DESC:CROSS REFERENCE TO RELATED APPLICATIONS
This application claims priority to the filing dates of Indian provisional Application No. IN202041004777, filed on Feb 04, 2020 & Indian provisional Application No. IN202041014131, filed on Mar 30, 2020; each of the preceding are hereby incorporated by reference in their entirety.
FIELD OF THE INVENTION
The present invention provides a process for the preparation of Ripasudil or its pharmaceutically acceptable salts. It also provides novel acid addition salts of formula II, which is a key intermediate in the preparation of Ripasudil and process for the preparation of 4- fluoroisoquinoline-5-sulfonyl chloride intermediate of formula IIa.
BACKGROUND OF THE INVENTION:
Ripasudil is a protein kinase inhibitor. The chemical name of Ripasudil is 4-Fluoro-5-[{(2S)-2-methyl-1,4-diazepan-1-yl} sulfonyl] isoquinoline. Ripasudil is understood to be represented by the following structural formula I.

U.S. patent No. 6,153,608 reports ripasudil and its hydrochloride salt. It is approved as ripasudil hydrochloride dihydrate.
U.S. patent No. 7,858,615 claims ripasudil hydrochloride dihydrate.
OBJECT AND SUMMARY OF THE INVENTION:
The principle aspect of the present invention encompasses a process for the preparation of Ripasudil or its pharmaceutically acceptable salts using novel acid addition salts of formula II. It also provides a process for the preparation of 4-fluoroisoquinoline-5-sulfonyl chloride of formula IIa.

In one aspect, the present invention provides a process for the preparation of an acid addition salt of formula II comprising the steps of:
a) reacting formula II with a suitable acid; and

b) isolating an acid addition salt of formula II.
In another aspect, the present invention provides oxalate salt; camphor sulfonate salt, phosphate salt and fumarate salts of formula II.

In one more aspect, the present invention provides an improved process for the preparation of 4- fluoroisoquinoline-5-sulfonyl chloride intermediate of formula IIa comprising the steps of:
a) forming a diazonium salt of 5-amino-4-fluoroisoquinoline of formula III;
b) reacting the above obtained diazonium salt with SOC12; and
c) isolating 4-fluoroisoquinoline-5-sulfonyl chloride of formula IIa.
Yet another aspect, the present invention provides a process for the preparation of Ripasudil hydrochloride alpha form comprising the steps of:
a) dissolving Ripasudil in a suitable solvent;
b) optionally seeding with Ripasudil hydrochloride alpha form;
c) adding isopropyl alcohol-HCl; and
d) isolating Ripasudil hydrochloride alpha form
BRIEF DESCRIPTION OF THE DRAWINGS
Further aspects of the present disclosure together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of embodiments of the disclosure which are shown in the accompanying drawing figures wherein:
Figure 1 shows a PXRD pattern of the Ripasudil Hydrochloride alpha form.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for the preparation Riapsudil HCl using novel intermediates. It also provides a process for preparing Ripasudil HCl alpha form.
Instrumentation:
Ripasudil HCl alpha form Powder X-ray diffraction measurements were made using Bruker axs D8 Advance powder diffractometer equipped with a goniometer of ?/? configuration and Lynx Eye detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 2? range of 2.0°-50.0° with 0.03° step size and 0.4 seconds step time.
The present invention provides a novel salt of formula II and process for the preparation of the same.

