DESC:FIELD OF INVENTION

The present invention relates to a process for preparation of oxygen linked pyrimidine derivative 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 D, Formula E & Formula IX, which is economically cost effective and industrially applicable process.

Another objective of the present invention is to provide intermediate compounds of Formula D, Formula E & Formula IX 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 (E)-1,4-dihalobut-2-ene compound of formula VII

wherein, X is a halogen
to obtain the compound of Formula IX;

(ii) condensing the compound of Formula IX with the compound of Formula VI;

to obtain the compound of Formula C;

(iii) reducing the compound of Formula C with a suitable reducing agent to obtain a compound of Formula D;

(iv) cyclizing the compound of Formula D to obtain compound of Formula E;

wherein, X is a halogen
(v) condensing the obtained compound of Formula E with pyrrolidine to obtain Pacritinib of Formula I; and
(vi) 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) condensing the compound of Formula E,

with pyrrolidine 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 E,

which comprises:
cyclizing the compound of Formula D

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

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

which comprises:
reducing the compound of Formula C;

wherein, X is a halogen
with a reducing agent to obtain the compound of Formula D.

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

which comprises:
condensing the compound of Formula IX

with the compound of Formula VI

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

The present invention also provides a process for the preparation of compound of formula IX

which comprises:
condensing the compound of formula III

with the (E)-1,4-dihalobut-2-ene compound of formula VII

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

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

wherein, X is a halogen
in the preparation of Pacritinib of Formula I and its pharmaceutically acceptable salt thereof.

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

wherein, X is a halogen
in the preparation of Pacritinib of Formula I and its pharmaceutically acceptable salt thereof.

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

wherein, X is a halogen
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 or its pharmaceutically acceptable salt thereof, which comprises: (A) condensing the compound of Formula E with pyrrolidine in presence or absence of a suitable base, in a suitable solvent 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 E, which comprises: cyclizing the compound of Formula D in presence or absence 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 compound of Formula E. The obtained compound of Formula E can be optionally isolated and optionally purified by conventional methods.

In another aspect of the present invention provides a process for the preparation of compound of Formula D, which comprises: reducing the compound of Formula C 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 hydrochloric acid, hydrobromic acid, ammonium chloride, stannic chloride (SnCl4); suitable hydrogenating agent in a hydrogen source; in presence or absence of a suitable base selected from the group comprising of organic or inorganic base to obtain the compound of Formula D. The obtained compound of Formula D 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 IX with the compound of Formula VI in presence or absence of a suitable base; in presence or absence of a phase transfer catalyst; in a suitable solvent 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 IX, which comprises: condensing the compound of Formula III with the compound of Formula VII 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 IX. The obtained compound of Formula IX can be optionally isolated and optionally purified by conventional methods.

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

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 E,

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 IX,

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:
condensing 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-nitrobenzaldehyde 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 a 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, tert-butanol, 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 diisopropylethyl amine, diisobutyl amine, triethyl amine, pyridine, 4-dimethylamino pyridine, N-Methylmorpholine; 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, potassium hydroxide, lithium hydroxide; alkali metal hydrides such as sodium hydride, sodium borohydride, potassium hydride; 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, sodium t-butoxide, potassium t-butoxide; 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, TBAC, BTEAC, TBPB and MTBAC.

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:
BTEAC : Benzyltriethylammonium chloride
TBAB : Tetrabutyl ammonium bromide
TBAC : Tetrabutyl ammonium chloride
TBPB : Tetrabutyl phosphonium bromide
MTBAC : Methyltributylammonium Chloride
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 hydrochloric acid (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 dichloromethane thrice and the combined organic extracts were washed with saturated sodium bicarbonate followed by brine, dried over sodium sulfate and concentrated under reduced pressure to furnish an oil, which was purified by column (ethyl acetate / 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 trifluoro acetic acid in dichloromethane 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, (3-Formylphenyl)boronic acid (100 gm), sodium carbonate (105 gm) & water at 25-35°C. To the obtained reaction mixture, added Pd(pph3)2Cl2, heated to 75-85°C, stirred for 15 hours. To the obtained solid, added dichloromethane and stirred for 15 minutes. Layers were separated, aqueous layer extracted with dichloromethane, combined the organic layers and washed with water, distilled under vacuum at below 50°C. To the obtained solid, added methanol, stirred for 2 hours, filtered the obtained solid and washed with methanol. Dried at 50°C to yield 3-(2-Chloropyrimidin-4-yl)benzaldehyde (87 gm).
Yield: 59%

