DESC:FIELD
The present disclosure relates to a process for the preparation of deucravacitinib intermediate. Particularly, the present disclosure relates to a process for preparation of 2-methoxy-3-(1-methyl-1H-1, 2, 4-triazol-3-yl) aniline.
DEFINITIONS
As used in the present disclosure, the following term is generally intended to have the meaning as set forth below, except to the extent that the context in which it is used indicate otherwise.
Hyflo filtration (Filtration carried out using hyflo powder): Hyflo powder is a water-insoluble substance that is commonly used as a filtration agent.
BACKGROUND
The background information herein below relates to the present disclosure but is not necessarily prior art.
Deucravacitinib, a triazole family drug, is a TYK2 inhibitor used for the treatment of moderate to severe plaque psoriasis. 2-methoxy-3-(1-methyl-1H-1, 2, 4-triazol-3-yl) aniline represented as Formula I is the key raw material (deucravacitinib intermediate) for the preparation of deucravacitinib.

Formula I
The conventional route for preparing deucravacitinib intermediate includes the use of Pd/C as a hydrogenation catalyst which is a costly reagent and also leads to hazardous waste. Thus, the conventional route for preparing deucravacitinib intermediate is neither economic nor eco-friendly. Moreover, the conventional methods for the preparation of 2-methoxy-3-(1-methyl-1H-1, 2, 4-triazol-3-yl) aniline are associated with the drawbacks such as harsh reaction conditions, longer reaction time and low purity of the product. In addition, there is no suitable scale-up procedure available to achieve the production of 2-methoxy-3-(1-methyl-1H-1, 2, 4-triazol-3-yl) aniline without using the noble metal catalyst on industrial scale.
Therefore, there is felt a need to provide a process for the preparation of deucravacitinib intermediate that mitigates the drawbacks mentioned hereinabove or at least provide a useful alternative.
OBJECTS
Some of the objects of the present disclosure, which at least one embodiment herein satisfies, are as follows:
It is an object of the present disclosure to ameliorate one or more problems of the background or to at least provide a useful alternative.
An object of the present disclosure is to provide a process for the preparation of deucravacitinib intermediate.
Another object of the present disclosure is to provide a process for the preparation of deucravacitinib intermediate that results in high yields and high purity.
Still another object of the present disclosure is to provide a simple, economical and eco-friendly process for the preparation of deucravacitinib intermediate.
Other objects and advantages of the present disclosure will be more apparent from the following description, which is not intended to limit the scope of the present disclosure.
SUMMARY
The present disclosure relates to a process for the preparation of 2-methoxy-3-(1-methyl-1H-1, 2, 4-triazol-3-yl) aniline (deucravacitinib intermediate). The process comprises methylating 2-hydroxybenzonitrile with a methylating agent in a first fluid medium by using a first base at a first predetermined temperature for a first predetermined time period to obtain 2-methoxybenzonitrile. 2-methoxybenzonitrile is chlorinated by using a chlorinating agent in a second fluid medium in the presence of an initiator at a second predetermined temperature for a second predetermined time period to obtain 5-chloro-2-methoxybenzonitrile (5ClMBN). 5-chloro-2-methoxybenzonitrile is condensed with N-methyl-N-formyl hydrazine and a second base in a third fluid medium at a third predetermined temperature for a third predetermined time period followed by nitration at a fourth predetermined temperature for a fourth predetermined time period to obtain 3-(5-chloro-2-methoxy-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole (5ClMMTN). 3-(5-chloro-2-methoxy-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole (5ClMMTN) is reduced by using a reducing agent and a third base at a fifth predetermined temperature at a first predetermined hydrogen pressure for a fifth predetermined time period to obtain 5-chloro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) aniline (5ClMMTA). The 5-chloro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) aniline (5ClMMTA) is dehalogenated at a second predetermined hydrogen pressure at a sixth predetermined temperature for a sixth predetermined time period to obtain a product mixture comprising 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) aniline (deucravacitinib intermediate).
The product mixture is filtered to obtain a filtrate. Water and a chlorinated fluid medium are added to the filtrate to obtain a biphasic mixture. The biphasic mixture is separated to obtain an organic layer and an aqueous layer followed by distillation of the organic layer to obtain 2-methoxy-3-(1-methyl-1H-1, 2, 4-triazol-3-yl) aniline (deucravacitinib intermediate).
The first fluid medium and second fluid medium are independently selected from the group consisting of acetonitrile (ACN), tetrahydrofuran (THF), methanol (MeOH), ethanol (EtOH), isopropyl alcohol (IPA) and toluene.
The chlorinated fluid medium is selected from the group consisting of dichloromethane and dichloroethane.
The first base and third base are independently selected from the group consisting of potassium carbonate, sodium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate and potassium bicarbonate.

