DESC:IMPROVED PROCESS FOR THE PREPARATION OF ALECTINIB HYDROCHLORIDE
FIELD OF THE INVENTION
The present application relates to an improved process for the preparation of Alectinib hydrochloride. Specifically, the present application also relates to an one-pot process for the preparation of Alectinib hydrochloride.

BACKGROUND OF THE INVENTION
Alectinib hydrochloride is the adopted name for a drug chemically described as 9-Ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl)piperidin-1-yl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride and is represented by structural Formula (I).

Formula (I)
Alectinib hydrochloride is a kinase inhibitor indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC). Alectinib hydrochloride was approved by USFDA in 2015 under the name Alecensa for the treatment of patients with metastatic non-small cell lung cancer. Alecensa has also been approved by the Europe commission for the treatment of lung cancer.
U.S. patent no. 9,126,931B2 first discloses Alectinib or its salt thereof and the process for its preparation.
WO2015/163447A1 discloses crystalline Form-I, Form-II and Form-III of Alectinib hydrochloride.
CN115677659A discloses a one-pot process for preparation of Alectinib using polyphosphroic acid.
There remains a need to develop a robust and green process, which is viable at commercial scale and can be scaled up easily at manufacturing unit for preparation of Alectinib hydrochloride.
Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, suitable methods, and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

SUMMARY OF THE INVENTION
In one embodiment, the present application provides a one-pot process for the preparation of Alectinib hydrochloride of Formula (I), comprising reacting a compound of Formula (II) or its salt thereof with chlorinating agent to produce Alectinib hydrochloride of Formula (I).

DETAILED DESCRIPTION OF THE INVENTION
As used herein, "comprising" means the elements recited, or their equivalent in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise.
All ranges recited herein include the endpoints, including those that recite a range "between" two values.
Terms such as "about," "generally," "substantially," and the like are to be construed as modifying a term or value such that it is not an absolute, but does not read on the prior art. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
In one embodiment, the present application provides a one-pot process for the preparation of Alectinib hydrochloride of Formula (I), comprising reacting a compound of Formula (II) or its salt thereof with chlorinating agent to produce a compound of Formula (I).

This reaction starting material is compound of Formula (II) or its salt. The preferred salt is a hydrochloride salt.
The above reaction may be carried out in the presence of suitable chlorinating agent and a solvent.
Suitable chlorinating agent that may be used in the above step include, but are not limited to thionyl chloride, oxalyl chloride, phosphorous oxychloride, phosphorus trichloride, phosphorus pentachloride, 1-chloro-N,N-2-trimethyl-1-propenylamine, cyanuric chloride or mixtures thereof.
Suitable organic solvent used in step a) include, but are not limited to water; ether solvents, such as, for example, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, 1, 4-dioxane or the like; alcoholic solvents such as t-butanol or the like; ketone solvents, such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, C3-C6 ketones or the like; aromatic hydrocarbon solvents, such as toluene, xylene, chlorobenzene, tetralin or the like; halogenated hydrocarbons such as dichloromethane, chloroform or the like; polar aprotic solvents, such as dimethyl formamide (DMF), dimethylacetamide (DMA), n-methyl pyrrolidine or the like; aliphatic hydrocarbon solvents, such as n-pentane, n-hexane, n-heptane or the like; nitrile solvent, such as acetonitrile, propionitrile, C2-C6 nitriles or the like; ester solvents, such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like; or mixtures thereof.
The temperature at which the above steps may be carried out in between about -20 °C and about 100 °C, preferably at about 0 °C and about 80 °C, most preferably at about 0 °C and about 50 °C, based on the solvent or mixture of solvent used in particular step.
The present application provides an extremely mild and concise one-pot process for preparation of Alectinib hydrochloride of Formula (I) as a crystalline solid directly from compound of Formula (II) or its salt thereof. The present process is operationally simple, scalable and prevents the formation of decarboxylation impurities which are observed in prior art process.
The removal of solvent at any stage of the process of the present application may be carried out by methods known in the art or any procedure disclosed in the present application. In preferred embodiments, removal of solvent may include, but not limited to: solvent evaporation or sublimation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Büchi® Rotavapor®, spray drying, freeze drying (Lyophilization), agitated thin film drying and the like.
The compounds at any stage of the process of the present application may be isolated using conventional techniques known in the art. For example, useful techniques include but are not limited to, decantation, centrifugation, gravity filtration, suction filtration, concentrating, cooling, stirring, shaking, combining with an anti-solvent, adding seed crystals, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying, freeze-drying, or the like. The isolation may be optionally carried out at atmospheric pressure or under reduced pressure. The solid that is obtained may carry a small proportion of occluded mother liquor containing a higher percentage of impurities and, if desired, the solid may be washed with a solvent to wash out the mother liquor.
The resulting solid may be optionally further dried. Drying may be suitably carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 100 °C, less than about 60 °C, less than about 40 °C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve a desired purity of the product, such as, for example, about 1 to about 15 hours, or longer.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner.

