FIELD OF INVENTION
[0001] The present invention relates to a process for the preparation of netarsudil or its pharmaceutically acceptable salts. The present invention further describes a process for preparation of amorphous form of netarsudil or its pharmaceutically acceptable salts.
BACKGROUND OF THE INVENTION
[0002] Netarsudil is a novel glaucoma medication acting as Rho Kinase inhibitor and norepinephrine transport inhibitor. As of December 18, 2017 the US FDA approved Aerie Pharmaceutical's Rhopressa® (netarsudil ophthalmic solution) 0.02% for the indication of reducing elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension.
[0003] Netarsudil dimesylate is chemically known as [4-[(2S)-3-amino-l-(isoquinolin-6-ytamino)-l-oxopropan-2-yl] phenyl] methyl 2,4-dimethylbenzoate dimesylate is represented by the chemical formula-I3

[0004] The patent US 8,450,344 generically discloses netarsudil and process for
preparation thereof.
[0005] The patent US 8,384,826 specifically discloses Netarsudil, salts and solvates
thereof and process for preparation thereof. The patent discloses a preparation
process of racemic N-protected netarsudil which is subjected to supercritical fluid
chromatography to obtain the corresponding S and R isomer. The N-protected S
isomer is treated with acid (HC1) to obtain netarsudil dihydrochloride.
[0006] The patent US 9,415,043 describes netarsudil dimesylate.
[0007] The patent US 9,643,927 describes a process for the preparation of netarsudil
or its pharmaceutically acceptable salt. Example 6 discloses a reaction of (S) isomer
of 3-((tert-butoxycarbonyl)amino)-2-(4-(((2,4- dimethyl benzoyl )oxy) methyl
)phenyl)propanoic acid with 6-aminoisoquinoline using 2,22-trichloro-l,l-
dimethylethyl chloroformate and collidine in DMF to obtain N-protected netarsudil
in crude form. The crude form is subjected to multiple recrystallization processes to
obtain a pure compound. The example 7 discloses that the pure N-Boc protected
netarsudil is treated with methane sulfonic acid to obtain netarsudil dimesylate. The
methods disclosed herein make use of tedious processes to obtain the final
compound meeting the yield and purity requirements.
[0008] The patent US 10442770 discloses crystalline forms Nl, N2, N3, N4, N5, N6
and N7 of netarsudil dimesylate and a process for preparation thereof.
[0009] The prior art processes for preparation of netarsudil or its pharmaceutically
acceptable salts and intermediate compound thereof are tedious and not industrially
viable.
[0010] Further, there is a need in the prior art to prepare netarsudil or its
pharmaceutically acceptable salt with high yield and purity and meeting the
standards of various regulatory agencies.

SUMMARY OF THE INVENTION
[0011] In one embodiment, the present invention provides a process for preparation of netarsudil or its pharmaceutically acceptable salt comprising the steps of:
a) Condensation of compound of formula-II with 6-amino isoquinoline to obtain the compound of formula-Ill.
b) Optionally purifying the compound of formula III obtained in step (a) using column chromatography,
c) Chiral resolution or separation of the compound of formula-Ill obtained in step (a) or (b) to the corresponding S isomer.
d) N-deprotection of the S-isomer obtained in step (c) using acid and
e) isolation.

[0012] In another embodiment of the present invention provides an amorphous form
of netarsudi! dimesylate.
[0013] In another embodiment the amorphous form of netarsudil dimesylate
described herein characterized by a PXRD substantially similar to the PXRD
as depicted in FIG. 1.
[0014] In another embodiment of the present invention provides a process for
preparation of amorphous form of netarsudil dimesylate comprising;
a) Dissolving netarsudil dimesylate in water or a mixture of water and organic solvent to obtain a solution
b) Optionally filtering the solution obtained in step (a) and
c) Lyophilizing the solution obtained in step (a) or (b).
[0015] In another embodiment of the present invention provides a process for preparation of netarsudil or its pharmaceutically acceptable salt as depicted in scheme-I