Within the context of this invention, "P" is an amine -protecting group. Examples of suitable amine protecting groups, as well as suitable conditions for protecting and deprotecting, can be found in prior art, such as J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973; T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999; "The Peptides"; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981 ; in "Methoden der organischenChemie", Houben-Weyl, 4th edition, Vol. 15/1, Georg Thieme Verlag, Stuttgart 1974; H.-D. Jakubke and H. Jescheit, "Aminosauren, Peptide, Proteine", Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982; and Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate", Georg Thieme Verlag, Stuttgart 1974.
Amine protecting groups include, for example, -Rp, =RQ, -C(0)R0, -C(O)OR0,-S(O)2R°, and 2-nitrophenylsulfenyl, wherein RP is a -C(RPI )3, wherein each RPI is hydrogen or optionally substituted aryl, provided that at least one RPI is not hydrogen;
RQ is =C(H)-R0; and
R0 is hydrogen, C1-10 alkyl, C2-10 alkenyl, C1-10 haloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein each alkyl, aryl, and heteroaryl group is optionally substituted.
"Optionally substituted" as used herein means the reference group is substituted by one or more groups (e.g., 1 to 5, or 1 to 3, or 1 to 2 groups, or 1 group) that are each independently halo, alkyl, alkoxy, nitro, cyano, tri(C1-3 alkyl)silyl (e.g., trimethylsilyl).
Particular examples of amine protecting groups include, carbonyls (e.g., methyl carbamate, 9-fluorenylmethyoxycarbonyl (Fmoc), trichloroethoxycarbonyl (Troc), t-butoxycarbonyl (BOC), 2-trimethylsilylethyloxycarbonyl (Teoc), allyloxycarbonyl (Alloc), p-methoxybenzyl carbonyl (Moz), and carboxybenzyl (Cbz)), sulfonyls (e.g., p-toluenesufonyl (Ts), trimethylsilylethanesulfoyl (Ses), t-butylsulfonyl (Bus), 4-methoxyphenylsulfonyl, 4-nitrobenzenesulfonyl (nosyl)), trityl (trt), benzyl (Bn), 3,4-dimethyoxybenzyl (Dmpm), p-methoxybenzyl (PMB), p-methoxyphenyl (PMP), acetyl (Ac), formyl, trifluoroacetyl (Tfa), benzoyl (Bz), or 2-nitrophenylsulfenyl (Nps).
As used herein, the term "alkenyl" means a straight or branched chain hydrocarbon containing from 2 to 10 carbons, unless otherwise specified, and containing at least one carbon-carbon double bond. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-l-heptenyl, 3-decenyl, and 3, 7-dimethylocta-2,6-dienyl.
The term "alkoxy" as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, t-butoxy, pentyloxy, and hexyloxy.
The term "alkyl" as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms, unless otherwise specified. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec -butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
The term "aryl," as used herein, means a monocyclic (i.e., phenyl), bicyclic, or tricyclic ring fused or bridged system containing at least one phenyl ring. Non-phenyl rings that are part of a bicyclic or tricyclic ring system may be fully or partially saturated, may contain one or more heteroatoms, each selected from N, S, and O, and may be optionally substituted with one or two oxo and/or thio groups. Examples of aryl groups include phenyl, napthyl, anthracenyl, and fluorenyl.
The term "arylalkyl" as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylalkylinclude, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, fluorenylmethyl and 2-naphth-2-ylethyl.
The term "halo" or "halogen" as used herein, means -CI, -Br, -I, or -F.
The term "haloalkyl" as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, perfluorononyl, and 2-chloro-3-fluoropentyl.
The term "heteroaryl," as used herein, means a monocyclic, bicyclic, or tricyclic ring system containing at least one heteroaromatic ring. Any additional rings that are part of a bicyclic or tricyclic ring system may be fully or partially saturated or may be aromatic rings, and each may optionally contain one or more heteroatoms, each selected from N, S, and O. Representative examples of monocyclic and bicyclic heteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, triazinyl,benzimidazolyl, benzofuranyl, benzothienyl, benzoxadiazolyl, benzoxathiadiazolyl, benzothiazolyl, cinnolinyl, dihydroquinolinyl, furopyridinyl, indazolyl, indolyl, isoquinolinyl, naphthyridinyl, quinolinyl, purinyl, and tetrahydroquinolin-yl.
The term "heteroarylalkyl" as used herein, means a heteroaryl, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heteroarylalkyl include, but are not limited to, furylmethyl, imidazolylmethyl, pyridinylethyl, pyridinylmethyl, pyrimidinylmethyl, and thienylmethyl.
The term "oxo" as used herein means a =O group. The term "thio" as used herein means a =S group.
In some embodiments, use of a t-butyloxycarbonyl(Boc) protecting group is found to be particularly useful as an amine -protecting group.
In one embodiment, the present invention provides an oxalate salt, camphor sulfonate salt, phosphate salt and fumarate salts of formula II.

