DESC:Field of the Invention:
The present application relates to crystalline forms of Netarsudil dimesylate salt and
process for the preparation of Netarsudil dimesylate , intermediates thereof, which is represented
by the following structural formula-I.
5
Formula-I
Background of the Invention:
10 Netarsudil is a Rho kinase inhibitor, Its chemical name is (S)-4-(3-amino-1-(isoquinolin-
6-yl-amino)-1oxopropan-
2-yl) benzyl 2,4-dimethylbenzoate dimesylate, ophthalmic solution
0.02% was approved by FDA in 2017 for the lowering of elevated intraocular pressure (IOP) in
patients with open-angle glaucoma or ocular hypertension. It was developed by Aerie
Pharmaceuticals Inc. under the brand name of Rhopressa .
15 The patent US8394826B2 first disclosed netarsudil and its process for preparation. The
said process involves, chiral chromatography for the separation of Netarsudil isomers from a
racemic mixture.
The patent US9415043B2 reported dimesylate salt of Netarsudil and a mixture of
Netarsudil salt and Latonoprost.
20 The patent US9643927B2 reported a process for the preparation of netarsudil dimesylate
salt by using chiral auxilary reagents.
US10442770B2 (herein after referred as US’770) patent describes crystalline form-N1,
N2, N3, N4, N5, N6 and N7 of Netarsudil dimesylate.
Polymorphism, the occurrence of different crystal forms, is a property of some molecules
25 and molecular complexes. A single molecule may give rise to a variety of polymorphs having
distinct crystal structures and physical properties like melting point, thermal behaviors (e.g.
3
measured by thermogravimetric analysis - "TGA", or differential scanning calorimetry - "DSC"), X-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound. Discovering new salts and new polymorphic forms and solvates of a pharmaceutical 5 product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire 10 of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional salts and solid state forms of Netarsudil dimesylate.
The present invention provides a crystalline form and its process for the preparation of 15 compound of formula-I.
Brief Description:
The first aspect of the present invention is to provide a novel crystalline form of (S)-4-(3-amino-1-(isoquinolin-6-yl-amino)-1oxopropan-2-yl) benzyl 2,4-dimethyl benzoate dimesylate compound of formula-I. Herein after designated as crystalline form-M of netarsudil 20 dimeyslate.
The second aspect of the present invention is to provide a process for the preparation of (S)-4-(3-amino-1-(isoquinolin-6-yl-amino)-1oxopropan-2-yl) benzyl 2,4-dimethyl benzoate dimesylate compound of formula-I.
Brief description of the drawings: 25
Figure 1: Illustrates the PXRD pattern of crystalline form of (S)--4--(3--amino--1--(iso quinolin--6--yl--amino)--1oxopropan--2--yl) benzyl 2,4--dimethyl benzoate dimesylate compound of formula--I obtained form example--16.
Figure 2: Illustrates the PXRD pattern of crystalline form of (S)--4--(3--amino--1--(iso quinolin--6--
4
yl--amino)--1oxopropan--2--yl) benzyl 2,4--dimethyl benzoate dimesylate compound of formula--I obtained form example--12.
Figure 3: Illustrates the IR spectrum of crystalline form of (S)--4--(3--amino--1--(iso quinolin--6--yl--amino)--1oxopropan--2--yl) benzyl 2,4--dimethyl benzoate dimesylate compound of formula--I obtained form example--12. 5
Detailed Description:
As used herein the term “suitable solvent” used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; “ether solvents” such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene 10 glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the 15 like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbontetra chloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-20 methoxyethanol, l,2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar solvents” such as water or mixtures thereof.
The first aspect of the present invention is to provide a novel crystalline form of (S)-4-(3-amino-1-(isoquinolin-6-yl-amino)-1oxopropan-2-yl) benzyl 2,4-dimethyl benzoate dimesylate 25 compound of formula-I. Herein after designated as crystalline form-M of netarsudil dimesylate.