BRIEF DESCRIPTION OF THE DRAWINGS
[0016] Figure. 1 shows a powder X-ray diffraction pattern (powder XR.D or powder XRPD) of amorphous form of netarsudil dimesylate.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0017] As used herein, the following terms and phrases shall have the meanings set forth below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art. [0018] The term as used herein "substantially pure" means a chemical purity equal to or greater than 99.8 %, and/or a total content of impurities less than or equal to 0.2%, and or each individual impurity being present in an amount less than or equal to 0.1%, as determined using high performance liquid chromatography (HPLC). [0019] The term as used herein purity is based on the "organic" purity of the compound. Purity does not include a measure of any amount of water, solvent, metal, inorganic salt, etc. In one aspect, the purity of desired compound is compared to the purity of the reference standard by comparing the area under the peak. [0020] The term as used herein "pharmaceutically acceptable salts" means salts derived from pharmaceutically acceptable inorganic and organic acids. The non-limiting examples of suitable acids include but are not limited to hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, toleune-p-sulphonic, tartaric, acetic, trifluoroacetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic, cysteic acid and benzenesulphonic acids .
[0021] The term as used herein "racemic mixture" means a chemical mixture comprising of an equimolar ratios of the R and S enantiomers. In one aspect the desired enantiomer is separated ideally by making use of chiral resolving agents or

by instrumental methods such as preparative HPLC, wherein the pure targeted
enantiomers are separated from the racemic mixture for further use.
[0022] The term as used herein "enantiomeric excess" means a measurement of
purity of chiral substance which ranges from about 1% to about 99%. In some
embodiments, the enantiomeric excess is equal to or greater than about 5%, about
10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about
80%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about
99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about
99.7%, about 99.8%, about 99.9%, or about 99.99%.
[0023] The term as used herein" purification by chromatography "means a method
of purification of the chemical compound or the drug molecule using the
chromatographic techniques. In another aspect of the present invention the
purification of the chemical compound or the drug molecule is achieved by the
column chromatography ,TLC, HPLC, flash chromatography, UPLC and likewise,
wherein the differences in the molecular characteristics related to the adsorption,
partition and affinity or molecular weight differences is used to purify the chemical
compound or the drug molecule.
[0024] The term used as herein "improved yield" means a sufficiently good overall
weight of the chemical compound or the drug molecule. In another aspect of the
present invention it essentially means the overall weight of the chemical compound
or the drug molecule is preferably increased by using the said process disclosed in
the present invention.
[0025] The term used herein" amorphous" means a non-crystalline form of a
chemical compound or a drug.
[0026] The term as used herein "lyophilization" means a process in which water is
removed from a product after it is frozen and placed under a vacuum, allowing the
ice to change directly from solid to vapor without passing through a liquid phase.

The process consists of mainly three separate, unique, and interdependent processes
called freezing, primary drying (sublimation), and secondary drying (desorption).
[0027] The term as used herein "vacuum drying" is used to speed up the moisture
removal process from the product by subjecting to reduced pressure which reduces
the boiling point and aids evaporation of the water or capillary transport.
[0028] The term as used herein "substantially removing" the solvent refers to at least
80%, specifically greater than about 85%, more specifically greater than about 90%,
still more specifically greater than about 99%, and most specifically essentially
complete (100%), removal of the solvent from the API.
[0029] The present invention provides a process for preparation of netarsudil or its
pharmaceutically acceptable salts comprising the steps of:
a) Condensation of compound of formula-II with 6-amino isoquinolineto obtain the compound of formula-Ill.
b) Optionally purifying the compound of formula III obtained in step (a) using column chromatography,

