DESC:FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(SECTION 10 and rule 13)

“PROCESS FOR PREPARATION OF NETARSUDIL DIMESYLATE”

Glenmark Pharmaceuticals Limited
Glenmark Life Sciences Limited;
an Indian Company, registered under the Indian company’s Act 1957 and having its registered office at
Glenmark House,
HDO- Corporate Bldg, Wing-A,
B. D. Sawant Marg, Chakala,
Andheri (East), Mumbai- 400 099

The following specification particularly describes the invention and the manner in which it is to be performed.
FIELD OF THE INVENTION
[0001] The present invention relates to process for the preparation of netarsudil dimesylate.

BACKGROUND OF THE INVENTION
[0002] Netarsudil Dimesylate, which is chemically known as (S)-4-(3-amino-1-(isoquinolin-6-yl-amino)-1oxopropan-2-yl) benzyl 2,4-dimethylbenzoate dimesylate, is represented by chemical formula II,

II
[0003] Netarsudil Dimesylate is indicated for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension.
SUMMARY OF THE INVENTION
[0004] In one embodiment, the present invention provides a process for the preparation of (S)-netarsudil or a salt thereof, a compound of formula I,

I
comprising the step of:
a) contacting ethyl-3-amino-2-(4-((triisopropylsilyloxy)methyl) phenyl) propanoate, compound of formula VI, with a chiral acid (HA) to form an isomeric mixture comprising desired chiral acid addition salt of ethyl-3-amino-2-(4-((triisopropylsilyloxy)methyl) phenyl) propanoate, a compound of formula VIIA and undesired chiral acid addition salt of ethyl-3-amino-2-(4-((triisopropylsilyloxy)methyl) phenyl) propanoate, compound of formula VIIB;
VI
b) separating the desired chiral acid addition salt of ethyl-3-amino-2-(4-((triisopropylsilyloxy)methyl) phenyl) propanoate, the compound of formula VIIA and undesired chiral acid addition salt of ethyl-3-amino-2-(4-((triisopropylsilyloxy)methyl) phenyl) propanoate, the compound of formula VIIB from the isomeric mixture of step a);
c) basifying the desired chiral acid addition salt of ethyl-3-amino-2-(4-((triisopropylsilyloxy) methyl) phenyl) propanoate, compound of formula VIIA to obtain the desired isomer VIIC; and
d) converting the desired isomer of ethyl-3-amino-2-(4-((triisopropylsilyloxy) methyl) phenyl) propanoate, compound of formula VIIC, to (S)-netarsudil or a salt thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0005] Fig. 1: XRPD pattern of D-Dibenzoyl tartaric acid salt of ethyl-3-amino-2-(4-((triisopropylsilyloxy) methyl) phenyl) propanoate.
[0006] Fig. 2: DSC pattern of D-Dibenzoyl tartaric acid salt of ethyl-3-amino-2-(4-((triisopropylsilyloxy) methyl) phenyl) propanoate.
[0007] Fig 3: TGA pattern of D-Dibenzoyl tartaric acid salt of ethyl-3-amino-2-(4-((triisopropylsilyloxy) methyl) phenyl) propanoate.
[0008] Fig 4; XRPD pattern of L-Dibenzoyl tartaric acid salt of ethyl-3-amino-2-(4-((triisopropylsilyloxy) methyl) phenyl) propanoate.
[0009] Fig 5: DSC pattern of L-Dibenzoyl tartaric acid salt of ethyl-3-amino-2-(4-((triisopropylsilyloxy) methyl) phenyl) propanoate according to example
[0010] Fig 6: TGA pattern of L-Dibenzoyl tartaric acid salt of ethyl-3-amino-2-(4-((triisopropylsilyloxy) methyl) phenyl) propanoate.
DETAILED DESCRIPTION OF THE INVENTION
[0011] In one embodiment, the present invention provides a process for the preparation of (S)-netarsudil or a salt thereof, a compound of formula I,