In one embodiment, the amine protecting group is a t-bultyloxycarbonyl (Boc) group.;
In one embodiment, formula II of the present invention may be prepared by the process known in literature WO199920620.
In one embodiment, the present invention provides a process for the preparation of an acid addition salt of formula II comprising the steps of:
a) reacting formula II with a suitable acid; and

b) isolating an acid addition salt of formula II.
In one embodiment, the amine protecting group is a t-bultyloxycarbonyl (Boc) group.
As per the above embodiment, formula II is reacted with a suitable acid or its derivatives to isolate an acid addition salt of formula II. The reaction of formula II with said suitable acid may be carried out in presence of a polar solvent includes, but not limited to acetone, butanone, methyl isobutyl ketone, methyl isopropyl ketone, methanol, ethanol, propanol, isopropanol, butanol, diethyl ether, methyl tertiary butyl ether, tetrahydrofuran, dioxane, acetonitrile, dimethyl sulfoxide, dimethyl formamide; preferably acetone.
The suitable acid for the above embodiments includes, but not limited to oxalic acid, camphor sulfonic acid, phosphoric acid, fumaric acid, sulfuric acid, hydrobromic acid, maleic acid, malic acid, citric acid, acetic acid, tartaric acid, succinic acid and malonic acid.
Additional examples of acids include, for example, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, bisulfonic acid, boric acid, butyric acid, camphoric acid, cyclopentanepropionic acid, digluconic acid, dodecylsulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, glucoheptanoic acid, glycerophosphonic acid, gluconic acid, hemisulfonic acid, heptanoic acid, hexanoic acid, hydroiodic acid, 2-hydroxy-ethanesulfonic acid, lactobionic acid, lacticacid, lauronic acid, lauryl sulfonic acid, malonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, nicotinic acid, nitric acid, oleic acid, palmic acid, pamoic acid, persulfonic acid, 3-phenylpropionic acid, phthalic acid, picric acid, pivalic acid, propionic acid, stearic acid, p-toluenesulfonic acid, undecanoic acid, and valerate salts.
In one embodiment, the suitable acid is oxalic acid, camphor sulfonic acid, phosphoric acid and fumaric acid.
Next, the isolation of acid addition salt of formula II may be carried out by methods well known in the art, for example, by filtering the reaction mixture to obtain a solid. The solid may be further processed by drying to obtain an acid addition salt of formula II.
The salts of the present invention are advantageous as diazepane freebase is a liquid compound which is tough in handling at large scale. There is a need to develop intermediates which could be in solid form. Certainly, we have developed salts to get diazepine intermediate as solid. The preparation of diazepane as a salt increases purity of the compound.
In a specific embodiment, the present invention provides oxalate salt, camphor sulfonate salt, phosphate salt and fumarate salt of formula II, wherein P is t-bultyloxycarbonyl (Boc) group as provided below.
tert-butyl (S)-3-methyl-1,4-diazepane-1-carboxylate oxalate;
;
tert-butyl (S)-3-methyl-1,4-diazepane-1-carboxylate camphor sulfonate;

tert-butyl (S)-3-methyl-1,4-diazepane-1-carboxylate phosphate; and

tert-butyl (S)-3-methyl-1,4-diazepane-1-carboxylate fumarate.

In another embodiment, the resulting oxalate, camphor sulfonate, phosphate and fumarate salts of formula II may be further converted into Ripasudil or its pharmaceutically acceptable salts or polymorphs as per the processes known in the art.
In one embodiment, the present invention provides an improved process for the preparation of 4- fluoroisoquinoline-5-sulfonyl chloride of formula IIa.
The schematic representation of the present invention is as depicted in Scheme-1.