c) Chiral resolution or separation of the compound of formula-Ill obtained in step (a) or (b) to the corresponding S isomer.
d) N-deprotection of the S-isomer obtained in step (b) using acid and
e) isolation.
[0030] Condensation of compound of formula-II with 6-amino isoquinoline to obtain the compound of formula-Ill. The present invention uses racemic mixture and enantiomeric excess of S isomer in the range of 1% to 100% of compound of formula-Ii in the said condensation process.
[0031] In another embodiment the 6-aminoisoquinoline used herein may be prepared by the reaction of 6-bromo isoquinoline with aqueous ammonia in presence of metal hydroxide such as copper (I) oxide and sodium hydroxide in a-suitable solvent. [0032] Jn another embodiment the non-limiting examples of the N-protecting groups corresponding to the compound of formula-II includes but are not limited to Fmoc (9-fluorenyl methyl carbamate), BOC (t-butyl carbamate),benzyl carbamate, acetamide, p-methoxybenzyl carbamate, trifluoroacetamide, phthalimide, benzylamine, triphenyl methyl amine, benzylidene amine , p-toluenesulfonamide. In one specific embodiment the N-protecting group used is preferably BOC (t-butyl carbamate).
[0033] In another embodiment the enantiomeric excess of the (S) isomer of the compound of formula-II may be selected from a range but is not limited to is equal to or greater than about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.1%, about 99.2%, about 99.3%, about 99.4%, about 99.5%, about 99.6%, about 99.7%, about 99.8%, about 99.9%, or about 99.99%. [0034] In another embodiment the non-limiting examples of the solvents used in the step (a) condensation reaction includes but are not limited to, polar aprotic solvents such as dimethyl formamide, dimethyl sulfoxide, and N-methylpyrrolidinone;

ethereal solvents such tetrahydrofuran, 2-methyl tetrahydrofuran, methyl t-butyl ether, dimethyl ether, diisopopyl ether, 1,4-dioxane and diethoxymethane; hydrocarbons such as benzene, toluene, hexanes, xylene and heptane; halogenated solvents such as dichloromethane, ethylene bromide, ethylene chloride, chloroform, carbon tetrachloride and 1,2-dichloroethane; acetates such as ethyl acetate, isopropyl acetate, and butyl acetate, and other solvents such as acetonitrile, methyl vinyl ketone, N,N-dimethylacetamide; and mixtures thereof. In a specific embodiment the solvent used is preferably dimethyl formamide.
[0035] In still another embodiment the non-limiting examples of the suitable bases
used in the step, condensation reaction include, but are not limited to organic bases
such as 2,4,6-trimethyl pyridine and the like, organolithiums, , triethylamine (TEA),
N-heterocyclic compounds, tetra alkylammonium compounds • and phosphonium
hydroxides, metal alkoxides and amides and metal silanoates such as n-butyllithium,
sec-butyllithium, tert-butyllithium, hexyllithium, isopropyllithium, 2,2,6,6-
tetramethylpiperidine, 4-(dimethylamino)pyridine, N,N diisopropylmethylamine,
diethylamine, morpholine, piperidine,(piperidinomethyl)polystyrene,4-
(dimethylamino)pyridine,N-ethyldiisopropylamine, lithium tert-butoxide, barium tert-butoxide, magnesium di-tert-butoxide, magnesiumethoxide, potassium ethoxide, sodium tert-butoxide, tetrabutylammonium hydroxide, tetramethylammonium hydroxide solution, trimethylphenyl ammonium hydroxide, tetrapropylammonium hydroxide, tetrahexylammonium hydroxide solution, sodiumtert-pentoxide, sodium ethoxide, sodiumtert-butoxide, potassiumtert-butoxide, lithium isopropoxide, lithium ethoxide, lithiumtert-butoxide, bariumtert-butoxide, sodium hydroxide, sodiumcarbonate, sodium-bi-carbonate, sodium methoxide and similar lithium, potassium, calcium, magnesium and barium compounds preferably 2,4,6- trimethyl pyridine.
[0036] In still another embodiment the non-limiting examples of the reagents used for the activation of the carboxylic acid group of compound of formula-II includes

