DESC:Field of the Invention:
The present application relates to process for the preparation of Netarsudil
dimesylate, its pharmaceutically acceptable salts, and intermediates thereof, which is
represented by the following structural formula-I.
5
Formula-I
Background of the Invention:
Netarsudil dimesylate, ophthalmic solution 0.02% was 10 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 .
The patent US8394826B2 first disclosed netarsudil and its process for preparation.
15 The said process involves, chiral chromatography for the separation of Netarsudil isomers
from a racemic mixture. The process involves costly reagents, and time taking process is
not suitable in the industrial scale.
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.
The CN107434780A reported a process for the preparation netarsudil and salts
thereof by using chiral auxilary reagents. However, the said patents are suffering from the
draw backs such as low yield and usage of column chromatography, which are not suitable
25 for industrial scale.
The present application describes an improved processes for the preparation of the
compound of formula-I.
3
Brief Description :
The first aspect of the present invention is to provide a chiral resolution process for
the preparation of the compound of formula-I,
The second aspect of the present invention is to provide a process for the preparation
of the 5 compound of formula-I,
The third aspect of the present invention is to provide a process for the preparation
of the compound of formula-I.
The fourth aspect of the present invention is to provide a process for the preparation
of the compound of formula-I,
10 The fifth aspect of the present invention is to provide an improved process for the
preparation of the compound of formula-I,
Brief description of the drawings:
Figure 1: Illustrates the PXRD pattern of racemic Netarsudil compound of formula-1.
Figure 2: Illustrates the PXRD pattern of racemic Netarsudil dimesylate salt obtained from
15 example-22
Figure 3: Illustrates the IR-absorption of Netarsudil dimesylate (compound of formula-I )
obtained from example-19.
Detailed Description:
As used herein the term “suitable solvent” used in the present invention refers to
20 “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, petether, 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 glycol dimethyl ether, ethylene glycol diethyl ether, diethylene
glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether,
25 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 like; “chloro solvents” such as
dichloromethane, dichloroethane, chloroform, carbontetrachloride and the like; “ketone
30 solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; “nitrile
solvents” such as acetonitrile, propionitrile, and the like; “alcoholic solvents” such as
4
methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2,2,2-
trifluoroethanol, ethylene glycol, 2-methoxy ethanol, l,2-ethoxyethanol, 1, 2, or 3-pentanol,
neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, benzyl alcohol,
phenol, or glycerol and the like; “polar solvents” such as water or mixtures thereof.
As used herein the present invention the term “suitable base” 5 refers to inorganic or
organic base. Inorganic base refers to “alkali metal carbonates” such as sodium carbonate,
potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as
sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as
sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal
10 alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium
ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like;
and organic bases like dimethylamine, diethylamine, diisopropyl amine, diisopropylethyl
amine, diisobutylamine, triethylamine, pyridine, 4-dimethylamino pyridine (DMAP), Nmethyl
morpholine (NMM), or mixtures thereof. Metal azides such as LiHMDS, NaHMDS,
15 KHMDS, and alkali metals such as BuLi.
As used herein the present invention the term “suitable chiral reagents” refers to L-tartaric
acid, D-tartaric acid, camphorsulphonic acid, di-para-toluoyl-L-tartaric acid ,di-para-toluoyl
-D-tartaric acid, Phenylalanine, S-(+)mandelicacid, R-(-)mandelicacid, L-(+)tartaric acid,
D-(-) tartaric acid, L-malicacid, D-malic acid, D-(+)-maleicacid, (1R)-(-) camphor sulfonic
20 acid, (1S)-(+)- camphor sulfonic acid, (1R)-(+)-bromocamphor-10-sulfonic acid, (1S)-(-)-
bromo camphor-10-sulfonic acid, (-)-Dibenzoyl-L-tartaric acid, (-)-Dibenzoyl-L-tartaricacid
monohydrate, (+)-Dibenzoyl-D -tartaric acid, (+)-Dibenzoyl-D -tartaric acid monohydrate,
(+)-dipara-tolyl-D-tartaric acid, (-)-dipara tolyl-L-tartaric acid, mixtures thereof;
The present invention relates to various processes for the preparation of Netarsudil
25 and its salts in step wise manner.
