DESC:FIELD OF THE INVENTION

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

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 further 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 requires minimal steps and provides highly pure Latanoprostene Bunod in high yields and commercially viable process. Hence, present invention is focussed toward the development of the process for the preparation of Latanoprostene Bunod which not only provides pure Latanoprostene Bunod in high 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 and its intermediate by involving commercially viable process which results in improved yield and purity.

SUMMARY OF THE INVENTION

Main aspect of the present invention provides process for the preparation of Latanoprostene Bunod by using intermediate of Formula II wherein said Latanoprostene Bunod intermediate of Formula II is prepared in fewer reaction steps with simple purification process and provides Latanoprostene Bunod with high purity and yields.

Another aspect of the present invention provides a process for the preparation of Latanoprostene Bunod intermediate of Formula II,

wherein R1 is chloro, iodo or OR2, R2 is hydrogen or hydroxyl protecting group;
wherein said process is selected from:
1) comprising reacting Latanoprost acid of Formula IV

with compound of Formula VI

wherein R2 is as defined above and X is halogen;
or,

2a) converting Latanoprost acid of Formula IV to compound of Formula VII,
; and
2b) converting compound of Formula VII to compound of Formula II by reacting with compound of Formula VIII,
wherein R1 is choro or iodo,
or
converting compound of Formula VII to compound of Formula II by reacting with compound of Formula VIII,
wherein R1 is choro or iodo,
or
reacting compound of Formula N with compound of Formula VIII followed by de-protection to give compound of Formula II, wherein intermediates are not isolated,
,
wherein, R2 is hydroxyl protecting group,
R1 is choro or iodo,
or,
3a) converting Latanoprost acid to its acyl halide or its anhydride in presence of acylating agent,
,
wherein R6 is halogen or –OCOalkyl;
3b) treating compound of Formula IX with tetrahydrofuran to give compound of Formula X,
and
3c) converting compound of Formula X to compound of Formula II.

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;

wherein R1 is chloro, iodo or OR2, R2 is hydrogen or hydroxyl protecting group; and optionally purifying compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

There are several processes known for the preparation of Latanoprostene Bunod, however known processes suffer from drawbacks such as involvement of multiple steps like protection and de-protection of ring hydroxyl groups or 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 intermediate of Formula II wherein the process requires minimal reaction steps and simple purification processes and use of said intermediate of Formula II in preparing Latanoprostene Bunod in high yields and purity.

Accordingly, in one embodiment, the present invention provides a process for the preparation of Latanoprostene Bunod intermediate of Formula II,

wherein R1 is chloro, iodo or OR2, R2 is hydrogen or hydroxyl protecting group;
wherein said process is selected from:
1) comprising reacting Latanoprost acid of Formula IV

with compound of Formula VI

wherein R2 is as defined above and X is halogen;
or,

2a) converting Latanoprost acid of Formula IV to compound of Formula VII,
; and
2b) converting compound of Formula VII to compound of Formula II by reacting with compound of Formula VIII,
wherein R1 is choro or iodo,

or,
3a) converting Latanoprost acid to its acyl halide or its anhydride in presence of acylating agent,

wherein R6 is halogen or –OCOalkyl;
3b) treating compound of Formula IX with tetrahydrofuran to give compound of Formula X,

and
3c) converting compound of Formula X to compound of Formula II.

In another embodiment, the the present invention provides process for the preparation of Latanoprostene Bunod of Formula I, comprising the steps of:
a) conversion of compound of Formula II to compound of Formula I in presence of nitration source;
wherein R1 is chloro, iodo or OR2, R2 is hydrogen or hydroxyl protecting group; and
b) optionally purifying compound of Formula I.

In another embodiment, the present invention provides a process for the preparation of Latanoprostene Bunod of Formula I, comprising the steps of:
a) preparing compound of Formula II

wherein R1 is OR2, R2 is hydrogen or hydroxyl protecting group,
by reacting Latanoprost acid of Formula IV

with compound of Formula VI

wherein R2 is as defined above and X is halogen; and
b) converting compound of Formula II to Latanoprostene Bunod of Formula I, in presence of nitration source.

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

In another embodiment, the compound of Formula VI can be prepared by a process comprising reaction of 4-hyroxy-butane halide of Formula XI with suitable hydroxyl protecting agent,

Formula XI Formula VI
wherein X is halogen selected from Cl, I, Br and R2 is hydroxyl protecting group;
wherein the hydroxyl protecting group is selected from alkyl, alkyl aryl, C1-C6 acyl, -CO(C1-C10) aryl, -(CO)C1-C16 alkyl ¬aryl, -(COO)C1-C10 alkyl ¬aryl, mesyl, tosyl, and C1-C10 silyl. Preferably, the hydroxyl protecting group is tert-butyloxycarbonyl, benzoyl, benzyl, paraphenyl benzoyl, acetyl, mesyl, triethyl silyl, tertiary butyl dimethylsilyl, trimethyl silyl, triisopropyl silyl and the like.

In another embodiment, the present invention provides a process for the preparation of Latanoprostene Bunod of Formula I, comprising the steps of:
a) converting Latanoprost acid of Formula IV to compound of Formula VII,

b) converting compound of Formula VII to compound of Formula II by reacting with compound of Formula VIII,
wherein R1 is choro or iodo, and
c) converting compound of Formula II to Latanoprostene of Formula I, in presence of nitration source.

In another embodiment, the conversion of Latanoprost acid of Formula IV to cyano compound of Formula VII, 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, ammonia 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 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, chloroform, acetonitrile, ethylacetate, propyl acetate, benzene, toluene, cyclohexane, and the like. In another embodiment, the conversion reaction of Latanoprost acid of Formula IV to cyano compound of Formula VII, may be carried out in presence of catalyst such as trifluoroacetic anhydride.

