DESC:FIELD OF INVENTION

The present invention relates to a process for preparation of Pacritinib, its pharmaceutically acceptable salts and intermediates thereof.

BACKGROUND OF THE INVENTION

Pacritinib Citrate is a kinase inhibitor and is chemically known as (2E,16E)-11-[2­(pyrrolidin-1-yl)ethoxy]-14,19-dioxa-5,7,27-triazatetracyclo[19.3.1.1(2,6).1(8,12)] heptacosa1(25),2,4,6,8,10,12(26),16,21,23-decaene citrate, which has been approved as a capsule having dosage strength 100 mg under the trade name VONJO® for the treatment of for the treatment of adults with intermediate or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis. Pacritinib Citrate is structurally represented as follows:

Pacritinib as well as its pharmaceutically acceptable salts were disclosed in US 8,153,632 B2 (US ‘632) of CTI Biopharma Corp. Further, discloses the synthesis of Pacritinib, which is as shown below:

This process involves the condensation of 4-(3-But-3-enyloxy-phenyl)-2-chloro-pyrimidine with 3-Allyloxymethyl-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine to give [4-(3-Allyloxymethyl-phenyl)-pyrimidin-2-yl]-[3-allyloxymethyl-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine and is further cyclized using Grubbs catalyst to yield Pacritinib. This process involves the Grubbs catalyst, which is highly expensive, this reaction consumes the high volumes of solvents and yields Pacritinib having E/Z (trans/cis) mixture 85:15 ratio, which is difficult to separation. Hence, this process is economically not effective and industrially not viable.

CN 105061467 B discloses the synthesis of Pacritinib, which is as shown below:

CN 105017282 B also discloses the synthesis of Pacritinib, which is as shown below:

The present inventors have repeated the prior-art process and found that process yields Pacritinib having low yield and purity.

Further the present inventors have now found a process which resolves the issues of the prior art processes and yields Pacritinib with high yield and purity.

OBJECTIVES

One objective of the present invention is to provide a process for the preparation of Pacritinib of Formula I and its pharmaceutically acceptable salt thereof using intermediate compounds of Formula A, Formula B & Formula C, which is economically cost effective and industrially applicable process.

Another objective of the present invention is to provide intermediate compounds of Formula A, Formula B & Formula C and process for the preparation thereof.

Another objective of the present invention is to provide a process for the preparation of Pacritinib of Formula I and its pharmaceutically acceptable salt thereof, which has higher yield and purity with acceptable level of impurities.

SUMMARY OF THE INVENTION

The present invention provides a process for the preparation of Pacritinib of Formula I and its pharmaceutically acceptable salt thereof:

which comprises:
(i) condensing the compound of Formula III;

with the compound of Formula VIII;

to obtain the compound of Formula C;

(ii) condensing the compound of Formula C with pyrrolidine to obtain the compound of Formula B;

(iii) reducing the compound of Formula B with a suitable reducing agent to obtain a compound of Formula A;

wherein, X is a halogen
(iv) cyclizing the compound of Formula A to obtain Pacritinib of Formula I; and
(v) optionally converting the Pacritinib of Formula I to its pharmaceutically acceptable salt thereof.

The present invention provides a process for the preparation of Pacritinib of Formula I and its pharmaceutically acceptable salt thereof:

which comprises:
(A) cyclizing the compound of Formula A,

to obtain Pacritinib of Formula I; and
wherein, X is a halogen
(B) optionally converting the Pacritinib of Formula I to its pharmaceutically acceptable salt thereof.

The present invention also provides a process for the preparation of the compound of Formula A,

which comprises:
reducing the compound of Formula B

wherein, X is a halogen
with a suitable reducing agent to obtain a compound of Formula A.

The present invention also provides a process for the preparation of the compound of Formula B,

which comprises:
condensing the compound of Formula C;

wherein, X is a halogen
with pyrrolidine to obtain the compound of Formula B.

The present invention also provides a process for the preparation of the compound of Formula C;

which comprises:
condensing the compound of Formula III

with the compound of Formula VIII

wherein, X is a halogen
to obtain the compound of Formula C.

The present invention also provides a process for the preparation of the compound of Formula VIII:

which comprises:
condensing compound of Formula VI;

with 1,4-Dihalo-2-butene of Formula VII;

wherein, X is a halogen
to obtain the compound of Formula VIII.