The first aspect of the present invention is to provide a process for the preparation
of compound of formula-I,
comprising of:
30 a) resolution of compound of formula-1 using a suitable chiral reagent in a suitable
solvent,
5
b) converting to mesylate salt of compound of formula-1a in a suitable solvent to provide
compound of formula-I.
wherein in step-a) the suitable chiral reagents include L-tartaric 5 acid, D-tartaric acid,
camphor sulphonic acid, di-para-toluoyl-L-tartaric acid, di-para-toluoyl-D-tartaric acid or
any other suitable chiral reagents, etc ; suitable solvent is selected form ketone, ester,
alcohol, polar, water and mixture thereof;
The second aspect of the present invention provides a process for the preparation of
10 compound of formula-I, described in the following scheme-I:
Scheme-I:
6
The present invention also provides a process for the preparation of
compound of formula-I as described in the following scheme-II:
Scheme-II:
5
The third aspect of the present invention provides a process for the preparation of
compound of formula-I, described in the following scheme-III:
Scheme-III
10
7
The fourth aspect of the present invention provides a process for the preparation of
compound of formula-I, described in the following scheme-IV:
Scheme-IV:
5
The fifth aspect of the present invention provides a process for the preparation of
compound of formula-I , comprising of
Formula-I
10
a) reacting the compound of formula-2A, with an alcohol in presence of suitable reagent to
provide the compound of formula-3,
8
Formula-2 Formula-3 (R’ is alkyl, methyl, ethyl, propyl)
b) reacting the compound of formula-3 with compound-B in presence of suitable base,
solvent to provide the compound of formula-17A,
c) reacting the compound of formula-17 with suitable reagent, 5 solvent to provide
compound of formula-17C,
Formula-17A Formula-17C
10 d) reacting the compound of formula-17C with 2,4-dimethylbenzoic acid in presence of
suitable reagent, solvent to provide the compound of formula-22A,
Formula-22A
e) hydrolyzing the compound of formula-22A with suitable reagent, solvent to provide
15 formula-23,
f) cyclising the compound of formula-23 with suitable reagents, to provide formula-24,
Formula-23 Formula-24
9
g) reacting the compound of formula-24 with 6-aminoisoquinoline in presence of suitable
reagent, solvent to provide compound of formula-25,
h) deprotecting the compound of formula-25 in presence of suitable reagent, solvent to
provide compound of formula-1,
5
Formula-1 Formula-1a
i) resolution of the compound of formula-1 using chiral preparative HPLC, in suitable
solvents to provide compound 10 of formula-1a,
J) optionally purifying the compound obtained in step-i) by making suitable acid addition
salt followed by basification with suitable base,
k) reacting the compound obtained in step-i) or j) with methane sulphonicacid in suitable
solvent to provide compound of formula-I, and optionally purifying in suitable solvent.
15
Wherein step-a) the suitable solvent is selected from alcohol solvent, suitable regents
sulfuric acid, thionyl chloride, oxalyl chloride, ethylchloroformate, methylchloroformate,
and mixture thereof; suitable temperature is 0°C to 100°C; step-b) suitable reagent is
selected form 2-(bromomethyl)isoindoline-1,3-dione, 2-(chloromethyl)isoindoline-1,3-
20 dione, 2-(iodomethyl)isoindoline-1,3-dione; suitable base is organic base such as LiHMDS,
NaHMDS, KHMDS, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium
tert-butoxide and inorganic base; suitable solvent chloro solvent, ether solvent, ester solvent,
polar solvents and mixture thereof; suitable temperature is -80°C to 80°C; step-c) suitable
reagents N-bromosuccinimide, azobisisobutyronitrile, bromine, suitable solvent chloro
25 solvent, hydrocarbon solvent, ether solvent, ester solvent, nitrile solvent, polar solvents and
mixture thereof; suitable temperature is 0°C to 100°C;
step-d) suitable reagents are inorganic base, organic base, suitable solvent hydrocarbon
solvent, chloro solvent, ether solvent, ester solvent, nitrile solvent, acetone solvent, polar
10
solvents, alcohol solvent, toluene and mixture thereof; suitable temperature is 0°C to 100°C;
step-e, f) suitable reagents EDC, HOBT, DMAP, inorganic base, suitable solvent
hydrocarbon solvent, chloro solvent, ether solvent, ester solvent, nitrile solvent, acetone
solvent, polar solvents, water, toluene, alcohol solvent and mixture thereof; suitable
temperature is 0°C to 150°C; pH range is 0-5; step-g) suitable reagents 5 are ethyl-(N’,N’-
dimethylamino) propyl carbodiimide hydrochloride (EDC), 1-hydroxy
benzotriazole (HOBt), 4-(N,N-dimethylamino) pyridine (DMAP), thionylchloride,
oxalylchloride; suitable base is organic base; inorganic base, suitable solvent hydrocarbon
solvent, pyridine, DMF, chloro solvent, ether solvent, ester solvent, nitrile solvent, acetone
10 solvent, polar solvents, water, toluene, alcohol solvent and mixture thereof; suitable
temperature is 0°C to 80°C;