I
comprising the step of:
a) contacting ethyl-3-amino-2-(4-((triisopropylsilyloxy)methyl) phenyl) propanoate compound of formula VI, with a chiral acid (HA) to form an isomeric mixture comprising desired chiral acid addition salt of ethyl-3-amino-2-(4-((triisopropylsilyloxy)methyl) phenyl) propanoate, a compound of formula VIIA and undesired chiral acid addition salt of ethyl-3-amino-2-(4-((triisopropylsilyloxy)methyl) phenyl) propanoate, a compound of formula VIIB;
VI
b) separating the desired chiral acid addition salt of ethyl-3-amino-2-(4-((triisopropylsilyloxy)methyl) phenyl) propanoate, the compound of formula VIIA and undesired chiral acid addition salt of ethyl-3-amino-2-(4-((triisopropylsilyloxy)methyl) phenyl) propanoate, the compound of formula VIIB from the isomeric mixture of step a);
c) basifying the desired isomer of ethyl-3-amino-2-(4-((triisopropylsilyloxy) methyl) phenyl) propanoate, compound of formula VIIA to obtain the desired isomer VIIC; and
d) converting the desired isomer of ethyl-3-amino-2-(4-((triisopropylsilyloxy) methyl) phenyl) propanoate, compound of formula VIIC to (S)-netarsudil or a salt thereof.
[0012] In one embodiment, in step a) of the above process, the chiral acid is selected from the group consisting of camphor sulfonic acid, bromocamphorsulfonic acid, camphanic acid, camphoric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, dibenzyl tartaric acid, diethyl tartrate, diisopropyl tartrate, tartaric acid, di-para-tolyl tartaric acid, pyroglutamic acid, phenylpropionic acid, malic acid, mandelic acid, lactic acid, glutamic acid, and mixtures thereof.
[0013] In one embodiment, the reaction of the above step a) may be carried out in presence of a suitable solvent. The suitable solvent includes but is not limited to alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, pentanol, octanol and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dimethoxyethane, tetrahydrofuran, dioxane and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; acetonitrile; dimethylformamide; dimethyl sulfoxide; water or mixtures thereof.
[0014] In one embodiment, the compound of formula VI is reacted with desired isomer of dibenzoyl tartaric acid to obtain an isomeric mixture comprising desired isomer of dibenzoyl tartaric acid salt of ethyl-3-amino-2-(4-((triisopropylsilyloxy)methyl) phenyl) propanoate and undesired isomer of dibenzoyl tartaric acid salt of ethyl-3-amino-2-(4-((triisopropylsilyloxy)methyl) phenyl) propanoate.
[0015] In one embodiment, the present invention provides D-dibenzoyl tartaric acid salt of ethyl-3-amino-2-(4-((triisopropylsilyloxy) methyl) phenyl) propanoate.
[0016] In one embodiment, the present invention provides L-dibenzoyl tartaric acid salt of ethyl-3-amino-2-(4-((triisopropylsilyloxy) methyl) phenyl) propanoate.
[0017] In one embodiment, the present invention provides D-di-para-toluoyl tartaric acid salt of ethyl-3-amino-2-(4-((triisopropylsilyloxy) methyl) phenyl) propanoate.
[0018] In one embodiment, the present invention provides L-di-para-toluoyl tartaric acid salt of ethyl-3-amino-2-(4-((triisopropylsilyloxy) methyl) phenyl) propanoate.
[0019] In one embodiment, in step b), separation of the desired chiral acid addition salt of ethyl-3-amino-2-(4-((triisopropylsilyloxy)methyl) phenyl) propanoate, a compound of formula VIIA and undesired chiral acid addition salt of ethyl-3-amino-2-(4-((triisopropylsilyloxy)methyl) phenyl) propanoate, compound of formula VIIB from the isomeric mixture of step a)comprises the step of filtering the isomeric mixture comprising the chiral acid addition salt of desired isomer of ethyl-3-amino-2-(4-((triisopropylsilyloxy)methyl) phenyl) propanoate, compound of formula VIIA and the chiral acid addition salt of undesired isomer ethyl-3-amino-2-(4-((triisopropylsilyloxy)methyl) phenyl) propanoate, compound of formula VIIB from the isomeric mixture in a suitable solvent, wherein either the desired chiral acid addition salt of ethyl-3-amino-2-(4-((triisopropylsilyloxy)methyl) phenyl) propanoate, a compound of formula VIIA is soluble in the solvent and the undesired chiral acid addition salt of ethyl-3-amino-2-(4-((triisopropylsilyloxy)methyl) phenyl) propanoate, a compound of formula VIIB is insoluble or the desired chiral acid addition salt of ethyl-3-amino-2-(4-((triisopropylsilyloxy)methyl) phenyl) propanoate, a compound of formula VIIA is insoluble or the undesired chiral acid addition salt of ethyl-3-amino-2-(4-((triisopropylsilyloxy)methyl) phenyl) propanoate, a compound of formula VIIB is soluble.
[0020] The suitable solvent includes but is not limited to alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, pentanol, octanol and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dimethoxyethane, tetrahydrofuran, dioxane and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; acetonitrile; halogenated solvent such as methylene dichloride, ethylene dichloride and the like; dimethylformamide; dimethyl sulfoxide; water or mixtures thereof.
[0021] In one embodiment, in step c) of the above process, base for basifying the desired chiral acid addition salt includes but is not limited to inorganic base such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate; organic base such as triethylamine, diisopropylethylamine, pyridine; or mixtures thereof.
[0022] In one embodiment, the undesired isomer, the compound of formula VIID is optionally racemised and resolved to obtain the desired isomer of compound of formula VIIC.
[0023] In one embodiment, in step d), the desired isomer, compound of formula VIIC, is converted to (s)-netarsudil by a process comprising the steps of:
Di) N-protecting (PG) the amino group in the desired isomer, compound of formula VIIC, to obtain an N-protected (PG), compound of formula VIII;
wherein PG is a suitable protecting group selected from the group consisting of tert-butyloxycarbonyl, benzyl oxycarbonyl, acetyl and the like;
Dii) hydrolyzing the compound of formula VIII to obtain a compound of formula IX;
Diii) reacting the compound of formula IX with 6-aminoisoquinoline to obtain a compound of formula X;
Div) deprotecting the hydroxy group of the compound of formula X to obtain a compound of formula XI;
Dv) reacting the compound of formula XI with 2, 4-dimethyl benzoic acid to obtain a compound of formula XII;
Dvi) deprotecting the amino group of the compound of formula XII to obtain (S)-netarsudil, the compound of formula I; and
Dvii) optionally converting (S)-netarsudil, the compound of formula I to a salt thereof.
[0024] In one embodiment, in step Di) of the above process, the reaction of protecting the amino group of the desired isomer, the compound of formula VIIC is carried out in a suitable solvent. The suitable solvent includes but is not limited to; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dimethoxyethane, tetrahydrofuran, dioxane and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; acetonitrile; halogenated solvent such as methylene dichloride, ethylene dichloride and the like; dimethylformamide; dimethyl sulfoxide; or mixtures thereof.
[0025] In one embodiment, the above step Di), may be carried out in presence of a suitable base selected from organic or inorganic base. The base includes but is not limited to inorganic base such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate; organic base such as triethylamine, diisopropylethylamine, pyridine; or mixtures thereof.
[0026] In one embodiment, in step Di) of the above process, the desired isomer, the compound of formula VIIC is reacted with di-tert-butyl dicarbonate in a suitable solvent.
[0027] In one embodiment, in step Di) of the above process, the desired isomer, the compound of formula VIIC is reacted with di-tert-butyl dicarbonate in methylene dichloride.
[0028] In one embodiment, in step Di) of the above process, the desired isomer, the compound of formula VIIC is reacted with di-tert-butyl dicarbonate in methylene dichloride to obtain a compound of formula VIIIA.
[0029] In one embodiment, in step Dii) of the above process, the compound of formula VIII may be hydrolyzed using suitable base selected from the group consisting of hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; alkoxides such as sodium methoxide, tert-butoxide and the like or a suitable acid such as hydrochloric acid, sulphuric acid and the like.
