of sodium hydride, lithium hydride and potassium hydride; a metal alkoxide is selected from the group consisting of sodium t-butoxide and potassium t-butoxide; a metal carbonate is selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, caesium carbonate and barium carbonate; and a metal phosphate is potassium phosphate. In an exemplary embodiment of the present disclosure, the alkali solution is sodium bicarbonate solution.
In an embodiment of the present disclosure, the process for the preparation of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5] pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate is an in-situ reaction. Conventionally ethyl(6bR, 10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3’4’:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate forms multiple impurities when left untreated and is unstable. This drawback is solved by the process of the present disclosure wherein the reaction is performed in-situ at a temperature in the range of 0 °C to 15 °C thereby avoiding the generation of impurities/by-products during this step.
Step III: Preparation of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate salts
In this step, a predetermined amount of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate is reacted with an acid in a third fluid medium at a third predetermined temperature for a third predetermined time period to obtain ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate salt.
In an embodiment of the present disclosure, ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate obtained in step II is mixed with a predetermined amount of an acid in a third fluid medium under stirring at a third predetermined temperature for a third predetermined time period to obtain ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate salt.
In an embodiment of the present disclosure, the acid is selected from the group consisting of p-toluene sulfonic acid, hydrochloric acid, oxalic acid and phosphoric acid. In an exemplary embodiment of the present disclosure, the acid is p-toluene sulfonic acid.
The ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate salts are selected from the group consisting of:
• ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate tosylate;
• ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido [3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate hydrochloride;
• ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido [3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate oxalate; and
• ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido [3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate phosphate.
In an embodiment of the present disclosure, the third fluid medium is selected from the group consisting of ethyl acetate, butyl acetate, isobutyl acetate, isopropyl acetate, propyl acetate, methyl acetate. acetonitrile, acetone, methanol, ethanol, butanol, isopropyl alcohol, pentanol, sulfolane, dichloromethane, toluene, m-xylene and 1,4-dioxane. In an exemplary embodiment of the present disclosure, the third fluid medium is ethyl acetate.
In an embodiment of the present disclosure, the third predetermined temperature is in the range of 15 °C to 40 °C. In an exemplary embodiment of the present disclosure, the third predetermined temperature is 25 °C.
In an embodiment of the present disclosure, the third predetermined time period is in the range of 5 hours to 15 hours. In an exemplary embodiment of the present disclosure, the third predetermined time period is 8 hours.
In an embodiment of the present disclosure, the yield of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate salt is in the range of 85% to 95%. In an exemplary embodiment of the present disclosure, the yield of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate tosylate is 90%.
In an embodiment of the present disclosure, the HPLC purity of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate salt is in the range of 98.5% to 99.99%. In an exemplary embodiment of the present disclosure, the HPLC purity of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5] pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate tosylate is 99.95%.
In accordance with the present disclosure, ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate salt obtained is stable.
In accordance with the present disclosure, ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate obtained after reduction step has less purity (i.e. around 90% only) and the purity of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (free base) is increased after it is isolated from its salt form (more than 99.5%).
The process for the preparation of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate tosylate of the present disclosure is simple, environment friendly, economical, commercially scalable and is carried out under mild reaction conditions.
In accordance with one of the embodiment of the present disclosure, a schematic representation for the preparation of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3’,4’:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate tosylate is given as Scheme A below:

Scheme A
In a third aspect, the present disclosure provides a process for the preparation of ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3’,4’:4,5] pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate.
The process for the preparation of ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3’,4’:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (free base) comprises the following steps:
i. cyclizing ethyl(4aS,9bR)-6-bromo-5-(2-(methylamino)-2-oxoethyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate by using a first base and a chelating agent, in the presence of a first catalyst in a first fluid medium at a first predetermined temperature for a first predetermined time period in an inert atmosphere to obtain ethyl (6bR,10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate;
ii. reducing ethyl(6bR,10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate by using a reducing agent in the presence of a second catalyst in a second fluid medium at a second predetermined temperature for a second predetermined time period to obtain ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate;
iii. reacting ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate with an acid in a third fluid medium at a third predetermined temperature for a third predetermined time period to obtain ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate salts; and
iv. reacting ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate salts with a second base followed by extracting using a fourth fluid medium to obtain ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline -8(7H)-carboxylate.
The first base is selected from an organic base and an inorganic base.
The organic base is selected from the group consisting of triethylamine, trimethylamine, N, N-dimethyl ethylene diamine, N, N’-diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU), l,4-diazabicyclo[2.2.2]octane (DABCO), sodium t-butoxide and potassium t-butoxide.
The inorganic base is selected from the group consisting of a metal hydride, a metal carbonate, a metal bicarbonate and a metal phosphate.
The metal hydride is selected from the group consisting of sodium hydride, lithium hydride and potassium hydride.
The metal carbonate is selected from the group consisting of sodium carbonate, potassium carbonate, caesium carbonate and barium carbonate.
The metal bicarbonate is sodium bicarbonate, potassium bicarbonate, caesium bicarbonate and barium bicarbonate.
The metal phosphate is potassium phosphate.
The chelating agent is selected from the group consisting of N, N-dimethyl ethylene diamine 1,2-diamine, l,2-aminoalcohol, l,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, 2-(aminomethyl)pyridine,4,7-diphenyl-1,10-phenanthroline, 4,7-dimethyl-1,10-phenanthroline, 5-methyl-1,10-phenanthroline, 5-chloro-l,10-phenanthroline, and 5-nitro-l,10-phenanthroline.
The first catalyst is selected from the group consisting of copper iodide (CuI), copper bromide (CuBr), copper chloride (CuCl), copper (II) acetate (Cu(OAc)2), copper (I) benzoate (CuBn), copper sulphate (CuSO4), copper (I) oxide (Cu2O), potassium iodide (KI) and lithium iodide (LiI).
The mole ratio of ethyl(4aS, 9bR)-6-bromo-5-(2-(methylamino)-2-oxoethyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate to the first base is in the range of 1:3 to 1:5.
The mole ratio of ethyl(4aS, 9bR)-6-bromo-5-(2-(methylamino)-2-oxoethyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate to the chelating agent is in the range of 1:0.2 to 1:0.5.
The mole ratio of ethyl(4aS, 9bR)-6-bromo-5-(2-(methylamino)-2-oxoethyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate to the first catalyst is in the range of 1:0.1 to 1:0.3.

The inert atmosphere is selected from nitrogen and argon.
The reducing agent is selected from the group consisting of sodium borohydride (NaBH4), lithium aluminum hydride (LiAlH4), sodium cyanoborohydride (NaBH3CN), hydrogen in presence of nickel (H2/Ni), hydrogen in presence of palladium on charcoal (H2/Pd/C), hydrogen in presence of nickel boride (H2/NiB), hydrogen in presence of platinum (H2/Pt), hydrogen in presence of platinum oxide (H2/PtO), hydrogen in presence of rhodium (H2/Rh), hydrogen in presence of ruthenium (H2/Ru), hydrogen in presence of zinc oxide (H2/ZnO) and hydrogen in presence of pentacyanocobaltate(II) (H2/[Co(CN)5]3?).
The second catalyst is selected from the group consisting of
• a metal hydride selected from diisobutyl aluminum hydride (DIBAL), sodium bis(2-methoxyethoxy) aluminum hydride and sodium cyanoborohydride;
• a borane selected from boron trifluoride etherate, borane tetrahydrofuran complex (borane-THF), borane-dimethylsulfide complex, diborane and borane-ammonia;
• an organoborane selected from bis(benzyloxy)borane, 9-borabicyclo[3.3. 1]nonane (BBN) and trialkylboranes; and
• a transition metal catalyst selected from nickel catalyst, platinum catalyst, palladium catalyst, rhodium catalyst and ruthenium catalyst.
The acid is selected from the group consisting of p-toluene sulfonic acid, hydrochloric acid, oxalic acid and phosphoric acid.
The ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate salts are selected from the group consisting of:
• ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate tosylate;
• ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido [3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate hydrochloride;
• ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido [3',4':4,5] pyrrolo [1,2,3-de]quinoxaline-8(7H)-carboxylate oxalate; and
• ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido [3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate phosphate.