The second base is selected from the group consisting of potassium tertiary butoxide and sodium tertiary butoxide.
The third fluid medium is selected from acetonitrile (ACN), tetrahydrofuran (THF), methanol (MeOH), ethanol (EtOH), isopropyl alcohol (IPA) and toluene.
The first predetermined temperature is in the range of 25 °C to 45 °C. The second predetermined temperature is in the range of 25 °C to 45 °C. The third predetermined temperature is in the range of 25 °C to 45 °C. The fourth predetermined temperature is in the range of 0 °C to 20 °C. The fifth predetermined temperature is in the range of 65 °C to 85 °C. The sixth predetermined temperature is in the range of 80 °C to 100 °C.
The first predetermined time period is in the range of 1 hour to 5 hours. The second predetermined time period is in the range of 6 hours to 14 hours. The third predetermined time period is in the range of 1 hour to 5 hours. The fourth predetermined time period is in the range of 1 to 3 hours. The fifth predetermined time period is in the range of 1 hour to 5 hours. The sixth predetermined time period is in the range of 10 hours to 18 hours.
The methylating agent is selected from the group consisting of dimethyl sulphide and methyl iodide.
The chlorinating agent is selected from the group consisting of sulfuryl chloride (SO2Cl2), thionyl chloride (SOCl2), phosphoryl chloride (POCl3), and phosphorous pentachloride (PCl5).
The initiator is selected from the group consisting of azobisisobutyronitrile (AIBN) and 1, 1'-azobis (cyclohexane carbonitrile (ABCN).
The nitration is carried out by using a nitrating agent selected from the group consisting of nitric acid, oleum and sodium nitrate and a nitrating mixture (mixture of sulfuric acid and nitric acid).
The reducing agent is an aqueous suspension of Raney Ni.
The first predetermined hydrogen pressure is in the range of 4 bar to 8 bar.
The second predetermined hydrogen pressure is in the range of 5 bar to 12 bar.
The weight ratio of 2-hydroxy benzonitrile to methylating agent is in the range of 1:1 to 1:3.
The weight ratio of 2-methoxy benzonitrile to chlorinating agent is in the range of 1:1 to 1:3.
The weight ratio of 5-chloro-2-methoxy benzonitrile to N-methyl-N-formyl hydrazine is in the range of 1:1 to 1:3.
The yield of 2-methoxy-3-(1-methyl-1H-1, 2, 4-triazol-3-yl) aniline (deucravacitinib intermediate) is in the range of 65 % to 80 % and the purity of 2-methoxy-3-(1-methyl-1H-1, 2, 4-triazol-3-yl) aniline (deucravacitinib intermediate) is in the range of 98% to 99.9%.
DETAILED DESCRIPTION
The present disclosure relates to a process for the preparation of 2-methoxy-3-(1-methyl-1H-1, 2, 4-triazol-3-yl) aniline (deucravacitinib intermediate).
Embodiments are provided so as to thoroughly and fully convey the scope of the present disclosure to the person skilled in the art. Numerous details are set forth, relating to specific components, and methods, to provide a complete understanding of embodiments of the present disclosure. It will be apparent to the person skilled in the art that the details provided in the embodiments should not be construed to limit the scope of the present disclosure. In some embodiments, well-known processes, well-known apparatus structures, and well-known techniques are not described in detail.
The terminology used, in the present disclosure, is only for the purpose of explaining a particular embodiment and such terminology shall not be considered to limit the scope of the present disclosure. As used in the present disclosure, the forms "a,” "an," and "the" may be intended to include the plural forms as well, unless the context clearly suggests otherwise. The terms "comprises," "comprising," “including,” and “having,” are open ended transitional phrases and therefore specify the presence of stated features, integers, steps, operations, elements, modules, units and/or components, but do not forbid the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. The particular order of steps disclosed in the method and process of the present disclosure is not to be construed as necessarily requiring their performance as described or illustrated. It is also to be understood that additional or alternative steps may be employed.
As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed elements.
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.
Deucravacitinib, a triazole family drug, is a TYK2 inhibitor used for the treatment of moderate to severe plaque psoriasis. 2-methoxy-3-(1-methyl-1H-1, 2, 4-triazol-3-yl) aniline represented as Formula I is the key raw material (deucravacitinib intermediate) for the preparation of deucravacitinib.
