CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of the earlier filing date of Indian Provisional Patent Application No. IN 202141004943 filed on February 05, 2021.

FIELD OF THE INVENTION

The present disclosure generally relates to the field of pharmaceutical sciences and more specifically relates process for the preparation of an intermediate compound of Formula IV, which is a useful intermediate for Larotrectinib or its pharmaceutically acceptable salts. It also provides a process for the preparation of amorphous Larotrectinib or its pharmaceutically acceptable salts.

BACKGROUND OF THE INVENTION

Larotrectinib sulfate, chemically known as (3S)-N-{5-[(2R)-2-(2,5-difluorophenyl)-l- pyrrolidinyl] pyrazolo [ 1 , 5 - a] pyrimidin- 3 -yl } - 3 -hydroxy- 1 -pyrrolidinec arboxamide sulfate having the structure shown in Formula-I, is a kinase inhibitor.

Larotrectinib sulfate is approved and is being marketed under the brand name Vitrakvi® for the treatment of adult and pediatric patients with solid tumors that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity and have no satisfactory alternative treatments.

United States Pat. No. US 8513263 discloses Larotrectinib, its pharmaceutically acceptable salt and process for the preparation of same. United States Pat. No. US 9127013 discloses Larotrectinib sulfate and a process for the preparation of amorphous form of Larotrectinib sulfate in methanol, followed by concentration of methanol by the distillation.

The present invention provides a process for the preparation of Larotrectinib sulfate which is cost effective and industrially viable.

OBJECT AND SUMMARY OF THE INVENTION

In one object, the present invention provides a process for the preparation of an intermediate compound of Formula IV comprising the steps of: a) converting Formula II into a Formula IV ; and b) isolating Formula IV. wherein R is-SCLRi; -CO-R2; Ri is selected from alkyls, substituted alkyls, phenyls, substituted phenyls; R2 is selected from alkyls, substituted alkyls, phenyls, substituted phenyls; halides such as -Cl, -F, -Br and -I.

In another object, the present invention provides a novel intermediate compound of Formula Ila. wherein R is-SO2Ri; -CO-R2; Ri is selected from alkyls, substituted alkyls, phenyls, substituted phenyls; R2 is selected from alkyls, substituted alkyls, phenyls, substituted phenyls; halides such as -Cl, -F, -Br and -I.

In one more embodiment, the present invention provides a process for the preparation of amorphous Larotrectinib sulfate comprising the steps of: a) taking larotrectinib in a solvent selected from polar aprotic solvent and nonpolar solvents or mixtures thereof; b) adding sulfuric acid; and c) isolating amorphous Larotrectinib sulfate.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for the preparation of Larotrectinib or its pharmaceutically acceptable salts using a novel intermediate of Formula Ila. Also, provides a process for the preparation of amorphous larotrectinib sulfate.

In one embodiment of the present invention provide a process for the preparation of an intermediate of Formula IV comprising the steps of: a) converting Formula II into a Formula IV ; and b) isolating Formula IV. wherein R is-SChRi; -CO-R2; Ri is selected from alkyls, substituted alkyls, phenyls, substituted phenyls; R2 is selected from alkyls, substituted alkyls, phenyls, substituted phenyls; halides such as -Cl, -F, -Br and -I.

Within the context of the present invention, R is-SChRl; -CO-R2; Rl is selected from alkyls, substituted alkyls, phenyls, substituted phenyls; R2 is selected from alkyls, substituted alkyls, phenyls, substituted phenyls; halides such as -Cl, -F, -Br and -I. Substitutions are selected from halo includes -F, -Cl,-Br, -I, nitro, amino, alkyloxy, Alkyl includes methyl, ethyl, propyl, butyl, iso propyl, isobutyl, t-butyl.

In one embodiment, Formula II is converted into Formula IV by reacting Formula II preferably with a suitable leaving group containing -SO2R1 in presence of a base and solvent to give Formula Ila. The suitable base is organic base includes, but not limited to trialkyl amines include, but not limited to triethyl amine, diisopropyl ethyl amine, dimethyl amine, dimethyl amino pyridine, trimethyl amine, , DBU and Inorganic bases includes, but not limited to hydroxides such KOH, NaOH, LiOH, carbonates Na2COs, K2CO3 and bicarbonates such as KHCO3, NaHCOs; preferably diisopropyl ethyl amine.

The suitable solvent for the reaction is selected from polar solvents includes, but not limited to dichloromethane, tetrahydrofuran, acetone, dimethyl formamide, dimethylacetamide, N-methyl-2-pyrrolidone, ethyl acetate, isopropyl acetate, n-butyl acetate, dimethyl sulfoxide; non polar solvents includes, but not limited to toluene, methyl isobutyl ketone, methyl ethyl ketone, anisole; preferably dichloromethane.

In another embodiment, the Formula Ila resulting from the above embodiment is optionally isolated and reacted with Formula III to give Formula IV.

The preparation of Formula IV using the intermediate of formula Ila a cost-effective process. In one more embodiment, the Formula IV may be further converted into Larotrectinib or its pharmaceutically acceptable salts as per the process known in the literature WO 2010048314 and WO 2017201241.

The present invention also provides a novel intermediate of Formula Ila.

In one embodiment R is tosyl, acyl.

Yet another embodiment, the process of preparing Larotrectinib or its pharmaceutically acceptable salts as per the present invention depicted in scheme-I.

In another embodiment, the obtained Larotrectinib or its pharmaceutically acceptable salts can be further converted into suitable polymorphic forms or their solid dispersions.