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

To the 3-(2-Chloropyrimidin-4-yl)benzaldehyde (100 gm), added tetrahydrofuran and the obtained reaction mass was cooled to 0-10°C. Added, sodium borohydride (8 gm) at 0-10°C and stirred for 1 hour at 25-35°C, cooled to 0-10°C. To the obtained reaction mixture, added water, dichloromethane and stirred for 15 minutes. Layers were separated, aqueous later extracted with dichloromethane, combined the organic layers and washed with water, distilled under vacuum at below 40°C, co-distilled with diisopropyl ether. To the obtained solid, added dichloromethane and stirred for 3 hours at 25-35°C. Filtered the obtained solid and washed with dichloromethane. Dried at 40°C to yield (3-(2-Chloropyrimidin-4-yl)phenyl)methanol (90 gm).
Yield: 89%

Example 3: Preparation of (E)-4-(3-(((4-bromobut-2-en-1-yl)oxy)methyl)phenyl)-2-chloropyrimidine

To the (3-(2-Chloropyrimidin-4-yl)phenyl)methanol (100 gm), added dichloromethane, TBPB (2 gm), (E)-1,4-dibromobut-2-ene (170 gm) at 25-35°C and stirred for 10 minutes. Added sodium hydroxide solution to the reaction mass and stirred for 24 hours at 25-35°C. Layers were separated, aqueous later extracted with dichloromethane, combined organic layers and washed with water, distilled under vacuum at below 50°C to yield 2-(2-Chloroethoxy)-5-nitro benzaldehyde (100 gm).
Yield: 62.5%

Example 4: Preparation of (2-(2-Chloroethoxy)-5-nitrobenzaldehyde

To the 2-Hydroxy-5-nitrobenzaldehyde (100 gm), added dimethyl formamide, potassium carbonate (165 gm) at 25-35°C and stirred for 10 minutes. Added 1-Bromo-2-chloroethane (171 gm), heated to 60-70°C and stirred for 15 hours. The reaction mixture was cooled to 25-35°C, the obtained solid was filtered, washed with dimethyl formamide and added water. Cooled to 0-10°C, added cooled water and stirred for 15 hours at 25-35°C. Filtered the obtained solid, washed with water and dried at 50-55°C to yield (2-(2-Chloroethoxy)-5-nitrobenzaldehyde (110 gm).
Yield: 80%

Example 5: Preparation of 2-(2-chloroethoxy)-5-nitrophenyl)methanol

To the (2-(2-Chloroethoxy)-5-nitrobenzaldehyde (100 gm), added tetrahydrofuran and the obtained reaction mixture was cooled to 0-10°C. Added sodium borohydride (8 gm) and stirred for 1 hour at 25-35°C. Cooled to 0-10°C, added water, dichloromethane and stirred for 15 minutes. Layers were separated, aqueous layer extracted with dichloromethane, combined the organic layers and washed with water, distilled under vacuum at below 50°C and co-distilled with diisopropyl ether. Added diisopropyl ether to the above obtained solid and stirred for 3 hours at 25-35°C. Filtered the obtained solid and washed with diisopropyl ether. Dried at 40°C to yield 2-(2-chloroethoxy)-5-nitrophenyl)methanol (83.7 gm).
Yield: 83%

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)-4-(3-(((4-bromobut-2-en-1-yl)oxy)methyl)phenyl)-2-chloropyrimidine (100 gm), added dichloromethane, 2-(2-chloroethoxy)-5-nitrophenyl)methanol (78 gm), TBPB (2 gm) at 25-35°C and stirred for 15 minutes. Added sodium hydroxide solution to the above reaction mixture and stirred for 24 hours. Layers were separated, aqueous layer extracted with dichloromethane, combined organic layers and washed with water, distilled under vacuum 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 (100 gm).
Yield: 70%

Example 7: Preparation of (E)-4-(2-chloroethoxy)-3-(((4-((3-(2-chloropydimidin-4- yl)benzyl)oxy)but-2-en-1-yl)oxy)methyl)aniline

