Description:
FIELD OF THE INVENTION

Present invention provides process for the preparation of Latanoprostene Bunod and advance intermediate thereof.

Present invention further provides novel compound of Formula III and V which may be used as an intermediate for the preparation of Latanoprostene Bunod,

Formula III ,
wherein P is H or amino protecting group and X is a halogen.

BACKGROUND OF THE INVENTION

Latanoprostene Bunod is an effective ophthalmic drug used to lower down the pressure inside the eye that is caused by open-angle glaucoma or ocular hypertension.

Latanoprostene Bunod is known from U.S. Patents 6,211,233 B1 and 7,273,946 B1 which also discloses process for the preparation of Latanoprotene Bunod.

U.S. Patent 7,273,946 discloses process for the preparation of Latanoprostene Bunod by treating Latanoprost acid with 4-bromobutylnitrate in presence of DMF, K2CO3 and KI. The major drawback of said disclosed process is formation of large amounts of by-products which are generated during the processes.
U.S. Patent 10,870,621 discloses process for the preparation of Latanoprostene Bunod by treating Latanoprost acid with dibromo butane followed by nitration of obtained bromo intermediate. The major drawback of said disclosed process is formation of unwanted side products such as dimer which requires an extra purification step to get pure Latanoprostene Bunod.

U.S Patent 11,332,433 discloses process for the preparation of Latanoprostene Bunod by treating protected Latanoprost acid with 1,4-butanediol dinitrate to get the desired compound. The major drawback of above disclosed process involve decreased yield and commercially not viable.

In view of the literature known for the preparation of Latanoprostene Bunod, there is a need to develop a novel process for the preparation of Latanoprostene Bunod that provides highly pure Latanoprostene Bunod in high yields and commercially viable process. Hence, present invention is focussed towards the development of the process for the preparation of Latanoprostene Bunod by using novel intermediate(s) and which not only provides pure Latanoprostene Bunod in high yields but is reproducible and easy to handle during large scale production.

OBJECT OF THE INVENTION

Main object of the present invention is to provide a process for the preparation of Latanoprostene Bunod wherein said Latanoprostene Bunod is isolated with high yields and purity.

Another object of the present invention is to provide a process for the preparation of Latanoprostene Bunod by using novel intermediate(s), wherein the intermediates used for the preparation of Latanoprostene Bunod are optionally not isolated.

Another object of the present invention is to provide a process for the preparation of Latanoprostene Bunod and its intermediate(s) by involving commercially viable process.

SUMMARY OF THE INVENTION

Main aspect of the present invention provides process for the preparation of Latanoprostene Bunod by using novel intermediate of Formula III,
.
Formula III,
wherein P is H or amine protecting group.

One aspect of the present invention provides a process for the preparation of Latanoprostene Bunod, wherein said process comprising the steps of:
a) converting Latanoprost acid of Formula IV to compound of Formula III by reacting with compound of Formula V, wherein said compound of Formula III is optionally not isolated,

Formula IV Formula III
wherein P is H or amine protecting group,
R3 is halogen, OR4
R4 is hydrogen, alkyl, -COR5 and R5 is substituted and unsubstituted alkyl or aryl; and
b) converting compound of Formula III to Latanoprostene Bunod.

Another aspect of the present invention provides a process for the preparation of Latanoprostene Bunod, wherein said process comprising the steps of:
a) converting Latanoprost acid of Formula IV to compound of Formula III by reacting with compound of Formula V, wherein said compound of Formula III is optionally not isolated,

Formula IV Formula III
wherein P is H or amine protecting group,
R3 is halogen, OR4
R4 is hydrogen, alkyl, -COR5 and R5 is substituted and unsubstituted alkyl or aryl;
b) optionally deprotecting the compound of Formula III to give compound of Formula IIIa;

Formula IIIa ;
c) converting compound of Formula III or compound IIIa to compound of Formula II by reacting with halogenating agent;

Formula III /IIIa Formula II ;
wherein P is H or amine protecting group,
R1 is either chloro or iodo, and
d) converting compound of Formula II to Latanoprostene Bunod.

In another aspect, the present invention provides a process for the preparation of Latanoprostene Bunod of Formula I by converting compound of Formula II to compound of Formula I in presence of nitration source;

Formula II Formula I;
wherein R1 is either Chloro or Iodo; and
optionally purifying the compound of Formula I.