The crystalline form-M of the present invention is characterized by it powder X-ray diffraction pattern having peak at about 12.154 + 2-theta value.The said crystalline form-M is further characterized by its powder X-Ray diffraction pattern substantially in accordance with figure-1. 30
5
The second aspect of the present invention provides a process for the preparation of the crystalline form of (S)--4--(3--amino--1--(isoquinolin--6--yl--amino)--1oxopropan--2--yl) benzyl 2,4--dimethyl benzoate dimesylate compound of formula-I ; comprising of:
a) suspending compound of formula--1(S--isomer obtained from chiral HPLC) in suitable solvent, 5
b) treating with methansulphonic acid at a suitable temperature,
c) purifying the compound obtained in step--b) in suitable solvent to provide the crystalline form of (S)--4--(3--amino--1--(isoquinolin--6--yl--amino)--1oxopropan--2--yl) benzyl 2,4--dimethyl benzoate dimesylate compound of formula-I.
Wherein in step--a, b) the suitable temperature is 20 to 100°C, preferably 30--85°C; 10
the solvent system may be a single solvent or mixture of solvents and is selected from hydrocarbon solvents, ester solvents, ether solvents, chloro solvents, ketone solvents; hydrocarbon solvents; alcohol solvents, polarprotic solvents, polaraprotic solvents, water and mixture thereof.
An other aspect of the present invention is step--a) the compound of formula--1 (S--15 isomer) is optionally obtained form any chiral resolution or prep HPLC method.
The embodiment of the present invention provides a process for the preparation of the crystalline form of (S)--4--(3--amino--1--(isoquinolin--6--yl--amino)--1oxopropan--2--yl) benzyl 2,4--dimethyl benzoate dimesylate compound of formula-I ; comprising of:
a) suspending compound of formula--1(S)--4--(3--((tert--butoxycarbonyl)amino)--1--(isoquinolin--6--20 ylamino)--1--oxopropan--2--yl)benzyl 2,4--dimethylbenzoate(obtained from chiral HPLC) in dichloromethane,
b) treating with methansulphonic acid to the solution obtained is step--a) at 25--35°C,
c) isolating the compound obtained in step--b) in isopropanol to provide the crystalline form of (S)--4--(3--amino--1--(isoquinolin--6--yl--amino)--1oxopropan--2--yl) benzyl 2,4--dimethyl benzoate 25 dimesylate compound of formula-I.
The other aspect of the present invention provides a process for the preparation of the crystalline form of (S)--4--(3--amino--1--(isoquinolin--6--yl--amino)--1oxopropan--2--yl) benzyl 2,4--dimethyl benzoate dimesylate compound of formula-I, comprising of:
a) suspending compound of netarsudil dimesylate in suitable solvent, 30
b)stirring the reaction mixture at a suitable temperature,
6
c)isolating the solid obtained in step--b) to provide the crystalline form of (S)--4--(3--amino--1--(isoquinolin--6--yl--amino)--1oxopropan--2--yl) benzyl 2,4--dimethyl benzoate dimesylate compound of formula-I.
Wherein in step--a, b) the suitable temperature is 20 to 100°C, preferably 30--85°C;
the solvent system may be a single solvent or mixture of solvents and is selected from 5 hydrocarbon solvents, ester solvents, ether solvents, chloro solvents, ketone solvents; hydrocarbon solvents; alcohol solvents, polarprotic solvents, polaraprotic solvents, water and mixture thereof.
(S)--4--(3--amino--1--(isoquinolin--6--yl--amino)--1oxopropan--2--yl) benzyl 2,4--dimethyl benzoate dimesylate produced by the present invention can be further micronized or milled to get 10 the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
15
PXRD analysis of (S)-4-(3-amino-1-(isoquinolin-6-yl-amino)-1oxopropan-2-yl) benzyl 2,4-dimethyl benzoate dimesylate was carried out using BRUKER D8 ADVANCED/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min. IR spectra were recorded on a Perkin-Elmer FTIR spectrometer.