The first fluid medium is selected from the group consisting of 1,4-dioxane, dimethoxyethane (DME), toluene, xylene and chlorobenzene.
The second fluid medium is selected from the group consisting of tetrahydrofuran (THF), methanol, dioxane and diethyl ether.
The third fluid medium is selected from the group consisting of ethyl acetate, butyl acetate, isobutyl acetate, isopropyl acetate, propyl acetate, methyl acetate, acetonitrile, acetone, methanol, ethanol, butanol, isopropyl alcohol, pentanol, sulfolane, dichloromethane, toluene, m-xylene and 1, 4-dioxane.
The first predetermined temperature is in the range of 75 °C to 150 °C.
The second predetermined temperature is in the range of 0 °C to 15 °C.
The third predetermined temperature is in the range of 15 °C to 40 °C.
The first predetermined time period is in the range of 20 hours to 30 hours.
The second predetermined time period is in the range of 5 hours to 15 hours.
The third predetermined time period is in the range of 5 hours to 15 hours.
In an embodiment of the present disclosure, the predetermined amount of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3’,4’:4,5] pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate salt is mixed with water followed by adjusting pH to 7 by the addition of a second base to obtain a fourth mixture. The fourth mixture is extracted by using a fourth fluid medium to obtain ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5] pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (free base).
In an embodiment of the present disclosure, the second base is selected from an organic base and an inorganic base.
The organic base is selected from the group consisting of triethylamine, trimethylamine, N,N’-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and l,4-diazabicyclo[2.2.2]octane (DABCO).
The inorganic base is selected from the group consisting of sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide and ammonia. In an exemplary embodiment of the present disclosure, the second base is sodium bicarbonate.
In an embodiment of the present disclosure, a weight by volume ratio of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo [1,2,3-de]quinoxaline-8(7H)-carboxylate salt to the second base is in the range of 1:10 to 1: 20. In an exemplary embodiment of the present disclosure, the weight by volume ratio of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo [1,2,3-de]quinoxaline-8(7H)-carboxylate salt to the second base is 1:15.
In an embodiment of the present disclosure, the fourth fluid medium is selected from the group consisting of ethyl acetate, butyl acetate, isobutyl acetate, isopropyl acetate, propyl acetate, methyl acetate, acetonitrile, acetone, methanol, ethanol, butanol, isopropyl alcohol, pentanol, sulfolane and 1,4-Dioxane. In an exemplary embodiment of the present disclosure, the fourth fluid medium is ethyl acetate.
In an embodiment of the present disclosure, ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (free base) obtained from ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate salt form i.e. free base is more stable because of high purity and easily precipitates after free base formation.
In accordance with the present disclosure, ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate is obtained with a comparatively higher yield and higher purity from ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate salt.
The present disclosure provides a simple, economical, and environment friendly process for the preparation of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate with a comparatively higher yield and higher purity.
In an embodiment of the present disclosure, the yield of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate is in the range of 93 % to 99%. In an exemplary embodiment of the present disclosure, the yield of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate is 95%.
In an embodiment of the present disclosure, the purity of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate is in the range of 98% to 99.99%. In an exemplary embodiment of the present disclosure, the purity of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate is 99.95%.
A schematic representation for the preparation of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (free base) is given as Scheme B below:

SCHEME B
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 purposes only and not to be construed for limiting the scope of the disclosure. The following experiments are scalable to industrial/commercial processes.
EXPERIMENTAL DETAILS
EXAMPLE 1A: Preparation of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate tosylate in accordance with the present disclosure
Step I: Process for the preparation of ethyl(6bR, 10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3’4’:4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate in accordance with the present disclosure
100 g of ethyl(4aS, 9bR)-6-bromo-5-(2-(methylamino)-2-oxoethyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate was charged into a reactor followed by addition of 150 g of potassium carbonate, 10 g of copper iodide (CuI), 8 g of N,N-dimethyl ethylene diamine and 750 ml of 1,4-dioxane to obtain a first mixture. The first mixture was refluxed at a temperature of 100 °C to 110 °C for 24 hours in nitrogen atmosphere to obtain a first reaction mass comprising ethyl(6bR,10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3’4’4,5] pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate. The reaction was monitored by TLC.
The so obtained first reaction mass was cooled to 25°C to 30°C and filtered to obtain a wet cake and a filtrate. The wet cake was separated followed by addition of 500 ml of water and 500 ml of toluene to the wet cake and stirred for 30 minutes to obtain a first biphasic mixture comprising a first organic layer (toluene layer) and a first aqueous layer. The first organic layer (toluene layer) and the first aqueous layer were separated to obtain a separated first organic layer and a separated first aqueous layer. The separated first aqueous layer was extracted twice with 500 ml of toluene to obtain a second biphasic mixture comprising a second organic layer (toluene layer) and a second aqueous layer. A toluene layer (second organic layer) was separated from the second biphasic mixture and combined with the first separated organic layer (toluene layer) followed by distillation at 700 mmHg pressure to obtain ethyl(6bR,10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3’4’:4,5] pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate.
Step II: Process for the preparation of ethyl(6bR, 10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3’4’4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate in accordance with present disclosure
In a reactor, 300 ml of tetrahydrofuran (THF) was mixed with ethyl(6bR, 10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3’4’:4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate obtained in step I and cooled to 5°C to obtain a second mixture. The second mixture was maintained at 5°C and 36 gm of sodium borohydride was added to the second mixture followed by adding 320 ml of boron trifluoride etherate to obtain a third mixture. The third mixture was maintained at 5°C for 7 hours to obtain a resultant. The reaction was monitored by TLC.
To the resultant, 500 ml of water was slowly added while maintaining a temperature of 5°C, followed by the addition of 1450 ml of sodium bicarbonate solution (20%) to adjust the pH to 7 to obtain a second reaction mass. The second reaction mass was extracted using 500 ml of ethyl acetate, three times to obtain ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3’4’4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate in ethyl acetate.
Step III: Process for the preparation of ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate tosylate in accordance with the present disclosure
45 g of p-toluene sulfonic acid (p-TSA) was charged into a reactor comprising ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3’4’4,5] pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate in ethyl acetate obtained in step II followed by stirring for 8 hours at 25°C to obtain (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate tosylate (PTSA salt). The PTSA salt is off-white to white in colour.
The yield of (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5] pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate tosylate (tosylate salt) was 90% and the HPLC purity was 99.95%.
EXAMPLE 1B: Preparation of ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate hydrochloride in accordance with the present disclosure
The same process was followed as in example 1 except that hydrochloric acid was used instead of p-toluene sulfonic acid (p-TSA) in Step-III to obtain (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate hydrochloride (hydrochloride salt).
EXAMPLE 1C: Preparation of ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate oxalate in accordance with the present disclosure
The same process was followed as in example 1 except that oxalic acid was used instead of p-toluene sulfonic acid (p-TSA) in Step-III to obtain (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate oxalate (oxalate salt).
EXAMPLE 1D: Preparation of ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate phosphate in accordance with the present disclosure
The same process was followed as in example 1 except that phosphoric acid was used instead of p-toluene sulfonic acid (p-TSA) in Step-III to obtain (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate phosphate (phosphate salt).
EXAMPLE 2: Preparation of ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (free base) in accordance with present disclosure
100 g of ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate tosylate (pTSA) obtained in step III of Example 1 was charged into a reactor followed by the addition of 500 ml of water and pH was adjusted to 7 by the addition of 1500 ml of aqueous sodium bicarbonate solution to obtain a fourth mixture. The fourth mixture was extracted by using 500 ml of ethyl acetate to obtain ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (free base).
The yield of ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate was 95% and the purity was 99.95%.
1H NMR and 13C NMR data of ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate was provided below.
1H NMR (CDCl3, 400 MHz) d: 1.22 (t, 3H), 1.77-1.98 (m, 2H), 2.27 (s, 3H), 3.04 (s, 3H), 3.23-3.44 (m, 6H), 3.67-3.87 (m, 4H), 4.03-4.10 (m, 2H), 6.85- 6.86 (m, 4H), 7.05-7.07- (d, 2H), 7.58-7.60 (d, 2H).
13C- NMR (CDCl3, 100 MHz) d: 14.67, 21.29, 22.77, 23.13, 39.49, 40.52, 41.65, 43.52, 50.62, 61.49, 65.31, 76.94, 77.26, 77.58, 116.41, 124.44, 125.79, 125.84, 133.17, 140.21, 141.77, 155.30.
The same process was followed as in example 2 by varying the salts such as ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate hydrochloride, ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate oxalate and ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate phosphate instead of ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate tosylate to obtain (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate.
The process of the present disclosure provides ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate salt and ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (free base) with high yield and high purity thereby making the process more efficient. Moreover, the process of the present disclosure is carried out under mild reaction conditions thereby avoiding the formation of impurities. Due to the formation of less impurities and achieving highly pure ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate salt, the purity of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (free base) is also enhanced thereby increasing the stability.
TECHNICAL ADVANCEMENT
The present disclosure described hereinabove has several technical advantages including, but not limited to, the realization of
? ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate salt that:
• provides stable, ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a hexahydro-1H-pyrido[3',4':4,5]pyrrolo [1,2,3-de] quinoxaline-8(7H)-carboxylate; and