Another aspect of the present invention provides compound of Formula III,

Formula III,
wherein P is H or amine protecting group.

Another aspect of the present invention provides crystalline form of compound of Formula III.

Another aspect of the present invention provides amorphous form of compound of Formula III.

Another aspect of the present invention provides process for the preparation of Latanoprostene bunod by using novel compound of Formula V, wherein said process comprising the steps of:
a) converting compound of Formula VI to compound of Formula VII in presence of suitable solvent;

wherein R6 is suitable hydroxyl protecting group,
wherein said compound of Formula VII is formed by reacting the compound of Formula VI with compound of Formula V,

wherein X is halogen, and
b) de-protecting compound of Formula VII in presence of suitable acid to give Latanoprostene Bunod.

Another aspect of the present invention provides novel compound of Formula V, wherein said compound may be used for the preparation of Latanoprostene Bunod,

wherein X is halogen.

DETAILED DESCRIPTION OF THE INVENTION

There are several processes known for the preparation of Latanoprostene Bunod, however known processes suffer from drawbacks such tedious purification process such as column chromatography is required to isolate pure Latanoprostene Bunod. Present invention has dealt with aforesaid drawbacks by developing a novel process for the preparation of Latanoprostene Bunod advance intermediate of Formula II wherein said advance intermediate is prepared by using novel compound of Formula III,

Formula III,
wherein P is H or amine protecting group.

One embodiment of the present invention provides a process for the preparation of Latanoprostene Bunod, wherein said process comprising the steps of:
a) converting Latanoprost acid of Formula IV to compound of Formula III by reacting with compound of Formula V, wherein said compound of Formula III is optionally not isolated,

Formula IV Formula III
wherein P is H or amine protecting group,
R3 is halogen, OR4
R4 is hydrogen, alkyl, -COR5 and R5 is substituted and unsubstituted alkyl or aryl; and
b) converting compound of Formula III to Latanoprostene Bunod.

In another embodiment, the reaction of Latanoprost acid of Formula IV with protected amine of Formula V, wherein R3 is halogen, or any other leaving group selected from hydroxyl (R4 is H), alkoxy (R4 is alkyl) or acyl group (R4 is –COR5 with R5 is as defined above), may be carried out in presence of organic base selected from, but not limited to, 1,8-diazabiciclo[5.4.0]undec-7-ene (DBU), N,N-diisopropyl amine, N,N-diisopropyl ethyl amine, triethyl amine, pyridine, dimethyl amino pyridine and the like, or inorganic amine selected from, but not limited to, alkaline earth metal carbonate or hydroxides such as potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide , potassium iodide, and the like, in an inert organic solvent selected from, but not limited to, dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidone, acetone, methyl ethyl ketone, dichloromethane (methylene dichloride), chloroform, acetonitrile, ethylacetate, propyl acetate, benzene, toluene, cyclohexane, water, and mixture thereof.

In another embodiment, the reaction of Latanoprost acid of Formula IV with protected amine of Formula V may be carried out in presence of catalyst such as potassium iodide, crown ethers, phase transfer catalysts, ammonium iodide, ammonium bromide, trimethyl ammonium iodide, triethyl ammonium iodide, tripropyl ammonium iodide, tributyl ammonium iodide, tributyl ammonium bromide, sodium iodide, lithium iodide and cesium iodide.

In another embodiment, the amine protecting group “P” is selected from H, C1-C6 acyl group, -CO(C1-C10) aryl, -O(CO)C1-C6¬alkyl, -O(CO)C1-C6¬aryl, -O(CO)C1-C16 alkyl ¬aryl, -O(COO)C1-C10 alkyl ¬aryl, -C(C6H4)3 and other silyl groups. Preferably, the amine protecting group is tert-butyloxycarbonyl, benzoyl, fluorenylmethyloxy carbonyl, benzyloxy carbonyl, trityl and the like.

In another embodiment, the condensation reaction of compound of Formula IV to Formula V is carried out at a suitable temperature ranging from ambient temperature to boiling point of the reaction solvent. In another embodiment, the condensation is optionally carried out in dark at a temperature from room temperature to the boiling temperature of the solvent.