The conventional route for preparing deucravacitinib intermediate includes the use of Pd/C as a hydrogenation catalyst which is a costly reagent and also leads to hazardous waste. Thus, the conventional route for preparing deucravacitinib intermediate is neither economic nor eco-friendly. Moreover, the conventional methods for the preparation of 2-methoxy-3-(1-methyl-1H-1, 2, 4-triazol-3-yl) aniline are associated with the drawbacks such as harsh reaction conditions, longer reaction time and low purity of the product. In addition, there is no suitable scale-up procedure available to achieve the production of 2-methoxy-3-(1-methyl-1H-1, 2, 4-triazol-3-yl) aniline without using the noble metal catalyst on industrial scale.
The process of the present disclosure is simple, environment friendly, economical, results in improved yield and higher purity of 2-methoxy-3-(1-methyl-1H-1, 2, 4-triazol-3-yl) aniline (deucravacitinib intermediate) and is commercially scalable.
The present disclosure provides a process for the preparation of
2-methoxy-3-(1-methyl-1H-1, 2, 4-triazol-3-yl) aniline (deucravacitinib intermediate) comprising the following steps:
i. methylating 2-hydroxybenzonitrile with a methylating agent in a first fluid medium by using a first base at a first predetermined temperature for a first predetermined time period to obtain 2-methoxybenzonitrile;
ii. chlorinating 2-methoxybenzonitrile by using a chlorinating agent in a second fluid medium in the presence of an initiator at a second predetermined temperature for a second predetermined time period to obtain 5-chloro-2-methoxybenzonitrile (5ClMBN);
iii. condensing 5-chloro-2-methoxybenzonitrile with N-methyl-N-formyl hydrazine and a second base in a third fluid medium at a third predetermined temperature for a third predetermined time period followed by nitration at a fourth predetermined temperature for a fourth predetermined time period to obtain 3-(5-chloro-2-methoxy-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole (5ClMMTN);
iv. reducing 3-(5-chloro-2-methoxy-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole by using a reducing agent and a second base at a fifth predetermined temperature at a first predetermined hydrogen pressure for a fifth predetermined time period to obtain 5-chloro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) aniline (5ClMMTA); and
v. dehalogenating 5-chloro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) aniline at a second predetermined hydrogen pressure at a sixth predetermined temperature for a sixth predetermined time period to obtain a product mixture comprising 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) aniline (deucravacitinib intermediate).
The process for preparing the 2-methoxy-3-(1-methyl-1H-1, 2, 4-triazol-3-yl) aniline (deucravacitinib intermediate) in accordance with the present disclosure is described in detail herein below.
Step I: Preparation of 2-methoxybenzonitrile
In a first step, a predetermined amount of 2-hydroxybenzonitrile is methylated with a methylating agent in a first fluid medium by using a first base at a first predetermined temperature for a first predetermined time period to obtain a first product mixture comprising 2-methoxybenzonitrile.
The first product mixture is filtered and washed with a first fluid medium to obtain a solid and a filtrate.
The methylating agent is selected from the group consisting of dimethyl sulphide and methyl iodide. In an exemplary embodiment the methylating agent is dimethyl sulphide.
The weight ratio of 2-hydroxy benzonitrile to methylating agent is in the range of 1:1 to 1:3. In an exemplary embodiment, the weight ratio of 2-hydroxy benzonitrile to methylating agent is 1:1.2.
The first fluid medium is selected from the group consisting of tetrahydrofuran (THF), acetonitrile (ACN), tetrahydrofuran (THF), methanol (MeOH), ethanol (EtOH), isopropyl alcohol (IPA) and toluene. In an exemplary embodiment of the present disclosure, the first fluid medium is acetonitrile.
The first base is selected from the group consisting of potassium carbonate, sodium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide sodium bicarbonate and potassium bicarbonate. In an exemplary embodiment of the present disclosure, the first base is potassium carbonate.
The first predetermined temperature is in the range of 25 °C to 45 °C. In an exemplary embodiment of the present disclosure, the first predetermined temperature is in the range of 30°C.
The first predetermined time period is in the range of 1 hour to 5 hours. In an exemplary embodiment of the present disclosure, the first predetermined time period is 2.5 hours.
Step II: Preparation of 5-chloro-2-methoxybenzonitrile (5ClMBN)