To the (E)-2-chloro-4-(3-(((4-((2-(2-chloroethoxy)-5-nitrobenzyl)oxy)but-2-en-1-yl)oxy)methyl)phenyl)pyrimidine (100 gm), added methanol, Fe powder (55 gm) at 25-35°C. To the above reaction mixture, added ammonium chloride solution (ammonium chloride dissolved in water) and heated to 70-80°C. The obtained reaction mixture was stirred for 6 hours at 70-80°C, cooled to 25-35°C and filtered the obtained reaction mass through hiflow bed and washed with methanol. To the above reaction mixture, added water, ethyl acetate at 25-35°C and stirred for 15 minutes. Layers were separated, aqueous layer was extracted with ethyl acetate, combined the organic layers and washed with water, distilled under vacuum at below 50°C to yield (E)-4-(2-chloroethoxy)-3-(((4-((3-(2-chloropydimidin-4-yl)benzyl)oxy)but-2-en-1-yl)oxy)methyl)aniline (82 gm).
Yield: 87%

Example 8: Preparation of (E)-44-(2-chloroethoxy)-6,11-dioxa-3-aza-2(4,2)-pyrimidina-1,4(1,3)-dibenzenacyclododecaphan-8-ene

To the (E)-4-(2-chloroethoxy)-3-(((4-((3-(2-chloropydimidin-4-yl)benzyl)oxy)but-2-en-1-yl)oxy)methyl)aniline (100 gm), added 1,4-Dioxane, trifluoroacetic acid (180 gm) at 25-35°C, heated to 60-70°C and stirred for 4 hours. Cooled to 0-10°C, pH adjusted to 7-8 with saturated sodium bicarbonate solution. To the obtained reaction mixture, added ethyl acetate and stirred for 15 minutes. Layers were separated, aqueous layer extracted with ethyl acetate, combined the organic layers and washed with water, distilled under vacuum at below 50°C to yield (E)-44-(2-chloroethoxy)-6,11-dioxa-3-aza-2(4,2)-pyrimidina-1,4(1,3)-dibenzenacyclododecaphan-8-ene (70 gm).
Yield: 76%

Example 9: Preparation of Pacritinib
To the (E)-44-(2-chloroethoxy)-6,11-dioxa-3-aza-2(4,2)-pyrimidina-1,4(1,3)-dibenzenacyclododecaphan-8-ene (100 gm), added pyrrolidine (200 ml) at 25-35°C, heated to 70-80°C. To the obtained reaction mixture, added isopropanol at 70-80°C, cooled to 25-35°C and stirred for 1 hour. Filtered the obtained solid, washed with isopropanol and dried at below 50°C to yield Pacritinib.
Yield: 84%

Example 10: Preparation of Pacritinib Citrate
To the Pacritinib (100 gm), added toluene and heated to 80-90°C. To the obtained clear solution, added citric acid solution (citric acid dissolved in water) and stirred for 2 hours. Cooled to 25-35°C and stirred for 4 hours. Filtered the obtained solid, washed with toluene. To the obtained solid, added acetone and stirred for 2 hours at 25-35°C. The obtained solid was filtered and washed with acetone, dried at 60°C to yield Pacritinib Citrate.
Yield: 78% ,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 (E)-1,4-dihalobut-2-ene compound of formula VII

wherein, X is a halogen
to obtain the compound of Formula IX;

(ii) condensing the compound of Formula IX with the compound of Formula VI;

to obtain the compound of Formula C;

(iii) reducing the compound of Formula C with a suitable reducing agent to obtain a compound of Formula D;

(iv) cyclizing the compound of Formula D to obtain compound of Formula E;

wherein, X is a halogen
(v) condensing the obtained compound of Formula E with pyrrolidine to obtain Pacritinib of Formula I; and
(vi) 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 VII 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 hydrochloric acid, hydrobromic acid, ammonium chloride, stannic chloride; suitable hydrogenating agent in a hydrogen source; in presence or absence of 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 D has been carried out using an acid, a suitable base, metal catalyst or combination thereof; in a suitable 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, wherein Step (V) condensation of compound of Formula E with pyrrolidine has been carried out in presence or absence of a suitable base selected from the group comprising of organic base, inorganic base, in a suitable solvent thereof.

6. The process as claimed in claim 1, wherein Step (VI) conversion of Pacritinib of Formula I has been carried out using acid selected from the group comprising organic acid or inorganic acid.

7. The process as claimed in claim 1, the process including the steps for the preparation of compound of Formula III,

wherein, X is a halogen
which comprises:
condensing 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.
8. The process as claimed in claim 1, the process including the steps for the preparation of compound of Formula VI:

wherein, X is a halogen
which comprises:
condensing 2-hydroxy-5-nitrobenzaldehyde 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.

9. The process as claimed in claims 7 & 8, wherein used suitable reducing agent selected from the group comprising of organic bases and inorganic bases.

10. A compound having the Formula D, E, or IX:

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