In another embodiment, the present invention provides an improved process for the preparation of ripasudil intermediate of 4-fluoroisoquinoline-5-sulfonyl chloride of formula IIa comprising the steps of:
a) forming a diazonium salt of 5-amino-4-fluoroisoquinoline of formula III;
b) reacting the above obtained diazonium salt with SOC12; and
c) isolating 4-fluoroisoquinoline-5-sulfonyl chloride of formula IIa.
Within the context of the present invention, the formation of diazonium salt of 5-amino-4- fluoroisoquinoline of formula III is carried out by reacting formula III with a reagent NaNO2. Diazotization reaction is carried out at -20 to +5 °C preferably at -15 to 0 °C.
The resulting diazonium salt is reacted with SOC12 to isolate 4-fluoroisoquinoline-5-sulfonyl chloride of formula IIa. The reaction of above diazonium salt with SOC12 is carried out in presence of a catalyst includes, but not limited to Copper (II) chloride dihydrate. This reaction is carried out at -20 to +5 °C preferably at - 15 to 0 °C.
The isolation of the resulting 4-fluoroisoquinoline-5-sulfonyl chloride of formula IIa may be carried out by methods well known in the art, for example, by filtering the reaction mixture or by distillation, or by concentration or by making salt formation to obtain a solid. The solid may be further processed by drying to obtain 4-fluoroisoquinoline-5-sulfonyl chloride of formula IIa.
The process disclosed in WO1999020620 for the preparation of 4-fluoroisoquinoline-5-sulfonyl chloride of formula IIa employs sulfur dioxide. The handling of sulfur dioxide during the reaction is not user friendly as it exists in gaseous state and it is highly toxic and difficult to handle to at commercial scale. According to the present invention, the SOC12 is user friendly in the preparation of 4-fluoroisoquinoline-5-sulfonyl chloride of formula IIa in bulk scale.
In on embodiment, the resulting 4-fluoroisoqu inoline-5-sulfonyl chloride of formula IIa is further converted into Ripasudil or its pharmaceutically acceptable salts as per the process known in literature.
Yet another embodiment, the present invention provides a process for the preparation of Ripasudil hydrochloride alpha form comprising the steps of:
a) dissolving Ripasudil in a suitable solvent;
b) optionally seeding with Ripasudil hydrochloride alpha form;
c) adding isopropyl alcohol-HCl; and
d) isolating Ripasudil hydrochloride alpha form.
Within the context of the present invention, the ripasudil is dissolved in a suitable solvent selected from methanol, ethanol, isopropanol, butanol, ethyl acetate, iso propyl ether or mixtures thereof and optionally seeded with ripasudil hydrochloride alpha form. Isopropyl alcohol-HCl is added to Ripasudil solution and isolated Ripasudil HCl alpha form.
The isolation of the resulting Ripasudil hydrochloride alpha form may be carried out by methods well known in the art, for example, by filtering the reaction mixture or by distillation, or by concentration or by making salt formation to obtain a solid. The solid may be further processed by drying to obtain Ripasudil hydrochloride alpha form.
In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.
Examples:
Example-I: tert-butyl (S)-3-methyl-1,4-diazepane-1-carboxylate oxalate.

1.0 g (0.0046 mol) of tert-butyl (S)-3-methyl-1,4-diazepane-1-carboxylate and 0.64 g (0.0051 mol) of oxalic acid dihydrate were taken in 10 ml of acetone and stirred for 120 min at 25±5 °C. The resulting solid was filtered and washed the wet compound with 2 ml of acetone (2ml). The solid was dried in hot air over at 40±2 °C for 5 hrs to yield 1.1 g of tert-butyl (S)-3-methyl-1,4-diazepane-1-carboxylate oxalate salt as white powder.
Example-II: tert-butyl (S)-3-methyl-1,4-diazepane-1-carboxylate camphor sulfonate