but are not limited to coupling agents like benzo triazole -1-yl-
oxytris(dimethylamino)phosphoniumhexafluoro-phosphate(BOP), N3N' -
dicyclohexylcarbodiimide (DCC), 1-hydroxibenzotriazol anhydrous(HOBt), N-(3-
dimethylaminopropyl)-N-ethylcarbodiimide(EDC)5(l
[Bis(dimethylamino)methylene] -lH-l,2,3-triazolo[4,5-b] pyridinium3-oxidhexa fluorophosphate, Hexafluorophosphate AzabenzotriazoleTetramethyl Uronium) (HATU), 2-(lHBenzotriazole-l-yl)-l,ls3,3-tetramethylaminium tetrafluoroborate N. 2-( 1 H-Benzotriazole-1 -yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU), (2-(lH-benzotriazol-l-yl)-l,l,3,3- tetramethyluroniumhexafhexafluorophosphate, Hexafluorophosphate Benzotriazole Tetramethyl Uronium) (RBTU), N,N'-Diisopropylcarbodiimide (DIC). In a specific embodiment the reagents used for the activation of carboxylic acid group in formula-II by conversion into corresponding mixed acid anhydride or halide includes but not limited to propyl phosphonic anhydrides and the like, (2, 2, 2-trichloro-l, l-dimethylethyl chloroformate), n-octyl chloroformate, methyl chloroformate, ethyl chloroformate, or isobutyl chloroformate, benzyl chloroformate, [(2-ethylcyclohexan-l-ol)yl] chloroformate, tert-butyl chloroformate preferably 2, 2, 2-trichloro-l, l-dimethylethyl chloroformate).
[0037] In still another embodiment the step (a) reaction may be performed at temperatures -50° C. to about 150° C, preferably in the range of from -25° C. to about 100° C, preferably in the range of from -20° C. to about 80° C, preferably in the range of from -15° C. to about 60° C and more preferably in the range of from -10° C. to about 50° C.
[0038] In another embodiment the step (a) reaction may be carried out for any desired time periods to achieve the desired product yield and purity, with time periods from about 1 to 20 hours, or longer, as required for the reaction completion. [0039] In still another embodiment of the present invention, the compound of formula (III) is isolated by conventional methods such as solvent evaporation,

precipitation etc. In still another embodiment the non-limiting examples of the solvents used for the extraction of the intermediate compounds formed in the step (a) condensation reaction include, but are not limited to ethyl acetate, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, monoglyme, diglyme, methanol, ethanol, n-propanol, 2-ethylhexanol isopropanol, n-butanol, isobutanol, tert-butanol, amy! alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl isopropyl ketone, mesityl oxide, methyl tert-butyl ketone, acetonitrile, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, trichloroethylene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride and mixtures thereof. In one embodiment, solvent used for the extraction is preferably ethyl acetate.
[0040] In still another embodiment the compound of formula (III) is optionally purified using column chromatography. The stationary phase of the column is selected from silica gel. The mobile phase is selected from suitable organic solvents such as methanol, methylene chloride, methyl propanediol, 2-ethyl-l,3-heaxanediol, benzyl alcohol, ethylene glycol, 1,3-butanediol, 1,6-heaxanediol, pyrocatechol, triethylene glycol, 1,4-butanediol, 1,2-octanediol, resorcinol, glycerol, 1,2,4-butanetriol, 1,8-octanediol, hydroquinone, tributyl phosphate and 1,9-nonaediol or mixtures thereof preferably methanol-methylene chloride.
[0041] In still another embodiment of the present invention involves chiral resolution or separation of the compound of formula-Ill to the corresponding S isomer of formula (III). In another embodiment, the chiral preparative HPLC system using chiralcel OX CSP as stationary phase and 70% acetonitrile + 30% methanol + 0.1% diethyl amine as mobile phase is used for purification of compound of formula III. The purification process of the present invention provides the S-isomer of compound of formula (III) having purity, greater than 80%, preferably greater than 90%, more preferably greater than 97%.N-deprotection of the S-isomer obtained in step (b) using acid