20
Chiral HPLC method: Chromatographic conditions:
HPLC System : Make YMC; model: K--Prep lab 300 G
Column Dimensions : 100*250 mm
Media : CHIRALART SC,10micron 25
Flow : 250 ml/min
Injection volume : 100 ml
Run time : 30 min
Wave length : 320 nm
Feed (sample)concentration : 40 mg/mL 30
7
Mobile Phase : n-hexane : isopropylalcohol : DEA (50 : 50 : 0.1 v/v/v)
Diluent : IPA: n-Hexane (70/30,v/v), (sample first soluble in IPA and after add n-Hexane).
Connect 100*250 DAC column to preparative HPLC pumps.
5 The polymorphs of Netarsudil dimesylate compound of formula-I of the present invention
prepared as described in the following scheme:
8
The present invention for the preparation of Netarsudil dimesylate form (2S)-2-((tertbutoxy
carbonylamino) methyl)-3-(isoquinolin-6-ylamino)-3-oxo-1-phenylpropyl-2,4-dimethyl
benzoate is prepared according to the process for Netarsudil analogues disclosed in the art in
5 US9415043B2. The obtained compound PXRD is shown in figure -2.
The process for the preparation of Netarsudil dimesylate developed by the present
inventors produces highly pure Netarsudil dimesylate with good yield. All the related substances
and residual solvents are controlled well within the limits as suggested by ICH guidelines and
most of the related substances are controlled in non-detectable levels.
10 The compound of formula-I produced by the process of the present invention is having
chemical purity of greater than 99.5%, preferably greater than 99.7%, more preferably greater
than 99.9% by HPLC.
The compound of formula-I produced by the process of the present invention is having
chiral purity of greater than 99.5%, preferably greater than 99.7%, more preferably greater than
15 99.9% by chiral HPLC.
The process described in the present invention was demonstrated in examples illustrated
below. These examples are provided as illustration only and therefore should not be construed as
limitation of the scope of the invention.
Examples:
20 Example-1: Preparation of 2-(hydroxymethyl)isoindoline-1,3-dione
A round bottom flask was charged with phthalimide (2000 g) and aqueous formaldehyde (1380
mL), heated the reaction mixture to 95-105°C and stirred for 7 hr. Cooled to 25-35°C, the
reaction mixture was filtered and washed with water (2L). The obtained wet compound was
charged with water (3L) and stirred for 1 hr at 25-35°C and filtered the solid and washed with
25 water (2L) to get the title compound .
Yield: 2288 g
Example-2: Preparation of 2-(bromomethyl)isoindoline-1,3-dione
9
A round bottom flask was charged with Conc.sulfuric acid (1L), 2--(hydroxymethyl) isoindoline--1,3--dione (500 g) at 25--35°C and stirred for 15 min. The above reaction mixture was added slowly to aqueous HBr (1426 mL) at 5--15°C and stirred for 3 hr at 25--35°C. Cooled the reaction mixture to 0--10°C, charged with water (2.5L), dichloromethane (2.5L) and stirred at 20--30°C for 15 min. Separated the both layers, the aqueous layer was extracted with dichloromethane (1.5 L). 5 The combined organic layer was washed with sodium thiosulfate solution and separated layers. The organic layer was dried, distilled off 80% of solvent and cooled the resulting solution to 25--35°C and charged with heptane (2.5L), stirred for 30 min. Filtered the obtained solid, washed with heptane (500 mL) and dried to get the title compound.
Yield: 436 g 10 Example-3: Preparation of methyl --p--tolylacetate (Formula--3).
A round bottom flask was charged with 2--(p--Tolyl)acetic acid (500 g) and methanol (3L), and cooled to 5--10°C added Conc. sulfuric acid (136.2 g) and stirred at 25--35°C for 3 hr. Cooled the reaction mixture to 10--20°C, charged with ice--cold water (2.5L) followed by dichloromethane (2.5L) and separated the layers. The aqueous layer was extracted with dichloromethane (500 mL) 15 and combined organic layer was washed with 10% of aq.NaHCO3 solution. The organic layer was dried over Na2SO4 and distilled off the solvent to get title compound.