[0030] In one embodiment, in step Dii) of the above process, the hydrolysis may be carried out using a suitable solvent. The suitable solvent includes but is not limited to alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, pentanol, octanol and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dimethoxyethane, tetrahydrofuran, dioxane and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; acetonitrile; dimethylformamide; dimethyl sulfoxide; water or mixtures thereof.
[0031] In one embodiment, in step Dii) of the above process, the compound of formula VIIIA is subjected to hydrolysis using lithium hydroxide in the presence of methanol to obtain the compound of formula IXA.
[0032] In one embodiment, in step Diii) of the above process, the compound of formula IX is reacted with 6-aminoisoquinoline in presence of a coupling agent to obtain a compound of formula X.
[0033] Suitable coupling agent may be selected from the group consisting of benzotriazole-1-yl-oxy-tris (dimethylamino)phosphoniumhexafluoro-phosphate (BOP),N,N'-dicyclohexylcarbodiimide (DCC), 1-hydroxibenzotriazol anhydrous(HOBt), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide(EDC),(1[Bis(dimethylamino) methylene] -1H-1,2,3-triazolo[4,5-b]pyridinium3-oxidhexafluorophosphate, Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium) (HATU), 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate Novabiochem®. CAS 125700-67-6, molar mixture 321.09g/mol., 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafhexafluorophosphate, Hexafluorophosphate Benzotriazole Tetramethyl Uronium) (HBTU) and the like.
[0034] The reaction may be carried out in presence of suitable organic bases selected from the group consisting of triethyl amine, trimethyl amine, pyridine, diisopropyl ethyl amine, pyridine and dimethyl amino pyridine or a mixture thereof.
[0035] In one embodiment, in step Diii) of the above process, the compound of formula IX is reacted with 6-aminoisoquinoline in the presence of a suitable solvent.
[0036] The suitable solvent includes but is not limited to; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dimethoxyethane, tetrahydrofuran, dioxane and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; acetonitrile; dimethylformamide; dimethyl sulfoxide; or mixtures thereof.
[0037] In one embodiment, in step Diii) of the above process, the compound of formula IXA is reacted with 6-aminoisoquinoline in pyridine in presence of N-(3-dimethylaminopropyl)-N-ethylcarbodiimide. hydrochloride (EDC. HCl) and dimethylaminopyridine to obtain a compound of formula Xa.
[0038] In one embodiment, in Div) of the above process, the hydroxy group of compound of formula X is deprotected using a suitable agents selected from the group consisting of sulfuric acid, hydrochloric acid, TFA (Trifluoroacetic acid),lithium borofluoride, tetrabutylammonium fluoride.
[0039] In one embodiment, in Div) of the above process, the hydroxy group is deprotected using a suitable agents in presence of a suitable solvent.
[0040] The suitable solvent includes but is not limited to alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, pentanol, octanol and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dimethoxyethane, tetrahydrofuran, dioxane and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; acetonitrile; halogenated solvent such as methylene dichloride, ethylene dichloride and the like; dimethylformamide; dimethyl sulfoxide; water or mixtures thereof.
[0041] In one embodiment, in Div) of the above process the oxy group of the compound of formula XA is deprotected using tetrabutylammonium fluoride in presence of tetrahydrofuran to obtain a compound of formula XIA.
[0042] In one embodiment, in step Dv) of the above process, the compound of formula XI is reacted with 2, 4-dimethyl benzoic acid in presence of a coupling agent to obtain a compound of formula XII.
[0043] Suitable coupling agent may be selected from the group consisting of Suitable coupling agent may be selected from the group consisting of benzotriazole-1-yl-oxy-tris (dimethylamino)phosphoniumhexafluoro-phosphate (BOP),N,N'-dicyclohexylcarbodiimide (DCC), 1-hydroxibenzotriazol anhydrous(HOBt), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide(EDC), (1 [Bis(dimethylamino) methylene] -1H-1,2,3-triazolo[4,5-b] pyridinium3-oxidhexa fluorophosphate, Hexafluorophosphate AzabenzotriazoleTetramethyl Uronium) (HATU), 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate Novabiochem®. CAS 125700-67-6, molar mixture 321.09g/mol., 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafhexafluorophosphate, Hexafluorophosphate Benzotriazole Tetramethyl Uronium) (HBTU) and the like.
[0044] The reaction may be carried out in presence of suitable organic bases selected from the group consisting of triethyl amine, trimethyl amine, pyridine, diisopropyl ethyl amine, pyridine and dimethyl amino pyridine or a mixture thereof
[0045] In one embodiment, in step Dv) of the above process, the compound of formula XI is reacted with 2, 4-dimethyl benzoic acid in the presence of a suitable solvent. [0046] In one embodiment, in step Dv) of the above process, the compound of formula XIA is reacted with 2, 4-dimethyl benzoic acid in pyridine in presence of N-(3-dimethylaminopropyl)-N-ethylcarbodiimide. hydrochloride (EDC. HCl) and dimethylaminopyridine to obtain a compound of formula XIIA.
[0047] In one embodiment, the step Dvi) of the above process involves deprotecting the amino group of the compound of formula XII in presence of a suitable deprotecting agent. The deprotecting agent may be selected from the group consisting of acid such as hydrochloric acid, sulfuric acid and the like.
[0048] In one embodiment, in step Dvi) of the above process, deprotection of the amino group of the compound of formula XII is carried out in in presence of a suitable deprotecting agent and a suitable solvent. The suitable solvent includes but is not limited to alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, pentanol, octanol and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dimethoxyethane, tetrahydrofuran, dioxane and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; halogenated solvents such as methylene dichloride, ethylene dichloride and the like; acetonitrile; dimethylformamide; dimethyl sulfoxide; water or mixtures thereof.
[0049] In one embodiment, in step Dvi) of the above process, deprotection of the amino group of the compound of formula XIIA is carried out in in presence of a hydrochloric acid and methylene dichloride and dioxane to obtain (S)-netarsudil, the compound of formula I.
[0050] In one embodiment, in step Dvii) of the above process, (S)-netarsudil is converted to its dimesylate salt by reacting with methanesulfonic acid in the presence of a suitable solvent.
[0051] The suitable solvent includes but is not limited to alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, pentanol, octanol and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dimethoxyethane, tetrahydrofuran, dioxane and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; acetonitrile; halogenated solvent such as methylene dichloride, ethylene dichloride and the like; dimethylformamide; dimethyl sulfoxide; water or mixtures thereof.
[0052] In one embodiment, the present invention provides a compound selected from the group consisting of:
VIIA VIIB
[0053] In one embodiment, the compound of formula I or a salt thereof may be prepared by a process represented by the scheme below:
[0054] In one embodiment, 4-(iodophenyl) methanol, compound of formula III is reacted with triisopropyl chloride (TIPS) to protect the hydroxy group in a suitable solvent to obtain a compound of formula IV. The suitable solvent is as discussed supra. [0055] The compound of formula IV is reacted with ethyl cyano acetate to obtain a compound of formula V. The compound of formula V is subjected to reduction to obtain a compound of formula VI.
[0056] The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention.