[0042] N-deprotection of the compound of formula (111) is carried by treating the compound of formula (III) with suitable acid to obtain netarsudil or its pharmaceuticaUy acceptable salts.
[0043] In another embodiment the non-limiting examples of the acids used in the step.c N-deprotection includes but are not limited to suitable acids include but are not limited to hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, toleune-p-sulphonic, tartaric, acetic, trifluoroacetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic, cysteic acid and benzenesulphonic acids In a specific embodiment the acid used is preferably methanesulfonic acid.
[0044] In another embodiment, the N-deprotection may involve presence or absence of organic solvent.
[0045] In another embodiment the non-limiting examples of the solvents used in the step (c) N-deprotection reaction includes but are not limited to, polar protic solvents such as water, methanol, ethanol, , n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, pentanol, octanol, acetic acid, polar aprotic solvents such as dimethyl formamide, dimethyl sulfoxide, and N-methylpyrrolidinone; ethereal solvents such as tetrahydrofuran, 2-methyl tetrahydrofuran, methyl t-butyl ether, dimethyl ether, diisopopyl ether, 1,4-dioxne and diethoxymethane; hydrocarbons such as benzene, toluene, hexanes, xylene and heptane; halogenated solvents such as methylene dichloride, ethylene bromide, ethylene chloride, chloroform, carbon tetrachloride and 1,2-dichloroethane; acetates such as ethyl acetate, isopropyl acetate, and butyl acetate, and other solvents such as acetonitrile, methyl vinyl ketone, N,N-dimethylacetamide; and mixtures thereof. In a specific embodiment the solvent is preferably methylene dichloride and isopropyl alcohol.
[0046] In another embodiment the step (c) reaction may be performed at temperatures -50° C. to about 150° C, preferably in the range of -25° C to about

100° C, preferably in the range of from -20° C to about 90° C, preferably in the
range of-15° C to about 80° C and more preferably in the range of from 0° C to
about 70° C.
[0047] In another embodiment the step (c) reaction may be carried out for any
desired time periods to achieve the desired product yield and purity, with time
periods from about 1 to 48 hours, or longer, as required for the reaction completion.
[0048] Isolation of netarsudil or its pharmaceutically acceptable salts is carried out
by conventional methods such as evaporation, precipitation etc.
[0049] In another embodiment of the present invention provides an amorphous form
of netarsudil dimesylate.
[0050] In another embodiment of the amorphous form of netarsudil dimesylate
described herein characterized by a PXRD substantially similar to the PXRD
as depicted in FIG . 1.
[0051] The amorphous form netarsudil dimesylate according to the present invention
is substantially pure and more stable.
[0052] In another embodiment of the present invention provides a process for
preparation of amorphous form of netarsudil dimesylate comprising;
d) Dissolving netarsudil dimesylate in water or a mixture of water and organic solvent to obtain a solution
e) Optionally filtering the solution obtained in step (a) and
f) Lyophilizing the solution obtained in step (a) or (b).
[0053] In another embodiment a process for preparation of amorphous netarsudil dimesylate is carried out by dissolving the compound in suitable solvents such as water or mixture of water and organic solvent. The solution is optionally filtered through 0.22 micron capsule filter. The solution is lyophilized by freezing the solution to -60°C and drying under reduced pressure of 300 millitorr. to obtain amorphous form of netarsudil dimesylate.

[0054] In another embodiment the non-limiting examples of the solvents used lyophilization reaction includes but are not limited to water, acetonitrile, acetone, methanol, ethanol or mixtures thereof. In a specific embodiment the solvent used is preferably water.
[0055] In another embodiment the lyophilization may be performed at temperatures -50° C to about 150° C, preferably in the range of-25° C to about -100° C, preferably in the range of-20° C to about -90° C, preferably in the range of-15° C to about -80° C and more preferably in the range of-10° C to about -60° C. [0056] The inventors surprisingly found that the amorphous form of netarsudil according to the present invention has residual solvent content within the ICH limit and the amorphous form can be directly used in a pharmaceutical composition for ophthalmic, parenteral and oral administration. The- below Table 1 provides a comparison of residual solvent content before and after lyophilization of netarsudil dimesylate. The lyophilization process provides amorphous netarsudil dimesylate having residual solvent content well within the ICH limit. Compared to the prior art processes, the present process to obtain netarsudil or its pharmaceutically acceptable salt having low level of residual solvent is simple, cost effective and industrially viable. Further, the amorphous form of netarsudil dimesylate obtained according to the present invention is stable. Table 1: Comparison of residual solvent.