In another embodiment, the reaction of cyano compound of Formula VII with 4-hydroxy-butane derivative of Formula VIII, wherein R1 is either chloro or bromo, may be carried out in presence of 1H-imidazole-1-propanesulfonic acid and tetrafluoroborate, Diisobutylaluminum hydride and iodine in an inert organic solvent selected from, but not limited to, dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidone, acetone, methyl ethyl ketone, dichloromethane, chloroform, acetonitrile, ethylacetate, propyl acetate, benzene, toluene, cyclohexane, hexane, ammonia and the like.

In another embodiment, the cyano compound of Formula VII may be prepared by following scheme:

In another embodiment, the conversion of compound of Formula A to Formula B is carried out in presence of brominating agent such as bromine in methanol or NBS or the like. The reaction is preferably carried out at lower temperature ranging from 0oC to ambient temperature.

The iodination reaction for converting compound of Formula B to Formula C is carried out in presence of sodium iodide in ketone solvent like acetone, methyl ethyl ketone and the like. The iodination reaction is preferably carried out in at ambient temperature conditions.

The preparation of compound of formula D is performed by reacting compound of Formula C with trimethyl phosphate in polar solvents such as acetonitrile at a temperature ranging from 25-100oC. The phosphate intermediate of Formula D is optionally purified with non-polar solvent such as hexane, heptane or cyclohexane.

For the preparation of cyano compound of Formula VII, Corey lactone is used as major starting material wherein Corey lactone is firstly protected by using triethyl silyl chloride or any other suitable hydroxyl protecting group, in presence of base such as organic base selected from pyridine, triethyl amine, diisopropyl amine, dipropyl ethyl amine and the like; or inorganic base such as alkaline earth metal hydroxides, carbonates, bicarbonates and the like. The said protection reaction is carried out in a suitable solvent at a temperature ranging from 25-100oC.

The compound of Formula F once synthesized is then reacted with acid such as oxalyl chloride or thionyl chloride in presence of polar solvent followed by reaction with phosphate intermediate of Formula D in presence of suitable solvent and base without isolation of intermediate of Formula G, wherein suitable solvent is selected from dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidone, acetone, methyl ethyl ketone, dichloromethane, chloroform, acetonitrile, ethylacetate, propyl acetate, benzene, toluene, cyclohexane, hexane, methyl tert butyl ether, water or combination thereof; and wherein suitable base is selected from alkaline earth metal hydroxides, carbonates, bicarbonates and the like.

The compound of Formula H once synthesized is then reduced by using reducing agents such as sodium hydride, sodium borohydride, sodium borohydride and BF3 complex, and the reduced compound of Formula J is then protected by suitable hydroxyl protecting group, preferably by triethyl silyl chloride.

The ketone of the lactone ring of compound of Formula K is reduced using suitable reducing agent such as diisopropyl aluminium hydride in presence of ether solvent at lower temperature of -80oC to 0oC, which is then reacted with triphenyl phosphino cyanide side chain of Formula M to give compound of Formula N as represented in the scheme above.

Compound of Formula N is optionally de-protected to give compound of Formula VII, which is used for the preparation of Latanoprostene Bunod. The protected compound of Formula N may directly be converted to Latanoprostene Bunod.

Accordingly in another embodiment, the present invention provides process for the preparation of Latanoprostene Bunod, comprising the steps of:
a) reacting protected cyano compound of Formula N with compound of Formula VIII followed by de-protection to give compound of Formula II, wherein intermediates are not isolated,
,
wherein, R2 is hydroxyl protecting group, R1 is choro or iodo, and
b) converting compound of Formula II to Latanoprostene bunod of Formula I, in presence of nitration source.
In another embodiment, the present invention provides a process for the preparation of compound of formula N

comprising the steps of:
a) reaction of compound of formula S

with base in the presence of solvent to give compound of formula R

b) hydrogenation of compound of formula R to give compound of formula Q

c) protection of hydroxyl groups of formula Q to give compound of P

d) reduction of compound of formula P to give compound of formula O
; and
e) reaction of compound of formula O with a 4-cyano butyl triphenyl phosphonium bromide compound of formula M

to give compound of formula N; wherein R2 is hydroxyl protecting group.

In another embodiment, the present invention provides a process for the preparation of compound of formula II or compound of formula I, comprising conversion of conversion of compound of formula N to compound of formula I or compound of formula II.

In another embodiment, the present invention provides a process for the preparation of compound of formula I, comprising the steps of:
a) reaction of compound of formula S

with a base in the presence of solvent to give compound of formula R

b) hydrogenation of compound of formula R to give compound of formula Q

c) protection of hydroxyl groups of formula Q to give compound of P

d) reduction of compound of formula P to give compound of formula O
; and
e) reaction of compound of formula O with a 4-cyano butyl triphenyl phosphonium bromide of formula M

to give compound formula N
;
f) reacting protected cyano compound of Formula N with compound of Formula VIII

followed by de-protection to give compound of Formula II,
, and
g) converting compound of Formula II to Latanoprostene of Formula I, in presence of nitration source; wherein, R2 is hydroxyl protecting group, R1 is choro or iodo.
In another embodiment, the present invention provides a process for the preparation of compound of formula M,

comprising: reacting 5-bromovaleronitrile with triphenylphosphine in the presence of a solvent to give 4-cyanobutyltriphenylphosphonium bromide of formula M.

In another embodiment, the present invention provides a compound of formula N

wherein, R2 is hydroxyl protecting group.

In another embodiment, base used is selected from organic base such as pyridine, triethyl amine, diisopropyl amine, dipropyl ethyl amine and the like; or inorganic base such as alkaline earth metal hydroxides, carbonates, bicarbonates and the like. The said protection reaction is carried out in a suitable solvent at a temperature ranging from 25-100oC.