Yet another embodiment, the present invention provides a process for the preparation of amorphous Larotrectinib sulfate comprising the steps of: a) taking larotrectinib in a solvent selected from polar aprotic solvent and nonpolar solvents or mixtures thereof; b) adding sulfuric acid; and c) isolating amorphous Larotrectinib sulfate.

According to the present invention, larotrectinib is taken into a solvent selected from polar aprotic solvent and non-polar solvents or mixtures thereof. The polar aprotic solvent includes, but not limited to dimethyl formamide, dichloromethane, dimethyl sulfoxide, acetonitrile, ketonic solvents, ester solvents and ether solvents. Ketonic solvents includes, but not limited to methyl isobutyl ketone, acetone, methyl ethyl ketone, di iso butyl ketone. Ester solvents includes, but not limited to ethyl acetate, n- butyl acetate, tert- butyl acetate, ethyl salicylate, ether solvents include, but not limited to tetrahydrofuran, 1,4-doixane, diethyl ether, diisopropyl ether, dimethyl ether, diisopropyl ether; The non-polar solvents include, but not limited to toluene, diethyl ether, hexane, heptane, pentane, cyclohexane, decaline and anisole etc.

To the above larotrectinib mixture added sulfuric acid, preferably the sulfuric acid is in a suitable solvent selected from polar aprotic solvent includes, but not limited to dimethyl formamide, dichloromethane, dimethyl sulfoxide, acetonitrile, ketonic solvents, ester solvents and ether solvents. Ketonic solvents includes, but not limited to methyl isobutyl ketone, acetone, methyl ethyl ketone, di iso butyl ketone. Ester solvents includes, but not limited to ethyl acetate, n-butyl acetate, tert- butyl acetate, ethyl salicylate, ether solvents include, but not limited to tetrahydrofuran, 1,4- doixane, diethyl ether, diisopropyl ether, dimethyl ether, diisopropyl ether; preferably methyl isobutyl ketone and tetrahydrofuran filtered to isolate amorphous Larotrectinib sulfate.

In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure. EXAMPLES

Preparation of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-l-yl)-3-nitropyrazol o[l,5- a] pyrimidine IV:

25 g of 3-nitropyrazolo[l,5-a]pyrimidin-5-ol of Formula II, 26.98 g of p-toluene sulfonyl chloride and 25.11g of diisopropyl ethyl amine were taken in 100 ml of dichloromethane and stirred it at ambient temperature. To the reaction mixture, 25.43 g of (R)-difluorophenyl pyrrolidine and 25 ml dichloromethane mixture was added and continued stirring for 3 hrs. After completion of the reaction, the reaction mixture was quenched by adding 125 ml of water and 10 ml aq. ammonia. The reaction mixture was filtered through hyflo and washed with 25 ml of dichloromethane. The dichloromethane layer was separated and washed with water (125ml X 2), concentrated volatiles at vacuuo to yield 3-Nitropyrazolo[l,5-a]pyrimidin-5-ol of Formula IV. Weight: 46g.

Preparation of (R) -5- (2- (2,5 -difluorophenyl)pyrrolidin- 1 -yl)pyrazolo[ 1 ,5 - a]pyrimidin-3-amine V:

34.95 g ammonium chloride in 175 ml water solution was added to of slurry of 35 g Formula IV and 34.91g of Zn-dust in 175 ml of methanol at 35-40°C. The reaction mixture was heated to 50-60 °C for 2 hrs. After completion of the reaction, the reaction mixture was cooled to ambient temperature. To the reaction mixture, charged 175 ml of ethyl acetate and 70 ml of aqueous ammonia. The reaction mixture was filtered through hyflo and washed hyflo with 175 ml of ethyl acetate to remove inorganic materials. The ethyl acetate layer separated. The aqueous layer was back extracted with ethyl acetate and combined with ethyl acetate layer washed with water and 10% brine. Ethyl acetate layer was treated with 3.5 g of activated carbon, filtered and concentrated at vacuuo to yield solid of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin- l-yl)pyrazolo[l,5-a]pyrimidin-3-amine of Formula V. Weight 30g.

Preparation of Larotrectinib:

Solution of 5g Formula V and 25 ml of dichloromethane was added to slurry of 2.82 g l,l'-carbonyldiimidazole and 50 ml of dichloromethane at -10 to 0°C. The reaction mixture was stirred for 4 hrs. To the reaction mixture were added 2.36g (S)-3- hydroxypyrrolidine hydrochloride and 2.25 g of triethyl amine and allowed to warm the reaction mixture to ambient temperature. After completion of the reaction, added 10% of citric acid aqueous solution and was separated organic layer. The organic layer was washed with water, then treated with 0.25g of activated carbon and filtered. Distilled out the volatiles at vacuuo to yield Larotrectinib crude. Weight 6.6g.

Preparation of amorphous Larotrectinib sulfate:

5 g of Larotrectinib, 150 ml of THF and 150 ml toluene were stirred at ambient temperature. To the reaction mixture was added solution of 1.09g cone, sulfuric acid in 25ml THF and stirred for 1-2 hrs. The solid was filtered and washed with the mixture of 20ml THF/Toluene (1:1). The resulting product was dried in vacuum oven

14 hrs at 40-42°C. to obtained amorphous Larotrectinib sulfate. Weight 5.92g.

Preparation of amorphous Larotrectinib sulfate:

0.5 g of Larotrectinib and 30 ml methyl isobutyl ketone (MIBK) were stirred at ambient temperature. To the reaction mixture was added solution of 0.108g cone. sulfuric acid in 2.5ml MIBK and stirred for 1-2 hrs. The solid was filtered and dried in vacuum oven 14 hrs at ambient temperature to obtained amorphous Larotrectinib sulfate. Weight 0.45g.