? a process for the preparation of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-
hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate salt that
• proceeds under mild reaction conditions;
• is a simple and environment friendly process;
• is economical and easily scalable;
• in-situ reduction process reduces the formation of impurities; and
• provides ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-
1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (free base) having a comparatively high purity and high yield.
The embodiments herein and the various features and advantageous details thereof are explained with reference to the non-limiting embodiments in the following description. Descriptions of well-known components and processing techniques are omitted so as to not unnecessarily obscure the embodiments herein. The examples used herein are intended merely to facilitate an understanding of ways in which the embodiments herein may be practiced and to further enable those of skill in the art to practice the embodiments herein. Accordingly, the examples should not be construed as limiting the scope of the embodiments herein.
The foregoing description of the specific embodiments so fully reveal the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. Therefore, while the embodiments herein have been described in terms of preferred embodiments, those skilled in the art will recognize that the embodiments herein can be practiced with modification within the spirit and scope of the embodiments as described herein.
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.
Any discussion of documents, acts, materials, devices, articles or the like that has been included in this specification is solely for the purpose of providing a context for the disclosure. It is not to be taken as an admission that any or all of these matters form a part of the prior art base or were common general knowledge in the field relevant to the disclosure as it existed anywhere before the priority date of this application.
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:WE CLAIM:
1. Ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5] pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate salts selected from the group consisting of

