DESC:Related Patent Applications:

This application claims priority to and benefits from Indian provisional patent application No. 202341064703 filed on September 26, 2023; the disclosure of which is incorporated herein by reference.

Field of the Invention

The present invention relates to a novel process for the preparation of omidenepag isopropyl. Particularly, the invention relates to an alternative and an improved process for preparation of omidenepag isopropyl.

Background of the Invention

Omidenepag isopropyl is chemically known as glycine, N-[6-[[[[4-(1H-pyrazol-1-yl) phenyl] methyl]-(3-pyridinylsulfonyl) amino] methyl]-2-pyridinyl]-1-methyl-ethyl-ester having the formula as mentioned below.

Omidenepag isopropyl was first approved in Japan on 2018 and then in USA on 2022 for the treatment of the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. Omidenepag isopropyl is a non-prostaglandin topical ocular hypotensive agent behaves as a selective E-prostanoid subtype 2 (EP2) receptor agonist. This drug avoids the prostaglandin-associated periorbitopathy related side effects caused by prostaglandin latonoprost and bimatoprost. The active metabolite omidenepag (OMD) of the drug is formed after the topical instillation and during corneal penetration.

The product omidenepag isopropyl was first disclosed in the Patent US 8648097. The Patent US 8648097 discloses the preparation of omidenepag isopropyl involving the steps of reacting N-[4-(1H-pyrazol-1-yl)-benzyl]-pyridine-3-sulfonamide with tert-butyl[tert-butoxycarbonyl-(6-hydroxymethyl-pyrdin-2-yl)-amino]acetate in the presence of N,N,N’,N’-tetramethylazodicarbxamide and tri-n-butyl-phosphine in tetrahydrofuran followed by the removal of the protecting group and addition of the isopropyl ester group in the presence of acid as mentioned below.

The Patent US 10428046 discloses the process for the preparation of omidenepag isopropyl from the reaction of N-[4-(1H-pyrazol-1-yl)-benzyl]-pyridine-3-sulfonamide with isopropyl-2-{[6-(chloromethyl)-pyridin-2-yl]-amino}-acetate in the presence of cesium carbonate in acetonitrile as mentioned below.

The Patent application US 20120226036 discloses the preparation of derivatives of omidenepag derivatives including the preparation of tert-butyl[6-aminomethyl-pyridin-2-yl)-tert-butoxycarbonylamino]acetate from ethyl-6-tert-butoxycarbonylaminopyridin-2-carboxylate; the preparation of tert-butyl(tert-butoxycarbonyl){6-[(pyridin-3-ylsulfonyl)aminomethyl]pyridine-2-yl}amino-acetate from the reaction of tert-butyl[6-aminomethyl-pyridin-2-yl)-tert-butoxycarbonylamino]acetate with 3-pyridyl-sufonyl-chloride; and the preparation of 6-{[4-pyrazol-1-yl)benzyl](pyrdin-3-ylsulfonyl)aminomethyl] pyrdin-2-yl}amino)acetic acid from the tert-butyl(tert-butoxycarbonyl){6-[(pyridin-3-ylsulfonyl)aminomethyl]pyridine-2-yl}aminoacetate.
The preparation of tert-butyl [6-aminomethyl-pyridin-2-yl)-tert-butoxycarbonyl-amino]acetate from ethyl-6-tert-butoxycarbonylaminopyridin-2-carboxylate as disclosed in the Patent application US 20120226036 as mentioned below.

The preparation of tert-butyl(tert-butoxycarbonyl){6-[(pyridin-3-ylsulfonyl)-aminomethyl] pyridine-2-yl}aminoacetate from the reaction of tert-butyl[6-aminomethyl-pyridin-2-yl)-tert-butoxycarbonylamino]acetate with 3-pyridyl-sufonyl-chloride as disclosed in the Patent application US 20120226036 is mentioned below.

The preparation of 6-{[4-pyrazol-1-yl) benzyl](pyrdin-3-ylsulfonyl)aminomethyl] pyrdin-2-yl}amino) acetic acid from the tert-butyl(tert-butoxycarbonyl){6-[(pyridin-3-ylsulfonyl) aminomethyl] pyridine-2-yl}aminoacetate as disclosed in the Patent application US 20120226036 is mentioned below.

The aforementioned process employs column chromatography and cumbersome work-up procedures after the reaction which is difficult in large scale productions.
Thus, there is a need to develop an alternative route in the preparation of omidenepag isopropyl that is simple at a large scale production with economically significance.

Objects of the Invention

The main object of the present invention is to provide a novel process for preparation of omidenepag isopropyl of compound of formula-I.

Another object of the present invention is to provide an improved process for preparation of compound of formula-III from compound of formula XI.

Another object of the present invention is to provide an improved process for preparation of formula-III from compound of formula XIV.