Another embodiment of the present invention provides a process for the preparation of Latanoprostene Bunod, wherein said process comprising the steps of:
a) converting Latanoprost acid of Formula IV to compound of Formula III by reacting with compound of Formula V, wherein said compound of Formula III is optionally not isolated,

Formula IV Formula III
wherein P is H or amine protecting group,
R3 is halogen, OR4
R4 is hydrogen, alkyl, -COR5 and R5 is substituted and unsubstituted alkyl or aryl;
b) optionally deprotecting the compound of Formula III to give compound of Formula IIIa;

Formula IIIa ;
c) converting compound of Formula III or compound IIIa to compound of Formula II by reacting with halogenating agent;

Formula III /IIIa Formula II ;
wherein P is H or amine protecting group,
R1 is either chloro or iodo, and
d) converting compound of Formula II to Latanoprostene Bunod.

In another embodiment, when in compound of Formula III, P is amine protected group, then said compound of Formula III is optionally de-protected by using acid such as hydrochloric acid, trifluoroacetic acid, acetic acid, hydrobromic acid, sulphuric acid or mixture thereof. Solvent used for de-protection are selected from, but not limited to, dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidone, acetone, methyl ethyl ketone, dichloromethane (methylene dichloride), chloroform, acetonitrile, ethylacetate, propyl acetate, benzene, toluene, cyclohexane, hexane, heptane, water, methanol, ethanol, isopropanol, n-butanol and mixture thereof.

In another embodiment, the halogenation of compound of Formula III/IIIa to compound of Formula II in step c) above is carried out in presence of suitable solvent selected from, but not limited to, alcohols such as methanol, ethanol, isopropanol, butanol and the like, ethers such as methyl tert-butyl ether, dioxane, tetrahydrofuran and the like, esters such as ethyl acetate, propyl acetate, hydrocarbons such as toluene, xylene and the like, halogenated solvents such as dichloromethane (methylene dichloride), dichloroethane, dichloro benzene, tetrachloromethane, nitriles such as acetonitrile, propionitrile, ketones such as acetone, methyl ethyl ketone and the like, polar solvents such as N-methyl pyrrolidone, N-methyl acetamide, water, or combination thereof. The said halogenation reaction may be carried out at a temperature ranging from ambient temperature to boiling point of the reaction solvent.

In another embodiment, the halogenation of compound of Formula III/IIIa to compound of Formula II is carried out in presence of sodium nitrate and acid such as HCl, HBr or known in literature.

In another embodiment, the halogenation of compound of Formula III/IIIa to compound of Formula II is carried out in halogenating agent selected from, but not limited to, Copper (I) Iodide; Copper (I) Chloride or any suitable halogenating agent known in the literature.

In another embodiment, the halogenation is carried out at a suitable temperature ranging from ambient temperature to boiling point of the reaction solvent. In another embodiment, the halogenation is optionally carried out in dark at a temperature from room temperature to the boiling temperature of the solvent.

In another embodiment, the the present invention provides process for the preparation of Latanoprostene Bunod of Formula I, comprising the steps of:
a) converting compound of Formula II to compound of Formula I in presence of nitration source;

Formula II Formula I;
wherein R1 is Chloro or Iodo; and
b) optionally purifying the compound of Formula I.

In another embodiment, the preparation of Latanoprostene Bunod in step a) above, is carried out in presence of suitable solvent selected from, but not limited to, inert organic solvent such as dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidone, acetone, methyl ethyl ketone, dichloromethane (methylene dichloride), chloroform, acetonitrile, ethyl acetate, propyl acetate, benzene, toluene, cyclohexane, water, and the like.

In another embodiment, the nitration source or nitrate source used for the preparation of compound of Formula I from compound of Formula II is selected from, but not limited to, lithium nitrate, sodium nitrate, potassium nitrate, magnesium nitrate, calcium nitrate, iron nitrate, zinc nitrate or tetraalkylammonium nitrate, silver nitrate, and the like.

In another embodiment, the present invention provides a process for the preparation of Latanoprostene Bunod of Formula I,

Formula I,
comprising the steps of:
a) converting Latanoprost acid of Formula IV to compound of Formula III by reacting with compound of Formula V, wherein said compound of Formula III is optionally not isolated;

Formula IV Formula III
wherein P is H or amine protecting group,
R3 is halogen, OR4
R4 is hydrogen, alkyl, -COR5 and R5 is substituted and unsubstituted alkyl or aryl;
b) optionally deprotecting the compound of Formula III to give compound of Formula IIIa,

Formula IIIa ;
c) converting compound of Formula III or compound of Formula IIIa to compound of Formula II by reacting with halogenating agent,

Formula III /IIIa Formula II
wherein P and R1 are as defined above; and
d) converting compound of Formula II to Latanoprostene Bunod.