Yield: 564 g Example-4: Preparation of methyl 3--(1,3--dioxoisoindolin--2--yl)--2--p--tolyl propanoate (Formula--4). 20
A round bottom flask was charged with THF (200 mL), LiHMDS (150 mL; 1.4M in THF) under N2 atmosphere and cooled to --78°C and stirred for 1.5 hr. A solution of methyl--p--tolylacetate (200.0 g) in THF (200 mL) was added drop wise to the above reaction mixture at --78°C and maintained the reaction mass at same temperature for 2 hr. A solution of 2--(bromomethyl) iso indoline--1,3--dione (349 g) in THF (2.2L) was added to the above reaction mixture at same 25 temperature and stirred for 4 hr. The reaction mixture temperature was brought to 25--35°C and stirred for 12 hr at same temperature. The reaction mixture was cooled to 5--15°C, quenched with saturated aqueous ammonium chloride solution (50 g in 500 mL) and separated the layers. The organic layer was distilled off, co--distilled with ethyl acetate (100 mL) to obtain crude compound. The crude compound was charged with ethyl acetate (300 mL) and stirred the 30
10
reaction mass for 3 hr, the obtained solid was filtered and washed with ethyl acetate (25 mL), was dried to get the title compound.
Yield: 209 g
Example-5: Preparation of methyl 2-(4-(bromomethyl)phenyl)-3-(1,3-dioxoisoindolin-2-yl) propanoate (Formula-5). 5
A round bottom flask was charged with compound of formula--4 (230 g), acetonitrile (2.3L) and stirred for 10 min. N--bromosuccinamide (126.5 gr), catalytic amount of AIBN (4.66 g) were added, the resulting solution was heated to 75--85°C and stirred for 12 hr. The solvent was distilled off completely, the obtained residue was charged with water (1150 mL) and stirred for 0.5 hr. Filtered the precipitated solid and washed with water (230 mL), the obtained wet solid 10 was stirred in methanol (1150 mL) for 2 hr. Filtered the obtained solid and washed with methanol (230 mL) and dried to get the title compound.
Yield: 238 g
Example-6: Preparation of 4-(3-(1,3-dioxoisoindolin-2-yl)-1-methoxy-1-oxopropan-2-yl) benzyl -2,4-dimethylbenzoate (Formula-6). 15
A round bottom flask was charged with compound of formula--5 (25.0 g) and acetonitrile (250 mL) stirred for 10 min at 25--35°C. A compound of 2,4--di methylbenzoic acid (9.8 g) and sodium carbonate (13.16 g) were added to the above reaction mixture and stirred for 8 h at 70--80°C. Cooled the reaction mixture to 25--35°C, filtered the unwanted solid and washed with acetonitrile (25.0 mL). Distilled off the filtrate completely, the obtained compound was charged with ethyl 20 acetate (125 mL), water (125 mL) and stirred for 15 min. Separated the layers, aqueous layer was extracted with ethyl acetate (50 mL) and the combined organic layer was dried over anhydrous Na2SO4 evaporated the solvent to obtain residue. Toluene (75 mL) was charged to the obtained residue to get the clear solution, heptane (175 mL) was charged to the solution and stirred for 3 hr at 25--35°C. Filtered the precipitated solid, washed with heptane (25 mL) and dried to get the 25 title compound.
Yield: 27.13 g
Example-7: Preparation of 2-(4-((2,4-dimethylbenzoyloxy)methyl)phenyl)-3-(1,3-dioxo iso indolin-2-yl) propanoic acid (Formula-8).
A round bottom flask was charged with compound--6 (40.0 g) and THF (400 mL) stirred for 10 30 min at 25--35°C. The reaction mixture was cooled to 5--10°C, charged aqueous solution of LiOH
11
(7.12 g in 600 mL of water) and stirred for 6 hr at 15--25°C. Adjusted the reaction mass pH to ~ 3 with Con. HCl (20 mL) and charged ethyl acetate (200 mL) stirred for 15 min, separated the layers. The aqueous layers was extracted with ethyl acetate (80 mL), the combined organic layer was washed with brine solution, water and evaporated the solvent to get gummy solid. The obtained solid was charged with toluene (200 mL) stirred for 10 hr at 110--120°C to collect water 5 through azeotropic distillation. Cooled the reaction mixture to 25--35°C, stirred for 3 h. Filtered the obtained solid and washed with toluene (40 mL) and dried to get the compound.