Step-h) suitable reagent is hydrazine hydrate, methylamine; suitable solvent hydrocarbon
solvent, chloro solvent, ether solvent, ester solvent, nitrile solvent, acetone solvent, polar
solvents, water, toluene, alcohol solvent and mixture thereof; suitable temperature is 0°C to
15 120°C; step-i, j) suitable reagents are methane sulphonic acid, hydrochloric acid,
hydrobromic acid, phosphoric acid, tartaric acid, trifluoro acetic acid, acetic acid, sulphate,
PTSA; suitable solvent hydrocarbon solvent, chloro solvent, ether solvent, ester solvent,
nitrile solvent, acetone solvent, polar solvents, water, toluene, alcohol solvent and mixture
thereof;
20 The other embodiment of the present invention is to provide a process for the
preparation of compound of formula-I, comprising of
Formula-I
25 a) reacting the compound of formula-2A, with methanol in presence of sulfuric acid to
provide the compound of formula-3A,
11
Formula-2A Formula-3A
b) reacting the compound of formula-3A with 2-(bromomethyl)isoindoline-1,3-dione in
presence of LiHMDS in tetrahydrofuran to provide formula-17A,
c) reacting the compound of formula-17A with N-bromosuccinamide, 5 AIBN (catalytic) in
acetonitrile to provide compound of formula-17B,
Formula-17A Formula-17B
d) reacting compound of formula-17B with 2,4-dimethylbenzoic acid in presence of
10 Na2CO3 in acetonitrile to provide compound of formula-22,
Formula-22
e) hydrolysing the compound of formula-22 with lithium hydroxide in tetrahydrofuran,
15 water to provide compound of formula-23,
f) cyclising the compound of formula-23 in toluene to provide the compound of formula-
24,
Formula-23 Formula-24
12
g)reacting the compound of formula-24 with 6-aminoisoquinoline in presence of EDC,
HOBt, in pyridine to provide the compound of formula-25,
5 Formula-25
h) deprotecting the compound of formula-25 with methylamine in isopropanol to provide
compound of formula-1,
10 Formula-1 Formula-1a
i) resoluting the compound of formula-1 using chiral preparative HPLC to get Compound
of formual-1a,
j) treating the compound of formula-1a with methanesulphonic acid in MDC, followed by
15 basification using ammonia in isopropanol to get pure compound of Formula-1a,
k) converting to mesylate salt of compound of formula-1a in dichloromethane to provide
compound of formula-I, purifying in isopropanol to get pure compound.
The other preferred embodiment of the invention is a compound of formula-17.
17A: R-hydrogen
20 Where R: bromo, chloro, iodo, Pivaloyl ; R’: alkyl;methyl, ethyl, propyl, butyl.
13
The Schematic representation of an improved process for the process preparation of
compound of formula-I, as described in the following scheme-V:
Scheme-V:
5
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 10 scope of the invention.
Examples:
Example-1: Preparation of Compound of Formula-3A.
A round bottom flask was charged with 2-(p-Tolyl)acetic acid (100 gr) and methanol (600
15 mL), cooled to 5-10°C and charged sulfuric acid (32.62 gr) and stirred for 6 hr at 25-35°C.
14
The reaction mixture was charged with ice-cold water (500 mL) followed by dichloro
methane (500 mL) and separated the layers. The aqueous layer was extracted with dichloro
methane (2x100 mL) and combined organic layer was washed with 10% of aq.NaHCO3
solution. The organic layer dried and evaporated the solvent to get title compound.
5 Yield: 105.0 gr
Example-2: Preparation of Compound of Formula-17A.
A round bottom flask was charged with compound of formula-3A (85 gr), THF (55 mL),
LiHMDS (480 mL) under N2 atmosphere charge and cooled to -78°C and maintained the
reaction mass at same temperature for 1.5 hr. A solution of 2-(bromomethyl) isoindoline-
10 1,3-dione (96.0 gr) in THF (600 mL) was added drop wise to the above reaction mixture at -
78°C and maintained the reaction mass at same temperature for 5 hr. The reaction mixture
temperature brought 25-35°C and stirred for 12 hr at same temperature. The reaction
mixture was quenched with saturated aqueous ammonium chloride solution (550 mL) and
separated the layers, the organic layers was distilled to obtain crude material compound.
15 The crude compound was charged with ethyl acetate (550 mL) and stirred 3 hr, obtained
solid was filtered and washed with ethyl acetate (110 mL) and dried to get the title
compound.
Yield: 75.0 gr
20 Example-3: Preparation of Compound of Formula-17B.
A round bottom flask was charged with compound of formula-17A (65 gr), acetonitrile
(325 mL) and stirred for 10 min. To the resulting mixture NBS (35 gr), catalytic amount of
AIBN (0.65 gr) were added, heated to 80°C and stirred for 8 hr. The solvent wasdistilled off
completely, the resulting residue was charged with MDC (325 mL) and followed by water
25 (325 mL) separated the layers. The organic layer was washed with water. The combined
organic layer was dried, evaporated to get the residue. The residue was purified with
heptane (325 mL), the obtained wet material was dried to get the title compound.