In another embodiment, the present invention provides a process for the preparation of Latanoprostene Bunod of Formula I, comprising the steps of:
a) converting Latanoprost acid to its acyl halide or its anhydride in presence of acylating agent,

wherein R6 is halogen or –OCOalkyl;
b) treating compound of Formula IX with tetrahydrofuran to give compound of Formula X,

c) converting compound of Formula X to compound of Formula II,
d) converting compound of Formula II to Latanoprostene of Formula I, in presence of nitration source.

In another embodiment, the acylating agent are selected from the group comprising of oxalyl chloride, thionyl chloride, and phosgene.

In another embodiment, the nitration source used for the preparation of compound of Formula I from compound of Formula II is selected from, but not limited to, nitric acid: sulphuric acid, silver nitrate, and the like., in an inert solvent such as dichloromethane, acetonitrile, dimethyl acetamide or dimethyl formamide, or N-methyl pyrrolidone.

In another embodiment, the present invention provides process for the preparation of Latanoprostene Bunod of Formula I, comprising the steps of:
a) coupling of Latanoprost acid of Formula IV with compound of Formula XI in presence of suitable coupling agent;
; and
b) optionally purifying compound of Latanoprostene Bunod of Formula I.

Another embodiment of the present invention provides a process for the purification of Latanoprostene Bunod of Formula I, comprising the steps of:
a) adding suitable one or more solvents to the compound of Formula I to get reaction mass;
b) optionally, heating the reaction mass; and
c) cooling the reaction mass and isolate the pure compound of Formula I.

Another embodiment of the present invention provides a process for the purification of Latanoprostene Bunod of Formula I, comprising purification of Latanoprostene Bunod by preparative high-performance liquid chromatography.

Another embodiment of the present invention provides a process for the purification of compound of Formula II, comprising the steps of:
a) adding suitable one or more solvents to the compound of Formula II to get reaction mass;
b) optionally, heating the reaction mass; and
c) cooling the reaction mass and isolate the pure compound of Formula II.

Another embodiment of the present invention provides a process for the purification of compound of Formula N, comprising the steps of:
a) adding suitable one or more solvents to the compound of Formula N to get reaction mass;
b) optionally, heating the reaction mass; and
c) cooling the reaction mass and isolate the pure compound of Formula N.

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.

In another embodiment, the one or more solvents used are selected from methanol, ethanol, 1-propanol, 2-propanol, n-butanol, isobutanol, nitromethane, chloroform, acetonitrile, acetone, MIBK, MEK, toluene, heptane, (ethyl acetate, propyl acetate, n-pentyl acetate, isopropyl acetate, butyl acetate, propionitrile, diethylether, dimethylether, diisopropylether, diphenylether, MTBE, tetrahydrofuran, methyl tetrahydrofuran, 1,4-dioxane, dimethoxyethane, o-xylene, m-xylene, p-xylene, n-pentane, cyclopentane, n-hexane, cyclohexane, benzene, dichloromethane, dichloroethane, tetrachloromethane, chlorobenzene, dimethyl acetamide (DMA), dimethylformamide (DMF), water.

In another embodiment, hydroxyl protecting group is selected from alkyl, alkyl aryl, C1-C6 acyl, -CO(C1-C12) aryl, -(CO)C1-C16 alkyl ¬aryl, -(COO)C1-C10 alkyl -aryl, mesyl, tosyl, and C1-C10 silyl. Preferably, the hydroxyl protecting group is tert-butyloxycarbonyl, benzoyl, benzyl, paraphenyl benzoyl, acetyl, mesyl, triethyl silyl, tertiary butyl dimethylsilyl, trimethyl silyl, triisopropyl silyl and the like.

In another embodiment, hydroxyl protecting group is selected from benzoyl, benzyl, paraphenyl benzoyl, triethyl silyl, tertiary butyl dimethylsilyl, trimethyl silyl, and triisopropyl silyl.

In another embodiment, the suitable coupling agent used for preparation of Latanoprostene Bunod from Latanoprost acid is selected from, but not limited to, N,N'-dicyclohexylcarbodiimide, Hydroxybenzotriazole, (3-Dimethylamino-propyl)-ethyl-carbodiimide Hydrochloride, (benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate), (benzotriazolyloxy-tris[pyrrolidino]-phosphonium hexafluorophosphate), (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Oxide Tetrafluoroborate, 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate, 1,8-Diazabicyclo[5.4. 0]undec-7-ene and the like.

Preferably, in one embodiment, said coupling of Latanoprost acid with compound of Formula XI is carried out in presence of base such as dimethyl amino pyridine, triethyl amine, pyridine, N,N-diisopropyl ethyl amine and other suitable organic bases.

In another embodiment, said coupling is carried out in presence of solvent selected from dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidone, acetone, methyl ethyl ketone, dichloromethane, chloroform, acetonitrile, ethylacetate, propyl acetate, benzene, toluene, cyclohexane, and the like; preferably, dimethyl formamide, dimethyl acetamide, and N-methyl pyrrolidone.

EXAMPLES
Example 1: Synthesis of 1-bromo-4-phenylbutan-2-one (Formula A)
Charged 50 ml of methanol into round bottom flask followed by addition of 10 g of 4-phenylbutan-2-one at 20 to 30°C, cooled to 0 to 8 °C. Charged slowly bromine solution (16.2 g of bromine in 50.0 ml of methanol) at 0 to 8°C. Stirred for 2 to 5 hours at 0 to 8°C. Reaction monitored by checking TLC (mobile phase15% ethylacetate:Hexane), after the completion of reaction, charged 100 ml of DM water and stirred the reaction mass for 2 to 5 hours at 20 to 30°C. Extracted two times with 100 ml of dichloromethane, organic layer washed with 50 ml of saturated solution of sodium metabisulfite, dried over sodium sulphate and concentrated under reduced pressure at 30 to 40°C to obtain residue. The residue obtained was charged into 50 ml of hexane and stirred at -20 to -30°C for 30 min to 60 min then filtered and washed with 5.0 ml of chilled hexane and dried to obtain title compound as off white colour powder (Yield: 7.8 g).