Summary of the Invention

The main aspect of the present invention is to provide a process for preparation of omidenepag isopropyl compound of formula-I,

comprising, the reaction of a compound of formula-III,

with a compound of formula-II; and

in presence of a base and a solvent to obtain a compound of formula-I,
wherein, R1 is an amino protecting group; and X is a halogen group selected from iodo, chloro, fluoro and bromo groups.

Wherein the base is selected from organic base and inorganic base.

In one aspect, the organic base is selected from the group comprising of heterocyclic compounds such as pyridine and diazabicycloundec-7-ene (DBU); amines such as diisopropylethylamine (DIPEA), N,N-dimethyl-4-amino-pyridine (DMAP), 1,8-, dicyclohexylamine (DCHA), triethylamine; organometallic agents such as butyllithium; organosilicon compounds such as Lithium bis(trimethylsilyl)amide and sodium hexamethyldisilazide or mixtures thereof.
In another aspect the inorganic base is selected from the group comprising of alkali or alkaline earth carbonates such as potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate and potassium bicarbonate; alkali or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide and calcium hydroxide; alkali or alkaline earth metal hydride sodium hydride and potassium hydride or mixtures thereof.

In another aspect, the solvent is selected from the group comprising of alcohols such as ethanol, methanol, propanol, n-butanol and tert-butanol, ethers such as tetrahydrofuran, diethylether, dioxan, dimethoxyethane isopropyl ether and methyl-tert-butyl-ether (MTBE), alkyl-hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as benzene, toluene and xylene, nitriles such as acetonitrile, propionitrile and butyronitrile, dimethyl formamide, dimethyl sulfoxides and dimethylacetamide or mixtures thereof.

In another aspect the invention provides a process for preparation of compound of formula-II, by halogenation of the isopropyl acetate compounds.

In one aspect the compound of formula-II, is prepared by halogenation of the isopropyl acetate compounds, preferably a halo substituted isopropyl acetate compound, more preferably isopropyl bromoacetate.

In another aspect the invention provides a process for preparation of compound of formula-III, from compound of formula XI, by a method illustrated herein below in Scheme-I:

Scheme-I
wherein, R1 and R2 are same or different amino protecting groups; and X is a halogen group selected from iodo, chloro, fluoro and bromo groups.

In yet another aspect the invention provides a process for preparation of compound of formula-III, from compound of formula XIV, by a method illustrated herein below in Scheme-II

Scheme-II

wherein, R1 and R2 are same or different amino protective groups; and X is any halogen group selected from iodo, chloro, fluoro and bromo groups.

In yet another aspect the invention provides a process for preparation of compound of formula-IV,

comprising, the reaction compound of formula-VI,

with the compound of formula-V,

in the presence of base and a solvent to form a compound of formula-IV;

wherein, R1 and R2 are same or different amino protective groups; and X is any halogen group selected from iodo, chloro, fluoro and bromo groups.

The amino protecting groups in process of the invention are selected from the group of 9-Fluorenylmethyloxycarbonylation (Fmoc), tert-Butoxycarbonylation (Boc) reagents, Allyloxycarbonylation (Alloc) reagents, Benzyloxycarbonylation (Cbz) reagents, Benzylation (Bn) reagents, Allylation (All) reagents, and 2,2,2-Trichloroethoxycarbonylation (Troc) reagents or mixtures thereof.

In one aspect of the invention, the amino protecting group is preferably tert-Butoxycarbonylation (Boc) reagents, more preferably mono or di-tert-butyl decarbonate.

In another aspect the invention provides a process for preparation of compound of formula I comprising an Impurity-A less than about 2% by HPLC
.

In another aspect the invention provides a process for preparation of compound of formula I comprising an Impurity-A less than about 0.1% by HPLC.

Another aspect of the invention is to provide a compound of formula I having a purity of more than 99% by HPLC.

Yet another aspect of the present invention is to provide the composition of omidenepag isopropyl comprising an impurity-A, less than 0.1% by HPLC.

Another aspect of the present invention is to provide a compound of formula I that is used in preparation of medicament.

Another aspect of the present invention is to provide the compound of formula I that is used for treating elevated intraocular pressure in patients.

Another aspect of the invention is to provide compounds of formula II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, & XIV, which are novel intermediates whose R1 and R2 are same or different amino protective groups; and X is any halogen group selected from iodo, chloro, fluoro and bromo groups, preferably formula IIa, IIIa, IVa, Va, VIa, VIIa, VIIIa, IXa, Xa, XI, XII, XIII, & XIV, are novel intermediates whose R1 and R2 are same or different amino protective groups; and X is any halogen group selected from iodo, chloro, fluoro and bromo groups.