In a second step, 2-methoxybenzonitrile is chlorinated by using a chlorinating agent in a second fluid medium in the presence of an initiator at a second predetermined temperature for a second predetermined time period to obtain a second product mixture comprising 5-chloro-2-methoxybenzonitrile.
After the completion of the reaction, 250 ml to 350 ml of water is added into the second product mixture at a temperature in the range of 25 °C to 35 °C followed by cooling at a temperature in the range of 0 °C to 10 °C under stirring for a time period in the range of 1 hour to 4 hours to obtain a cooled second product mixture. The cooled second product mixture is filtered to obtain 5-chloro-2-methoxybenzonitrile (5ClMBN).
The chlorinating agent is selected from the group consisting of sulfuryl chloride (SO2Cl2), thionyl chloride (SOCl2), phosphoryl chloride (POCl3), and phosphorous pentachloride (PCl5). In an exemplary embodiment of the present disclosure, the chlorinating agent is sulfuryl chloride (SO2Cl2).
Use of chlorinating agents like sulfuryl chloride aids in obtaining 5-chloro-2-methoxybenzonitrile with high purity without the formation of by-products.
The weight ratio of 2-methoxy benzonitrile to chlorinating agent is in the range of 1:1 to 1:2. In an exemplary embodiment, the weight ratio of 2-methoxy benzonitrile to chlorinating agent is in the range of 1:1 to 1:1.5.
The second fluid medium is selected from the group consisting of acetonitrile (ACN) and tetrahydrofuran (THF), alcohol and toluene. In an exemplary embodiment of the present disclosure, the second fluid medium is acetonitrile.
The initiator is selected from the group consisting of azobisisobutyronitrile (AIBN) and 1, 1'-azobis (cyclohexane carbonitrile (ABCN). In an exemplary embodiment of the present disclosure, the initiator is azobisisobutyronitrile (AIBN).
The second predetermined temperature is in the range of 25 °C to 45 °C. In an exemplary embodiment of the present disclosure, the second predetermined temperature is 30 °C.
In an embodiment of the present disclosure, the second predetermined time period is in the range of 6 hours to 14 hours. In an exemplary embodiment of the present disclosure, the second predetermined time period is 12 hours.
Step III: Preparation of 3-(5-chloro-2-methoxy-3-nitrophenyl)-1-methyl-1H-1, 2, 4-triazole (5ClMMTN)
In a third step, 5-chloro-2-methoxybenzonitrile is condensed with N-methyl-N-formyl hydrazine and a second base in a third fluid medium at a third predetermined temperature for a third predetermined time period followed by nitration at a fourth predetermined temperature for a fourth predetermined time period to obtain 3-(5-chloro-2-methoxy-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole (5ClMMTN).
5-chloro-2-methoxybenzonitrile is condensed with N-methyl-N-formyl hydrazine and a second base in a third fluid medium at a third predetermined temperature for a third predetermined time period followed by extraction and isolation to obtain a third product mixture comprising 3-(5-Chloro-2-methoxy-phenyl)-1-methyl-1H-1, 2, 4-triazole (5ClMMT). Nitrating agent is added to the third product mixture at a fourth predetermined temperature for a fourth predetermined time period to obtain 3-(5-chloro-2-methoxy-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole (5ClMMTN).
The weight ratio of 5-chloro-2-methoxy benzonitrile to N-methyl-N-formyl hydrazine is in the range of 1:1 to 1:3. In an exemplary embodiment, the weight ratio of 5-chloro-2-methoxy benzonitrile to N-methyl-N-formyl hydrazine is 1:1.7.
The second base is selected from the group consisting of potassium t-butoxide and sodium t-butoxide. In an exemplary embodiment, the first base is potassium t-butoxide.
The third fluid medium is selected from the group consisting of tetrahydrofuran acetonitrile (ACN), tetrahydrofuran (THF), methanol (MeOH), ethanol (EtOH), isopropyl alcohol (IPA) and toluene. In an exemplary embodiment, the third fluid medium is tetrahydrofuran (THF).
In an embodiment of the present disclosure, the third predetermined temperature is in the range of 25 °C to 45 °C. In an exemplary embodiment of the present disclosure, the third predetermined temperature is 30 °C.
In an embodiment of the present disclosure, the third predetermined time period is 1 hour to 5 hours. In an exemplary embodiment of the present disclosure, the third predetermined time period is 2 hours.
The nitrating agent is selected from the group consisting of nitric acid, nitrating mixture (mixture of sulfuric acid and nitric acid), oleum and sodium nitrate. In an exemplary embodiment of the present disclosure, the nitrating agent isa nitrating mixture (mixture of sulfuric acid and nitric acid).