embodiment, the purity is greater than about 98.5%. In another embodiment, the
purity is greater than about 99.0%. In another embodiment, the purity is greater than
about 99.5.
J0058] In one embodiment, the purity is determined by HPLC.
[0059] In one embodiment, the present invention relates to the desired final
compound of formula-I having enantiomeric purity greater than about 98%. Jn one
embodiment, the purity is greater than about 98.5%. In one embodiment, the purity is
greater than about 99.0%. In one embodiment, the purity is greater than about 99.5.
In one embodiment, the enantiomeric purity is determined by chiral HPLC
technique.
[0060] In another embodiment, the present invention relates to a pharmaceutical
composition of netarsudil dimesylate produced by a process comprising; dissolving
netarsudil dimesylate in pharmaceutically acceptable carrier. The pharmaceutical
acceptable carrier includes any and all solvents, dispersion media, coatings, isotonic
and absorption delaying agents and the like known in the art.
[0061] Certain specific aspects and embodiments of the invention will be explained
in more detail with reference to the following examples, which are provided for
purposes of illustration only and should not be construed as limiting the scope of the
invention in any manner.
[0062] The invention can be illustrated with the few examples shown below which
are no way limit the scope of the present invention.

[0064] To the NMP solvent (5ml/g), 6-bromoisoquinoline (10 g), copper (I) oxide (0.05 eq.) and sodium hydroxide (2.0 eq.) were added at room temperature into a pressure vessel. The reaction mixture was cooled to 0 to 10 °C and then aqueous ammonia 30 ml/g (30%) was added to the reaction mass and heated 90-l00°C and stirred for 24 h. The reaction mass was cooled to 25 to 30 °C and evaporated under high vacuum and the resulted residue was suspended in aq. citric acid solution (30%). The aqueous solution was washed with dichloromethane (2 x 10 ml/g), and filtered through hyflo and separated. The pH of the aqueous layer was adjusted to 11-13 with aq. sodium hydroxide solution and the precipitate was filtered. The crude product was purified using silica gel column chromatography to get the 6-aminoisoquinoline (4.0 g Yield: 30-40%w/w, purity: >99.0%).
[0066] Dimethyl formamide (8 ml/g) was charged into a flask and cooled to -5 to -10°C under nitrogen atmosphere and 3-((tert-Butoxycarbonyl)amino)-2-(4-(((2,4-

dimethylbenzoyl)oxy)methyl)phenyl)propanoic acid (25 g) was added and stirred. To the reaction mixture at -5 to -10°C, 6-aminoisoquinoline (0.44g/g; 1.3 eq.) was added and then 2, 4, 6-trimethy! pyridine (0.40 ml/g 1.3 eq.) was added at -5 to -10°C and stirred for 10-15 minutes. 2, 2, 2-trichlorol,l-dimethylethylchloroformate (0.73g/g 1.3 eq.) in DMF (4ml/g) was added to the reaction mixture at -5 to -I0°C and stirred at same temperature for 10-15 minutes followed by the temperature was raised to 10-15°C and stirred for 6 hours. The reaction mass was added to pre-cooled water (50 ml/g) at 0 to 5°C. Ethyl acetate (2 x 25 ml/g) was added and the layers were separated and evaporated under vacuum at 700 mm of Hg at 40-45°C and dried the material under high vacuum at 40-45°C. The obtained crude compound 4-(3-((tert-butoxycarbonyl)amino)-l-(isoquinolin-6-ylamino)-l-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate was purified using column chromatography using silica gel as stationary phase and methanol-methylene chloride as solvent for elution. (Yield = 22 g 75-95%; Purity - NLT 98.0 %).
[0067] Example 3: Chiral resolution of 4-(3-((tert-butoxvcarbonvl)amino)-l-(isoquinolin-6-vlamino)-l-oxopropan-2-vDbenzyl 2,4-dimethylbenzoate
[0068] The compound 4-(3-((tert-butoxycarbonyl)amino)-1-(isoquinolin-6-ylamino)-l-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate obtained in Example 2 (1,0 g) subjected to chiral preparative HPLC system using chiralcel OX CSP as stationary phase and 70% acetonitrile (0.94L/g) + 30% methanol (0.44 L/g) + 0.1% diethyl amine (1.38 ml/g) as mobile phase. Pure fractions were collected and concentrated under vacuum at 25-30°C. Yield: 80-85% w/w; purity: NLT 98.0%; Chiral purity: R-enantiomer NMT 0.15%].