Example-4: Preparation of Compound of Formula-22.
A round bottom flask was charged with compound of formula-17B (70.0 gr) and acetonitrile
30 (700 mL) stirred for 10 min to obtain clear solution. Sodium 2,4-dimethylbenzoate (37.0 gr)
and K2CO3 (26.0 gr) were added to the reaction mixture and refluxed for 8 hr. The reaction
15
mixture was filtered and washed with acetonitrile (140.0 mL). The filtrate layer was
distilled off completely to obtain crude compound. The obtained compound was charged
with ethyl acetate (350.0 mL), water (350.0 mL) and stirred for 15 min. Separated the both
layers, aqueous layer was extracted with ethyl acetate (140.0 mL) and the combined organic
layer was dried over anhydrous Na2SO4 evaporated the solvent to obtain 5 residue. Toluene
(140.0 mL) was charged to the residue to get a clear the solution, charged heptane (350.0
mL) to the clear solution in drop wise manner, the resulting solution was cooled 5-10°C and
stirred for 6 hr. The obtained solid was filtered, washed with heptane (70.0 mL) and dried to
get the title compound.
10 Yield: 56.0 gr.
Example-5: Preparation of Compound of Formula-23.
A round bottom flask was charged with compound of formula-22 (60.0 gr) and THF (300
mL) stirred for 10 min. The reaction mixture was cooled to 5-10°C, charged with 1.0 % of
aqueous LiOH solution ( 6.5 gr) in drop wise manner and stirred for 5 hr. The reaction mass
15 pH was adjusted to 2.5 with dil.HCl, charged with ethyl acetate (300 mL) and separated the
both layers. The aqueous layers was extracted with ethyl acetate, the combined organic
layers was washed with water (60 mL) and evaporated to get gummy solid. The obtain
compound was purified with heptane (300 mL) and dried to get the titled compound.
Yield: 50.0 gm
20 Example-6: Preparation of Compound of Formula-24.
A round bottom flask was charged with compound of formula-23 (50 gr), MDC (680.0 mL)
and stirred for 15 min. Followed by addition of HOBt (19.32 gr) to the reaction mixture.
The reaction mass was cooled to 0-5°C, added triethylamine (68.0 mL), EDC.HCl (27.4 gr)
and stirred for 8 hr at 25-35°C. The reaction mixture was distilled off to get the residue,
25 added water (340 mL) and adjusted the pH to 2-3 with 10% aqueous HCl (50 mL). The
obtained solid was filtered, washed with water (60 mL) to get wet solid. The wet compound
was purified with water and dried to get the title compound.
Yield: 50 gr.
Example-7: Preparation of Compound of Formula-25.
30 A round bottom flask was charged with compound of formula-24 (30 gr), EDC.HCl (17.52
gr), THF (150 mL) and stirred for 1hr. The reaction mixture was charged with DMAP
16
(11.01 gr) and a solution of 6-aminoisoquinoline (11.33 gr) in THF (750 mL), stirred for 12
hr at 25-35°C. 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 the residue. The obtained residue was charged with 5 ethyl acetate (30 mL)
and stirred for 2 hr, the obtained solid was filtered and dried to get the title compound.
Example-8: Preparation of Compound of Formula-1.
A round bottom flask was charged compound of formula-25 (3.0 gr), ethanol (60 mL)
stirred for 10 min. The reaction mixture was cooled to 0-5°C added hydrazine hydrate (99%,
10 2.57 gr) in drop wise manner, the reaction mass heated to 70-74°C and stirred for 4 hr. The
unwanted solid was filtered and distilled off the solvent to get the gummy solid. The
gummy obtained solid was charged with heptane (20 mL) and stirred at 25-35°C for 4 hr.
The obtained solid was filtered and washed with heptane (20 mL) to get wet material. The
obtained wet material was dried at 60-70°C to get the title compound.
15 Yield: 1.5 gr
Example-9: Preparation of methyl 2-(4-(bromomethyl)phenyl)acetate.
A round bottom flask was charged with 2-(4-(bromomethyl)phenyl) acetic acid (50 gr) in
methanol (150 mL) and stirred for 10 min. To the reaction mixture sulfuric acid (1.5 mL)
was added slowly at 0°C the resulting mixture was stirred for 12 hr at 25-35°C. The reaction
20 mixture was poured into water (200 mL) and extracted with ethyl acetate. The combined
organic layers were washed with saturated aq. NaHCO3 solution (200 mL) and then brine
solution. The organic phase was dried over Na2SO4, filtered and concentrated to give the
methyl 2-(4-(bromomethyl)phenyl)acetate.
Yield: 48 gr.
25 Example-10: Preparation of Compound of Formula-24.
A round bottom flask was charged with compound of formula-23 (50 gr), toluene (680.0
mL) and stirred the reaction mass for 8 hrs under azeotropic distillation conditions. Cooled
the reaction mixture to room temperature and maintained at the same temperature for 30-40
min. The obtained solid was filtered and washed with toluene (40 mL), dried to get the title
30 compound.