The fourth predetermined temperature is in the range of 0 °C to 20 °C. In an exemplary embodiment, the fourth predetermined temperature is 5 °C.
The fourth predetermined time period is in the range of 1 hour to 5 hours. In an exemplary embodiment, the fourth predetermined time period is 2 hours.
Step IV: Preparation of 5-chloro-2-methoxy-3-(1-methyl-1H-1, 2, 4-triazol-3-yl) aniline (5ClMMTA)
In a fourth step, 3-(5-chloro-2-methoxy-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole is reduced by using a reducing agent and a third base at a fifth predetermined temperature and at a first predetermined hydrogen pressure for a fifth predetermined time period to obtain 5-chloro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) aniline (5ClMMTA).
The reducing agent is an aqueous suspension of Raney nickel.
The third base is selected from the group consisting of potassium carbonate, sodium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate and potassium bicarbonate. In an exemplary embodiment of the present disclosure, the third base is sodium carbonate.
The fifth predetermined temperature is in the range of 65 °C to 85 °C. In an exemplary embodiment of the present disclosure, the fourth predetermined temperature is 75 °C.
The first predetermined hydrogen pressure is in the range of 4 bar to 8 bar. In an exemplary embodiment of the present disclosure, the predetermined hydrogen pressure is 5 bar.
The fifth predetermined time period is in the range of 1 hour to 5 hours. In an exemplary embodiment of the present disclosure, the fifth predetermined time period is 2 hours.
In accordance with the present disclosure, aqueous phase hydrogenation of 3-(5-chloro-2-methoxy-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole is carried out using Raney/Ni in water at 70 °C to 80 °C instead of Pd/C which is cost effective and environment friendly.
Step V: Preparation of 2-methoxy-3-(1-methyl-1H-1, 2, 4-triazol-3-yl) aniline (deucravacitinib intermediate)
In a fifth step, 5-chloro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) aniline is dehalogenated at a second predetermined hydrogen pressure at a sixth predetermined temperature for a sixth predetermined time period to obtain a product mixture comprising 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) aniline.
Hyflo filtration of the product mixture is carried out to obtain a filtrate. Water and a chlorinated fluid medium are added to the filtrate to obtain a biphasic mixture. The biphasic mixture is separated to obtain an organic layer and an aqueous layer followed by distilling the organic layer to obtain a product mass.
450-550 ml of a chlorinated fluid medium is added to the product mass and stirred at a temperature in the range of 25 °C to 35 °C for a time period in the range of 1 hour to 5 hours followed by hyflo filtration to obtain a filtrate comprising the product 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) aniline. The chlorinated fluid medium is distilled out from the filtrate under vacuum at a temperature in the range of 30 °C to 40 °C to obtain 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) aniline solid. The solid is filtered and washed with 40 ml to 60 ml of hexane to obtain 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) aniline (deucravacitinib intermediate).
The second predetermined hydrogen pressure is in the range of 5 bar to 12 bar. In an exemplary embodiment of the present disclosure, the predetermined hydrogen pressure is 8 bar.
The sixth predetermined temperature is in the range of 80 °C to 100 °C. In an exemplary embodiment of the present disclosure, the fifth predetermined temperature is 90 °C.
The sixth predetermined time period is in the range of 10 hours to 18 hours. In an exemplary embodiment of the present disclosure, the fourth predetermined time period is 14 hours.
In an embodiment of the present disclosure, 2-methoxy-3-(1-methyl-1H-1, 2, 4-triazol-3-yl) aniline (deucravacitinib intermediate) has a purity (HPLC purity) in the range of 98 % to 99.9 %. In an exemplary embodiment, the purity of 2-methoxy-3-(1-methyl-1H-1, 2, 4-triazol-3-yl) aniline (deucravacitinib intermediate) is 98 %.
In an embodiment of the present disclosure, the yield of 2-methoxy-3-(1-methyl-1H-1, 2, 4-triazol-3-yl) aniline (deucravacitinib intermediate) is in the range 65 % to 80 %. In an exemplary embodiment, the yield of 2-methoxy-3-(1-methyl-1H-1, 2, 4-triazol-3-yl) aniline (deucravacitinib intermediate) is 72 %.
A schematic representation for the preparation of 2-methoxy-3-(1-methyl-1H-1, 2, 4-triazol-3-yl) aniline in accordance with an exemplary embodiment of the present disclosure is given below.