Yield: 35 g
Example-8: Preparation of 4-(3-(1,3-dioxoisoindolin-2-yl)-1-(isoquinolin-6-ylamino)-1-oxo propan-2-yl)benzyl 2,4-dimethylbenzoate (Formula-9). 10
A round bottom flask was charged with compound of formula--8 (50 g), pyridine (250.0 mL) and stirred for 15 min. EDC.HCl (25.14 g), 4--dimethylamino pyridine (16.01 g) and 6--aminoiso quinoline (15.75 g) were added to the above reaction mixture and stirred for 12 hr at 25--35°C.
A solution of sodium bicarbonate (25.7 g in 750 mL of water) was added to the above reaction mixture and stirred for 2 hr at 10--20°C, the separated solid was filtered, washed with water (50 15 mL). The obtained wet compound was charged with water (500 mL) and heated to 50--60°C stirred for 45 min, filtered the obtained solid and washed with water (50 mL). The obtained wet compound was charged with ethyl acetate (250 mL) stirred for 45 min at 25--35°C. Filtered the obtained solid, washed with ethyl acetate (50 mL) and dried to get the title compound,
Yield: 39.22 g. 20
Example-9: Preparation of 4-(3-(1,3-dioxoisoindolin-2-yl)-1-(isoquinolin-6-ylamino)-1-oxo propan-2-yl) benzyl 2,4-dimethylbenzoate (Formula-9).
A round bottom flask was charged with 2--(4--(((2,4--dimethylbenzoyl) oxy)methyl) phenyl)--3--(1,3--dioxoisoindolin--2--yl)propanoic acid (30 g), EDC.HCl (17.52 g), THF (150 mL) and stirred for 1hr. The reaction mixture was charged with DMAP (11.01 g) and a solution of 6--25 aminoisoquinoline (11.33 g) in THF (750 mL), stirred at 25--35°C for 10--12 hr. The reaction mixture was distilled off completely, charged with 2.5% of aqueous NaHCO3 solution (150 mL) and ethyl acetate. Separated the two layers, the aqueous layers was extracted with ethyl acetate, the combined organic layer was dried and evaporated to get a residue. The obtained residue was charged with ethyl acetate (30 mL) and stirred for 2 hr, the obtained solid was filtered and dried 30 to get the title compound.
12
Yield: 25 g
Example-10: Preparation of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate (Netarsudil free base racemic Formula-10).
A round bottom flask was charged compound of formula--9 (40 g), ethanol (1000 mL) stirred for 10 min at 25--35°C. Cooled the reaction mixture to 0--5°C, added slowly hydrazine hydrate (99%, 5 34.26 g) and stirred for 12 hr at 25--35°C. Cooled the reaction mixture to 0--5°C, stirred for 2.5 hr, unwanted solid was filtered and distilled off the solvent to get a gummy solid. The obtained compound was charged with heptane (200 mL) and stirred at 25--35°C for 1 hr, hexane layer was decanted, charged with water (200 mL) and heated to 50--60°C stirred for 1 hr. Filtered the obtained solid and washed with water (40 mL), the obtained solid was charged with ethyl acetate 10 (200 mL) and stirred for 2 hr at 50--60°C, cooled the solution and stirred for 1 hr at 25--35°C. Filtered the obtained solid and dried to get the title compound.
Yield: 25.3 g
Example-11: Preparation of (3--(tert--butoxycarbonylamino)--1--(isoquinolin--6--ylamino)--1 --oxo propan--2--yl)benzyl 2,4--dimethylbenzoate ( Formula-11). 15
A round bottom flask was charged with compound of formula--10 (25 g), dichloromethane (250 mL) stirred for 10 min at 25--35°C. Cooled the reaction mixture to 0--5°C, slowly added Di--tert--butyl dicarbonate (16.4 g) and stirred for 12 hr at 25--35°C. Distilled off the reaction mixture, charged with ethyl acetate (25 mL) stirred for 10 min, added heptane (40 mL) and stirred for 6 hr at 25--35°C. Filtered the obtained solid, washed with heptane (200 mL) and dried to get the title 20 compound.