Example 2: Synthesis of 1-Iodo-4-phenylbutan-2-one (Formula C)
Charged 150 ml of acetone into round bottom flask, followed by addition of 7.5 g of 1-bromo-4-phenylbutan-2-one, stirred to get cleared solution at 20-30°C. Charged 5.94 g of sodium iodide at 20 to 30°C. Stirred for 12 to 15 hours at 20 to 40°C. Filtered and washed with 22 ml of acetone. Distilled and degassed at 30 to 40°C, charged 50 ml of DM water and extracted with 3 times with 50 ml of dichloromethane. Combined organic layers were washed with 22 ml of saturated solution of sodium metabisulfite, dried over anhydrous Na2SO4, organic layer distilled under reduced pressure at 30-40°C to get title compound as black colour residue (Yield: 8.2 g).

Example 3: Synthesis of dimethyl 2-oxo-4-phenylbutylphosphonate (Formula D)
Charged 8.0 g of 1-Iodo-4-phenylbutan-2-one into round bottom flask, followed by the addition of 80 ml of acetonitrile at 20 to 30°C. Slowly added trimethyl phosphite solution (6.5 g in 16 ml of acetonitrile) at 10 to 30°C. Heated to 55 to 85°C and stirred at same temperature. Progress of reaction monitored by TLC (Mobile phase 10% ethyl acetate: hexane). After completion of reaction distilled under reduced pressure at 40-45°C to the solvent then desired compound purified by HVD (High vacuum distillation) at 60 to 120°C and 2 to 20 mbar vacuum to get title compound as light yellow oil (Yield: 5.0 g).

Example 4: Synthesis of (3aR,4R,5R,6aS)-5-((triethylsilyl)oxy)-4-(((triethylsilyl)oxy)methyl)hexahydro-2H-cyclopenta[b]furan-2-one (Formula F, where R2= triethylsilyl)
To a solution of (-)-Corey lactone diol (10 g in 100 ml of DMF) in round bottom flask, charged 29.32 g of triethylamine and stirred for 20 to 30 min at 20-30°C then 15.75 g of triethyl silyl chloride at 10-30°C, heated to 40 to 60°C and stirred at the same temperature for 6 to 12 hours. Reaction monitored by checking TLC (mobile phase25% ethyl acetate: hexane), after completion of reaction, charged 100 ml of DM water and extracted 2 times with 100 ml of dichloromethane, combined organic layer washed with 50 ml of saturated brine solution, dried over sodium sulphate and concentrated under reduced pressure at 30 50°C to get title compound as colourless oil (Yield: 11.5 g).

Example 5: Synthesis of (3aR,4S,5R,6aS)-2-oxo-5-((triethylsilyl)oxy)hexahydro-2H-cyclopenta[b]furan-4-carbaldehyde (Formula G, where R2= triethylsilyl)
Charged 5 ml of dichloromethane to the 50 ml of 4N round bottom flask and cooled to -70 to -78°C then charged 0.26 ml of oxalyl chloride and 0.44 ml of dimethyl sulfoxide, stirred for 5 min at -70 to -78°C. Charged solution of (3aR,4R,5R,6aS)-5-((triethylsilyl)oxy)-4-(((triethylsilyl)oxy)methyl)hexahydro-2H-cyclopenta[b]furan-2-one (1 g in 2 ml of dichloromethane) to the reaction mass at -70 to -80°C and stirred for 30-50 min at -70 to -80°C. Charged 1.82 ml of triethylamine and allow to RT slowly. Charged 20 ml of DM water and layers separated, and organic layer washed with 5 ml of brine solution. (Title compound obtained as organic layer which is used for further step).

Example 6: Synthesis of (3aR,4R,5R,6aS)-4-((E)-3-oxo-5-phenylpent-1-en-1-yl)-5-((triethylsilyl)oxy)hexahydro-2H-cyclopenta[b]furan-2-one (Formula H, where R2= triethylsilyl)
Charged 20 ml of methyl tertiary butyl ether to the 100 ml of 4N round bottom flask, cooled to 0 to -20°C then charged 0.7 g of lithium hydroxide and stirred at -20 to 30°C for 1 to 2 hours. Charged organic layer of (3aR,4S,5R,6aS)-2-oxo-5-((triethylsilyl)oxy)hexahydro-2H-cyclopenta[b]furan-4-carbaldehyde from example 5, stirred for 1-2 hours at -20 to 30°C. After the completion of reaction, charged 10 ml of DM water and layers separated, again extracted with 10 ml of ethyl acetate and combined organic layers were washed with 10 ml of brine solution, dried over sodium sulphate and concentrated under reduced pressure at 30-40°C. (Title compound obtained as organic layer which is used for further step).