The present disclosure provides a simple and economic process for the preparation of deucravacitinib intermediate with a comparatively higher yield and better purity.
The foregoing description of the embodiments has been provided for purposes of illustration and not intended to limit the scope of the present disclosure. Individual components of a particular embodiment are generally not limited to that particular embodiment, but, are interchangeable. Such variations are not to be regarded as a departure from the present disclosure, and all such modifications are considered to be within the scope of the present disclosure.
The present disclosure is further described in light of the following experiments which are set forth for illustration purpose only and not to be construed for limiting the scope of the disclosure. The following experiments can be scaled up to industrial/commercial scale and the results obtained can be extrapolated to the industrial scale.
EXPERIMENTAL DETAILS

Experiment 1: Preparation of 2-methoxy-3-(1-methyl-1H-1, 2, 4-triazol-3-yl) aniline (deucravacitinib intermediate) in accordance with the present disclosure:
Step (i): Preparation of 2-methoxybenzonitrile (2MBN)
In a reactor, 100 g of 2-hydroxybenzonitrile (HBN) was charged along with 450 ml acetonitrile (ACN) followed by the addition of 175 g (1.51 moles) of potassium carbonate and again flushed with 50 ml acetonitrile into the reactor at 30 °C to obtain a first reaction mixture. 122 g (1.15 moles) of dimethyl sulphide (DMS) was added to the first reaction mixture in a dropwise manner by maintaining the temperature at 30 °C and further stirred at 30 °C for 2.5 hours to obtain a first product mixture.
The first product mixture was filtered and washed with 100ml acetonitrile to obtain a solid and filtrate.
The obtained filtrate was charged in another reactor and distillation was carried out under vacuum at NMT 60 °C to obtain a residue and a distillate. After distillation, heating was stopped, vacuum was removed, and the residue was cooled at 30 ° C to obtain a cooled residue. 500ml water was charged to the cooled residue and stirred for 30 minutes and allowed to settle for 30 minutes to obtain an organic layer and an aqueous layer. The solvent in the lower organic layer containing 2-methoxybenzonitrile was distilled out to obtain 105.0 g of 2-methoxybenzonitrile having purity of not less than (NLT) 97%.
Step (ii): Preparation of 5-chloro-2-methoxybenzonitrile (5ClMBN)
100 g of 2-methoxybenzonitrile so obtained was charged into a reactor along with 80 ml acetonitrile followed by the addition of 2g of (2.0 % w/w) azobisisobutyronitrile (AIBN) and again flushing with 20 ml acetonitrile into the reactor at 30 °C to obtain a second reaction mixture. 152 g (1.50 mole) of sulfuryl chloride was added to the second reaction mixture in a dropwise manner by maintaining the temperature at 30 °C and further maintaining the same temperature for 12 hours to obtain a second product mixture.
After addition of sulfuryl chloride and completion of the reaction, 300 ml water was added into the second product mixture at 30 °C followed by cooling up to 5 °C under stirring for 2 hours to obtain a cooled second product mixture. The cooled second product mixture was filtered to obtain a crude solid of 5-chloro-2-methoxybeonitrile (yellow to white colour solid). The wet cake was dried in oven at 50 °C to obtain a pure 5-chloro-2-methoxybenzonitrile (dry weight is 70 g, HPLC purity is NLT 95 %).
Step (iii): Preparation of 3-(5-Chloro-2-methoxy-3-nitrophenyl)-1-methyl-1H-1, 2, 4-triazole (5ClMMTN)
100 g of 5-chloro-2-methoxybenzonitrile so obtained was condensed with 167 g N-methyl-N-formyl hydrazine (2.26 moles) in presence of 158g potassium tert-butoxide (2.35 moles) in THF at 30 °C to obtain a third reaction mixture. The third reaction mixture was stirred at 30 °C for 2 hours followed by extraction and isolation in ethyl acetate: methanol (7:6) to obtain a third product mixture comprising 3-(5-Chloro-2-methoxy-phenyl)-1-methyl-1H-1, 2, 4-triazole (5ClMMT). To the product mixture nitrating mixture (31g (1.08 moles) sulphuric acid and 250.0 ml (2.50 times) nitric acid was added at 5 °C and stirred for 120 minutes to obtain 3-(5-Chloro-2-methoxy-3-nitrophenyl)-1-methyl-1H-1, 2, 4-triazole (5ClMMTN) having the purity of NLT 99.0 % and yield of 70.0 g.