Formula (I),
. HCl;
Formula (II),
. H2C2O4; and
Formula (III),

. H3PO4.
Formula (IV)
2. Ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate salts as claimed in claim 1 have a purity in the range of 98.5 % to 99.99 %.
3. A process for the preparation of ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate salts (Lumateperone intermediate salts), said process comprising the following steps:
i. cyclizing ethyl(4aS,9bR)-6-bromo-5-(2-(methylamino)-2-oxoethyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate by using a first base and a chelating agent, in the presence of a first catalyst in a first fluid medium at a first predetermined temperature for a first predetermined time period in an inert atmosphere to obtain ethyl (6bR,10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate;
ii. reducing ethyl(6bR,10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate by using a reducing agent in the presence of a second catalyst in a second fluid medium at a second predetermined temperature for a second predetermined time period to obtain ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate; and
iii. reacting ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate with an acid in a third fluid medium at a third predetermined temperature for a third predetermined time period to obtain said ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate salts (Lumateperone intermediate salts).
4. The process as claimed in claim 3, wherein said first base is selected from an organic base and an inorganic base.
5. The process as claimed in claim 4, wherein said organic base is selected from the group consisting of triethylamine, trimethylamine, N,N-dimethyl ethylene diamine, N,N’-diisopropylethylamine, pyridine, 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU), l,4-diazabicyclo[2.2.2]octane (DABCO), sodium t-butoxide and potassium t-butoxide.
6. The process as claimed in claim 4, wherein said inorganic base is selected from the group consisting of a metal hydride, a metal carbonate, a metal bicarbonate and a metal phosphate; wherein
• said metal hydride is selected from the group consisting of sodium hydride, lithium hydride and potassium hydride;
• said metal carbonate is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate and barium carbonate;
• said metal bicarbonate is selected from the group consisting of sodium bicarbonate, potassium bicarbonate, cesium bicarbonate and barium bicarbonate; and
• said metal phosphate is potassium phosphate.
7. The process as claimed in claim 3, wherein said chelating agent is selected from the group consisting of N, N-dimethyl ethylene diamine, 1,2-diamine, l,2-aminoalcohol, l,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, 2- (aminomethyl)pyridine, 4,7-diphenyl-1,10-phenanthroline, 4,7-dimethyl- 1,10-phenanthroline, 5-methyl-1,10-phenanthroline, 5-chloro-l,10-phenanthroline, and 5-nitro-l,10-phenanthroline.
8. The process as claimed in claim 3, wherein said first catalyst is selected from the group consisting of copper iodide (CuI), copper bromide (CuBr), copper chloride (CuCl), copper (II) acetate (Cu(OAc)2), copper (I) benzoate (CuBn), copper sulphate (CuSO4), copper (I) oxide (Cu2O), potassium iodide (KI) and lithium iodide (LiI).
9. The process as claimed in claim 3, wherein
• the mole ratio of ethyl(4aS,9bR)-6-bromo-5-(2-(methylamino)-2-oxoethyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate to said first base is in the range of 1:3 to 1:5;
• the mole ratio of ethyl(4aS,9bR)-6-bromo-5-(2-(methylamino)-2-oxoethyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate to said chelating agent is in the range of 1:0.2 to 1:0.5; and
• the mole ratio of ethyl(4aS,9bR)-6-bromo-5-(2-(methylamino)-2-oxoethyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate to said first catalyst is in the range of 1:0.1 to 1:0.3.
10. The process as claimed in claim 3, wherein said inert atmosphere is selected from nitrogen and argon.
11. The process as claimed in claim 3, wherein said reducing agent is selected from the group consisting of sodium borohydride (NaBH4), lithium aluminum hydride (LiAlH4), sodium cyanoborohydride (NaBH3CN), hydrogen in presence of nickel (H2/Ni), hydrogen in presence of palladium on charcoal (H2/Pd/C), hydrogen in presence of nickel boride (H2/NiB), hydrogen in presence of platinum (H2/Pt), hydrogen in presence of platinum oxide (H2/PtO), hydrogen in presence of rhodium (H2/Rh), hydrogen in presence of ruthenium (H2/Ru), hydrogen in presence of zinc oxide (H2/ZnO) and hydrogen in presence of pentacyanocobaltate(II) (H2/[Co(CN)5]3?).
12. The process as claimed in claim 3, wherein said second catalyst is selected from the group consisting of:
• a metal hydride is selected from the group consisting of diisobutyl aluminum hydride (DIBAL), sodium bis(2-methoxyethoxy) aluminum hydride and sodium cyanoborohydride;
• a borane is selected from the group consisting of boron trifluoride etherate, borane tetrahydrofuran complex (borane-THF), borane-dimethylsulfide complex, diborane and borane-ammonia;
• an organoborane is selected from the group consisting of bis(benzyloxy)borane, 9-borabicyclo[3.3.1]nonane(BBN) and trialkylboranes; and
• a transition metal catalyst is selected from the group consisting of nickel catalyst, platinum catalyst, palladium catalyst, rhodium catalyst and ruthenium catalyst.
13. The process as claimed in claim 3, wherein said acid is selected from the group consisting of p-toluene sulfonic acid, hydrochloric acid, oxalic acid and phosphoric acid.

14. The process as claimed in claim 3, wherein said ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate salts are selected from the group consisting of:

• ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate tosylate;
• ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate hydrochloride;
• ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate oxalate; and
• ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate phosphate.