In another embodiment, the present invention provides Latanoprostene Bunod having purity above 99.0% by HPLC, preferably above 99.5% by HPLC and most preferably above 99.9% by HPLC.

Another embodiment of the present invention provides compound of Formula III,

Formula III,
wherein P is H or amine protecting group.

Another embodiment of the present invention provides crystalline form of compound of Formula III.

Another embodiment of the present invention provides amorphous form of compound of Formula III.

In another embodiment, the present invention provides process for the preparation of Latanoprostene bunod by using novel compound of Formula V, wherein said process comprising the steps of:
a) converting compound of Formula VI to compound of Formula VII in presence of suitable solvent;

wherein R6 is suitable hydroxyl protecting group,
wherein said compound of Formula VII is formed by reacting the compound of Formula VI with compound of Formula V,

wherein X is a halogen, and
b) deprotecting compound of Formula VII in presence of suitable acid to give Latanoprostene Bunod.

In another embodiment, the present invention provides novel compound of Formula V, wherein said compound may be used for the preparation of Latanoprostene Bunod,

wherein X is a halogen.

In another embodiment, the conversion of compound of Formula VI to VII is carried out in presence of suitable solvent selected from, but not limited to, alcohols such as methanol, ethanol, isopropanol, butanol and the like, ethers such as methyl tert-butyl ether, dioxane, tetrahydrofuran and the like, esters such as ethyl acetate, propyl acetate, hydrocarbons such as toluene, xylene and the like, halogenated solvents such as dichloromethane (methylene dichloride), dichloroethane, dichloro benzene, tetrachloromethane, nitriles such as acetonitrile, propionitrile, ketones such as acetone, methyl ethyl ketone and the like, polar solvents such as N-methyl pyrrolidone, N-methyl acetamide, water, or combination thereof. Said reaction is carried out in presence of suitable base selected from potassium t-butoxide, sodium tert-butoxide, LDA (Lithium diisopropyleamide 2.0M in THF solution), n-BuLi (1.6 to 2.5M solution), Sodium HMDS ( Sodium hexamethyldisilazane), TBD (Triazabicyclodecene) and the like.

In another embodiment, the suitable hydroxyl protecting group is selected from carbon and silyl containing moieties, that protect the hydroxyl group from undergoing any kind of reaction.

In another embodiment, the suitable acid used for de-protection of compound of Formula VII is selected from, but not limited to, aqueous hydrochloric acid, trifluoroacetic acid, aqueous sulphuric acid, acetic acid and the like.

In another embodiment, the present invention provides process for the preparation of Latanoprostene Bunod by following the Scheme 1 as mentioned below,
Scheme 1:

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. 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.

EXAMPLES
Example 1: Synthesis of 4-chloro-N-tritylbutan-1-amine:
Charged 50 ml of methylene dichloride followed by addition of 10 g of 4-chlorobuatne-1 amine at room temperature to round bottom flask. Added 18.81 ml of triethylamine and stirred for 30 min at room temperature followed by addition of 31.96 g of triphenylmethyl Chloride to the reaction mass, and then stirred at room temperature for 4 to 12 hr. After completion of reaction, quenched the reaction by adding 50 ml of water and extracted the compound in dichloromethane. Separated the layers and washed the organic layer with 20 ml of brine solution. Concentrated the organic layer and dried under reduced pressure at 40 to 42°C to get crude solid mass (16.14g).

Example 2: Synthesis of 4-(tritylamino) butyl (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoate, compound of Formula III with P = trityl group:
Charged 50 ml of N,N-Dimethylformamide to round bottom flask and added 10 g of latanoprost acid. Added 9.9 g of potassium carbonate and 3.61 g of potassium iodide and stirred for 20 to 30 min at room temperature. Charged 16.14 g of 4-chloro-N-tritylbutan-1-amine to the reaction mass and heated to 40oC to 50°C and stirred at the same temperature for 3 to 4 hr. After completion of reaction, quenched the reaction by adding 50 ml of water and extracted by 2x50 ml of dichloromethane. Collected the organic layer and washed with 20 ml of brine solution, dried over sodium sulfate and concentrated under reduced pressure to get solid mass. Obtained solid mass is crystallized in ethylacetate : hexane to get pure 15.0g of desired compound (83.3% yield).

