DESC:FORM 2
The Patents Act, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE
“A PROCESS FOR THE PREPARATION OF INTERMEDIATES FOR THE PREPARATION OF A TRIAMINOPYRIMIDINE COMPOUND”
We, ZYDUS LIFESCIENCES LIMITED, an Indian company incorporated under the Companies Act, 1956, of Zydus Corporate Park, Scheme No. 63, Survey No. 536, Khoraj (Gandhinagar), Nr. Vaishnodevi Circle, Ahmedabad, Gandhinagar, Gujarat, 382481, India.

The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to a process for the preparation of intermediates for the preparation of a triaminopyrimidine compound. Particularly, the invention relates to an improved process for the preparation of 4-cyclopropyl-5-fluoro-6-methylpyridin-2-amine, a compound of Formula I

or a salt, or hydrate thereof. The compound of Formula I is one of the useful intermediate for the preparation of a triaminopyrimidine compound of Formula VII.

BACKGROUND OF THE INVENTION
International (PCT) Publication No. WO 2015/165660 A1 (the WO '660) discloses triaminopyrimidine compounds, intermediates, pharmaceutical compositions and methods for use for preventing or treating malaria, wherein one of the triaminopyrimidine compound disclosed is a compound of Formula VII as represented below:
.
The WO '660 discloses a process for the preparation of compound of Formula VII and intermediates thereof. Further WO ‘660 discloses the compound of Formula I as hydrochloride salt and process for its preparation.

The journal article: Nature Communications, 6(1) (2015): 6715 also discloses a process for the preparation of a triaminopyrimidine compound of Formula VII, and its use for treating malaria.

International (PCT) Publication No. WO 2019/049021 A1 (WO ‘021) discloses a process for the preparation of compound of Formula VII and a process for the preparation compound of Formula I as hydrochloride salt.

Still there is need to develop an alternative process that is economically viable and industrially scalable for preparing the compound of Formula I or a salt, or hydrate thereof, as an intermediate for the preparation of compound of Formula VII.

SUMMARY OF THE INVENTION
In one general aspect, the present invention provides a process for the preparation of a compound of Formula I, or a salt, or a hydrate thereof,

the process comprising:
(a) reacting a compound of Formula IV, or a salt thereof,

with a compound of Formula V,

in the presence of a transition metal catalyst and one or more base in one or more solvent,
to obtain a compound of Formula III;

(b) reacting the compound of Formula III, with diphenylmethanimine in the presence of a transition metal catalyst, and one or more base in one or more solvent, to obtain a compound of Formula II;

and
(c) hydrolyzing the compound of Formula II to obtain the compound of Formula I, or a salt, or hydrate thereof;
wherein the transition metal catalyst at step (a) and step (b) is independently selected from [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(Pd(dppf)Cl2), bis(diphenylphosphino)ferrocene]dichloropalladium(II).DCM (Pd(dppf)Cl2.DCM), palladium-tetrakis(triphenylphosphine) (Pd(PPh3)4), tris(dibenzylideneacetone)dipalladium (0) (Pd2(dba)3), and Xphos-Pd-G2.

In another general aspect, the present invention provides a process for the preparation of a compound of Formula I, or a salt, or a hydrate thereof, the process comprising:
(a) reacting a compound of Formula IV, or a salt thereof,

with a compound of Formula V,

in presence of a transition metal catalyst and one or more base in one or more solvent,
to obtain a compound of Formula III;

and
(b) converting the compound of Formula III to the compound of Formula I, or a salt, or a hydrate thereof;
wherein the transition metal catalyst at step (a) is selected from Pd(dppf)Cl2, Pd(dppf)Cl2.DCM, Pd(PPh3)4, Pd2(dba)3, and Xphos-Pd-G2.

The compound of Formula I, or a salt, or hydrate thereof obtained by the process of the present invention can be further converted to the compound of Formula VII or a pharmaceutically acceptable salt thereof.