Step (iv): Preparation of 5-chloro-2-methoxy-3-(1-methyl-1H-1, 2, 4-triazol-3-yl) aniline
100 g of 3-(5-Chloro-2-methoxy-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole (5ClMMTN) so obtained was charged in a stainless-steel reactor followed by the addition of 20 g (20% w/w) of Raney/Ni in 1500 ml water and 103.0 g (3.28 moles) of sodium carbonate (for neutralization of by-product hydrochloric acid) to obtain a fourth reaction mixture. The fourth reaction mixture was maintained at 5 bar hydrogen pressure at 75 °C for 2 hours to obtain 5-chloro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) aniline (5ClMMTA).
Step (v): Preparation of 2-methoxy-3-(1-methyl-1H-1, 2, 4-triazol-3-yl) aniline
5-chloro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) aniline was dehalogenated by maintaining the hydrogen pressure at 8 bar at 90 °C for 14 hours to obtain a product mixture comprising 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) aniline (MMTA).
Hyflo filtration of the hot product mixture was carried out to obtain a filtrate. Water and a chlorinated fluid medium were added to the filtrate to obtain a biphasic mixture. The filtrate was washed with 200 ml of water and 200ml of dichloromethane to obtain an aqueous layer and an organic layer. The solvent in the dichloromethane layer was distilled out to obtain a solid product mass.
500 ml of dichloromethane was added to the solid product mass and stirred at 30 °C for 3 hours followed by hyflo filtration and washing with 100ml of dichloromethane to remove the inorganic salts to obtain a filtrate comprising the product 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) aniline. MDC was distilled out under high vacuum at NMT 35°C to get the pure brown to off-white to white solid. The obtained solid was filtered and washed with 50ml hexane to get 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) aniline having a purity of NLT 98% and a melting point of 120-126 °C. Yield=72%.
TECHNICAL ADVANCEMENT
The present disclosure described hereinabove has several technical advantages including, but not limited to, the realization of a process for the preparation of deucravacitinib intermediate that:
- provides comparatively high purity and high yield;
- employs inexpensive reagents and has industrial applicability;
- is simple and environment friendly; and
- is commercially scalable.
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. A process for the preparation of 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) aniline (deucravacitinib intermediate), said process comprising the following steps:
i. methylating 2-hydroxybenzonitrile with a methylating agent in a first fluid medium by using a first base at a first predetermined temperature for a first predetermined time period to obtain 2-methoxybenzonitrile;
ii. chlorinating 2-methoxybenzonitrile by using a chlorinating agent in a second fluid medium in the presence of an initiator at a second predetermined temperature for a second predetermined time period to obtain 5-chloro-2-methoxybenzonitrile (5ClMBN);
iii. condensing 5-chloro-2-methoxybenzonitrile with N-methyl-N-formyl hydrazine and a second base in a third fluid medium at a third predetermined temperature for a third predetermined time period followed by nitration at a fourth predetermined temperature for a fourth predetermined time period to obtain 3-(5-chloro-2-methoxy-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole (5ClMMTN);
iv. reducing 3-(5-chloro-2-methoxy-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole by using a reducing agent and a third base at a fifth predetermined temperature at a first predetermined hydrogen pressure for a fifth predetermined time period to obtain 5-chloro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) aniline (5ClMMTA); and
v. dehalogenating 5-chloro-2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) aniline at a second predetermined hydrogen pressure at a sixth predetermined temperature for a sixth predetermined time period to obtain a product mixture comprising 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) aniline (deucravacitinib intermediate).