The present invention also provides use of compound of Formula A,

in the preparation of Pacritinib of Formula I and its pharmaceutically acceptable salt thereof.

The present invention also provides use of compound of Formula B,

in the preparation of Pacritinib of Formula I and its pharmaceutically acceptable salt thereof.

The present invention also provides use of compound of Formula C,

in the preparation of Pacritinib of Formula I and its pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect of the present invention provides a process for the preparation of Pacritinib of Formula I, which comprises: (A) cyclizing the compound of Formula A in presence of an acid, a suitable base, metal catalyst, or combination thereof; in a suitable solvent selected from the group comprising of halogenated solvents, alcohols, ketones, ethers, esters, hydrocarbons, nitriles, polar solvents, polar-aprotic solvents or mixture of solvents thereof; to obtain Pacritinib of Formula I; (B) optionally converting the Pacritinib of Formula I to its pharmaceutically acceptable salt thereof.

In another aspect of the present invention provides a process for the preparation of compound of Formula A, which comprises: reducing the compound of Formula B with suitable reducing agent selected from the group comprising of a metal ion in presence or absence of an acid selected from the group comprising of HCl, HBr, Ammonium chloride, Stannic chloride; suitable hydrogenating agent in a hydrogen source; a suitable base selected from the group comprising of organic or inorganic base to obtain the compound of Formula A. The obtained compound of Formula A can be optionally isolated and optionally purified by conventional methods.

In another aspect of the present invention also provides a process for the preparation of compound of Formula B, which comprises: condensing the compound of Formula C with pyrrolidine in presence or absence of a suitable base, in a suitable solvent to obtain the compound of Formula B. The obtained compound of Formula B can be optionally isolated and optionally purified by conventional methods.

In another aspect of the present invention also provides a process for the preparation of compound of Formula C, which comprises: condensing the compound of Formula III with the compound of Formula VIII in presence of a base selected from the group comprising of organic base, inorganic base; in presence or absence of a phase transfer catalyst; in a suitable solvent selected from the group comprising of halogenated solvents, alcohols, ketones, ethers, esters, hydrocarbons, nitriles, polar solvents, polar-aprotic solvents or mixture of solvents thereof to obtain the compound of Formula C. The obtained compound of Formula C can be optionally isolated and optionally purified by conventional methods.

In another aspect of the present invention also provides a process for the preparation of compound of Formula VIII, which comprises: condensing the compound of Formula VI with 1,4-Dihalo-2-butene compound of Formula VII in presence of a suitable base; in presence or absence of a phase transfer catalyst; in a suitable solvent to obtain a compound of Formula VIII. The obtained compound of Formula VIII can be optionally isolated and optionally purified by conventional methods.

In another aspect of the present invention also provides use of compound of Formula A,

in the preparation of Pacritinib of Formula I and its pharmaceutically acceptable salt thereof.

In another aspect of the present invention also provides use of compound of Formula B,

in the preparation of Pacritinib of Formula I and its pharmaceutically acceptable salt thereof.

In another aspect of the present invention also provides use of compound of Formula C,

in the preparation of Pacritinib of Formula I and its pharmaceutically acceptable salt thereof.

The raw-materials used in the present invention, can be prepared or synthesized by known methods in the available literature.

The present invention also provides a process for the preparation of compound of Formula III,

wherein, X is a halogen
which comprises:
condencing the 2,4-Dihalopyrimidine compound of Formula (i):

with aldehyde compound of Formula (ii)

to obtain the compound of Formula II;

followed by reduction with a suitable reducing agent in a suitable solvent to obtain the compound of Formula III.

The present invention also provides a process for the preparation of the compound of Formula VI;

wherein, X is a halogen
which comprises:
condensing 2-hydroxy-5-nitrobenzaldehy with 1,2-Dihaloethane to obtain compound of Formula V; and

reducing the compound of Formula V with a suitable reducing agent to obtain the compound of Formula VI.

In another aspect of the present invention obtained Pacritinib of Formula I can be optionally isolated and optionally purified by conventional methods.

In another aspect of the present invention obtained Pacritinib of Formula I can be optionally converted to its pharmaceutically acceptable salt thereof, which comprises: treating the Pacritinib of Formula I with an pharmaceutically acceptable acid selected from the group comprising organic acid or inorganic acid; or a base selected from the group comprising of organic base or inorganic base; in a suitable solvent thereof.