Example 7: Synthesis of (3aR,4R,5R,6aS)-4-(3-hydroxy-5-phenylpentyl)-5-((triethylsilyl)oxy)hexahydro-2H-cyclopenta[b]furan-2-one (Formula J, where R2= triethylsilyl)
To a stirred solution of (3aR,4R,5R,6aS)-4-((E)-3-oxo-5-phenylpent-1-en-1-yl)-5-((triethylsilyl)oxy)hexahydro-2H-cyclopenta[b]furan-2-one from example 6 (1 gm in 10 ml of methanol) 0.273 g of NaBH4 (4.56 g) and 0.031 g of nickel chloride were added at 0 to 10°C and the mixture was stirred for 3 h at the same temperature. After completion of the reaction, the reaction mixture was quenched 1N HCL solution at 0°C. Organic solvent was removed under reduced pressure, aqueous layer was extracted 2 times with 15 ml of dichloromethane and organic layer washed with brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure to get title compound as colourless liquid (Yield: 1.0 g)
OR
To a stirred solution of (3aR,4R,5R,6aS)-4-((E)-3-oxo-5-phenylpent-1-en-1-yl)-5-((triethylsilyl)oxy)hexahydro-2H-cyclopenta[b]furan-2-one (1 g in 20 ml of methanol) 0.10 gm of palladium on carbon was charged followed by 5 to 10 kg Hydrogen, stirred at RT for 6 to 12 hours, on completion of reaction, filtered through celite pad and washed with 5 ml of methanol. Distilled under reduced pressure to get residue. The residue obtained was charged to 10 ml of tetrahydrofuran under nitrogen atmosphere and cooled to 0° to -40°C. A 60% solution of (-) DIP Chloride in heptane (2.88 ml) charged slowly, the conversion was completed under the nitrogen atmosphere for 2 to 4 hours. Reaction monitored by checking TLC, after completion of reaction, 2 ml of methanol was added followed by 10 mL of water and extracted 3 times with 10 ml of ethyl acetate. The combined organic layers were washed with 5 ml of brine and concentrated at 40°C under reduced pressure affording the crude product as an oil. Desired compound purified through 100-200 mesh silica and ethyl acetate: hexane as mobile phase to get title compound as colourless liquid (Yield: 0.70 g).

Example 8: Synthesis of (3aR,4R,5R,6aS)-4-(5-phenyl-3-((triethylsilyl)oxy)pentyl)-5-((triethylsilyl)oxy)hexahydro-2H-cyclopenta[b]furan-2-one (Formula K, where R2= triethylsilyl)
To a solution of (3aR,4R,5R,6aS)-4-(3-hydroxy-5-phenylpentyl)-5-((triethylsilyl)oxy)hexahydro-2H-cyclopenta[b]furan-2-one (1 gm in 20 ml of dichloromethane), charged 2.65 g of triethylamine and stirred for 20 to 30 min at 20-30°C then 0.64 g of triethyl silyl chloride at 10-30°C, heated to 30 to 45°C and stirred at the same temperature for 6 to 12 hours under nitrogen atmosphere. Reaction monitored by checking TLC (mobile phase 40% ethyl acetate: hexane), after the completion of reaction, charged 10 ml of DM water and extracted 2 times with 10 ml of dichloromethane, combined organic layer washed with 50 ml of saturated brine solution, dried over sodium sulphate and concentrated under reduced pressure at 30 50°C to get title compound colourless liquid (Yield: 0.9 g).

Example 9: Synthesis of (3aR,4R,5R,6aS)-4-(5-phenyl-3-((triethylsilyl)oxy)pentyl)-5-((triethylsilyl)oxy)hexahydro-2H-cyclopenta[b]furan-2-ol (Formula L, where R2= triethylsilyl)
Charged 9 ml of tetrahydrofuran followed by 0.9 gm of (3aR,4R,5R,6aS)-4-(5-phenyl-3-((triethylsilyl)oxy)pentyl)-5-((triethylsilyl)oxy)hexahydro-2H-cyclopenta[b]furan-2-one in to round bottom flask, cooled to -70 to 78°C, charged slowly 3.38 ml of DIBAL-H 1M in heptane dropwise at -70 to -78°C and stirring was continued for 1-3 h under nitrogen atmosphere. After completion of the reaction as indicated by TLC, the reaction mixture was quenched with methanol (2 ml) at below -70°C, reaction temperature was raised to 5°C and charged 5 ml of ammonium chloride solution and 10 ml of ethyl acetate. Filtered through celite and separated the layers. Again, extracted 2 times with 10 ml of ethyl acetate. Combined organic layer were washed with brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Desired compound purified through 100 to 200 mesh silica and 10% methanol: dichloromethane as mobile phase to get title compound as colourless liquid (Yield: 0.60 g).

Example 10: Synthesis of (4-cyanobutyl)(triphenyl)phosphonium bromide (Formula M)
Charged 60 ml of toluene/acetonitrile, followed by 5.0 g of 5-bromovaleronitrile and 8.9 g of triphenylphosphine into round bottom flask, heated to reflux for 48 to 72 hours. Reaction monitored by checking TLC (Mobile Phase: 15% Ethyl acetate:hexane), after completion of reaction cooled to 10 to 20°C, filtered and washed with 10 ml of acetonitrile /toluene to get residue. The residue dried under reduced pressure at 50 to 60°C. was heated under reflux in acetonitrile (50 ml) for 48 hours. By allowing to cool, 12.8 g (about 89%) of 4-cyanobutyltriphenylphosphonium bromide was obtained as colourless crystals.

Example 11: Synthesis of (Z)-7-((1R,2R,3R)-5-hydroxy-2-(5-phenyl-3-((triethylsilyl)oxy)pentyl)-3-((triethylsilyl)oxy)cyclopentyl)hept-5-enenitrile (Formula N)
Charged 20 ml of Tetrahydrofuran, followed by 4.76 g of (4-cyanobutyl)(triphenyl)phosphonium bromide in to round bottom flask and cooled to 0 to -20°C. slowly charged 11.14 ml of Potassium tert butoxide 1M in tetrahydrofuran and stirred at -20 to 30°C for 1 to 4 hours. charged a solution of (3aR,4R,5R,6aS)-hexahydro-5-trie- thylsilane-4-((S,E)-3-triethylsilane-5-phenylpent-cyclo- penta[b]furan-2-ol (1.0 g in 5 ml of THF), stirred at -20 to 20°C. Reaction monitored by checking TLC (Mobile Phase: 80% Ethyl acetate:hexane) after completion of reaction cooled to 0°C, and quenched by adding 20 ml of water and extracted 3 times with 10 ml of ethyl acetate, combined organic layers were washed with 5 ml of brine solution and dried over sodium sulfate and concentrated under reduced pressure, crude compound obtained was purified through 100 to 200 mesh size silica and methanol:dichloromethane as mobile phase to get title compound as colourless liquid (Yield: 0.8 g, Purity by HPLC: 97.5%).