Yield: 50 gr.
17
Example-11: Preparation of Compound of Formula-3A.
A round bottom flask was charged with compound of formula-2A (500 gr) and methanol (3
L), cooled to 5-10°C and charged sulfuric acid (163.28 gr), was stirred for 3 hr at 25-35°C.
The reaction mixture was cooled to 10-20°C, charged with ice-cold water (2.5 L) followed
by dichloromethane (2.5 L) and separated the layers. The aqueous layer 5 was extracted with
dichloromethane (500 mL) and the combined organic layer was washed with 10% of
aq.NaHCO3 solution (500 mL). The organic layer was dried over Na2SO4 and distilled off
the solvent, co-distilled with tetrahydrofuran (50 mL) to get title compound.
Yield: 564.0 gr.
10 Example-12: Preparation of Compound of Formula-17A.
A round bottom flask was charged with THF (200 mL), LiHMDS (150 mL) under N2
atmosphere, cooled to -78°C and stirred for 1.5 hr. A solution of compound of formula-3A
(200 gr) in tetrahydrofuran (200 mL) was added slowly to the above reaction mass and
stirred at same temperature for 90 min. A solution of 2-(bromomethyl) isoindoline-1,3-dione
15 (175.0 gr) in THF (1.1 L) was added slowly to the above reaction mixture at -78°C and
stirred for 4 hr at same temperature. The reaction mixture temperature was gradually
brought to 25-35°C and stirred for 12 hr. The reaction mixture was quenched with saturated
aqueous ammonium chloride solution (550 mL) at 5-15°C, and separated the layers. The
organic layers was distilled off completely, co-distilled with ethyl acetate (100 mL), charged
20 with ethyl acetate (300 mL) and stirred for 1 hr at 10-20°C. Filtered the precipitate solid and
washed with ethyl acetate (25 mL) dried to get the title compound.
Yield: 196.0 gr.
Example-13: Preparation of Compound of Formula-17B.
A round bottom flask was charged with compound of formula-17A (230 gr), acetonitrile
25 (2.3 L) and stirred for 10 min. N-bromosuccinimide (126.3 gr), catalytic amount of AIBN
(4.66 gr) were added, heated to 75-85°C stirred for 4 hr. The solvent was distilled off
completely, the resulting residue was cooled to 25-35°C, charged with ethyl acetate (1150
mL) and water (1.15 L) and separated the both layers. The aqueous layer was extracted with
ethyl acetate (230 mL), the combined organic layer was washed with water (120 mL). The
30 organic layer was dried and 90 % of solvent was distilled off, charged with n-heptane (600
mL) and stirred for 90 min. Filtered the precipitate solid and dried to get the title compound.
18
Yield: 203.0 gr.
Example-14: Preparation of Compound of Formula-22.
A round bottom flask was charged with compound of formula-17B (190.0 gr) and
acetonitrile (1900 mL) stirred for 10 min to obtain clear solution. 2,4-dimethylbenzoic acid
(85.12 gr) and sodium carbonate (100.0 gr) were added to the above 5 reaction mixture and
heated to 80-90°C and stirred for 6 hr. The reaction mixture was cooled to 25-35°C, filtered
the unwanted solid, distilled off the solvent completely under reduced pressure to obtain
crude compound. The obtained compound was charged with ethyl acetate (950.0 mL), water
(950.0 mL) and stirred for 15 min. Separated the both layers, aqueous layer was extracted
10 with ethyl acetate (380.0 mL) and the combined organic layer was dried over anhydrous
Na2SO4 evaporated the solvent to obtain residue. Toluene (380.0 mL), heptane (1520.0 ml)
were charged to the obtained residue, the resulting solution was cooled 5-10°C and stirred
for 6 hr. Filtered the precipitate solid, washed with heptane (60.0 mL) and dried to get the
title compound.
15 Yield: 117.0 gr.
Example-15: Preparation of Compound of Formula-24.
A round bottom flask was charged with compound of formula-22 (220 gr), tetrahydrofuran
(2.0 L) and stirred for 15 min. The reaction mixture was cooled to 0-10°C, charged with a
solution of LiOH (20.3 gr, in 3.0 L of water) in drop wise manner and stirred for 5 hr at 20-
20 30°C. The reaction mass was cooled to 0-10°C, adjusted the pH to 2.5 with dil.HCl (55 mL),
heated to 25-35°C, charged with ethyl acetate (1 L) and separated the layers. The aqueous
layers was extracted with ethyl acetate (2x400 mL), the combined organic layers was
washed with brine solution. The organic layer was distilled off completely under reduced
pressure to get crude compound of formula-23.