In another aspect of the present invention, suitable organic acid is selected from the group comprising of citric acid, maleic acid, oxalic acid, tartaric acid, fumaric acid, succinic acid; suitable inorganic acid is selected from the group comprising of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid.

In another aspect of the present invention obtained Pacritinib of Formula I and its pharmaceutically acceptable salt thereof is in the form of solution, liquid, foamy solid, solid, any crystalline form or amorphous form.

In another aspect of the invention, a suitable solvent is selected from the group comprising of alcohols, ketones, halogenated solvents, ethers, esters, hydrocarbons, nitriles, polar solvents, polar-aprotic solvents or mixture of solvents thereof; alcohols are selected from the group comprising of methanol, ethanol, butanol, t-BuOH, isopropanol; ketones are selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone; the halogenated solvents are selected from the group comprising of dichloromethane, dichloroethane, chloroform, carbon tetrachloride; ethers are selected from the group comprising of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, isopropyl ether, diisopropyl ether, methyl isobutylether, methyl t-butyl ether, dioxane, anisole; esters are selected from the group comprising of ethyl acetate, isopropyl acetate; hydrocarbons are selected from the group comprising of n-hexane, n-heptane, cyclohexane, cycloheptane, benzene, toluene, m-, o- or p-xylene; nitriles are selected from the group comprising of acetonitrile, propionitrile, butyronitrile, acrylonitrile; polar solvents are selected from group comprising of water; polar aprotic solvents are selected from the group comprising of N,N-dimethylformamide, dimethylacetamide, dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP).

In another aspect of the invention, the mixture of solvents means two or more solvents.

In another aspect of the invention, suitable reducing agent is selected from the group comprising of metal ion, selected from the group comprising of iron (Fe), tin (Sn), zinc (Zn); suitable hydrogenating agent selected from the group comprising of Pd, Pt, Ni, Raney Ni; a suitable base is selected from the group comprising of organic bases and inorganic bases.

In another aspect of the invention, suitable base is selected from the group comprising of organic bases, inorganic bases; organic bases are selected from the group comprising of N,N-Diisopropylethylamine, diisobutylamine, Triethyl amine, pyridine, Dimethylaminopyridine, N-Methyl morpholine; organosilicon base selected from the group comprising of lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS); inorganic bases are selected from the group comprising of alkali metal hydroxides such as Sodium hydroxide, Ptassium hydroxide, Lithium hydroxide; alkali metal carbonates and bicarbonates are selected from the group comprising of sodium carbonate, sodium bicarbonate, Potassium carbonate, potassium bicarbonate; alkali metal alkoxides selected from the group comprising of Sodium methoxide, Sodium ethoxide, Potassium methoxide, Potassium ethoxide, t-BuONa, t-BuOK; and alkali metal amides selected from the group comprising of Sodium amide, Potassium amide.

In another aspect of the invention, suitable metal catalyst is selected from the group comprising of selected from the group comprising of Pd, Pt, Ni, Raney Ni.

In another aspect of the invention, suitable phase transfer catalyst selected from the group comprising of TBAB (Tetrabutyl ammonium bromide), TBAC Tetrabutyl ammonium chloride), BTEAC (Benzyltriethylammonium chloride), and MTBAC (Methyltributylammonium Chloride).

In another aspect of the invention, as used herein the term “halogen” selected from the group comprising of fluorine, chlorine, bromine, iodine.

In another aspect, obtained Pacritinib of Formula I and its intermediate compounds can be optionally isolated and optionally purified by conventional methods.

In another aspect throughout the invention, isolation of Pacritinib of Formula I and its pharmaceutically acceptable salt thereof, as well as its intermediate compounds can be performed by conventional methods such as cooling, removal of solvents, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent, filtration, centrifugation.

In another aspect of the present invention, the Pacritinib of Formula I and its pharmaceutically acceptable salt thereof, obtained by removing the solvent by using suitable techniques which may be used for the removal of the solvent include evaporation techniques such as a Büchi® Rotavapor®, spray drying, agitated thin film drying, freeze drying (lyophilization) or any other suitable technique of downward atmospheric distillation, the solvent may be removed. The solvent may be removed optionally adjusting / the optimizing atmospheric pressure as well as temperatures.