Examples:
Example 1: Preparation of (4-iodobenzyloxy) triisopropylsilane
To a stirred solution of (4-iodophenyl) methanol (100 g) in methylene dichloride, (36.35 g) imidazole was added at about 25°C to about 30°C. The reaction mixture was cooled to about 5°C to about 10°C and tri isopropyl silyl chloride (102.95g) was added. The reaction mixture was warmed to about 20°C to about 30°C and was stirred for about 8hrs to about 10hrs. After completion of reaction, water was added to the reaction mixture, and the aqueous and organic layer were separated. The organic layer was washed with 0.5 N hydrochloric acid solution, sodium bicarbonate solution, followed by brine solution and then distilled to obtain an oily residue (165g). The obtained oil was passed through silica column and eluted with hexane to obtain 162g of title product as oil.
Example 2: Preparation of ethyl 2-cyano-2-(4-(triisopropylsilyloxy) methyl) phenyl) acetate
To a stirred solution of (4-iodobenzyloxy) triisopropylsilane (100g) in dimethyl sulfoxide (700mL) ethyl cyano acetate (43.46g) and potassium carbonate (77.8g) were added at about 25°C to about 30 °C under nitrogen. Copper iodide and L-proline was then charged to the reaction mixture. The reaction mixture was heated to about 70°C to about 80°C and stirred for about 6 hour to about 8 hour. On completion of reaction, the reaction mixture was cooled to about 25°C to about 30°C. Water, methyl tert-butyl ether (1500mL) were added to reaction mixture and the two layers were separated. The organic layer was washed with brine solution and then concentrated to obtain crude ethyl 2-cyano-2-(4-(triisopropylsilyloxy) methyl) phenyl) acetate (70g) as oil. The obtained oil was passed through silica column and eluted with hexane and ethyl acetate to obtain title product (39g) as oil.