25 The obtained compound was charged into a round bottom flask with azeotropic distillation
setup with toluene (660.0 mL) and heated to 115-125°C, stirred for 10 hr. Toluene was
distilled off upto 90-95% under azeotropic conditions, the resulting solution was cooled to -
5 to 5°C, and stirred for 4 hr. Filtered the precipitate solid, washed with toluene (220 mL)
and dried to get the title compound.
30 Yield: 161.0 gr.
Example-16: Preparation of Compound of Formula-25.
19
A round bottom flask was charged with compound of formula-24 (75 gr), pyridine (375 mL)
stirred for 10 min under nitrogen atmosphere. EDC.HCl (43.82 gr), DMAP (24.20 gr), 6-
amino isoquinoline (21.24 gr) were added to the above reaction mixture at 25-35°C and
stirred for 6 hr. The reaction mixture was quenched with a saturated solution of sodium
bicarbonate (100 mL) and stirred at 25-35°C for 30 min. Filtered the 5 precipitate solid and
washed with water (200 mL). The obtained wet compound was charged with ethyl acetate
(100 mL) and stirred for 2 hr at 25-35°C. Filtered the obtained solid, washed with ethyl
acetate (40 mL) and dried to get the title compound.
Yield: 59.0 gr.
10 Example-17: Preparation of Compound of Formula-1 (Netarsudil free base racemic)
A round bottom flask was charged compound of formula-25 (2.0 gr), isopropanol (20 mL)
at 25-35°C and stirred for 10 min. Methylamine (20 mL; 45 % aqueous) was added the
reaction mixture at 25-35°C and stirred for 10 hr. The reaction mixture was cooled to -5 to
10°C, charged with water (20 mL) and stirred for 2 hr. Filtered the obtain solid, purified in
15 ethyl acetate (20 mL) and dried to get the title compound.
Yield: 0.5 gr
Example-18: Purification of Compound of Formula-1 (Netarsudil free base racemic)
A round bottom flask was charged compound of formula-1 (20.0 gr), dichloromethane (200
mL) at 25-35°C and stirred for 10 min. Cooled the reaction mixture to 0-10°C, added a
20 solution of methane sulphonic acid (9.22 gr) in dichloromethane (40 mL) and stirred for 48
hr at 25-35°C. The above reaction mixture was charged with isopropanol (200 mL) and
stirred for 2 hr, and filtered the solid, washed with isopropanol (40 mL) and dried. The
obtained compound was charged with isopropanol (200 mL), adjusted the pH to 8.0 with
aqueous ammonia solution and stirred for 2 hr. Filtered the precipitate solid, washed with
25 isopropanol (40 mL) and dried to get the title compound .
Yield: 10.0 gr
Example-19: Preparation of Compound of Formula-I. (Netarsudil Dimesylate salt)
A round bottom flask was charged Netarsudil freebase (S-isomer, obtained from chiral prep
HPLC) (20.0 gr), dichloromethane (200 mL) at 25-35°C and stirred for 10 min under
30 nitrogen atmosphere. Cooled the reaction mixture to 0-10°C, added a solution of methane
sulphonic acid (9.22 gr) in dichloromethane (40 mL) and stirred for 48 hr at 25-35°C. The
20
above reaction mixture was charged with isopropanol (200 mL) and stirred for 2 hr, under
nitrogen atmosphere. and filtered the solid, washed with isopropanol (40 mL) and dried to
get the title compound .
Yield: 25.0 gr
Purity by HPLC: > 99.5 %; M.R: 120-125°5 C; obtained SOR: -153
Example-20: Preparation of 2-(hydroxymethyl)isoindoline-1,3-dione.
A round bottom flask was charged phthalimide (2 kg), water (3 L) formaldehyde (49 %,
1.35 L) and heated to 95-105°C, and stirred for 7 hr. The reaction mixture was cooled to 25-
35°C, precipitate compound was filtered and washed with water ( 2 L). The obtained wet
10 compound was stirred in water (3 L) for 1 hr at 35-40°C. Filtered the obtained compound
and dried to get the title compound.
Yield: 2288.0 gr.
Example-21: Preparation of 2-(bromomethyl)isoindoline-1,3-dione.
A round bottom flask was charged aq. HBr (1.426 mL) and cooled to 5-15°C and stirred for
15 30 min. A premixed solution of 2-(hydroxymethyl)isoindoline-1,3-dione (500 gr), sulfuric
acid (1 L) was added slowly to the above reaction mixture at 5-15°C and stirred for 3 hr.
The reaction mixture further cooled to 0-10°C, charged slowly with water (2.5 L), dichloro
methane (2.5 L) and gradually heated to 20-30°C separated the layers. The aqueous layer
was extracted with dichloromethane (1.5 L) . The combined organic layer was washed with
20 5 % solution of sodium thiosulphate (25 gr ), dried the organic layer and evaporated to get
the title compound.