The process of the present invention is a better alternative process that is economically viable and industrially scalable for preparing the compound of Formula I or a salt or hydrate thereof, which ultimately led to an improved process for the preparation of the triaminopyrimidine compound of Formula VII. The process of the present invention is very cost effective, require only simple work-up and does not require any column chromatography for the purification. Also, the present invention provides the improved process for the preparation of intermediate compounds, which gives an advantage by providing a product with better quality for final drug substance in terms of purity and yield.

DETAILED DESCRIPTION OF THE INVENTION
The invention can further be understood in light of the description of the embodiments provided herein after. It is to be understood that the description, in no way, is intended to limit the scope of the invention to the expressly specified embodiments only. The equivalents and variants thereof or trivial modifications thereof which are apparently obvious to those skilled in the art, are also intended to be included within the scope of the present invention.

Detailed description of routine and conventional unit operations, which are easily understood by the skilled artisan, are not included herein. Such routine unit operations are to be construed as ordinarily understood and as routinely practiced by the person skilled in the field of the invention, unless otherwise specifically described.

The following definitions are used in connection with present application, unless it is indicated otherwise.

The terms “treating”, or “reacting” as used herein have meanings as widely used by general prior art in the field of invention and can be easily understood by those skilled in the art.

The term “about” as used herein is intended to mean approximately, in the region of, roughly, or around. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” may be used herein to modify a numerical value above and below the stated value by a variance of, for example, 10%.

The product(s) obtained may further be purified to obtain them in purer form. The product(s) obtained may further be dried additionally to achieve desired level of moisture and/or residual solvents.

The product(s) obtained may further be converted to any other physical forms thereof which includes but not specifically limited to polymorph(s), salt(s), solvate(s), or hydrate(s); and crystalline or amorphous forms thereof.

The product(s) obtained may further be subjected to physical processing which includes, but not limited to, pressing, crushing, triturating, milling or grinding to adjust the particle size of the product(s) to desired levels.

Thus, in one general aspect, the present invention provides a process for the preparation of a compound of Formula I, or a salt, or a hydrate thereof,

the process comprising:
(a) reacting a compound of Formula IV, or a salt thereof,

with a compound of Formula V,

in the presence of a transition metal catalyst and one or more base in one or more solvent,
to obtain a compound of Formula III;

(b) reacting the compound of Formula III, with diphenylmethanimine in the presence of a transition metal catalyst, and one or more base in one or more solvent, to obtain a compound of Formula II;

and
(c) hydrolyzing the compound of Formula II to obtain the compound of Formula I, or a salt, or hydrate thereof;
wherein the transition metal catalyst at step (a) and step (b) is independently selected from [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(Pd(dppf)Cl2), bis(diphenylphosphino)ferrocene]dichloropalladium(II).DCM (Pd(dppf)Cl2.DCM), palladium-tetrakis(triphenylphosphine) (Pd(PPh3)4), tris(dibenzylideneacetone)dipalladium (0) (Pd2(dba)3), and Xphos-Pd-G2.

In one embodiment, the transition metal catalyst at step (a) and step (b) of the above process is independently selected from [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II)(Pd(dppf)Cl2), bis(diphenylphosphino)ferrocene]dichloropalladium(II).DCM (Pd(dppf)Cl2.DCM), palladium-tetrakis(triphenylphosphine) (Pd(PPh3)4), tris(dibenzylideneacetone)dipalladium (0) (Pd2(dba)3), and Xphos-Pd-G2. In particular, the transition metal catalyst is Pd(dppf)Cl2, Pd(dppf)Cl2.DCM, or Pd(PPh3)4. More particularly, the transition metal catalyst at step (a) and step (b) of the above process is Pd(dppf)Cl2 or Pd(dppf)Cl2.DCM.

In another embodiment, the transition metal catalyst at step (a) of the above process is selected from Pd(dppf)Cl2, Pd(dppf)Cl2.DCM, Pd(PPh3)4, Pd2(dba)3, and Xphos-Pd-G2. In particular, the transition metal catalyst at step (a) is Pd(dppf)Cl2, Pd(dppf)Cl2.DCM, or Pd(PPh3)4. More particularly, the transition metal catalyst at step (a) is Pd(dppf)Cl2, or Pd(dppf)Cl2.DCM.