Detailed Description of the Invention

The main embodiment of the present invention is to provide a process for preparation of omidenepag isopropyl compound of formula-I,

comprising, the reaction of a compound of formula-III,

with a compound of formula-II; and

in presence of a base and a solvent to obtain a compound of formula-I,
wherein, R1 is an amino protecting group; and X is a halogen group selected from iodo, chloro, fluoro and bromo groups.

Wherein the base is selected from organic base and inorganic base.

In one aspect, the organic base is selected from the group comprising of heterocyclic compounds such as pyridine and diazabicycloundec-7-ene (DBU); amines such as diisopropylethylamine (DIPEA), N,N-dimethyl-4-amino-pyridine (DMAP), 1,8-, dicyclohexylamine (DCHA), triethylamine; organometallic agents such as butyllithium; organosilicon compounds such as Lithium bis(trimethylsilyl)amide and sodium hexamethyldisilazide or mixtures thereof.
In another aspect the inorganic base is selected from the group comprising of alkali or alkaline earth carbonates such as potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate and potassium bicarbonate; alkali or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide and calcium hydroxide; alkali or alkaline earth metal hydride sodium hydride and potassium hydride or mixtures thereof.

In another aspect, the solvent is selected from the group comprising of alcohols such as ethanol, methanol, propanol, n-butanol and tert-butanol, ethers such as tetrahydrofuran, diethylether, dioxan, dimethoxyethane isopropyl ether and methyl-tert-butyl-ether (MTBE), alkyl-hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as benzene, toluene and xylene, nitriles such as acetonitrile, propionitrile and butyronitrile, dimethyl formamide, dimethyl sulfoxides and dimethylacetamide or mixtures thereof.

In another aspect the invention provides a process for preparation of compound of formula-II, by halogenation of the isopropyl acetate compounds.

In one aspect the compound of formula-II, is prepared by halogenation of the isopropyl acetate compounds, preferably a halo substituted isopropyl acetate compound, more preferably isopropyl bromoacetate.

In another aspect the invention provides a process for preparation of compound of formula-III, from compound of formula XI, by a method illustrated herein below in Scheme-1:

Scheme-1
wherein, R1 and R2 are same or different amino protecting groups; and X is a halogen group selected from iodo, chloro, fluoro and bromo groups.

In yet another aspect the invention provides a process for preparation of compound of formula-III, from compound of formula XIV, by a method illustrated herein below in Scheme-2

Scheme-2

wherein, R1 and R2 are same or different amino protective groups; and X is any halogen group selected from iodo, chloro, fluoro and bromo groups.

In yet another aspect the invention provides a process for preparation of compound of formula-IV,

comprising, the reaction compound of formula-VI,

with the compound of formula-V,

in the presence of base and a solvent to form a compound of formula-IV;

wherein, R1 and R2 are same or different amino protective groups; and X is any halogen group selected from iodo, chloro, fluoro and bromo groups.

The amino protecting groups in process of the invention are selected from the group of 9-Fluorenylmethyloxycarbonylation (Fmoc), tert-Butoxycarbonylation (Boc) reagents, Allyloxycarbonylation (Alloc) reagents, Benzyloxycarbonylation (Cbz) reagents, Benzylation (Bn) reagents, Allylation (All) reagents, and 2,2,2-Trichloroethoxycarbonylation (Troc) reagents or mixtures thereof.

In one aspect of the invention, the amino protecting group is preferably tert-Butoxycarbonylation (Boc) reagents, more preferably mono or di-tert-butyl decarbonate.

In another aspect the invention provides a process for preparation of compound of formula I comprising an Impurity-A less than about 2% by HPLC
.

In another aspect the invention provides a process for preparation of compound of formula I comprising an Impurity-A less than about 0.1% by HPLC.

Another aspect of the invention is to provide a compound of formula I having a purity of more than 99% by HPLC.

Yet another aspect of the present invention is to provide the composition of omidenepag isopropyl comprising an impurity-A, less than 0.1% by HPLC.

Another aspect of the present invention is to provide a compound of formula I that is used in preparation of medicament.

Another aspect of the present invention is to provide the compound of formula I that is used for treating elevated intraocular pressure in patients.

Another embodiment of the present invention is to provide the process for the preparation of omidenepag isopropyl as in Scheme-3 as mentioned below:

A preferred embodiment of the present invention is to provide a process for the preparation of omidenepag isopropyl as in Scheme-4 as mentioned below:

Another aspect of the invention is to provide compounds of formula II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, & XIV, which are novel intermediates whose R1 and R2 are same or different amino protective groups; and X is any halogen group selected from iodo, chloro, fluoro and bromo groups, preferably formula IIa, IIIa, IVa, Va, VIa, VIIa, VIIIa, IXa, Xa, XI, XII, XIII, & XIV, are novel intermediates whose R1 and R2 are same or different amino protective groups; and X is any halogen group selected from iodo, chloro, fluoro and bromo groups.