Example 3: Preparation of ethyl-3-amino-2-(4-((triisopropylsilyloxy) methyl) phenyl) propanoate
To a solution of ethyl 2-cyano-2-(4-(triisopropylsilyloxy) methyl) phenyl) acetate in methanol was added Raney Nickel in an autoclave to obtain a reaction mixture. The reaction mixture was stirred under hydrogen pressure of about 5 kg to about 6 kg at about 20°C to about 30°C for about 3 hours to about 4 hours. On completion of reaction, the reaction mixture was filtered through hyflo bed. The filtrate was distilled under vacuum to get a residue which was purified by column chromatography to obtain title product.

Example 4: Preparation of isomer of ethyl-3-amino-2-(4-((triisopropylsilyloxy) methyl) phenyl) propanoate
To a solution of ethyl 2-cyano-2-(4-(triisopropylsilyloxy) methyl) phenyl) acetate in methanol was added Raney nickel in an autoclave to obtain a reaction mixture. The reaction mixture was stirred under hydrogen pressure from about 5 kg to about 6 kg at about 25°C to about 30°C for about 3hrs to about 4hrs. On completion of the reaction, the reaction mixture was filtered through hyflo bed and washed with methanol. The filtrate was distilled under vacuum to get a residue. Ethyl acetate was charged into the obtained residue to obtain a solution. To this solution of (+)-Dibenzoyl-D-tartaric acid in ethyl acetate was charged. The reaction mixture was heated to about 50°C to about 60°C. The reaction mixture was gradually cooled to about 25°C to about 30°C and maintained for about 1 hour. The reaction mixture was filtered and washed with ethyl acetate. The wet cake was charged in dichloromethane and water and charged with triethyl amine. The reaction mixture was stirred for about 1 hour at about 25°C to about 30°C. The two layers were separated. The organic layer was distilled to obtain the title product.