1.0 g (0.0046 mol) of tert-butyl (S)-3-methyl-1,4-diazepane-1-carboxylate and 1.19 g (0.0051 mol) of (1S)-(-)-10-camphorsulfonic acid were taken in 10 ml of acetone and stirred for 240 min at 25±5 °C. The resulting solid was filtered and washed the wet compound with 2 ml of acetone. The solid was dried in hot air over at 40±2 °C for 5 hrs to yeild 1.7 g of tert-butyl (S)-3-methyl-1,4-diazepane-1-carboxylate camphor sulfonate salt as a white powder.
Example-III: tert-butyl (S)-3-methyl-1,4-diazepane-1-carboxylate Phosphate

1.0 g (0.0046 mol) of tert-butyl (S)-3-methyl-1,4-diazepane-1-carboxylate and 0.45 g (0.0046 mol) of ortho phosphoric acid were taken in 10 ml of acetone and stirred for 720 min at 25±5 °C. The resulting solid was filtered and washed the wet compound with 2 ml of acetone. The solid was dried in hot air over at 40±2 °C for 5 hrs to yield 0.8 g of tert-butyl (S)-3-methyl-1,4-diazepane-1-carboxylate phosphate salt as a white powder.
Example-IV: tert-butyl (S)-3-methyl-1,4-diazepane-1-carboxylate Fumarate

0.5 g (0.0023 mol) of tert-butyl (S)-3-methyl-1,4-diazepane-1-carboxylate and 0.27 g (0.0023 mol) of fumaric acid were taken in 10 ml of acetone and stirred for 720 min at 25±5 °C. The resulting solid was filtered and washed the wet compound with 2 ml of acetone. The solid was dried in hot air over at 40±2 °C for 5 hrs to yield 0.8 g of tert-butyl (S)-3-methyl-1,4-diazepane-1-carboxylate fumarate salt as a white powder.
Example-V: Preparation of 4-Fluoroisoquinoline-5-sulfonyl chloride.

To a suspension of 2.0 g of 5-amino-4-fluoroisoquinoline of formula III in 15 ml of Con.hydrochloric acid was added a solution of 0.89 g of sodium nitrite in 5 ml of water slowly at -10 to —15 °C. The mixture was maintained 30 min at same temperature to get the diazonium salt. Simultaneously, In another flask to a solution of Copper (II) chloride dihydrate (0.33 g) in water (10 ml) was added 1.9 ml of thionyl chloride slowly dropwise for 10 min at 0-5 °C and maintained the reaction mass for 30 min at same temperature. The solution of thionyl chloride mixture was added to the diazonium salt solution at -10 to —15 °C and stirred the reaction mass 30 min at room temperature. The pH of the reaction mass was adjusted to 4 and extracted the product with ethyl acetate twice and washed the organic layer with 20 ml of water and concentrated the to get 4-Fluoro-5-sulfonyl chloride of formula IIa as a pale yellow solid. (2.6 g).
Example-VI : Preparation of Ripasudil dihydrochloride.

To a stirred solution of 100 g of Boc diazepane oxalate salt was dissolved in 100 ml water was cooled to 15-3 °C. To the reaction mixture was slowly added 39.4 g of sodium hydroxide dissolved in 100 ml of water to adjust pH:~12-13. 500 ml of dichloromethane was added to the reaction mixture and stirred the reaction for 15 mins. then, settle and separate the layers. The organic layer was washed with aqueous sodium chloride solution (50 g of NaCl dissolved in 400 ml of water) and stirred for 15 mins . The resulting organic layer was distilled off under atmospheric pressure followed by vacuum to get Boc diazepane freebase.
114.4 g of N,N-diisopropylethylamine was added to a stirred solution of 100 g of 4-Fluoroisoquinoline-5-sulfonyl chloride in 800 ml of dichloromethane at 7±3 °C. To this reaction mixture was added 83.49 g of Boc diazepane free base solution ( 83.49 g of Boc diazepane free base dissolved in 200 ml of dichloromethane) slowly dropwise at same temperature in 30-45 mins. Reaction mixture stirred for 5-6 hour at 30±5 °C After completion of the reaction, 800 ml of water was added to the reaction mixture and separated layers. The organic layer was washed with 800 ml of 5% aqueous sodium bicarbonate solution and collected organic layer. The resulting organic layer was distilled off under atmospheric pressure followed by vacuum to get residue, 100 mL of IPA was added to the residue and the solvent was distilled out completely under vacuum to get residue. 750 ml of isopropyl alcohol was added to the residue and stirred for 10-15 mins to get clear solution. 225 mL of IPA.HCl (~25%w/v solution) solution was slowly added and heated the reaction to 45±3 °C for 3-4 h. After completion of the reaction, cooled to 30-35 °C and maintained at same temperature for 2 hrs. The solid was filtered; washed with IPA and dried to give Ripasudil dihydrochloride(125g,89% yield)
Example-VII : Preparation of Ripasudil.