Yield: 436.0 gr.
Example-22: Preparation of racemic Netarsudil Dimesylate salt
A round bottom flask was charged Netarsudil freebase (10.0 gr), dichloromethane (100 mL)
25 at 25-35°C and stirred for 10 min under nitrogen atmosphere. Cooled the reaction mixture
to 0-10°C, added a solution of methane sulphonic acid (5.0 gr) in dichloromethane (20 mL)
and stirred for 12 hr at 25-35°C. The above reaction mixture was charged with isopropanol
(80 mL) and stirred for 2.5 hr, under nitrogen atmosphere. and filtered the solid, washed
with isopropanol (15 mL) and dried to get the title compound .
30 Yield: 5.5 gr. ,CLAIMS:1. A process for the preparation of compound of formula-I.
5 Formula-I
comprising of:
a) reacting the compound of formula-2A, with alcohol in presence of suitable reagent,
solvent to provide compound of formula-3,
10 Formula-2A Formula-3 (R’ is alkyl, methyl, ethyl, propyl)
b) reacting the compound of formula-3 with compound-of formula-B in presence of suitable
base, solvent to provide the compound of formula-17,
c) reacting the compound of formula-17 with suitable reagent, solvent to provide
15 compound of formula-17C,
Formula-17 Formula-17C
d) reacting the compound of formula-17C with 2,4-dimethylbenzoic acid in presence of
20 suitable reagent, solvent to provide compound of formula-22A,
22
Formula-22A
e)hydrolysing the compound of formula-22A in presence of suitable reagent, solvent to
provide the compound of formula-23,
f)cyclising the compound of formula-23 with suitable reagent, solvent 5 to provide formula-
24,
Formula-23 Formula-24
g) reacting the compound of formula-24 with 6-aminoisoquinoline in presence of suitable
10 reagent, solvent to provide compound of formula-25,
h) deprotecting the compound of formula-25 in presence of suitable reagent, solvent to
provide compound of formula-1,
i) resolving the compound of formula-1 with suitable chiral preparative HPLC, suitable
solvents to provide the compound of formula-1a,
15
Formula-25 Formula-1 Formula-1a
23
j) optionally purifying the compound obtained in step-i) by making suitable acid addition
salt followed by basification with suitable base,
k) reacting the compound obtained in step-i) or j) with methesulphonic acid in suitable
solvent to provide compound of formula-I, and optionally purifying in suitable solvent.
5
2. A process for the preparation compound of formula-I according to claim 1 wherein in
step-a) the suitable solvent is selected from an alcohol solvent, suitable regents sulfuric
acid, thionyl chloride, oxalylchloride; suitable temperature is 0°C to 100°C; step-b) selected
form 2-(bromomethyl)isoindoline-1,3-dione, 2-(chloromethyl)isoindoline-1,3-dione, 2-
(iodomethyl)isoindoline-1,3-dione; suitable base is organic 10 base such as LiHMDS,
NaHMDS, KHMDS, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium
tert-butoxide and inorganic base; suitable solvent chloro solvent, ether solvent, ester solvent,
polar solvents and mixture thereof; suitable temperature is -80°C to 80°C; step-c) suitable
reagents N-bromosuccinimide, azobisisobutyronitrile, bromine, suitable solvent chloro
15 solvent, hydrocarbon solvent, ether solvent, ester solvent, nitrile solvent, polar solvents and
mixture thereof; suitable temperature is 0°C to 100°C;
step-d) suitable reagents inorganic base, organic base, suitable solvent hydrocarbon solvent,
chloro solvent, ether solvent, ester solvent, nitrile solvent, acetone solvent, polar solvents,
alcohol solvent, toluene and mixture thereof; suitable temperature is 0°C to 100°C;
20 step-e, f) suitable reagents EDC, HOBT, DMAP, inorganic base, suitable solvent
hydrocarbon solvent, chloro solvent, ether solvent, ester solvent, nitrile solvent, acetone
solvent, polar solvents, water, toluene, alcohol solvent and mixture thereof; suitable
temperature is 0°C to 150°C; pH range is 0-5; step-g) suitable reagents are ethyl-(N’,N’-
dimethylamino)propylcarbodiimidehydrochloride (EDC), 1-hydroxy benzo triazole (HOBt),
25 4-(N,N-dimethylamino) pyridine (DMAP), thionylchloride, oxalylchloride; suitable base is
organic base; inorganic base, suitable solvent hydrocarbon solvent, pyridine, DMF, chloro
solvent, ether solvent, ester solvent, nitrile solvent, acetone solvent, polar solvents, water,
toluene, alcohol solvent and mixture thereof; suitable temperature is 0°C to 80°C;
Step-h) suitable reagent is hydrazine hydrade, methylamine; suitable solvent hydrocarbon
30 solvent, chloro solvent, ether solvent, ester solvent, nitrile solvent, acetone solvent, polar
solvents, water, toluene, alcohol solvent and mixture thereof; suitable temperature is 0°C to
24
80°C; step-i, j) suitable reagents are methane sulphonic acid, hydrochloric acid,
hydrobromic acid, phosphoric acid, tartaric acid, trifluoro acetic acid, acetic acid, sulphate,
PTSA; suitable solvent hydrocarbon solvent, chloro solvent, ether solvent, ester solvent,
nitrile solvent, acetone solvent, polar solvents, water, toluene, alcohol solvent and mixture
5 thereof;