2. The process as claimed in claim 1, wherein
• filtering said product mixture in step (v) to obtain a filtrate;
• adding water and a chlorinated fluid medium to said filtrate to obtain a biphasic mixture;
• separating said biphasic mixture to obtain an organic layer and an aqueous layer followed by distilling said organic layer to obtain 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl) aniline (deucravacitinib intermediate).

3. The process as claimed in claim 1, wherein said methylating agent in step (i) is selected from the group consisting of dimethyl sulphide and methyl iodide.

4. The process as claimed in claim 1, wherein said first fluid medium in step (i) and said second fluid medium in step (ii) are independently selected from the group consisting of acetonitrile (ACN), tetrahydrofuran (THF), methanol (MeOH), ethanol (EtOH), isopropyl alcohol (IPA) and toluene.

5. The process as claimed in claim 1, wherein said first base in step (i) and said third base in step (iv) is independently selected from the group consisting of potassium carbonate, sodium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate and potassium bicarbonate.

6. The process as claimed in claim 1, wherein
• said first predetermined temperature in step (i) is in the range of 25 °C to 45 °C;
• said second predetermined temperature in step (ii) is in the range of 25 °C to 45 °C;
• said third predetermined temperature in step (iii) is in the range of 25 °C to 45 °C;
• said fourth predetermined temperature in step (iii) is in the range of 0 °C to 20 °C;
• said fifth predetermined temperature in step (iv) is in the range of 65 °C to 85 °C; and
• said sixth predetermined temperature in step (v) is in the range of 80 °C to 100 °C.

7. The process as claimed in claim 1, wherein
• said first predetermined time period in step (i) is in the range of 1 hour to 5 hours;
• said second predetermined time period in step (ii) is in the range of 6 hours to 14 hours;
• said third predetermined time period in step (iii) is in the range of 1 hour to 5 hours;
• said fourth predetermined time period in step (iii) is in the range of 1 hour to 5 hours; and
• said fifth predetermined time period in step (iv) is in the range of 1 hour to 5 hours; and
• said sixth predetermined time period in step (v) is in the range of 10 hours to 18 hours.

8. The process as claimed in claim 1, wherein said chlorinating agent in step (ii) is selected from the group consisting of sulfuryl chloride (SO2Cl2), thionyl chloride (SOCl2), phosphoryl chloride (POCl3), and phosphorous pentachloride (PCl5).

9. The process as claimed in claim 1, wherein said initiator in step (ii) is selected from the group consisting of azobisisobutyronitrile (AIBN) and 1,1'-azobis (cyclohexane carbonitrile (ABCN).

10. The process as claimed in claim 1, wherein said second base in step (iii) is selected from the group consisting of potassium tertiary butoxide and sodium tertiary butoxide.

11. The process as claimed in claim 1, wherein said third fluid medium is selected from acetonitrile (ACN), tetrahydrofuran (THF), methanol (MeOH), ethanol (EtOH), isopropyl alcohol (IPA) and toluene.

12. The process as claimed in claim 1, wherein said nitration in step (iii) is carried out by using a nitrating agent selected from the group consisting of nitric acid, oleum, sodium nitrate and a nitrating mixture (mixture of sulfuric acid and nitric acid).

13. The process as claimed in claim 1, wherein said reducing agent in step (iv) is an aqueous suspension of Raney nickel.

14. The process as claimed in claim 1, wherein said first predetermined hydrogen pressure in step (iv) is in the range of 4 bar to 8 bar.

15. The process as claimed in claim 1, wherein said second predetermined hydrogen pressure in step (v) is in the range of 5 bar to 12 bar.

16. The process as claimed in claim 2, wherein said chlorinated fluid medium is selected from the group consisting of dichloromethane and dichloroethane.

17. The process as claimed in claim 1, wherein
• weight ratio of 2-hydroxy benzonitrile to said methylating agent is in the range of 1:1 to 1:3.
• weight ratio of 2-methoxy benzonitrile to said chlorinating agent is in the range of 1:1 to 1:3.
• weight ratio of 5-chloro-2-methoxy benzonitrile to said N-methyl-N-formyl hydrazine is in the range of 1:1 to 1:3.

18. The process as claimed in claim 1, wherein the yield of 2-methoxy-3-(1-methyl-1H-1, 2, 4-triazol-3-yl) aniline (deucravacitinib intermediate) is in the range of 65 % to 80 % and the purity of 2-methoxy-3-(1-methyl-1H-1, 2, 4-triazol-3-yl) aniline (deucravacitinib intermediate) is in the range of 98% to 99.9%.

Dated this 27th day of January, 2024

_______________________________
MOHAN RAJKUMAR DEWAN, IN/PA – 25
of R.K.DEWAN & CO.
Authorized Agent of Applicant

TO,
THE CONTROLLER OF PATENTS
THE PATENT OFFICE, AT MUMBAI