The present invention provides omidenepag isopropyl having a purity of more than 99% by HPLC. Certain specific aspect and embodiment of the present invention will be explained in 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 invention in any manner.

Examples of the Invention

Example-1: Preparation of 2-(Di-tert-butyloxycarbonyl)-amino-6-methylpyridine of formula-Xa:

A solution of 2-amino-6-methyl-pyridine of formula-XI (100 gm) in di-tert-butyl decarbonate (264 gm) was heated to 60? for 10 hours. The reaction mixture was cooled to 30? and then di-tert-butyl decarbonate (605.4 gm) and 4-dimethylaminopyridine solution (395.5 gm of 4-dimethylaminopyridine in 2750 ml of tetrahydrofuran) were added slowly and stirred for 3-5 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was treated with 1M aqueous ammonium chloride (1000 ml) and the formed product was extracted with ethyl acetate (1500 ml). The extracted ethyl acetate layer washed with 5% aqueous sodium bicarbonate solution (500 ml); 1M ammonium chloride solution (1000 ml) and brine solution (1000 ml). The washed layer was concentrated under vacuum to form a residue. The residue was mixed with hexane (200 ml); then stirred for 30 minutes and filtered. The solid obtained by filtration was mixed with water (1000 ml) at 30? and stirred for 1 hour at the same temperature. The resultant solid was filtered and dried. Yield: 239 gm.

Example-2: Preparation of 2-(di-tert-butyloxycarbonyl)-amino-6-(bromomethyl)-pyridine of formula IXa:

Step-A: To a solution of 2-(di-tert-butyloxycarbonyl)-amino-6-methylpyridine of formula-Xa (150 gm) and N-bromosuccinamide (138.5 gm) in carbontetrachloride (750 ml); azobisisobutyronitrile (7.98 gm) was added at room temperature. The reaction mixture was heated to 70-75? for 10 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to room temperature and filtered. The obtained filtrate was washed with water (3 x 450 ml) and concentrated under vacuum to obtain a residue. The residue was mixed with n-hexane (350 ml) at 15? and stirred for 1.5 hours at the same temperature. The resultant solid was filtered and dried at 45?. Yield: 167 gm.

Step-B: To a solution of the product obtained in step-A (157 gm) in anhydrous tetrahydrofuran (750 ml), diisopropylethylamine (81.73 gm) and diethyl phosphite (87.3 gm) was added successively at 5-10?. The reaction mixture was allowed to reach the room temperature and then stirred for 8 hours at the same temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass filtered and concentrated under vacuum to obtain a residue. The obtained residue was mixed with ethyl acetate (750 ml) and co-distilled with hexane (150 ml); followed by mixing with diisopropyl ether (150 ml). The contents were stirred for 1 hour at 0 to 10?. The resultant solid was filtered and dried. Yield: 101 gm.

Example-3: Preparation of 2-(di-tert-butyloxycarbonyl)-amino-6-(azidomethyl)-pyridine of formula-VIIIa:

To a solution of 2-(di-tert-butyloxycarbonyl)-amino-6-(bromomethyl)-pyridine of formula-IXa (100 gm) in dimethylformamide (200 ml), sodium azide (20.14 gm) was added at room temperature and heated to 50?. The reaction mixture was then maintained for 4 hours at 50?. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to room temperature followed by the addition of the water (600 ml). The contents were stirred for 5 hours. The resultant solid was filtered, dried under vacuum at 40-45? for 5 hours. Yield: 82 gm.

Example-4: Preparation of 2-(di-tert-butyloxycarbonyl)-amino-6-(aminomethyl)-pyridine of formula-VIIa:

To a solution of 2-(di-tert-butyloxycarbonyl)-amino-6-(azidomethyl)-pyridine of formula-VIIIa (20 gm) in methanol (200 ml), 10% of palladium-carbon (2 gm) was added and applied 3 kg of hydrogen atmosphere for about 1-2 hours at room temperature. The progress of the reaction was monitored by TLC. After completion of the completion of the reaction, the reaction mass was filtered through hyflo. The filtrate was concentrated to obtain a residue. Yield: 18 gm.

Example-5: Preparation of 2-(di-tert-butyloxycarbonyl)-amino-6-((pyridine-3-sulfonamido) methyl)pyridine of formula-Via:
Step-A:

To a solution of 2-(di-tert-butyloxycarbonyl)-amino-6-(azidomethyl)-pyridine of formula-VIIIa (50 gm) in ethylacetate (750 ml), 10% of palladium-carbon (5 gm) was added and applied 3 kg of hydrogen atmosphere for about 1-2 hours at room temperature. The progress of the reaction was monitored by TLC. After completion of the completion of the reaction, the reaction mass was filtered through hyflo.