3. A process for the preparation of compound of formula-I.
Formula-I
10 comprising of,
a) reacting the compound of formula-2A, with methanol in presence of sulfuric acid to
provide the compound of formula-3A,
Formula-2A Formula-3A
15 b) reacting the compound of formula-3A with 2-(bromomethyl)isoindoline-1,3-dione in
presence of LiHMDS in tetrahydrofuran to provide the compound of formula-17A,
c)reacting the compound of formula-17A with N-bromosuccinamide, AIBN (catalytic) in
acetonitrile to provide compound of formula-17B,
20 Formula-17A Formula-17B
d) reacting the compound of formula-17B with 2,4-dimethylbenzoic acid in presence of
Na2CO3 in acetonitrile to provide the compound of formula-22,
25
e) hydrolysing the compound of formula-22 with LiOH in THF, water to provide the
compound of formula-23,
f) cyclizing the compound of formula-23 in toluene to provide the compound of formula-24,
5 Formula-23 Formula-24
g) reacting the compound of formula-24 with 6-aminoisoquinoline in presence of EDC,
HOBt in pyridine to provide the compound of formula-25,
h) deprotecting the compound of formula-25 with methylamine in isopropanol to provide
the compound of formula-1,
10
Formula-1 Formula-1a
i) resolving the compound of formula-1 using chiral preparative HPLC to get the compound
of formual-1a, optionally purifying to get pure compound of Formula-1a,
j) treating the compound of formula-1a with methanesulphonic acid in MDC, followed by
15 basification using ammonia in isopropanol to get pure compound of Formula-1a,
k) converting to mesylate salt of compound of formula-1a in dichloromethane to provide
compound of formula-I, purifying in isopropanol to get pure compound.
4. Process for the preparation of compound of formula-17B , comprising of,
20 a) reacting the compound of formula-2A with methanol in presence of sulfuric acid to
provide compound of formula-3A,
b)reacting the compound of formula-3A with 2-(bromomethyl)isoindoline-1,3-dione in
presence of LiHMDS in tetrahydrofuran to provide the compound of formula-17A,
c) reacting the compound of formula-17A with N-bromosuccinamide, AIBN (catalytic) in
25 acetonitrile to provide the compound of formula-17B.
26
5. A compound of formula-17
Where R: hydrogen, bromo, chloro, iodo, Pivaloyl ; R’: alkyl;methyl, ethyl, propyl, butyl.
6. Process for the preparation of compound of formula-5 24, comprising of,
a) reacting the compound of formula-17B with 2,4-dimethylbenzoic acid in presence of
Na2CO3 in acetonitrile to provide compound of formula-22,
b) hydrolysing the compound of formula-22 with LiOH in THF, water to provide the
compound of formula-23,
10 c) cyclizing the compound of formula-23 in toluene to provide formula-24.
7. Process for the preparation of compound of formula-1, comprising of,
a) reacting the compound of formula-24 with 6-aminoisoquinoline in presence of EDC,
HOBt, pyridine to provide the compound of formula-25,
15 b) deprotecting the compound of formula-25 with methylamine in isopropanol to provide
the compound of formula-1.
8. A process for the purification of compound of formula-1, comprising of ,
a) treating the compound of formula-1 with suitable acid, followed by base in suitable
20 solvent, to get pure compound of Formula-1,
Wherein step-a) suitable reagents are methane sulphonic acid, hydrochloric acid,
hydrobromic acid, phosphoric acid, tartaric acid, trifluoro acetic acid, acetic acid, sulphate,
PTSA; suitable base is ammonia, organic base, inorganic base, suitable solvent hydrocarbon
solvent, chloro solvent, ether solvent, ester solvent, nitrile solvent, acetone solvent, polar
25 solvents, water, toluene, alcohol solvent and mixture thereof;
27
9. A process for the preparation of compound of formula-I
Comprising of,
a) treating the compound of formula-1a with methane sulphonic acid, in dichloromethane to
get the compound of Formula-I,
b) Purifying the compound of formula-I in iosporpanol 5 to get pure compound.
10. The compound of formula-I, obtained according to any of preceding claims having
purity by HPLC> 95%, preferably > 99% ; more preferably>99.5 %