In another embodiment, the transition metal catalyst at step (b) of the above process is selected from Pd(dppf)Cl2, Pd(dppf)Cl2.DCM, Pd(PPh3)4, Pd2(dba)3, and Xphos-Pd-G2. In particular, the transition metal catalyst at step (b) is Pd(dppf)Cl2, or Pd(dppf)Cl2.DCM.

In another embodiment, the transition metal catalyst at step (a) or step (b) is used in an amount ranging from about 0.001 to about 0.01 mole equivalent. In particular, the transition metal catalyst is used in an amount of about 0.005 to about 0.01 mole equivalent.

In another embodiment, the transition metal catalyst at step (a) is used in an amount of about 0.001 to about 0.01 mole equivalent with respect to compound of Formula IV. In particular, the transition metal catalyst at step (a) is used in an amount of about 0.005 to about 0.01 mole equivalent with respect to compound of Formula IV.

In another embodiment, the transition metal catalyst at step (b) is used in an amount of about 0.001 to about 0.01 mole equivalent with respect to compound of Formula III. In particular, the transition metal catalyst at step (b) is used in an amount of about 0.005 to about 0.01 mole equivalent with respect to compound of Formula III.

In another embodiment, the solvent at step (a) is selected from one or more of toluene, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, xylene, or mixtures thereof. In particular, the solvent is toluene or 1,4-dioxane.

In another embodiment, the base at step (a) is selected from one or more of potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, potassium phosphate, 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), , or mixtures thereof. In particular, the base is potassium carbonate or potassium phosphate. More particularly, the base is potassium phosphate.

In general, the base at step (a) is used in an amount of about 1.1 to about 2 mole equivalents with respect to the compound of Formula IV. In particular, the base is used in amount of about 2 mole equivalents with respect to the compound of Formula IV.

In general, the reaction at step (a) can be carried out at a temperature ranging from about 50 °C to the reflux temperature of the solvent used. Particularly, the reaction may be carried out at a temperature ranging from about 90 °C to about 120 °C. More particularly, the reaction may be carried out at a temperature ranging from about 95 °C to about 105 °C.

In general, the reaction at step (a) is carried out for a time of about 30 minutes to 4 hours. In particular, the reaction at step (a) is carried out for a time of about 30 minutes to 2 hours. More particularly, the reaction at step (a) is carried out for a time of about 1 hour to 2 hours. After completion of the reaction, the reaction mixture may be cooled and the compound of Formula III may be isolated from the reaction mixture by any of the processes under common knowledge of a person skilled in the art or can be used for the next step without isolation.

In another embodiment, the solvent at step (b) is selected from one or more of toluene, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, xylene, or mixtures thereof. In particular, the solvent is toluene.

In another embodiment, the base at step (b) is selected from one or more of potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, potassium phosphate, sodium tert-butoxide, potassium tert-butoxide, 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), or mixtures thereof. In particular, the base is sodium tert-butoxide, or potassium tert-butoxide. More particularly, the base is sodium tert-butoxide.

In general, the base at step (b) is used in an amount of about 1.1 to about 2 mole equivalents with respect to the compound of Formula III. In particular, the base is used in amount of about 1.5 to about 2 mole equivalents with respect to the compound of Formula III.

In general, the reaction at step (b) is carried out in presence of an amine protecting agent selected from tert-butyl carbonate (Boc anhydride), fluorenylmethyloxycarbonyl chloride (Fmoc-Cl), 9-fluorenylmethylsuccinimidyl carbonate (Fmoc-OSu), benzyl chloroformate (Cbz-Cl), dibenzyl pyrocarbonate (Cbz anhydride), acetyl chloride, acetic anhydride, trifluoroacetic anhydride (TFAA), phthalic anhydride, benzyl chloride, triphenylmethyl chloride, and tosyl chloride. In particular, the amine protecting agent used at step (b) is tert-butyl carbonate (Boc anhydride).

In another embodiment, the hydrolysis at step (c) is carried out by treating the compound of Formula II with one or more acids selected from acetic acid, citric acid, hydrobromic acid, hydrochloric acid, sulfuric acid and nitric acid. In particular, the acid is hydrochloric acid.