Step-B:

To the filtrate obtained in step-A containing 2-(di-tert-butyloxycarbonyl)-amino-6-(aminomethyl)-pyridine of formula-VIIa, triethylamine (28.95 gm) and pyridine-3-sulfonyl-chloride (21.6 gm) was added at 0-5? and stirred for 0.5 to 1 hour. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was washed with water (2 x 450 ml) and treated with activated carbon (2.5 gm). The treated reaction mass was filtered and dried over sodium sulphate (5 gm). The dried reaction mass was concentrated to obtain a residue. The residue was mixed with methyl-tert-butyl-ether (250 ml) and stirred for 2 hours at 25-30?. The resultant solid was filtered; washed with methyl-tert-butyl-ether (50 ml) and dried. Yield: 53.5 gm.

Example-6: Preparation of 2-(di-tert-butyloxycarbonyl)-amino-6-((pyridine-3-sulfonamido) methyl) pyridine of formula-VIa:

To a solution of 2-(di-tert-butyloxycarbonyl)-amino-6-(aminomethyl)-pyridine of formula-VIIa (17.5 gm) in dichloromethane (175 ml), triethylamine (10.9 gm) and pyridine-3-sulfonyl-chloride (8.16 gm) was added at 0-5? and stirred for 30 minutes. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was washed with water (2 x 53 ml) and dried over sodium sulphate (2 gm). The washed reaction mass was concentrated to obtain a residue. The residue was mixed with methyl-tert-ether (88 ml) at 30-35? and then stirred for 30 minutes at the same temperature. The resultant solid was filtered and dried. Yield: 18.7 gm.

Example-7: Preparation of N-(4-(1H-pyrazol-1-yl)-benzyl)-N-((6-di-tert-butyloxycarbonyl-amino)pyridin-2-yl)methyl)pyridine-3-sulfonamide of formula-IVa:

To a solution of 2-(di-tert-butyloxycarbonyl)-amino-6-((pyridine-3-sulfonamido) methyl)pyridine of formula-VIa (40 gm) in acetonitrile (500 ml), cesium carbonate (62 gm) and 1-(4-bromomethylphenyl)-1H-pyrazole of formula Va (20.41 gm) were added at room temperature and stirred for 0.5-1 hour at the same temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was filtered and the filtrate was concentrated under vacuum to obtain a residue. To the obtained residue, ethyl acetate (240 ml) was added and stirred to form a clear solution. The formed solution was washed with water (2 x 80 ml) twice and brine solution (80 ml); and concentrated under vacuum to obtain a residue. The obtained residue was crystallized with methyl-tert-butyl-ether (160 ml). The resultant solid was filtered and dried. Yield: 48.5 gm.

Example-8: Preparation of N-(4-(1H-pyrazol-1-yl)-benzyl)-N-((6-aminopyridin-2-yl)methyl)-pyridine-3-sulfonamide hydrochloride:

To solution of N-(4-(1H-pyrazol-1-yl)-benzyl)-N-((6-di-tert-butyloxycarbonyl-amino)pyridin-2-yl)methyl)pyridine-3-sulfonamide of formula-IVa (3.2 gm) in tetrahydrofuran (25 ml), 30-35% of aqueous hydrochloric acid (11 ml) was added at 0-5?. The reaction mixture was heated to 65-70? and maintained for 1 hours at the same temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was basified using saturated aqueous sodium bicarbonate solution (93 ml) and extracted twice with ethylacetate (2 x 100 ml). The extracted ethyl acetate solution was washed with water (100 ml) and concentrated under vacuum to obtain a residue. The residue was mixed methyl tert-butyl-ether (15 ml) at 30? and stirred for 30 minutes. The resultant solid was filtered and dried. Yield: 48.5 gm.

Example-9: Preparation of tert-butyl-[6-{(N-(4-(1H-pyrazol-1-yl)-benzyl)-pyridine-3-sulfonamido)-methyl}-pyridine-2-yl]-carbamate of formula-IIIa:

To solution of N-(4-(1H-pyrazol-1-yl)-benzyl)-N-((6-di-tert-butyloxycarbonyl-amino)pyridin-2-yl)methyl)pyridine-3-sulfonamide of formula-IVa (20 gm) in a mixture of methanol (10 ml), tetrahydrofuran (100 ml) and water (10 ml), lithium hydroxide monohydrate (3.10 gm) was added at 30±5?. The reaction mixture was heated to 50? and maintained about 3.5 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to 30?. To the cooled reaction mass, saturated ammonium chloride solution (28 gm of ammonium chloride in 75 ml of water) was added followed the addition of ethylacetate (100 ml) to form a biphasic mixture. The organic layer was separated washed with ammonium chloride solution (19 gm of ammonium chloride in 50 ml of water); and sodium chloride solution (24 gm of sodium chloride in 80 ml of water) at 25-30?. The washed organic layer was treated with activated carbon (2 gm) and filtered. The filtrate was concentrated to obtain a residue. The obtained residue was mixed with isopropyl ether (100 ml) at 25-30? and stirred for 30 minutes at the same temperature. The resulting solid was filtered; and dried at 50? under vacuum. Yield: 14.4 gm.