100 g of Ripasudil dohydrochloride, 150 mL of water; 600 mL of isopropyl alcohol were heated to 83±3°C and maintained at same temperature for 90±30 mins. The reaction mixture was cooled to 30±5 °C and stirred for 600±30 mins. The obtained solid was filtered and suck dried. 800 ml of water was added to the wet compound and was added 15 ml of CP.HCl and stirred for 15 mins. To this was added 500 mL of toluene and continued stirring for further 15 mins at 30±5 °C. The layers were separated, and aqueous layer was washed with toluene. Aqueous layer pH ~10-11 was adjusted with 40 g of sodium hydroxide dissolved in 400 ml of water. 500 ml of toluene was added to aqueous layer and stirred and separated the layers. The aqueous layer was extract with toluene and combined toluene layers and distilled under vacuum to get Ripasudil freebase (60g,74%).
Example-VIII: Preparation of Ripasudil HCl form alpha.
To a stirring solution of 5 gm of Ripasudil free base in 100 ml of isopropyl alcohol was added
50 mg of Ripasudil hydrochloride form alpha seed at 10±2°C followed by the addition of diluted solution of isopropyl alcohol hydrochloride (IPA-HCl 21% w/w, 2.5 ml) in 25 mL of isopropyl alcohol (25 ml) slowly for 15 min at 10±2°C and stirred for 60 min at same temperature. Filtered the precipitated solid under nitrogen atmosphere and dried under vacuum at 40°C for 15 hr to get Ripasudil hydrochloride.
Yield:4.4gm (79%)
,CLAIMS:
1) A process for the preparation of an acid addition salt of formula II comprising the steps of:
a) reacting formula II with a suitable acid; and

b) isolating an acid addition salt of formula II.

2) The process as claimed in claim 1, wherein the suitable acid is selected from oxalic acid, camphor sulfonic acid, phosphoric acid, fumaric acid, sulfuric acid, hydrobromic acid, maleic acid, malic acid, citric acid, acetic acid, tartaric acid, succinic acid and malonic acid.

3) A compound of formula II or its acid addition salts.

4) The compound as claimed in claim 3, wherein the acid addition salt is selected from oxalate, camphor sulfonate, phosphate and fumarate.

5) A process for the preparation of 4- fluoroisoquinoline-5-sulfonyl chloride intermediate of formula IIa comprising the steps of:
a) forming a diazonium salt of 5-amino-4-fluoroisoquinoline of formula III;
b) reacting the above obtained diazonium salt with SOC12; and
c) isolating 4-fluoroisoquinoline-5-sulfonyl chloride of formula IIa.

6) The process as claimed in claim, wherein the diazonium salt formation is carried out by reacting formula III with NaNO2.

7) The process as claimed in claim 5, wherein the step b) is carried out in presence of catalyst.

8) The process as claimed in claim 7, wherein the catalyst is Copper (II) chloride dihydrate.

9) A process for the preparation of Ripasudil HCl alpha form comprising the steps of:
a) dissolving Ripasudil in a suitable solvent;
b) optionally seeding with Ripasudil hydrochloride alpha form;
c) adding isopropyl alcohol-HCl; and
d) isolating Ripasudil hydrochloride alpha form.