In another embodiment, the present invention provides the process for preparation of a compound of Formula I, or a salt, or hydrate thereof, wherein the compound of Formula III and II are not isolated.

In another embodiment, the compound Formula I obtained at step (c) is in the form of monohydrochloride monohydrate.

In another embodiment, the compound Formula IV used at step (a) is prepared by a process comprising:
(i) treating a compound of Formula VI or a salt thereof,

with n-butyl lithium in one or more solvent to obtain a reaction mixture; and
(ii) reacting the reaction mixture of step (i) with iodine.

In general, the solvent at step (i) is selected from one or more of 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, toluene, xylene, or mixtures thereof. In particular, the solvent is tetrahydrofuran.

In another general aspect, the present invention provides a process for the preparation of a compound of Formula I, or a salt, or a hydrate thereof, the process comprising:
(a) reacting a compound of Formula IV, or a salt thereof,

with a compound of Formula V,

in presence of a transition metal catalyst and one or more base in one or more solvent,
to obtain a compound of Formula III;

and
(b) converting the compound of Formula III to the compound of Formula I, or a salt, or a hydrate thereof;
wherein the transition metal catalyst at step (a) is selected from Pd(dppf)Cl2, Pd(dppf)Cl2.DCM, Pd(PPh3)4, Pd2(dba)3, and Xphos-Pd-G2.

The step (a) of the above process can be carried out by following the process as already described supra.

The compound of Formula III can be converted to the compound of Formula I, or a salt, or hydrate thereof by following the process as already described supra.

The compound of Formula I or a salt or hydrate thereof obtained by the process of the present invention can further be converted to the compound of Formula VII.

The compound of Formula I or a salt, or hydrate thereof can be converted to the compound of Formula VII by following the process as disclosed in International (PCT) Publication no. WO 2019/049021 A1.

Thus, in another general aspect, the present invention provides a process for the preparation of a compound of Formula VII,

the process comprising:
(a) treating a compound of Formula VI or a salt thereof,

with n-butyl lithium in one or more solvent to obtain a reaction mixture;
(b) reacting the reaction mixture of step (a) with iodine to obtain a compound of Formula IV, or a salt thereof;

(c) reacting the compound of Formula IV, or a salt thereof,

with a compound of Formula V,

in presence of a transition metal catalyst and one or more base in one or more solvent,
to obtain a compound of Formula III;

(d) reacting the compound of Formula III with diphenylmethanimine in presence of a transition metal catalyst, and one or more base in one or more solvent, to obtain a compound of Formula II;

(e) hydrolyzing the compound of Formula II to obtain the compound of Formula I or a salt or hydrate thereof; and

(f) converting the compound of Formula I or a salt, or hydrate thereof to the compound of Formula VII;
wherein the transition metal catalyst at step (c) and step (d) is independently selected from Pd(dppf)Cl2, Pd(dppf)Cl2.DCM, Pd(PPh3)4, Pd2(dba)3, and Xphos-Pd-G2.
The product(s) obtained by the process of the present invention may further be purified to obtain them in purer forms. The product(s) obtained may further be dried additionally to achieve the desired level of moisture and/or residual solvents.

The product(s) obtained may further be converted to any other physical forms thereof which includes but not specifically limited to polymorph(s), salt(s), solvate(s), or hydrate(s); and crystalline or amorphous forms thereof.

The present invention is further illustrated by the following examples which is provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modification and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. The examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to limit its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those of ordinary skill in the art and are described in various publications.
Examples
Example 1: Preparation of 6-chloro-3-fluoro-4-iodo-2-methylpyridine (Compound of Formula IV):