Example 12: Synthesis of 4-Iodobutyl (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoate (Formula II, where R1=Iodo)
Charged 10.0 ml of dichloromethane/Chloroform followed by 500 mg of (Z)-7-((1R,2R,3R)-5-hydroxy-2-(5-phenyl-3-((triethylsilyl)oxy)pentyl)-3 ((triethylsilyl)oxy)cyclopentyl)hept-5-enenitrile into round bottom flask, stirred for 20 to 30 min at 0 to 5°C. Purged Hydrochloric gas for 10 to 20 min at 0 to 5°C and stirred for 1 to 4 hours at 0 to 5°C. Charged slowly 0.134 g of 4-chlorobutan-1-ol /0.249 g of 4-iodobutan-1-ol. After completion of the reaction, quenched by adding 20 ml of water and adjusted pH 7 to 8 by aqueous ammonia, layers separated. Aqueous layer extracted 2 times with 10 ml of dichloromethane. Combined organic layers were washed with 5 ml of brine solution and distilled under reduced pressure at 40-45°C to get title compound as dark brown liquid (Yield: 0.5 g, Purity by HPLC: 98%).

Example 13: Synthesis of (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoic acid (Latanoprost acid, Formula IV)
Charged 15.0 g of Latanoprost in 300 ml methanol in round bottom flask at temperature 20-30°C, followed by the addition of 60 ml of water. Stirred to get clear solution, cooled to 0 to 5°C and charged 7.27 of lithium hydroxide monohydrate. Stirred for 4 to 16 hours at 20-30°C, after the completion of reaction distilled and degassed at 35 to 50°C under vacuum. Charged 150 ml of DM water to residual mass obtained and adjusted pH 1.0 to 4.0 by using 1N HCl at temperature 5-20°C. Extracted 3 times with 150 ml of ethyl acetate. Organic layers were combined and washed with 75 ml of saturated brine solution. Dried over sodium sulphate and concentrated under reduced pressure at 30 to 50°C to give 13.5 g viscous oil as Latanoprost acid (Yield: 13.5 g (w/w=0.9), Purity by HPLC: 97 %).

Example 14: Synthesis of (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enenitrile (Formula VII) by using (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoic acid (Latanoprost acid)
Charged 2.0 ml of acetonitrile, 2.0 ml of carbon tetrachloride and 0.254 g of vanadyl acetylacetonate followed by 0.25 g of (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl) cyclopentyl) hept-5-enoic to the perkin vial. Close the Vial and heat for 10-12 hours at 70-95°C. After reaction completion, cooled to room temperature and filtered through celite and distilled under reduced pressure at 40 to 45°C to get title compound as brown oil (Yield: 0.2 g, Purity by HPLC: 97%).

Example 15: Synthesis of (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enenitrile (Formula VII) by using Latanoprost
Charged 0.25 g of Latanoprost to the 2.0 ml of dichloromethane or Tetrahydrofuran in a round bottom flask and cooled to -70 to 78°C. Charged 2.3 ml of DIBAL-H at -78°C, stirred for 4 to 5 hours at -70° to -78°C. Slowly allowed to warm to 0°C then charged 1 ml of aqueous ammonia and 0.733 g of iodine. Heated to 20 to 40°C and stirred for 10-15 hours. After reaction completion, charged 10 ml of DM water, extracted 3 times with 10 ml of ethyl acetate and dried over sodium sulphate and concentrated under reduced pressure at 40-45°C to get title compound as brown oil (Yield: 0.2 g, Purity by HPLC: 98%).

Example 16: Synthesis of 4-Iodobutyl (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoate (Formula II, where R1=Iodo)
Charged 4.0 ml of dichloromethane/Chloroform followed by 200 mg of (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl) hept-5-enenitrile into round bottom flask, stirred for 20 to 30 min at 0 to 5°C. Purged Hydrochloric gas for 10 to 20 min at 0 to 5°C stirred for 1 to 4 hours at 0 to 5°C and charged slowly 0.087 g of 4-chlorobutan-1-ol /0.161 g of 4-iodobutan-1-ol. After completion of the reaction, quenched by adding 10 ml of water and adjusted pH 7 to 8 by aqueous ammonia, layers separated. Aqueous layer extracted 2 times with 10 ml of dichloromethane. Combined organic layers were washed with 5 ml of brine solution and distilled under reduced pressure at 40-45°C. (Title compound obtained as organic layer which is used for further step). (Yield: 0.22 g, Purity by HPLC: 98%).

Example 17: Synthesis of 4-benzyloxy-butyl (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoate (Formula II, where R1=O-Benzyl)
Charged 4.0 ml of Chloroform followed by 200 mg of (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl) hept-5-enoic acid into round bottom flask, stirred for 20 to 30 min at 0 to 5°C. Purged Hydrochloric gas for 10 to 20 min at 0 to 5°C stirred for 1 to 4 hours at 0 to 5°C and charged slowly 0.087 g of 4-benzyloxybutyl chloride. After completion of the reaction, quenched by adding 10 ml of water and adjusted pH 7 to 8 by aqueous ammonia, layers separated. Aqueous layer extracted 2 times with 10 ml of dichloromethane. Combined organic layers were washed with 5 ml of brine solution and distilled under reduced pressure at 40-45°C to obtain 0.22g titled compound with purity 98% by HPLC. (Title compound obtained as organic layer may be used for further step).