Examples
Example 1: Preparation of tert-butyl 6-cyano-2-(2-(4-ethyl-3-(4-morpholinopiperidin-1-yl)phenyl)propan-2-yl)-1H-indole-3-carboxylate hydrochloride (Formula (II) hydrochloride).
NaHMDS (1.9M in THF, 562.8 mL) was added to a solution of tert-butyl 6-cyano-2-(2-(4-ethyl-3-iodophenyl)propan-2-yl)-1H-indole-3-carboxylate (100 g) and 4-(piperidin-4-yl)morpholine (99.29 g) in dry THF (1.5 L) maintained under nitrogen sparging at 20-25 °C. The nitrogen sparging was continued for 1 hour at 20-25 °C before adding allylchloro-[1,3-bis(2,6-di-i-propylphenyl)imidazol-2-ylidene]palladium(II) (1.220 g) to the reaction mixture at 20-25 °C. Nitrogen sparging was maintained while the reaction mixture was stirred at 20-25 °C for 2-3 hours. After completion of the reaction indicated by TLC, the reaction mixture was cooled to 10-15 °C and quenched at the same temperature with saturated ammonium chloride solution (1.5 L). The reaction mixture was stirred for 15-30 min at 10-15 °C. Thereafter ethyl acetate (1 L) was added in to the reaction mixture at 10-15 °C which was then stirred at the same temperature for 10-15 min. The organic layer was separated from the aqueous layer which was then extracted with ethyl acetate (300 mL). The separated organic layer and ethyl acetate extract were combined, washed successively with water (2X600 mL) and brine (2X600 mL), dried over sodium sulfate and concentrated at 45-50 °C under reduced pressure. The residue thus obtained was dissolved in ethyl acetate (600 mL) and warmed to 30-35°C. To this solution, maintained at 30-35°C, was added over a period of 15-30 min a solution of pyridine hydrochloride (22.46 g) in a mixture of acetone (100 mL) and ethanol (100 mL). The obtained mixture was stirred for 16-18 hours at room temperature after which it was cooled to 0-5 °C and stirred at same temperature for 1-2 hours. The precipitated solids were filtered and washed with ethyl acetate (200 mL). The obtained wet cake was dried at 45-50°C under reduced pressure for 1 hours to obtain the title compound as off-white colored powder.
Yield: 78.92%
Purity by HPLC: 95.84%.

Example 2: Preparation of Alectinib hydrochloride (I).
DMF (147.85 mg) and water (0.55 mL) was added to a solution of compound of Formula (II) hydrochloride (12.0 g) in DCM (300 mL) at 20-25 °C. Thionyl chloride (24 mL) was added dropwise in to the reaction mixture maintained at 20-25 °C which was then stirred at the same temperature for 3-4 hours. After completion of the reaction as indicated by TLC, the precipitated solids were filtered, washed with DCM (2X40 mL) and dried under suction at room temperature.
The solid (10.5 g) thus obtained was taken in methanol (126 mL) at 25-30 °C and stirred for 5 min. Water (63 mL) was slowly added to the mixture maintained at 25-30 °C which was then stirred at same temperature for 1 hour. The suspension was filtered; the obtained wet cake was washed with 25% methanol in water (21 mL) and dried at 50-55 °C under reduced pressure for 2 hours to obtain a brownish to off-white solid.
The obtained solid was taken in methanol (72 mL) at 25-30 °C and stirred for 5 min. Water (36 mL) was slowly added to the mixture maintained at 25-30 °C which was then stirred at same temperature for 1 hour. The suspension was filtered; the obtained wet cake was washed with 25% methanol in water (15 mL) and dried at 50-55 °C under reduced pressure for 2 hours to obtain Alectinib hydrochloride as an off-white solid.
Yield: 50.4%
Purity by HPLC: 99.52%.

WE CLAIM:

1) A one-pot process for the preparation of Alectinib hydrochloride of Formula (I), comprising reacting a compound of Formula (II) or its salt thereof with chlorinating agent to produce a compound of Formula (I).

2) The process as claimed in claim 1, wherein chlorinating agent is selected from thionyl chloride, oxalyl chloride, phosphorous oxychloride, phosphorus trichloride, phosphorus pentachloride, 1-chloro-N,N-2-trimethyl-1-propenylamine, cyanuric chloride or mixture thereof.

3) The process as claimed in claim 1, wherein solvent is selected from water, ether solvents, alcoholic solvents, ketone solvents, aromatic hydrocarbon solvents, halogenated hydrocarbons, polar aprotic solvents, aliphatic hydrocarbon solvents, nitrile solvent, ester solvents or mixture thereof.

,CLAIMS:WE CLAIM:

1) A one-pot process for the preparation of Alectinib hydrochloride of Formula (I), comprising reacting a compound of Formula (II) or its salt thereof with chlorinating agent to produce a compound of Formula (I).

2) The process as claimed in claim 1, wherein chlorinating agent is selected from thionyl chloride, oxalyl chloride, phosphorous oxychloride, phosphorus trichloride, phosphorus pentachloride, 1-chloro-N,N-2-trimethyl-1-propenylamine, cyanuric chloride or mixture thereof.

3) The process as claimed in claim 1, wherein solvent is selected from water, ether solvents, alcoholic solvents, ketone solvents, aromatic hydrocarbon solvents, halogenated hydrocarbons, polar aprotic solvents, aliphatic hydrocarbon solvents, nitrile solvent, ester solvents or mixture thereof.