In another aspect of the present invention provides a pharmaceutical composition comprising Pacritinib of Formula I and its pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable excipient. As used herein, the term “pharmaceutical composition” or “pharmaceutical formulation” include tablets, pills, powders, liquids, suspensions, emulsions, granuels, capsules, suppositories, or injection preparations.

The Abbreviations used throughout the invention are as follows:
t-BuONa : Sodium t-butoxide
t-BuOK : Potassium t-butoxide
Pd(pph3)Cl2 : Bis(triphenylphosphine)palladium(II) dichloride

The invention of the present application will be explained in more detail with reference to the following examples, which should not be construed as limiting the scope of the invention in any manner.

Examples

Reference Example 1: Preparation of [4-(3-Allyloxymethyl-phenyl)-pyrimidin-2-yl]-[3-allyloxymethyl-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]amine

To a mixture of 4-(3-Allyloxymethyl-phenyl)-2-chloro-pyrimidine (100 mg, 0.38 mmol) and 3-Allyloxymethyl-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (93.9 mg, 0.57 mmol) in n-butanol (15 mL) at ambient temperature was added 1N HCl (1.0 mL) and the resulting mixture was stirred at 100°C. for overnight. The reaction mixture was cooled to 0°C. and quenched with H2O. The product was extracted with CH2Cl2 thrice and the combined organic extracts were washed with saturated NaHCO3 followed by brine, dried over Na2SO4 and concentrated under reduced pressure to furnish an oil, which was purified by column (EtOAc/Hexane) to obtain 70 mg of [4-(3-Allyloxymethyl-phenyl)-pyrimidin-2-yl]-[3-allyloxymethyl-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]amine in 47% yield.

Reference Example 2: Preparation of Pacritinib

To a degassed solution of [4-(3-Allyloxymethyl-phenyl)-pyrimidin-2-yl]-[3-allyloxymethyl-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]amine and TFA in CH2Cl2 at ambient temperature was added Grubbs 2nd generation catalyst. The resulting mixture was stirred at 50°C. for overnight. The reaction mixture was cooled and concentrated under reduced pressure to furnish an oil, which was purified by preparative HPLC to obtain Pacritinib.

Example 1: Preparation of 3-(2-Chloropyrimidin-4-yl)benzaldehyde

To the 2,4-Dichloropyrimidine (100 gm), added acetonitrile (600 ml), (3-Formylphenyl)boronic acid (100 gm), Sodium carbonate (105 gm) & water (400 ml) at 25-35°C. Through the reaction mass, N2 passed for 1 hour, added Pd(pph3)2Cl2, heated to 80-85°C and stirred for 15 hours to 16 hours, cooled to 25-35°C. Filtered the obtained solid and washed with water (200 ml). Layers were separated, organic layer washed with water and Sodium chloride, distilled under reduced pressure. The obtained solid was filtered, washed with MeOH (100 ml) and dried in hot air oven to yield 3-(2-Chloropyrimidin-4-yl)benzaldehyde (101 gm).
Yield: 68.8%

Example 2: Preparation of (3-(2-Chloropyrimidin-4-yl)phenyl)methanol

To the 3-(2-Chloropyrimidin-4-yl)benzaldehyde (100 gm), added THF (1000 ml) and the obtained reaction mass was cooled to 15-20°C. Added, Sodium borohydride (8 gm) and heated to 25-35°C, stirred for 1 hour, cooled to 15-20°C. To the obtained reaction mixture, added water (1000 ml), Ethyl acetate (1000 ml) and stirred for 15 minutes. Layers were separated, organic layer was washed with water & Sodium chloride solution, distilled under reduced pressure at below 50°C to yield (3-(2-Chloropyrimidin-4-yl)phenyl)methanol.
Yield: 67%

Example 3: Preparation of 2-(2-Chloroethoxy)-5-nitro benzaldehyde

To the 2-hydroxy-5-nitro benzaldehyde (100 gm), added N,N-Dimethyl formamide (500 ml), Potassium carbonate (158 gm), 1-Bromo-2-chloroethane (128 gm) at 25-35°C, heated to 80-85°C, stirred for 5 hours to 7 hours, cooled to 15-20°C, added water (1000 ml), Ethyl acetate (1000 ml) and stirred for 15 minutes at 15-20°C. Layers were separated, organic layer was washed with water & Sodium chloride solution and distilled under reduced pressure at below 50°C. To the obtained solid, added hexane (500 ml) and stirred for 1 hour, filtered the obtained solid, washed with hexane (100 ml) and dried in hot air oven for 15 hours at 45-50°C to yield 2-(2-Chloroethoxy)-5-nitro benzaldehyde (84 gm).
Yield: 61%