Example 5: Preparation of isomer of DBTA salt of ethyl-3-amino-2-(4-((triisopropylsilyloxy) methyl) phenyl) propanoate
To a solution of ethyl-3-amino-2-(4-((triisopropylsilyloxy) methyl) phenyl) propanoate and ethyl acetate, a solution of Dibenzoyl-D-tartaric acid in ethyl acetate was charged. The reaction mixture was heated up to about 50°C to about 60°C. The reaction mixture was gradually cooled to about 25°C to about 30°C and reaction mixture was stirred for about 1 hour. The reaction mixture was filtered and title product was isolated and dried at about 40-50°C.

Example 6: Preparation of isomer of ethyl-3-amino-2-(4-((triisopropylsilyloxy) methyl) phenyl) propanoate
A solution of Dibenzoyl-D-tartaric acid (DBTA) salt of ethyl-3-amino-2-(4-((triisopropylsilyloxy) methyl) phenyl) propanoate was charged in a reaction mixture of methylene dichloride and water. Triethyl amine was charged and the reaction mixture was stirred for about 1 hour at about 25°C to about 30°C. The layers were separated. The organic layer was distilled to obtain the title product.

Example 7: Preparation of isomer of ethyl-3-(tert-butyloxycarbonylamino)-2-(4-((triisopropylsilyloxy) methyl) phenyl) propanoate
To a solution of isomer of ethyl-3-amino-2-(4-((triisopropylsilyloxy) methyl) phenyl) propanoate (9.0g) in methylene dichloride (90 mL), triethyl amine (4.8g) was charged to obtain a reaction mixture. The reaction mixture was cooled to about 0°C to about 10°C. To the reaction mixture, Boc anhydride was added (6.21g) and the reaction mixture was stirred for about 1 hour to about 2 hours. On completion of reaction, water was charged. The reaction mixture was stirred for about 10 minutes to about 15 minutes and the layers were separated. The organic layer was washed out with 0.5N HCl solution followed by water and brine. The organic layer was dried over sodium sulfate and concentrated. The title product was isolated as an oil after degassing.