Yield: 22.37 g
Example--12: Preparation of Compound of Formula--I. (Netarsudil Dimesylate salt)
A round bottom flask was charged with N--Boc Netarsudil (S--isomer, obtained from chiral prep
HPLC) (50.0 g), dichloromethane (500 mL) at 25--35°C and stirred for 10 min under nitrogen 25 atmosphere. Cooled the reaction mixture to 0--10°C, added methane sulphonic acid (22.7 g) slowly and stirred for 48 hr at 25--35°C. The reaction mixture was heated to 35--45°C stirred for 2 hr, distilled off the solvent to get thick syrup liquid. The obtained syrup was co--distilled with isopropanol (100 mL) again charged isopropanol (500 mL) and stirred at 40--50°C for 2 hr. The reaction mixture was gradually cooled to 25--35°C stirred for 26 hr, filtered the separated solid, 30 washed with isopropanol (50 mL) and heptane (100 mL). The wet compound was dried under
13
nitrogen atmosphere under vacuum dried for longer hours to get the title compound.
The obtained compound PXRD was depicted in figure --2.
Yield: 55.0 g
Purity by HPLC: > 99.8 %; purity by chiral HPLC: > 99.9 %
M.R: 120--125°C; obtained SOR: --153° 5
Example--13: Preparation of Compound of Formula--I. (Netarsudil Dimesylate salt)
A round bottom flask was charged with N--Boc Netarsudil (S--isomer, obtained from chiral prep
HPLC) (10.0 g), dichloromethane (100 mL) at 25--35°C and stirred for 10 min under nitrogen atmosphere. Cooled the reaction mixture to 0--10°C, added methane sulphonic acid (4.5 g) slowly and stirred for 48 hr at 25--35°C. The reaction mixture was heated to 35--45°C stirred for 2 hr, 10 distilled off the solvent to get thick syrup compound. The obtained compound was co--distilled with isopropanol (100 mL) and charged heptane (450 mL) and stirred at 40--50°C for 2 hr. The reaction mixture was gradually cooled to 25--35°C stirred for 26 hr, filtered the separated solid, washed with heptane (50 mL). The wet compound was dried under nitrogen atmosphere under vacuum to get the title compound. 15
Yield: 9.8 g
Example--14: Purification of Compound of Formula--I. (Netarsudil Dimesylate salt)
A round bottom flask was charged with Netarsudil dimesylate (S--isomer, 5.0 g), methanol (150 mL) stirred for 3 hr at 40--50°C. The reaction mixture was gradually cooled to 10--20°C stirred for 2 hr, the obtained solid was filtered and washed with methanol (10 mL). The wet compound was 20 dried under nitrogen atmosphere under vacuum to get the title compound.
Yield: 2.5 g
Example--15: Purification of Compound of Formula--I. (Netarsudil Dimesylate salt)
A round bottom flask was charged with Netarsudil dimesylate (S--isomer, 5.0 g), tetrahydrofuran (120 mL) stirred for 3 hr at 40--50°C. The reaction mixture was gradually cooled to 10--20°C 25 stirred for 2 hr, the obtained solid was filtered and washed with THF (15 mL). The wet compound was dried under nitrogen atmosphere, under vacuum to get the title compound.
Yield: 2.8 g
Example--16: Purification of Compound of Formula--I. (Netarsudil Dimesylate salt)
A round bottom flask was charged with Netarsudil dimesylate (S--isomer, 5.0 g), ethyl acetate 30 (150 mL) stirred for 3 hr at 60--70°C. The reaction mixture was gradually cooled to 15--25°C
14
stirred for 1 hr, the obtained solid was filtered and washed with ethyl acetate (15 mL), heptane (10 mL). The wet compound was dried under nitrogen atmosphere, under vacuum to get the title compound.
The obtained compound PXRD was depicted in figure --1.