Example-10: Preparation of Omidenepag isopropyl of formula-I:

Step-A: To a solution of tert-butyl-[6-{(N-(4-(1H-pyrazol-1-yl)-benzyl)-pyridine-3-sulfonamido)-methyl}-pyridine-2-yl]-carbamate of formula-IIIa (5 gm) in dimethylformamide (50 ml), sodium hydride (0.71gm) was added at 0-5? about 15 minutes. The reaction mixture was warmed to 25-35? and stirred for 1 hour at the temperature. The reaction was then cooled to 0-10?, followed by the addition of isopropyl bromoacetate of formula-IIa (2.1 gm) at 0-10?. The temperature of reaction mixture was raised to 140? and maintained for 22 hours. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mass was cooled to room temperature and then quenched with water (30 ml). The reaction mass was then extracted ethyl acetate (3 x 100 ml) and the combined extracts were washed with aqueous sodium chloride solution (300 ml). The washed organic extract was treated with activated carbon (5 gm) and filtered; dried over sodium sulphate (15 gm). The dried extract was concentrated under vacuum to yield oily compound. Yield: 3.6 gm.

Step-B: To the oil compound obtained in step-A (3.6 gm), toluene (40 ml) and 1M hydrochloric acid solution (30 ml) was added and stirred for 30 minutes to form a biphasic mixture. The aqueous layer was separated from the biphasic mixture. Toluene (40 ml) was added to the separated aqueous layer to form a biphasic mixture; followed by the neutralization of the aqueous layer of the biphasic mixture with 2M sodium hydroxide solution (15 ml). The biphasic mixture was then heated to 40? and stirred for 1 hour at the temperature. The stirred biphasic mixture was allowed to settle, and the organic layer was separated. The separated organic layer was washed with water (2 x 25 ml) and treated with activated carbon (0.5 gm). The treated organic layer was filtered. The filtrate was concentrated to obtain a residue. The obtained residue was mixed with isopropyl alcohol (10 ml) stirred at room temperature for 30 minutes, then cooled to 6-10? and stirred for 1 hour at the same temperature. The resultant solid filtered and dried under vacuum at 50?. Yield: 1.4 gm; Purity: 99.0% by HPLC; Content of Impurity-A: 0.20% by HPLC.

Example-11: Preparation of 2-(di-tert-butyloxycarbonyl)-amino-6-((pyridine-3-sulfonamido) methyl)pyridine of formula-VIa:

Step -A : To a solution of 2-(di-tert-butyloxycarbonyl)-amino-6-(bromomethyl)-pyridine of formula-IXa (4 gm) in methanol (300 ml) at 10-20°C, 3-5 kg of ammonia gas was applied maintaining the temperature not to exceed 30°C. The reaction mixture was stirred for 1.5 hours and maintaining the temperature not to exceed 30°C. The progress of the reaction was monitored by TLC. After completion of reaction, the excess ammonia in the reaction mass was degassed by nitrogen pressure for 1 hour. The degassed reaction mass was concentrated under vacuum to obtain a residue. Yield: 4.1 gm.

Step B: The residue obtained in step-A (3.6 gm) was dissolved in dichloromethane (30 ml), followed by the addition of triethylamine (2.19 gm). The rection mixture was cooled to 0-5°C. To the cooled reaction mixture, pyridine-3-sulfonyl-chloride (1.63 gm) was slowly added at 0-5°C and stirred for 1 hour at the same temperature. The progress of the reaction was monitored by TLC. After completion of the reaction, dichloromethane (75 ml) and water (25ml) were added to the reaction mass to form a biphasic mixture and then warmed to 25-30°C. The organic layer was separated from the biphasic mixture. The separated organic layer was washed with water (25 ml) and dried over sodium sulphate (2 gm). The dried organic layer was concentrated to obtain a residue. The residue was mixed with methyl-tert-ether (20 ml); and stirred for 30 minutes at 25-30°C. The resultant solid was filtered and dried. Yield: 2.2 gm.