The compound 4-(3-((tert-butoxycarbonyl) amino)-l-(isoquinolin-6-ylamino)-l-oxopropan-2-yl) benzyl 2,4-dimethylbenzoate (45 g) was added into a round bottomed flask containing dichtoromethane (lOml/g) at 20-25°C under nitrogen atmosphere and stirred. Methane sulfonic acid (0.434g) dissolved in dichloromethane (2 ml/g) was added to the reaction mixture at 0-5°C and stirred for 30-40 minutes and the temperature was raised to 20-30°C and stirred for 24 hours at 20-30°C. The reaction mass was concentrated under vacuum 600-700 mm Hg and dried at 40-45°C for 30 minutes. Isopropyl alcohol (20 ml/g) was added under nitrogen atmosphere and heated to 55-60°C followed by distillation of isopropyl alcohol 10 ml/g under vacuum. The reaction mass was cooled to 20-30°C and stirred for 24 hours under nitrogen atmosphere. The precipitated solid was filtered and washed with isopropyl alcohol (2 ml/g) under nitrogen atmosphere and then dried under high vacuum to get netarsudil dimesylate (46.45g). Yield w/w: 85-95% Purity: NLT 99.5%; Chiral purity: R-enantiomer -NMT0.15%.
[0070] Example 5: Lyophilization of netarsudil dimesylate
Netarsudil dimesylate (81g) obtained in Example 4 was dissolved in 10 ml/g water at 25-30°C and filtered through 2 micron followed by 0.22 micron capsule filter and the filtrate was charged into a lyophilizer flask and lyophilized for 24 hours to get netarsudil dimesylate as a lyophilized API (81 g). Yield w/w: 95-100% w/w; Purity: NLT 99.5%; chiral purity: NMT 0.15%. PXRD: Fig.l

We Claim:
1. A process for preparation of netarsudil or its pharmaceutically acceptable
salts comprising the steps of: a) Condensation of compound of formula-II with 6-amino isoquinoline to obtain
the compound of formula-Ill.
n
b) Optionally purifying the compound of formula III obtained in step (a) using column chromatography,
c) Chiral resolution or separation of the compound of formula-Ill obtained in step (a) or (b) to the corresponding S isomer.
d) N-deprotection of the S-isomer obtained in step (c) using acid and
e) isolation.
2. The process according to claim 1, wherein the compound of formula II, in step (a), is in the form of racemic or enantiomeric excess of S isomer equal to or greater than about 5, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 96%,' about 97%, about 98%, about 99%, about 99.1%, about 99.2%, about 99.3%,

about 99.4%, about 99.5%: about 99.6%, about 99.7%, about 99.8%, about 99.9%, or about 99.99%.
3. The process according to claim I, wherein the acid in step (d) is selected from hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, toleune-p-sulphonic, tartaric, acetic, trifluoroacetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene-2-sulphonic, cysteic acid and benzenesulphonic acid.
4. An amorphous form of netarsudil dimesylate.
5. The amorphous form according to claim 4, wherein the residual solvents content is in the range of <0.1%.
6. Amorphous form of netarsudil dimesylate described herein characterized by a PXRD substantially similar to the PXRD as depicted in FIG .1.
7. The amorphous form as claimed in claim 4, 5 and 6, wherein purity of amorphous netarsudil dimesylate isNLT 99%.
8. A process for preparation of amorphous form of netarsudil dimesylate comprising;

a) Dissolving netarsudil dimesylate in water or a mixture of water and organic solvent to obtain a solution
b) Optionally filtering the solution obtained in step (a) and
c) Lyophilizing the solution obtained in step (a) or (b).
9. The process according to claim 8, wherein the solvent is water in step (a).