Example 18: Synthesis of 4-iodobutyl 1H-imidazole-1-carboxylate
Charged 5 ml of acetonitrile to the 0.20 g of 4-iodobutan-1-ol in to round bottom flask, stirred at room temperature to get clear solution, then added portion wise 0.243 g of carbonyldiimidazole (CDI) and continued stirring at 25° to 50°C. Reaction monitored by checking TLC (mobile phase 70% ethyl acetate: hexane. After completion of reaction, filtered through celite and washed with 4 ml of ethyl acetate and distilled under reduced pressure at 35° to 45°C. Charged 5 ml of DM water and extracted 2 times with 5 ml of ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure at 35° to 45°C to get title compound dark brown oil (Yield: 0.25g).

Example 19: Synthesis of 4-Iodobutyl (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoate (Formula II, where R1=Iodo)
Charged 5.0 ml of Acetonitrile to the perkin vial followed by addition of 200 mg of Latanoprost acid and 0.15 g of 4-iodobutyl 1H-imidazole-1-carboxylate, heated to 80 to 85°C and continued heating and stirring at 80 to 85°C for 12 to 16 hours. Reaction monitored by checking TLC (Mobile Phase 5% methanol: dichloromethane). After completion of reaction, distilled under reduced pressure at 35-45°C and to this charged 5 ml of DM water and extracted 2 times with 5ml of ethyl acetate, combined organic layers were dried over sodium sulphate, concentrated under reduced pressure at 40-45°C to give title compound as brown oil (Yield: 0.22 g, Purity by HPLC: 98.5%).

Example 20: Synthesis of (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl) cyclopentyl)hept-5-enoyl chloride (Compound of formula IX, where R6 = Chloro)
Charged 20 ml of MDC to the 50 ml of 4 neck round bottom flask followed by the addition of 1.0 g of Latanoprost acid and 2-3 drops of dimethylformamide under nitrogen, stirred at room temperature to get cleared solution. The solution cooled to 0 to 5°C, charged dropwise 0.48 g of oxalyl chloride to it, allowed to warm to room temperature, and stirred at room temperature for 2-4 hr. After completion of reaction, distilled under reduced pressure at 25 to 40°C get title compound as colorless liquid. (0.8 g)

Example 21: Synthesis of 4-hydroxybutyl (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoate (Compound of formula X)
Charged 4.42 g of conc sulfuric acid to the 25.0 g of tetrahydrofuran in a round bottom flask at 0 to 20°C and followed by the addition of 107.42 g of 47% of aqueous HBr at 0 to 20°C. The reaction mixture stirred for 2 to 10 hours at 40 to 70°C and cooled to 0 to 5°C. Charged 125 ml of water to it, adjusted pH 5 to 9 by using 20% of aqueous sodium hydroxide solution and extracted 2 times with 100 ml of dichloromethane. The combined organic layers were washed with 50 ml of saturated brine solution and dried over sodium sulphate. Distilled off under reduced pressure at 30 to 45°C to get 20.0 g of light-yellow oil. In another 250 ml RBF charged 100 ml of DM water followed by the addition of 10.45 g of sodium hydroxide, stirred to get cleared solution and charged 20.0 g of light yellow oil obtained to it and heated to 50 to 100°C. After completion of reaction, adjusted pH 4 to 7 by adding 1N HCl and extracted 2 times with 100 ml of dichloromethane, organic layer washed with 50 ml of brine solution, dried over sodium sulfate and concentrated under reduced pressure, compound obtained as 10.0 g of colorless oil.
Charged 10 ml of dichloromethane to the 0.264 g (from 10.0 g of colorless oil) stirred to get clear solution and cooled to 0 to 20°C followed by 0.296 of triethylamine and stirred for 30 min to 60 min at 0 to 20°C. charged dropwise solution of (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoyl chloride (1.0 g in 10 ml of dichloromethane) to the reaction mass at 0°C to 20°C, stirred at 10 to 45°C. After the completion of reaction quenched by adding 5 ml of DM water and layers separated, again extracted 2 times with 10 ml of dichloromethane, combined organic layers were washed with 5 ml of brine solution, dried over sodium sulfate and concentrated under reduced pressure at 30 to 45°C to get title compound 1.0 g of colorless oil.

Example 22: Synthesis of 4-chlorobutyl (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoate (Compound of formula II, where R1 = chloro)
Charged 10 ml of dichloromethane to the 50 ml of 4 neck round bottom flask followed by the addition of 1.0 g of 4-hydroxybutyl (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoate, cooled to 0 to 10°C and charged dropwise 0.30 g of thionyl chloride under nitrogen, stirred at 2-4 hours at 10 to 40°C. After completion of the reaction, distilled under reduced pressure at 20 to 40°C, charged 10 ml of water and adjusted pH 6 to 7 by aqueous ammonia. Extracted 3 times with 10 ml of ethyl acetate, washed with 5 ml of brine solution, dried over sodium sulfate and concentrated under reduced pressure at 30 to 45°C, to get title compound as 1.0 g of colorless oil. (Purity by HPLC: 98.4%)

Example 23: 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 0.80 g of 4-Chorobutyl (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoate to the 16.0 ml of acetonitrile, followed by the addition of 0.565 g of silver nitrate at 5 to 30°C and heated to 35 to 75°C for 72 hours. Reaction monitored by checking TLC (50% Ethyl acetate:Hexane). After the completion of reaction filtered through celite pad and washed with 6 ml of ethyl acetate, distilled under reduced pressure, charged 10 ml of DM water and extracted 3 times with 15.0 ml of ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure at 35 to 45°C to get title compound as brown oil (Purity by HPLC=70-75%, Yield=0.78 g).