Example-12: Preparation of Omidenepag isopropyl of formula-I:

Step-A: To a solution of tert-butyl-[6-{(N-(4-(1H-pyrazol-1-yl)-benzyl)-pyridine-3-sulfonamido)-methyl}-pyridine-2-yl]-carbamate of formula-IIIa (25 gm) in dimethylformamide (200 ml), sodium hydride (3.6 gm) was added at 0-5? about 15 minutes. The reaction mixture was warmed to 25-35? and stirred for 1 hour. The reaction mixture was then cooled to 0-10? followed by the addition of isopropyl bromoacetate of formula-IIa (11.3 gm) at the same temperature. The temperature of reaction mixture was raised to 140? and maintained for 22 hours at the same temperature. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mass was cooled to room temperature and then quenched with water (120 ml). The reaction mass was then extracted ethyl acetate (3 x 200 ml). Th combined extracts were washed with saturated sodium chloride solution (4 x 100 ml) and treated with activated carbon (6.5 gm). The treated extract was filtered; and dried over sodium sulphate (25 gm). The dried extract was concentrated under vacuum to yield an oily compound. Yield: 23.4 gm.

Step-B: To the oil compound obtained in step-A (23.4gm), toluene (200 ml) and 1M hydrochloric acid solution (150 ml) was added and stirred for 30 minutes to form a biphasic mixture. The aqueous layer was separated from the biphasic mixture. To the separated aqueous layer, toluene (50 ml) was added to the to form a biphasic mixture; followed by the neutralization of the aqueous layer of the biphasic mixture with 2M sodium hydroxide solution (70 ml). To the biphasic mixture containing the neutralized aqueous layer, toluene (150 ml) was added. The biphasic mixture was then heated to 40? and stirred for 1 hour at the same temperature. The stirred biphasic mixture was allowed to settle, and the organic layer was separated. The separated organic layer was washed with water (2 x 125 ml) and then treated with activated carbon (2.5 gm). The treated organic layer was filtered. The filtrate was concentrated under vacuum to obtain a residue. The obtained residue was mixed with isopropyl alcohol (60 ml); then heated to 60°C. The heated contents were stirred about 1 hour at 60°C and then cooled to room temperature for 30 minutes. The cooled contents were further cooled to 6-10? and stirred for 1 hour at the same temperature. The resultant solid filtered and dried under vacuum at 50?. Yield: 13.5 gm; Purity: 98.4% by HPLC; content of Impurity-A: 0.08% by HPLC; and the content of Impurity-B: 1.17% by HPLC.

Example-13: Preparation of Omidenepag isopropyl of formula-I:

Step-A: To a solution of tert-butyl-[6-{(N-(4-(1H-pyrazol-1-yl)-benzyl)-pyridine-3-sulfonamido)-methyl}-pyridine-2-yl]-carbamate of formula-IIIa (40 gm) in dimethylformamide (320 ml), Sodium hydride (5.8gm) was added at 0-5? about 15 minutes under nitrogen atmosphere. The reaction mixture was warmed to 25-35? and stirred for 1 hour at the same temperature. The reaction mixture was then cooled 0-10?, followed by the addition of isopropyl bromoacetate of formula-IIa (18 gm) at 0-10?. The temperature of reaction mixture was raised to 140? and maintained for 20-22 hours at the same temperature. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mass was cooled to room temperature and then quenched with water (200ml). The reaction mass was then extracted ethyl acetate (4 x 200 ml) and the combined extracts were washed with saturated sodium chloride solution (3 x2 50 ml). The washed organic extract was treated with activated carbon (10 gm) and filtered; dried over sodium sulphate (25 gm). The dried extract was concentrated under vacuum to yield an oily compound. Yield: 37 gm.

Step-B: To the oil compound obtained in step-A (37gm) was mixed with isopropyl alcohol (70 ml) and heated to 60°C. The heated contents were stirred for 1hour at 60°C. The stirred contents were cooled to room temperature. The cooled contents were further cooled to 10-15°C and stirred 2 hours at the same temperature. The resultant solid was filtered and dried under vacuum at 50°C. Yield: 23 gm; Purity: 99.4 % by HPLC; Content of Impurity-A: 0.17% by HPLC.
,CLAIMS:
1. A process for preparation of omidenepag isopropyl compound of formula-I,

comprising, the reaction of a compound of formula-III,

with a compound of formula-II;

in presence of a base and a solvent to obtain a compound of formula-I,
wherein, R1 is an amino protecting group; and X is a halogen group selected from iodo, chloro, fluoro and bromo groups.

2. The process as claimed in claim 1, wherein the base is selected from the group comprising of organic base and inorganic base.

3. The process as claimed in claim 2, wherein the organic base is selected from the group comprising of heterocyclic compounds such as pyridine and diazabicycloundec-7-ene (DBU); amines such as diisopropylethylamine (DIPEA), N,N-dimethyl-4-amino-pyridine (DMAP), 1,8-, dicyclohexylamine (DCHA), triethylamine; organometallic agents such as butyllithium; organosilicon compounds such as Lithium bis(trimethylsilyl)amide and sodium hexamethyldisilazide or mixtures thereof.