Example 8: Preparation of isomer of 3-(tert-butoxycarbonylamino)-2-(3-((triisopropylsilyloxy) methyl) phenyl) propanoic acid
To a solution of isomer of ethyl-3-(tert-butyloxycarbonylamino)-2-(4-((triisopropylsilyloxy) methyl) phenyl) propanoate (11g) and methanol (110mL) lithium hydroxide solution (lithium hydroxide 2.41g in 55mL methanol) was charged at about 0°C to about 5°C to obtain a reaction mixture. The temperature of the reaction mixture was raised to about 20°C to about 25°C and was maintained for about 3hrs. On completion of reaction, methanol was distilled from the reaction mixture under vacuum at about 40°C. Water and ethyl acetate (165mL) were charged to the residue. The reaction mixture was cooled to about 0°C to about 10°C and the pH of reaction mixture was adjusted to about 5 to about 6 with hydrochloric acid. The reaction mixture was stirred for about 15min. The layers were separated. The organic layer was washed with water and followed by sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled to isolate the title product.
Example 9: Preparation of isomer of 3-(tert-butoxycarbonylamino)-2-(3-((triisopropylsilyloxy) methyl) phenyl) propoxy isoquinoline amine
To a solution of isomer of 3-(tert-butoxycarbonylamino)-2-(3-((triisopropylsilyloxy) methyl) phenyl) propanoic acid (3g) and pyridine (15mL), EDC. HCl (1.9g), dimethyl aminopyridine (0.6g) and 6-Amminoisoqunoline (1.005g) was charged. The reaction mixture was stirred for about 3 hour at about 25°C. On completion of reaction, ethyl acetate and 0.5N HCl solution (30mL) was charged to the reaction mixture. The reaction mixture was stirred for about 15min. The layers was separated. The organic layer was washed with 5% sodium carbonate solution followed by 10 % sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled from the organic layer. After distillation, heptane (15mL) was charged to the organic layer. The reaction mixture was stirred for about 60 min. The reaction mixture was filtered and washed with heptane. The wet cake was dried at about 40°C in tray dryer, to obtain the title compound.
Example 10: Preparation of isomer of 3-(tert-butoxycarbonylamino)-2-(3-(hydroxymethyl) phenyl) propoxy isoquinoline amine
To a solution of isomer of 3-(tert-butoxycarbonylamino)-2-(3-((triisopropylsilyloxy) methyl) phenyl) propoxy isoquinoline amine (1.2g) in tetrahydrofuran (12mL), tetra butyl ammonium fluoride (1.08g) was charged. The reaction mixture was stirred for about 4 hours. On completion of reaction, a saturated solution of ammonium chloride and ethyl acetate was charged to the reaction mixture. The reaction mixture was stirred for about 15min and the organic and aqueous layer were separated. The organic layer was washed with sodium chloride solution. The organic layer was dried over sodium sulfate followed by removal of sodium sulfate by filtration. The solvent was distilled under vacuum from the filtrate. Heptane (12mL) was charged in to the residue and stirred for about 30min. The reaction mixture was filtered. The solid obtained was dried in tray dryer to obtain the title compound.
Example 11: Preparation of isomer of 3-(tert-butoxycarbonylamino)-2-(3-(2,4-dimethylphenylcarbonyl methyl) phenyl) propoxy isoquinoline amine
To a solution of isomer of 3-(tert-butoxycarbonylamino)-2-(3-(hydroxymethyl) phenyl) propoxy isoquinoline amine (0.5g), pyridine (10mL), EDC.HCl (0.34g) and dimethyl amino pyridine (0.1g) were charged to obtain a reaction mixture. 2, 4-Dimethyl benzoic acid (0.19g) was charged to this reaction mixture. The reaction mixture was stirred for 2 hour at about 25°C. On completion of reaction ethyl acetate (20mL) and 0.5N HCl (20mL) were charged. The reaction mixture was stirred for 10 min and layers was separated. The ethyl acetate layer was combined and washed with 0.5 N HCl solution, 20 ml, 5 % Sodium carbonate solution followed by sodium chloride solution. The organic layer was dried over sodium sulfate, filtered and distilled under vacuum at 40°C. Heptane (10 mL) was charged to the residue and reaction mixture was stirred for 60min. Isolated wet product was dried at about 40°C in vacuum try dryer.
Example 12: Preparation of (S)-netarsudil
To a solution of isomer of 3-(tert-butoxycarbonylamino)-2-(3-(2,4-dimethylphenylcarbonyl methyl) phenyl) propoxy isoquinoline amine (0.4g) in methylene dichloride (4mL) was added dioxane. hydrochloric acid (2 mL) at about 0°C -5°C to obtain a reaction mixture. The temperature of reaction mixture was increased to about 25°C to about 30°C. The reaction mixture was stirred for 2.0 hour. On completion, the reaction mixture was concentrated. To the residue, ethyl acetate and water were charged followed by pH adjustment to about 9 with sodium carbonate solution. The two layers were separated and the organic layer was dried over sodium sulfate. The solvent was distilled to obtain (S)-netarsudil as oil.
Example 13: Preparation of (S)-netarsudil dimesylate
To a solution of (s)-netarsudil in methylene dichloride, methane sulfonic acid was added to obtain a reaction mixture. The reaction mixture was stirred for 12hours. The solvent was distilled and switched from to isopropyl alcohol. The reaction mixture was cooled to about 15°C to about 20°C and stirred for about 2 hour. Netarsudil dimesylate was isolated as a solid by filtration after washed with heptane. The resulting solid was dried in vacuum oven at about 65°C to get (S)-netarsudil dimesylate.
Example 14: Preparation of isomer of DBTA salt of ethyl-3-amino-2-(4-((triisopropylsilyloxy) methyl) phenyl) propanoate
To a solution of ethyl-3-amino-2-(4-((triisopropylsilyloxy) methyl) phenyl) propanoate in ethyl acetate, was charged a solution of (-)-Dibenzoyl-L-tartaric acid to obtain a reaction mixture. The reaction mixture was heated up to about 50°C to about 60°C. The reaction mixture was cooled to about 25°C to about 30°C and stirred for about 1 hour. The reaction mixture was filtered and the solid obtained was dried at 40-50°C.
Example 15: Preparation of isomer of ethyl-3-amino-2-(4-((triisopropylsilyloxy) methyl) phenyl) propanoate