Example 4: Preparation of (2-(2-Chloroethoxy)-5-nitrophenyl)methanol

To the 2-(2-Chloroethoxy)-5-nitro benzaldehyde (100 gm), added THF (1000 ml) at 25-35°C. Cooled to 15-20°C, added Sodium borohydride (8 gm), heated to 25-35°C and stirred for 1 hour. The reaction mixture was cooled to 15-20°C, added water (1000 ml), DCM (1000 ml), layers were separated, organic layer was washed with water & Sodium chloride solution, distilled under reduced pressure at below 50°C. To the obtained solid, added hexane (500 ml) and stirred for 1 hour, filtered and washed with hexane (200 ml) to yield (2-(2-Chloroethoxy)-5-nitrophenyl)methanol (87.7 gm).
Yield: 87%

Example 5: Preparation of (E)-2-(((4-bromobut-2-en-1-yl)oxymethyl)-1-(2-chloroethoxy)-4-nitrobenzene

To the (2-(2-Chloroethoxy)-5-nitrophenyl)methanol (100 gm), added DCM (500 ml), Potassium hydroxide (72 gm), (E)-1,4-dibromobut-2-ene (166 gm) and TBAB (1.5 gm) at 25-35°C, stirred for 10 minutes. The obtained reaction mass was heated to 40-45°C, maintained for 4 hours to 6 hours, cooled to 25-35°C, layers were separated, organic layer was washed with water & Sodium chloride solution and distilled under reduced pressure at below 50°C to yield (E)-2-(((4-bromobut-2-en-1-yl)oxymethyl)-1-(2-chloroethoxy)-4-nitrobenzene (126 gm).
Yield: 80%

Example 6: Preparation of (E)-2-chloro-4-(3-(((4-((2-(2-chloroethoxy)-5-nitrobenzyl)oxy)but-2-en-1-yl)oxy)methyl)phenyl)pyrimidine

To the (E)-2-(((4-bromobut-2-en-1-yl)oxymethyl)-1-(2-chloroethoxy)-4-nitrobenzene (70 gm), added DCM (50 ml), Potassium hydroxide (21 gm), (3-(2-Chloropyrimidin-4-yl)phenyl)methanol (44.5 gm), TBAB (0.7 gm) at 25-35°C and stirred for 15 hours to 16 hours. Layers were separated, organic layer was washed with water & Sodium chloride solution and distilled under reduced pressure at below 50°C to yield (E)-2-chloro-4-(3-(((4-((2-(2-chloroethoxy)-5-nitrobenzyl)oxy)but-2-en-1-yl)oxy)methyl)phenyl)pyrimidine.
Yield: 70%

Example 7: Preparation of (E)-2-chloro-4-(3-(((4-((5-nitro-2-(2-pyrrolidin-1-yl)ethoxy)benzyl)oxy)but-2-en-1-yl)oxy)methyl)phenyl)pyrimidine

To the (E)-2-chloro-4-(3-(((4-((2-(2-chloroethoxy)-5-nitrobenzyl)oxy)but-2-en-1-yl)oxy)methyl)phenyl)pyrimidine (50 gm), added ACN (350 ml), pyrrolidine (10 gm) at 25-35°C, heated to 75-80°C, stirred for 4 hours to 5 hours. Cooled to 25-35°C, distilled under vacuum at below 60°C, added water (500 ml), DCM (500 ml) and stirred for 15 minutes. Layers were separated, organic layer was washed with water & Sodium chloride solution, distilled under reduced pressure at below 50°C to yield (E)-2-chloro-4-(3-(((4-((5-nitro-2-(2-pyrrolidin-1-yl)ethoxy)benzyl)oxy)but-2-en-1-yl)oxy)methyl)phenyl)pyrimidine (40 gm).
Yield: 75%

Example 8: Preparation of (E)-3-(((4-((3-(2-chloropyrimidin-4-yl)benzyl)oxybut-2-en-1-yl)oxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline

To the (E)-2-chloro-4-(3-(((4-((5-nitro-2-(2-pyrrolidin-1-yl)ethoxy)benzyl)oxy)but-2-en-1-yl)oxy)methyl)phenyl)pyrimidine (40 gm), added Fe powder (40 gm), Ammonium chloride (79 gm), EtOH (800 ml) & water (200 ml) at 25-35°C. The obtained reaction mixture was heated to 80-90°C and stirred for 15 hours to 20 hours. Cooled to 25-35°C, filtered the reaction mass and washed with EtOH (200 ml). Distilled under vacuum at below 50°C, added DCM (400 ml), water (200 ml) and stirred for 15 minutes. Layers were separated, organic layer was washed with water & Sodium chloride solution and distilled under reduced pressure at below 50°C to yield (E)-3-(((4-((3-(2-chloropyrimidin-4-yl)benzyl)oxybut-2-en-1-yl)oxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline (27 gm).
Yield: 70%
Example 8: Preparation of Pacritinib

To the (E)-3-(((4-((3-(2-chloropyrimidin-4-yl)benzyl)oxybut-2-en-1-yl)oxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline (25 gm), added n-butanol (40 ml), HCl (40 ml), heated to 100°C and stirred for 15 hours to 20 hours. Cooled to 0-5°C, added water (20 ml) and adjusted the pH to 8-9 with Potassium carbonate solution. To the obtained reaction mass, added DCM (40 ml) and stirred for 15 minutes. Layers were separated, organic layer was washed with water & Sodium chloride solution and distilled under reduced pressure at below 50°C to yield Pacritinib (17 gm).
Yield: 70%

Example 8: Preparation of Pacritinib Citrate

To the Pacritinib (15 gm), added toluene (300 ml) and heated to 65-75°C. To the obtained clear solution, added citric acid (6 gm) and maintained for 1 hour at 65-75°C. Cooled to 0-5°C, maintained for 12 hours to 14 hours at 25-35°C. Filtered the obtained product, washed with toluene (30 ml) and dried under vacuum at 60-70°C for 15 hours to yield Pacritinib Citrate.
Yield: 90%

,CLAIMS:We Claim:

1. A process for the preparation of Pacritinib of Formula I and its pharmaceutically acceptable salt thereof:

which comprises:
(i) condensing the compound of Formula III;

with the compound of Formula VIII;

to obtain the compound of Formula C;

(ii) condensing the compound of Formula C with pyrrolidine to obtain the compound of Formula B;

(iii) reducing the compound of Formula B with a suitable reducing agent to obtain a compound of Formula A;

wherein, X is a halogen
(iv) cyclizing the compound of Formula A to obtain Pacritinib of Formula I; and
(v) optionally converting the Pacritinib of Formula I to its pharmaceutically acceptable salt thereof.

2. The process as claimed in claim 1, wherein Step (i) condensation of compound of Formula III with the compound of Formula VIII has been carried out in presence of a base selected from the group comprising of organic base, inorganic base; in presence or absence of a phase transfer catalyst.

3. The process as claimed in claim 1, wherein suitable reducing agent used in Step (iii) is selected from the group comprising of a metal ion in presence or absence of an acid selected from the group comprising of HCl, HBr, Ammonium chloride, Stannic chloride; suitable hydrogenating agent in a hydrogen source; a suitable base selected from the group comprising of organic or inorganic base.

4. The process as claimed in claim 1, wherein Step (iv) cyclization of compound of Formula A has been carried out using an acid, a suitable base, metal catalyst; in a solvent selected from the group comprising of selected from the group comprising of halogenated solvents, alcohols, ketones, ethers, esters, hydrocarbons, nitriles, polar solvents, polar-aprotic solvents or mixture of solvents thereof.

5. The process as claimed in claim 1, the process including the steps for the preparation of compound of Formula VIII:

which comprises:
condensing compound of Formula VI;

with 1,4-Dihalo-2-butene of Formula VII;

wherein, X is a halogen
to obtain the compound of Formula VIII.

6. The process as claimed in claim 5, wherein condensation of compound of Formula VI with Formula VII has been carried out using a suitable base, in presence or absence of a phase transfer catalyst.

7. A compound having the Formula A, B, or C,
used in the preparation of Pacritinib of Formula I and its pharmaceutically acceptable salt thereof.

Dated this 09th day of July, 2024

Dr. RATHNAKAR REDDY KURA
DIRECTOR
HETERO LABS LIMITED