4. The process as claimed in claim 2, wherein the inorganic base is selected from the group comprising of alkali or alkaline earth carbonates such as potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate and potassium bicarbonate; alkali or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide and calcium hydroxide; alkali or alkaline earth metal hydride sodium hydride and potassium hydride or mixtures thereof.

5. The process as claimed in claim 1, wherein the solvent is selected from the group comprising of alcohols such as ethanol, methanol, propanol, n-butanol and tert-butanol, ethers such as tetrahydrofuran, diethylether, dioxan, dimethoxyethane isopropyl ether and methyl-tert-butyl-ether (MTBE), alkyl-hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as benzene, toluene and xylene, nitriles such as acetonitrile, propionitrile and butyronitrile, dimethyl formamide, dimethyl sulfoxides and dimethylacetamide or mixtures thereof.

6. The process as claimed in claim 1, wherein the compound of formula-II is prepared by halogenation of the isopropyl acetate compounds.

7. The process as claimed in claim 6, wherein the compound of formula-II, halo substituted isopropyl acetate compound is preferably isopropyl bromoacetate.

8. The process as claimed in claim 1, wherein the compound of formula-III is prepared from compound of formula XI, by a method comprising the steps illustrated in below Scheme-1:

wherein, R1 and R2 are same or different amino protecting groups; and X is a halogen group selected from iodo, chloro, fluoro and bromo groups.

9. The process as claimed in claim 1, wherein the compound of formula-III is prepared from compound of formula XIV, by a method comprising the steps illustrated in below Scheme 2:

wherein, R1 and R2 are same or different amino protective groups; and X is any halogen group selected from iodo, chloro, fluoro and bromo groups.

10. A process for preparation of compound of formula-IV,

comprising, the reaction of compound of formula-VI,

with compound of formula-V,

in the presence of a base and a solvent to form a compound of formula-IV;

wherein, R1 and R2 are same or different amino protective groups; and X is any halogen group selected from iodo, chloro, fluoro and bromo groups.

11. The process as claimed in claim 10, wherein the base is selected from group comprising of organic base and inorganic base.

12. The process as claimed in the claim 11, wherein the organic base is selected from the group comprising of heterocyclic compounds such as pyridine and diazabicycloundec-7-ene (DBU); amines such as diisopropylethylamine (DIPEA), N,N-dimethyl-4-amino-pyridine (DMAP), 1, 8-, dicyclohexylamine (DCHA), triethylamine; organometallic agents such as butyllithium; organosilicon compounds such as Lithium bis(trimethylsilyl)amide and sodium hexamethyldisilazide or mixtures thereof.

13. The process as claimed in claim 11, wherein the inorganic base is selected from the group comprising of alkali or alkaline earth carbonates such as potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate and potassium bicarbonate; alkali or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide and calcium hydroxide; alkali or alkaline earth metal hydride sodium hydride and potassium hydride or mixtures thereof.

14. The process as claimed in claim 10, wherein the solvent is selected from the group comprising of alcohols such as ethanol, methanol and propanol; ethers such as tetrahydrofuran, diethylether, dioxan, dimethoxyethane and methyl-tert-butyl-ether (MTBE); alkyl-hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile, propionitrile and butyronitrile; dimethyl formamide; dimethyl sulfoxides or mixtures thereof.

15. The process as claimed in claim 1, wherein the amino protecting groups are selected from the group of 9-Fluorenylmethyloxycarbonylation (Fmoc), tert-Butoxycarbonylation (Boc) reagents, Allyloxycarbonylation (Alloc) reagents, Benzyloxycarbonylation (Cbz) reagents, Benzylation (Bn) reagents, Allylation (All) reagents and 2,2,2-Trichloroethoxycarbonylation (Troc) reagents or mixtures thereof.

16. The process as claimed in claim 15, wherein the amino protecting group is preferably tert-Butoxycarbonylation (Boc) reagents, more preferably mono or di-tert-butyl decarbonate.

17. The process as claimed in claim 1, wherein the compound of formula I comprises Impurity-A,

of less than about 2% by HPLC.

18. The process as claimed in claim 17, wherein the impurity A is less than about 0.1% by HPLC.

19. The process as claimed in claim 1, wherein the purity of compound of formula I is more than 99% by HPLC.

20. A composition of omidenepag isopropyl comprising the impurity-A, of less than 0.1% by HPLC.

21. The process as claimed in claim 1, wherein the compound of formula I is used in preparation of medicament.

22. The process as claimed in claim 1, wherein the compound of formula I is used for treating elevated intraocular pressure in patients.