15. The process as claimed in claim 3, wherein
• said first fluid medium is selected from the group consisting of 1,4-dioxane, dimethoxyethane, toluene, xylene and chlorobenzene;
• said second fluid medium is selected from the group consisting of tetrahydrofuran (THF), methanol, dioxane and diethyl ether; and
• said third fluid medium is selected from the group consisting of ethyl acetate, butyl acetate, isobutyl acetate, isopropyl acetate, propyl acetate, methyl acetate, acetonitrile, acetone, methanol, ethanol, butanol, isopropyl alcohol, pentanol, sulfolane, dichloromethane, toluene, m-xylene and 1,4-dioxane.
16. The process as claimed in claim 3, wherein
• said first predetermined temperature is in the range of 75 °C to 150 °C;
• said second predetermined temperature is in the range of 0 °C to 15 °C;
• said third predetermined temperature is in the range of 15 °C to 40 °C.
• said first predetermined time period is in the range of 20 hours to 30 hours;
• said second predetermined time period is in the range of 5 hours to 15 hours; and
• said third predetermined time period is in the range of 5 hours to 15 hours.
17. The process as claimed in claim 3, wherein the yield of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate salt is in the range of 85% to 95%.
18. The process as claimed in claim 3, wherein the purity of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate salt is in the range of 98.5% to 99.99%.
19. A process for the preparation of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate, said process comprising the following steps:
i. cyclizing ethyl(4aS,9bR)-6-bromo-5-(2-(methylamino)-2-oxoethyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate by using a first base and a chelating agent, in the presence of a first catalyst in a first fluid medium at a first predetermined temperature for a first predetermined time period in an inert atmosphere to obtain ethyl (6bR,10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate;
ii. reducing ethyl(6bR,10aS)-3-methyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate by using a reducing agent in the presence of a second catalyst in a second fluid medium at a second predetermined temperature for a second predetermined time period to obtain ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate;
iii. reacting ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate with an acid in a third fluid medium at a third predetermined temperature for a third predetermined time period to obtain ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate salts; and
iv. reacting ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate salts with a second base followed by extracting using a fourth fluid medium to obtain ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate.

20. The process as claimed in claim 19, wherein said first base is selected from an organic base and an inorganic base,
• wherein said organic base is selected from the group consisting of triethylamine, trimethylamine, N,N-dimethyl ethylene diamine, N,N’-diisopropylethylamine, pyridine, 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU), l,4-diazabicyclo[2.2.2]octane (DABCO), sodium t-butoxide and potassium t-butoxide, and
• wherein said inorganic base is selected from the group consisting of a metal hydride, a metal carbonate, a metal bicarbonate and a metal phosphate; wherein
o said metal hydride is selected from the group consisting of sodium hydride, lithium hydride and potassium hydride;
o said metal carbonate is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate and barium carbonate;
o said metal bicarbonate is selected from the group consisting of sodium bicarbonate, potassium bicarbonate, cesium bicarbonate and barium bicarbonate; and
o said metal phosphate is potassium phosphate.
21. The process as claimed in claim 19, wherein said chelating agent is selected from the group consisting of N, N-dimethyl ethylene diamine, 1,2-diamine, l,2-aminoalcohol, l,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, 2- (aminomethyl)pyridine, 4,7-diphenyl-1,10-phenanthroline, 4,7-dimethyl- 1,10-phenanthroline, 5-methyl-1,10-phenanthroline, 5-chloro-l,10-phenanthroline, and 5-nitro-l,10-phenanthroline.
22. The process as claimed in claim 19, wherein said first catalyst is selected from the group consisting of copper iodide (CuI), copper bromide (CuBr), copper chloride (CuCl), copper (II) acetate (Cu(OAc)2), copper (I) benzoate (CuBn), copper sulphate (CuSO4), copper (I) oxide (Cu2O), potassium iodide (KI) and lithium iodide (LiI).
23. The process as claimed in claim 19, wherein
• the mole ratio of ethyl(4aS, 9bR)-6-bromo-5-(2-(methylamino)-2-oxoethyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate to said first base is in the range of 1:3 to 1:5;
• the mole ratio of ethyl(4aS, 9bR)-6-bromo-5-(2-(methylamino)-2-oxoethyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate to said chelating agent is in the range of 1:0.2 to 1:0.5; and
• the mole ratio of ethyl(4aS, 9bR)-6-bromo-5-(2-(methylamino)-2-oxoethyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate to said first catalyst is in the range of 1:0.1 to 1:0.3.
24. The process as claimed in claim 19, wherein said inert atmosphere is selected from nitrogen and argon.
25. The process as claimed in claim 19, wherein said reducing agent is selected from the group consisting of sodium borohydride (NaBH4), lithium aluminum hydride (LiAlH4), sodium cyanoborohydride (NaBH3CN), hydrogen in presence of nickel (H2/Ni), hydrogen in presence of palladium on charcoal (H2/Pd/C), hydrogen in presence of nickel boride (H2/NiB), hydrogen in presence of platinum (H2/Pt), hydrogen in presence of platinum oxide (H2/PtO), hydrogen in presence of rhodium (H2/Rh), hydrogen in presence of ruthenium (H2/Ru), hydrogen in presence of zinc oxide (H2/ZnO) and hydrogen in presence of pentacyanocobaltate(II) (H2/[Co(CN)5]3?).
26. The process as claimed in claim 19, wherein said second catalyst is selected from the group consisting of
• a metal hydride is selected from the group consisting of diisobutyl aluminum hydride (DIBAL), sodium bis(2-methoxyethoxy) aluminum hydride and sodium cyanoborohydride;
• a borane selected from the group consisting of boron trifluoride etherate, borane tetrahydrofuran complex (borane-THF), borane-dimethylsulfide complex, diborane and borane-ammonia;
• an organoborane selected from the group consisting of bis(benzyloxy)borane, 9-borabicyclo[3.3.1]nonane(BBN) and trialkylboranes; and
• a transition metal catalyst selected from the group consisting of nickel catalyst, platinum catalyst, palladium catalyst, rhodium catalyst and ruthenium catalyst.
27. The process as claimed in claim 19, wherein said acid is selected from the group consisting of p-toluene sulfonic acid, hydrochloric acid, oxalic acid and phosphoric acid.