Example 24: 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 0.50 g of 4-Iodobutyl (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoate to the 10.0 ml of acetonitrile in round bottom flask, followed by the addition of 0.24 g of silver nitrate at 5 to 30°C and heated to 35 to 75°C for 72 hours. Reaction monitored by checking TLC (50% Ethyl acetate:Hexane). After completion of reaction filtered through celite pad and washed with 10 ml of ethyl acetate, distilled under reduced pressure and charged 10 ml of DM water and extracted 2 times with 10.0 ml of ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure at 35 to 45°C to get Latanoprostene Bunod as brown liquid (0.5 g, Purity by HPLC: 98.9%).

Example 25: 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 0.50 g of 4-benzyloxy-butyl (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoate to the 10.0 ml of acetonitrile in round bottom flask, followed by the addition of 0.24 g of silver nitrate at 5 to 30°C and heated to 35 to 75°C for 72 hours. Reaction monitored by checking TLC (50% Ethyl acetate:Hexane). After completion of reaction filtered through celite pad and washed with 10 ml of ethyl acetate, distilled under reduced pressure and charged 10 ml of DM water and extracted 2 times with 10.0 ml of ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure at 35 to 45°C to get Latanoprostene Bunod as brown liquid (0.5 g, Purity by HPLC: 99.3%).

Example 26: Purification of Latanoprostene bunod by preparative HPLC (High performance liquid chromatography)
0.5 g of Crude Latanoprostene bunod dissolved in 1.0 ml of acetonitrile and purified on preparative HPLC, using water: acetonitrile (80:20) (as mobile phase). The fractions were collected and purity of fractions were monitored by HPLC. Collected purest fractions charged to single neck round bottom flask, freezed at -40 to -80°C and Lyophilized to get the pure Latanoprostene bunod. Compound dissolved in 1-5 vol of ethanol and transferred to single neck round bottom flask, followed by 3-20 volumes of water, stirred to get mixed, freeze at -40° to -80°C then Lyophilized.
Sample sent for OVI analysis, if ethanol was present more than the ICH limit (NMT 5000 ppm), charged 4-20 vol of Water and mixed well with compound then lyophilized again and sent sample to check ethanol content as OVI. If still ethanol would be present more than the ICH limit, repeat the process to achieve the ICH limit of ethanol to get Colorless to light brown oil. (Purity by HPLC: 99.23%, Yield: 0.25 g.)
,CLAIMS:WE CLAIM
1. A process for the preparation of Latanoprostene Bunod of Formula I, wherein said process comprising, converting compound of Formula II to Latanoprostene Bunod of Formula I, in presence of nitration source;

wherein R1 is choro or iodo.

2. The process as claimed in claim 1, wherein said nitration source is selected from, nitric acid: sulphuric acid, and silver nitrate.

3. A process for the preparation of Latanoprostene Bunod intermediate of Formula II,

wherein R1 is chloro, iodo or OR2, R2 is hydrogen or hydroxyl protecting group;
wherein said process is selected from:
1) comprising reacting Latanoprost acid of Formula IV

with compound of Formula VI

wherein R2 is as defined above and X is halogen;
or,

2a) converting Latanoprost acid of Formula IV to compound of Formula VII,
;and
2b) converting compound of Formula VII to compound of Formula II by reacting with compound of Formula VIII,

wherein R1 is choro or iodo,

or,
3a) converting Latanoprost acid to its acyl halide or its anhydride in presence of acylating agent,

wherein R6 is halogen or –OCOalkyl;
3b) treating compound of Formula IX with tetrahydrofuran to give compound of Formula X,

and
3c) converting compound of Formula X to compound of Formula II,

wherein R1 is chloro, iodo or OR2, R2 is hydrogen or hydroxyl protecting group.

4. Compound of Formula II,

wherein R1 is chloro, iodo or OR2, R2 is hydrogen or hydroxyl protecting group;

5. A process for the preparation of Latanoprostene Bunod of Formula I, wherein said process comprising the steps of:
a) reacting protected cyano compound of Formula N with compound of Formula VIII followed by de-protection to give compound of Formula II,
,
and
b) converting compound of Formula II to Latanoprostene bunod of Formula I, in presence of nitration source;
wherein, R2 is hydroxyl protecting group and R1 is chloro or iodo.

6. A process for the preparation of compound of formula II or formula I,
or
wherein said process comprising the steps of:
a) reaction of compound of formula S

with base in the presence of solvent to give compound of formula R

b) hydrogenation of compound of formula R to give compound of formula Q

c) protection of hydroxyl groups of formula Q to give compound of P

d) reduction of compound of formula P to give compound of formula O

e) reaction of compound of formula O with a 4-cyano butyl triphenyl phosphonium bromide compound of formula M

to give compound formula N
; and
f) conversion of compound of formula N to compound of formula II or formula I, wherein R2 is hydroxyl protecting group.

8. Compounds of formula N and formula VII,

wherein R2 is hydroxyl protecting group.

9. The process according any of the preceding claims, wherein hydroxyl protecting group is selected from alkyl, alkyl aryl, C1-C6 acyl, -CO(C1-C12) aryl, -(CO)C1-C16 alkyl ¬aryl, -(COO)C1-C10 alkyl ¬aryl, mesyl, tosyl, tert-butyloxycarbonyl, acetyl and alkyl silyl.

10. A process for the purification of compound of formula I, comprising the steps of:
a) adding suitable one or more solvents to the compound of Formula I to get reaction mass;
b) optionally, heating the reaction mass; and
c) cooling the reaction mass and isolate the pure compound of Formula I.

Dated 26th Day of Feb, 2024 For Mankind Pharma Ltd.

Dr. Anil Kumar
Chief Scientific Officer