Example 3: Synthesis of 4-aminobutyl (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoate, compound of Formula IIIa with P = H:
Charged 50 ml of methylene dichloride followed by addition of 10 g of 4-(tritylamino) butyl (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoate, stirred to get cleared solution. Cooled to 0°C to 5°C followed by addition of 2.42 g of trifluoroacetic acid (TFA) or aqueous HCl. Increased the temperature of the reaction to room temperature and stirred for 2 to 3 hr. After completion of reaction, quenched the reaction by adding 50 ml of water and adjusted the pH 7.5 to 8.5 by adding saturated solution of aqueous sodium bicarbonate. Separated the layers and again extracted the compound from aqueous layer by 50 ml of methylene dichloride. Collected the organic layer and washed with brine and dried over sodium sulfate and concentrated under reduced pressure at 40 to 42°C to get desired compound. Obtained compound is crystallized in methanol to get 6.0 g of desired compound (92% yield).

Example 4: Synthesis of 4-chlorobutyl (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoate:
6.0 g of 4-aminobutyl (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoate was added to 30 ml of DM water followed by addition of 4.5 ml of Conc HCl and stirred the reaction mass for 2 to 3 hr at room temperature. Cooled to 0 to 5°C and added aqueous solution of sodium nitrite. Stirred the reaction mass for 1 to 2 hr at 0 to 5°C.
A solution of equimolar quantity of Copper (I) chloride in HCl was then added at 0 to 5°C to the above reaction mass under stirring for 1 to 2 hr. Slowly allowed to heat to 20 to 30°C and stirred for 1 to 2 hr. After completion of reaction, charged 30 ml of methylene dichloride and separated the layers. Washed the organic layer with 1N and dried over sodium sulfate and concentrated under reduced pressure to get 5.5g of desired compound (88.7% yield).

Example 5: 4-(nitrooxybutyl) (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoate (Latanoprostene Bunod):
To 5.0g of 4-chlorobutyl (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoate was added 50 ml of acetonitrile followed by 3.54 g of silver nitrate and heated to 30 to 40°C under continuous stirring for 24 to 30 hr. After completion of reaction, filtered the reaction mass by celite filtration, obtained filtrate is then distilled under reduced pressure. Added 50 ml of water to the solid mass so obtained and extracted the compound by 2x50 ml of ethyl acetate. Collected the organic layer and washed with 20 ml of brine solution and dried over sodium sulfate and concentrated under reduced pressure at 40 to 42°C. The resulting residue was purified by ethylacetate: cyclohexane to give pure compound 4-(nitrooxybutyl) (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoate; Latanoprostene bunod 2.5 g, 99.9%.

Example 6: Synthesis of 4-(nitrooxy)butyl (Z)-7-((1R,2R,3R)-5-hydroxy-2-(5-phenyl-3((triethylsilyl)oxy)pentyl)-3-((triethylsilyl)oxy)cyclopentyl)hept-5-enoate:
Charged 250 ml of Methylene dichloride (MDC) followed by addition of 52.38 g of (5-(4-(nitrooxy)butoxy)-5-oxopentyl) triphenylphosphonium bromide, 10.46 g of potassium tert-butoxide and cooled to 0 to 5.0°C. Added 25 g of (3aR,4R,5R,6aS)-4-(5-phenyl-3-((triethylsilyl)oxy)pentyl)-5-((triethylsilyl)oxy) hexahydro-2H-cyclopenta[b]furan-2-ol at 0 to 5°C and stirred at the same temperature for 8 to 10 hr. On completion of reaction, charged acetic acid to adjust the pH between 2 to 5 followed by addition of 250 ml of chilled water. Maintained the pH at 2-5 by adding acetic acid. Extracted the compound by 3x125 ml of ethyl acetate and washed the organic layer with 50 ml of brine solution and dried over anhydrous sodium sulfate and concentrated under reduced pressure at 35 to 40°C to obtain 32 g of crude compound which was further used in next step without purification.