To a 4-Neck 100 ml Round bottom flask, 6-chloro-3-fluoro-2-methylpyridine (5.0 g, 0.0344 mol) and THF (30 mL, 6V) were added under nitrogen atmosphere. The Reaction mixture was cooled at -65 °C to -80 °C using acetone dry ice fusion mixture. To this mixture 23% solution of n-butyl lithium in hexane (2.64 g, 0.0412 mol) were added within 30 min at -65 °C to -80 °C under nitrogen atmosphere and further reaction mass were stirred for 20-30 min at this temperature, followed by the addition of solution of iodine (9.15 g, 0.0361 mol) in THF (30mL, 6V) into the reaction at -65 °C to -80 °C temperature followed by stirring for 30 minutes. Upon completion of the reaction, the reaction mixture was added into aq. solution of 10% sodium thiosulphate (30 mL, 6V) and reaction was stirred for 1 hour, followed by solvent distillation under vacuum. The final product was filtered and was dried off to afford the desired product 8.2 g (Yield: 88%, Purity: 99%).
Example 2: Preparation of 6-chloro-4-cyclopropyl-3-fluoro-2-methylpyridine (Compound of Formula III):

To a 4-Neck 250 ml round bottom flask, toluene (40 mL, 8V), 6-chloro-3-fluoro-4-iodo-2-methylpyridine (5.0 g, 0.0184 mol), cyclopropyl boronic acid (1.74 g, 0.0203 mol) and potassium phosphate tribasic monohydrate (8.5 g, 0.0368 mol) were added under nitrogen atmosphere. To this mixture catalyst [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.074 g, 0.101 mmol) was added and the resultant reaction mixture was heated at 95-105 °C temperature. The reaction mixture was stirred for 4 hours at this temperature. Upon completion, the reaction mixture was allowed to cool and water (25 mL, 5V) was added. The reaction mixture was filtered over hyflo bed and layers were separated. The organic layer containing titled compound was taken for next conversion.
Example 3: Preparation of N-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-l, l-diphenyl-methanimine (Compound of Formula II):

To a round bottom flask, 6-chloro-4-cyclopropyl-3-fluoro-2-methylpyridine in toluene and Diphenylmethanimine (3.67 g, 0.02026 mol) were added, followed by the addition of BOC anhydride (1.21 g, 5.52 mmol), [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium (II) (67.4 mg, 0.09 mmol) under nitrogen atmosphere. To this, sodium-tert-butoxide (3.54 g, 0.0368 mol) was added and the resultant reaction mixture was heated at 95 °C to 105 °C under nitrogen atmosphere. Upon completion of reaction, the reaction mixture was cooled to 25 °C to 35 °C followed by the addition of water (25 mL). The reaction mixture was then filtered over hyflo bed and layers were separated. The organic layer containing titled compound was taken for next reaction.

Example 4: Preparation of 4-cyclopropyl-5-fluoro-6-methylpyridin-2-amine hydrochloride monohydrate (Compound of Formula I as monohydrochloride monohydrate):

To a round bottom flask, N-(4-cyclopropyl-5-fluoro-6-methylpyridin-2-yl)-l, l-diphenylmethanimine, water (45 mL) and conc. HCl (4 mL) were added and the reaction mixture was stirred for 2 hours at 25 °C to 35 °C. Upon completion of the reaction, layers were separated. The aqueous layer was treated with methylene dichloride and pH was adjusted to 8 to 10 using sodium carbonate solution, stirred for 15 min and layers were separated. The aqueous layer was extracted with methylene dichloride and acidified with aqueous HCl. The solvent was distilled completely, and acetonitrile (10 mL) was added. The reaction mixture was stirred for 1 hour at 25 °C to 35 °C. The crystallized product was filtered off and dried under vacuum to obtain title compound as a yellow crystalline monohydrate monohydrochloride, solid 2.8 g (Yield: 69%, Purity: 99%).

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
,CLAIMS:We Claim:
1. A process for the preparation of a compound of Formula I, or a salt, or a hydrate thereof,

the process comprising:
(a) reacting a compound of Formula IV, or a salt thereof,

with a compound of Formula V,

in the presence of a transition metal catalyst and one or more base in one or more solvent,
to obtain a compound of Formula III,