To the isomer of DBTA salt of ethyl-3-amino-2-(4-((triisopropylsilyloxy) methyl) phenyl) propanoate in a mixture of methylene dichloride and water was added triethyl amine and the reaction mixture was stirred for 1hr at to about 25°C to about 30°C. Organic and aqueous layer was separated. Organic layers was washed with water. The organic layer was distilled to isolate the product.
Example 16: Preparation of isomer of Di-p-toluoyl-L-tartaric acid salt of ethyl-3-amino-2-(4-((triisopropylsilyloxy) methyl) phenyl) propanoate
To a solution of ethyl-3-amino-2-(4-((triisopropylsilyloxy) methyl) phenyl) propanoate in ethyl acetate was charged a solution of Di-p-toluoyl-L-tartaric acid in ethyl acetate obtain a reaction mixture. The reaction mixture was heated up to about 50°C to about 60°C. The reaction mixture was cooled to about 25°C to about 30°C and maintained for 1hr. The reaction mixture was filtered and dried at about 40°C to about 50°C to obtain the title product.
Example 17: Preparation of isomer of ethyl-3-amino-2-(4-((triisopropylsilyloxy) methyl) phenyl) propanoate
To Di-p-toluoyl-L-tartaric acid salt of ethyl-3-amino-2-(4-((triisopropylsilyloxy) methyl) phenyl) propanoate in a mixture of methylene dichloride and water was added triethyl amine was charged and the reaction mixture was stirred for 1hr at about 25°C to about 30°C. The layers were separated and organic layer was distilled to isolate the title product.

,CLAIMS:We claim:
1] A process for the preparation of (S)-netarsudil or a salt thereof, a compound of formula I,

I
comprising the step of:
a) contacting ethyl-3-amino-2-(4-((triisopropylsilyloxy)methyl) phenyl) propanoate compound of formula VI, with a chiral acid (HA) to form an isomeric mixture comprising desired chiral acid addition salt of ethyl-3-amino-2-(4-((triisopropylsilyloxy)methyl) phenyl) propanoate, a compound of formula VIIA and undesired chiral acid addition salt of ethyl-3-amino-2-(4-((triisopropylsilyloxy)methyl) phenyl) propanoate, a compound of formula VIIB;

VI
b) separating the desired chiral acid addition salt of ethyl-3-amino-2-(4-((triisopropylsilyloxy)methyl) phenyl) propanoate, the compound of formula VIIA and undesired chiral acid addition salt of ethyl-3-amino-2-(4-((triisopropylsilyloxy)methyl) phenyl) propanoate, the compound of formula VIIB from the isomeric mixture of step a);
c) basifying the desired isomer of ethyl-3-amino-2-(4-((triisopropylsilyloxy) methyl) phenyl) propanoate, the compound of formula VIIA to obtain the desired isomer compound of formula VIIC; and
d) converting the desired isomer of ethyl-3-amino-2-(4-((triisopropylsilyloxy) methyl) phenyl) propanoate, the compound of formula VIIC to (S)-netarsudil or a salt thereof.
2] The process as claimed in claim 1, wherein in step a) the chiral acid is selected from the group consisting of camphor sulfonic acid, bromocamphorsulfonic acid, camphanic acid, camphoric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, dibenzyl tartaric acid, diethyl tartrate, diisopropyl tartrate, tartaric acid, di-para-tolyl tartaric acid, pyroglutamic acid, phenylpropionic acid, malic acid, mandelic acid, lactic acid, glutamic acid, and mixtures thereof.

3] The process as claimed in claim 1, wherein in step d), desired isomer of ethyl-3-amino-2-(4-((triisopropylsilyloxy) methyl) phenyl) propanoate is converted to (S)-netarsudil by a process comprising the steps of:
i) N-protecting (PG) the desired isomer of ethyl-3-amino-2-(4-((triisopropylsilyloxy) methyl) phenyl) propanoate, to give a compound of formula VIII,
wherein PG is a suitable protecting group selected from the group consisting of BOC, CBZ, acetyl;
ii) hydrolyzing the compound of formula VIII to obtain a compound of formula IX;
iii) reacting the compound of formula IX with 6-aminoisoquinoline to obtain a compound of formula X;
iv) deprotecting the hydroxy group of the compound of formula X to obtain a compound of formula XI;
v) reacting the compound of formula XI with 2, 4-dimethyl benzoic acid to obtain a compound of formula XII;
vi) deprotecting the amino group of the compound of formula XII to obtain (S)-netarsudil, the compound of formula I; and
vii) optionally converting (S)-netarsudil, the compound of formula I to a salt thereof.

4] A compound selected from the group consisting of:

VIIA VIIB.

Dated this 16th day of October, 2019

(Signed) __________________
DR. MADHAVI KARNIK
SENIOR GENERAL MANAGER-IPM
GLENMARK LIFE SCIENCES LIMITED