Example 7: Synthesis of 4-(nitrooxy)butyl (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5 phenylpentyl)cyclopentyl)hept-5-enoate (Latanoprostene Bunod):
Charged 320 ml of THF to the 1 liter of 4N RBF followed by addition of 32 g of compound obtained in example 6, cooled to 0 to 5°C then charged 160 ml of acetic and 160 ml of DM water. Slowly allowed the reaction mass to heat up to room temperature and stirred for 10 to 12 hr at the same temperature. On completion of reaction, charged 160 ml of DM water and extracted with 3x160 ml of ethyl acetate, organic layer was washed with 256 ml of saturated solution of NaHCO3. Collected the organic layer, washed with 160 ml of brine solution and dried over anhydrous sodium sulfate and concentrated under reduced pressure at 35 to 38°C.
Obtained crude compound was then purified by column chromatography by using 60 to 200 mesh size irregular silica using 80% of Ethyl acetate: MDC as colorless oil (14 g).
, Claims:WE CLAIM
1. A process for the preparation of Latanoprostene Bunod, wherein said process comprising the steps of:
a) converting Latanoprost acid of Formula IV to compound of Formula III by reacting with compound of Formula V, wherein said compound of Formula III is optionally not isolated,

Formula IV Formula III
wherein P is H or amine protecting group,
R3 is halogen, OR4
R4 is hydrogen, alkyl, -COR5 and R5 is substituted and unsubstituted alkyl or aryl; and
b) converting compound of Formula III to Latanoprostene Bunod.

2. The process as claimed in claim 1, wherein said conversion in step a) is carried out in presence of base selected from 1,8-diazabiciclo[5.4.0]undec-7-ene (DBU), N,N-diisopropyl amine, N,N-diisopropyl ethyl amine, triethyl amine, pyridine, dimethyl amino pyridine, potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, potassium iodide or mixture thereof, and catalyst selected from potassium iodide, crown ethers, phase transfer catalysts, ammonium iodide, ammonium bromide, trimethyl ammonium iodide, triethyl ammonium iodide, tripropyl ammonium iodide, tributyl ammonium iodide, tributyl ammonium bromide, sodium iodide, lithium iodide and cesium iodide; or combination thereof.

3. A process for the preparation of Latanoprostene Bunod, wherein said process comprising the steps of:
a) converting Latanoprost acid of Formula IV to compound of Formula III by reacting with compound of Formula V, wherein said compound of Formula III is optionally not isolated,

Formula IV Formula III
wherein P is H or amine protecting group,
R3 is halogen, OR4
R4 is hydrogen, alkyl, -COR5 and R5 is substituted and unsubstituted alkyl or aryl;
b) optionally deprotecting the compound of Formula III to give compound of Formula IIIa;

Formula IIIa ;
c) converting compound of Formula III or compound IIIa to compound of Formula II by reacting with halogenating agent;

Formula III /IIIa Formula II ;
wherein P is H or amine protecting group,
R1 is either chloro or iodo, and
d) converting compound of Formula II to Latanoprostene Bunod.

4. The process as claimed in claim 3, wherein said halogenating agent is selected from copper (I) iodide or copper (I) chloride.

5. The process as claimed in claim 3, wherein said process comprising the steps of:
a) converting compound of Formula II to a compound of Formula I in presence of nitration source,

Formula II Formula I;
wherein R1 is Chloro or Iodo; and
b) optionally purifying the compound of Formula I.

6. The process as claimed in claim 5, wherein said nitration source is selected from lithium nitrate, sodium nitrate, potassium nitrate, magnesium nitrate, calcium nitrate, iron nitrate, zinc nitrate or tetraalkylammonium nitrate and silver nitrate.
7. Compound of Formula III,

Formula III,
wherein P is H or amine protecting group.

8. The compound as claimed in claim 7, wherein said amine protecting group is selected from C1-C6 acyl group, -CO(C1-C10) aryl, -O(CO)C1-C6¬alkyl, -O(CO)C1-C6¬aryl, -O(CO)C1-C16 alkyl ¬aryl, -O(COO)C1-C10 alkyl ¬aryl, -C(C6H4)3 and silyl groups.

9. A process for the preparation of Latanoprostene Bunod comprising the steps of:
a) converting compound of Formula VI to compound of Formula VII in presence of suitable solvent;

wherein R6 is suitable hydroxyl protecting group,
wherein said compound of Formula VII is formed by reacting the compound of Formula VI with compound of Formula V,

wherein X is a halogen, and
b) de-protecting compound of Formula VII in presence of suitable acid to give Latanoprostene Bunod.

10. Compound of Formula V,

wherein X is a halogen.

Dated 10th Day of Mar, 2023 For Mankind Pharma Ltd.

Dr. Anil Kumar
Chief Scientific Officer