Yield: 3.7 g ,CLAIMS:Claims:
1. A process for the preparation of the crystalline form of ( 4--(3 amino 1--(isoquinolin 6 yl
1oxopropan 2 yl) benzyl 2,4 dimethyl benzoate dimesylate compound of formula-I ; comprising of:
a)suspending compound of formula 1(S isomer obtained from chiral HPLC) in suitable solvent, 5
b) treating with methane sulphonic acid at a suitable temperature,
c) purifying the compound obtained in step b) in a suitable solvent to provide the crystalline form of ( 4--(3 amino 1--(isoquinolin 6 yl 1oxopropan 2 yl) benzyl 2,4 dimethyl benzoate dimesylate compound of formula-I.
2. The process as per claim 1 wherein in step a, b) the suitable temperature is 20 to 100°C, 10 preferably 30 85°C; the solvent system may be a single solvent or mixture of solvents and is selected from hydrocarbon solvents, ester solvents, ether solvents, chloro solvents, ketone solvents; hydrocarbon solvents; alcohol solvents, polarprotic solvents, polaraprotic solvents, water and mixture thereof.
3. A process for the preparation of the crystalline form of ( 4--(3 amino 1--(isoquinolin 6 yl 15
1oxopropan 2 yl) benzyl 2,4 dimethyl benzoate dimesylate compound of formula-I ; comprising of:
a)suspending compound of formula 1( 4--(3--((tert butoxycarbonyl) 1--(isoquinolin 6
1 oxopropan 2 yl)benzyl 2,4 dimethylbenzoate (obtained from chiral HPLC) in dichloromethane, 20
b) treating with methane sulphonic acid to the solution obtained is step a) at 25 35°C,
c)isolating the compound obtained in step b) in isopropanol to provide the crystalline form of ( 4--(3 amino 1--(isoquinolin 6 yl 1oxopropan 2 yl) benzyl 2,4 dimethyl benzoate dimesylate compound of formula-I.
4. The crystalline form of netarsudil dimesylate compound of formula-I as per claim 3 is shown 25 in figure-3.
5. The process as per claim 1and 3, further preparation of ( 4--(3 amino 1--(iso quinolin 6 yl
1oxopropan 2 yl) benzyl 2,4 dimethyl benzoate
comprising of:
30
16
a) reacting the compound of formula-2, with methanol in presence of sulfuric acid to provide the
compound of formula-3,
Formula-2 Formula-3
b) reacting the compound of formula-3 with 2-(b 5 romomethyl)isoindoline-1,3-dione in presence
of LiHMDS in tetrahydrofuran to provide the compound of formula-4,
c)reacting the compound of formula-4 with N-bromosuccinamide, AIBN (catalytic) in
acetonitrile to provide compound of formula-5,
10 Formula-4 Formula-5
d) reacting the compound of formula-5 with 2,4-dimethylbenzoic acid in presence of Na2CO3 in
acetonitrile to provide the compound of formula-6,
e) hydrolysing the compound of formula-6 with LiOH in THF, water to provide the compound of
formula-7, further cyclizing in toluene to provide the compound of formula-8,
15
Formula-7 Formula-8
f) reacting the compound of formula-8 with 6-aminoisoquinoline in presence of EDC, HOBt in
pyridine to provide the compound of formula-9,
20 g) deprotecting the compound of formula-9 with methylamine in isopropanol to provide the
compound of formula-10,
17
Formula-10 Formula-1a
h)protecting the compound obtained in step-g) with di-tert-butyl dicarbonate in
dichloromethane, to get compound of formula-11,
i) further resolving the compound obtained in step-i) using chiral 5 preparative HPLC to get (S)-4-
(3-((tert-butoxy carbonyl) amino) -1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-
dimethyl benzoate.
6. The compound of formula-I, obtained according to any of preceding claims having purity by
HPLC> 95%, preferably > 99% ; more preferably>99.5 %
10 7. The compound of formula-I, obtained according to any of preceding claims having purity by
chiral HPLC> 95%, preferably > 99% ; more preferably>99.5 %