28. The process as claimed in claim 19, wherein said ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate salts are selected from the group consisting of:

• ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate tosylate;
• ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate hydrochloride;
• ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate oxalate; and
• ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate phosphate.

29. The process as claimed in claim 19, wherein
• said first fluid medium is selected from the group consisting of 1,4-dioxane, dimethoxyethane, toluene, xylene and chlorobenzene;
• said second fluid medium is selected from the group consisting of tetrahydrofuran (THF), methanol, dioxane and diethyl ether; and
• said third fluid medium is selected from the group consisting of ethyl acetate, butyl acetate, isobutyl acetate, isopropyl acetate, propyl acetate, methyl acetate, acetonitrile, acetone, methanol, ethanol, butanol, isopropyl alcohol, pentanol, sulfolane, dichloromethane, toluene, m-xylene and 1,4-dioxane.
30. The process as claimed in claim 19, wherein
• said first predetermined temperature is in the range of 75 °C to 150 °C;
• said second predetermined temperature is in the range of 0 °C to 15 °C; and
• said third predetermined temperature is in the range of 15 °C to 40 °C;
• said first predetermined time period is in the range of 20 hours to 30 hours;
• said second predetermined time period is in the range of 5 hours to 15 hours; and
• said third predetermined time period is in the range of 5 hours to 15 hours.
31. The process as claimed in claim 19, wherein said second base is selected from an organic base and an inorganic base, wherein
• said organic base is selected from the group consisting of triethylamine, trimethylamine, N,N’-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU) and l,4-diazabicyclo[2.2.2]octane (DABCO);
• said inorganic base is selected from the group consisting of sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, and ammonia; and
• said fourth fluid medium is selected from the group consisting of ethyl acetate, butyl acetate, isobutyl acetate, isopropyl acetate, propyl acetate, methyl acetate, acetonitrile, acetone, methanol, ethanol, butanol, isopropyl alcohol, pentanol, sulfolane and 1,4-Dioxane.
32. The process as claimed in claim 19, wherein the yield of ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] quinoxaline-8(7H)-carboxylate is in the range of 93% to 99%.
33. The process as claimed in claim 19, wherein the purity of ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H pyrido[3',4':4,5] pyrrolo [1,2,3-de] quinoxaline-8(7H)-carboxylate is in the range of 98% to 99.99%.
Dated this 04th day of January, 2025

_______________________________
MOHAN RAJKUMAR DEWAN, IN/PA – 25
OF R. K. DEWAN & CO.
AUTHORIZED AGENT TO THE APPLICANT

TO,
THE CONTROLLER OF PATENTS
THE PATENT OFFICE, MUMBAI