(b) reacting the compound of Formula III, with diphenylmethanimine in the presence of a transition metal catalyst, and one or more base in one or more solvent, to obtain a compound of Formula II,
; and
(c) hydrolysing the compound of Formula II to obtain the compound of Formula I or a salt or hydrate thereof,
wherein the transition metal catalyst at step (a) and step (b) is independently selected from [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(Pd(dppf)Cl2), bis(diphenylphosphino)ferrocene]dichloropalladium(II).DCM (Pd(dppf)Cl2.DCM), palladium-tetrakis(triphenylphosphine) (Pd(PPh3)4), tris(dibenzylideneacetone)dipalladium (0) (Pd2(dba)3), and Xphos-Pd-G2.
2. The process as claimed in claim 1, wherein the solvent at step (a) is selected from one or more of toluene, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, xylene, or mixtures thereof; and the base is selected from one or more of potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, potassium phosphate, 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), 1,1,3,3-tetramethyl guanidine (TMG), or mixtures thereof.
3. The process as claimed in claim 1, wherein the solvent at step (b) is selected from one or more of toluene, acetonitrile, 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, xylene, or mixtures thereof; and the base is selected from one or more of potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, potassium phosphate, sodium tert-butoxide, potassium tert-butoxide, 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), 1,1,3,3-tetramethyl guanidine (TMG), or mixtures thereof.
4. The process as claimed in claim 1, wherein the transition metal catalyst at step (a) is selected from Pd(dppf)Cl2, Pd(dppf)Cl2.DCM, and Pd(PPh3)4 and the reaction at step (a) is carried out for a time of about 30 minutes to 120 minutes.
5. The process as claimed in claim 1, wherein the transition metal catalyst at step (a) or step (b) is used in an amount ranging from about 0.01 to about 0.001 mole equivalent.
6. The process as claimed in claim 1, wherein the compound of Formula II and compound of Formula III are not isolated.
7. The process as claimed in claim 1, wherein the compound of Formula IV or a salt thereof is prepared by a process comprising:
(i) treating a compound of Formula VI or a salt thereof,

with n-butyl lithium in one or more solvent to obtain a reaction mixture, and
(ii) reacting the reaction mixture of step (i) with iodine.
8. The process as claimed in claim 7, wherein the solvent is selected from one or more of 1,4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, or mixtures thereof.
9. The process as claimed in claim 1, wherein the hydrolysis at step (c) is carried out by treating the compound of Formula II with one or more acid selected from hydrochloric acid, sulfuric acid, and nitric acid.
10. The process as claimed in claim 1, wherein the compound of Formula I obtained is in the form of monohydrochloride monohydrate.
11. The process as claimed in claim 1, wherein the reaction at step (b) is carried out in the presence of an amine protecting agent selected from tert-butyl carbonate (Boc anhydride), fluorenylmethyloxycarbonyl chloride (Fmoc-Cl), 9-fluorenylmethylsuccinimidyl carbonate (Fmoc-OSu), benzyl chloroformate (Cbz-Cl), dibenzyl pyrocarbonate (Cbz anhydride), acetyl chloride, acetic anhydride, trifluoroacetic anhydride (TFAA), phthalic anhydride, benzyl chloride, triphenylmethyl chloride, and tosyl chloride.
12. The process as claimed in claim 1, wherein the compound I or a salt or hydrate thereof is further converted to a compound of Formula VII,

or a pharmaceutically acceptable salt thereof.
13. A process for the preparation of a compound of Formula I, or a salt, or a hydrate thereof,

the process comprising:
(a) reacting a compound of Formula IV, or a salt thereof,

with a compound of Formula V,

in the presence of a transition metal catalyst and one or more base in one or more solvent,
to obtain a compound of Formula III,

wherein the transition metal catalyst is selected from [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II)(Pd(dppf)Cl2), bis(diphenylphosphino)ferrocene]dichloropalladium(II).DCM (Pd(dppf)Cl2.DCM), palladium-tetrakis(triphenylphosphine) (Pd(PPh3)4), tris(dibenzylideneacetone)dipalladium (0) (Pd2(dba)3), and Xphos-Pd-G2; and
(b) converting the compound of Formula III to the compound of Formula I, or a salt, or a hydrate thereof.

Dated this 21st day of March 2025

DR. AMAR RAJENDRA DESAI [IN/PA-2842]
Sr. GENERAL MANAGER
ZYDUS LIFESCIENCES LIMITED