WO2024142096A1 - Process for preparation of niraparib tosylate and its intermediates - Google Patents

Process for preparation of niraparib tosylate and its intermediates Download PDF

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WO2024142096A1
WO2024142096A1 PCT/IN2023/051221 IN2023051221W WO2024142096A1 WO 2024142096 A1 WO2024142096 A1 WO 2024142096A1 IN 2023051221 W IN2023051221 W IN 2023051221W WO 2024142096 A1 WO2024142096 A1 WO 2024142096A1
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formula
compound
preparation
niraparib
sodium
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PCT/IN2023/051221
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French (fr)
Inventor
Rajeev Rehani BUDHDEV
Nariyam Munaswamy Sekhar
Vsnvl VARA PRASAD
Chada NARSIHMA REDDY
Kiran Uttamrao KALANE
Soma Rani SARKAR
Ireni Babu
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Dr. Reddy’S Laboratories Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms

Definitions

  • the present application relates to a process for the preparation Niraparib of formula (II) and its tosylate salt of formula (I).
  • the present application also related to the novel intermediates and their application in the preparation of Niraparib of formula (II) and its tosylate salt of formula (I).
  • US8071623B2 (hereinafter the US’623 patent) and US8436185B2 (hereinafter the US’ 185 patent) assigned to Merck Sharp & Dohme, discloses niraparib and its tosylate salt.
  • Example 5 of US’ 623 and example 1 of US’ 185 discloses the process for preparation of niraparib tosylate (I). Numerous synthetic routes for preparation of niraparib tosylate (I) have been reported in the literature including process disclosed in US9580407B2, US11161834B2, US9738915B2, CN106467513A, US10927095B2, CN114195702A.
  • Niraparib of formula (II) or pharmaceutically acceptable salts thereof, particularly niraparib tosylate of formula (I).
  • Niraparib Niraparib tosylate (I) wherein, X is a halogen; Pi is an amino protecting groups and P is a hydrogen or amino protecting groups.
  • Third aspect of the present application relates to the process for the preparation of Niraparib of formula (II), comprising converting compound of formula (III) to niraparib of formula (II) or pharmaceutically acceptable salts thereof.
  • P is hydrogen or amino protecting group.
  • Fifth aspect of the present application relates to a process for preparation of niraparib of formula (II) or pharmaceutically acceptable salts thereof comprising steps of: a) converting ester compound of formula (VII) to amide compound of formula (VI) b) reacting compound of formula (VI) with a suitable halogenating agent to form compound of formula (V) c) reacting compound of formula (V) with compound of formula (IV) to form compound of formula
  • step b) the conversion of compound of formula (VI) to compound of formula (V) is carried out by reacting compound of formula (VI) with a suitable halogenating agent in presence of a suitable radical initiator in a suitable solvent.
  • the suitable halogenating agent may include but not limited to bromine, bromine - 1,4-Dioxane Complex, bromotrichloromethane, carbon tetrabromide, tetrabutylammonium tribromide, pyridinium bromide perbromide, Carbon Tetrabromide, phosphorus tribromide, N-bromosuccinimide (NBS), N-bromophthalimide, N-chlorosuccinimide (NCS), N- chlorophthalimide, N-Chlorosaccharin, Cyanuric Chloride, Oxalyl Chloride, Trichloroisocyanuric Acid, phosphorus trichloride, Iodine, Hydriodic Acid, N-io
  • halogenating agent is N-bromosuccinimide (NBS).
  • NBS N-bromosuccinimide
  • the suitable radical initiator may include bit not limited to dialkylperoxides, hydrogen peroxides and azo compounds.
  • radical initiator is azobisisobutyronitrile (AIBN).
  • step d) conversion of compound of formula (III) to compound of formula (II) is carried out in presence of a suitable acid reagent in a suitable solvent.
  • the suitable acid reagent may include but not limited to hydrochloric acid, polyphosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, phosphoric acid, and phosphotungstic acid, scandium trifluoromethane sulfonate, tin chloride, tin tetrachloride, ferric trichloride, titanium tetrachloride, tetraisopropyl titanyl, indium trifluoromethanesulfonate and copper trifluoromethanesulfonate, boron trifluoride.
  • Sixth aspect of the present application relates to a process for preparation of niraparib tosylate of formula (I) comprising steps of: a) converting ester compound of formula (VII) to amide compound of formula (VI) b) reacting compound of formula (VI) with a suitable halogenating agent to form compound of formula (V) c) reacting compound of formula (V) with compound of formula (IV) to form compound of formula (HI) d) converting compound of formula (III) to compound of formula (II) e) reacting niraparib (II) with p-tolunesulfonic acid to form Niraparib tosylate of formula (I)
  • Niraparib Niraparib tosylate (I) wherein, X is a halogen and Pi is an amino protecting groups; P is a hydrogen or amino protecting group.
  • Specific aspect of the present application relates to a process for preparation of niraparib tosylate of formula (I) comprising steps of: a) converting ester compound of formula (VII) to amide compound of formula (VI) b) reacting compound of formula (VI) with a suitable brominating agent to form compound of formula (Va) c) reacting compound of formula (Va) with compound of formula (IVa) to form compound of formula (Illa) d) converting compound of formula (Illa) to compound of formula (II)
  • Niraparib (II) Niraparib (II) e) reacting niraparib (II) with p-tolunesulfonic acid to form Niraparib tosylate of formula (I)
  • Another specific aspect of the present application relates to a process for preparation of niraparib tosylate of formula (I) comprising steps of: a) reacting compound of formula (VI) with a suitable halogenating agent to form compound of formula (Va)
  • Another aspect of the present application relates to a process for converting compound of formula (VII) to amide compound of formula (VI)
  • process steps disclosed in the present application may be carried out in situ, without isolation of intermediates for preparation of niraparib tosylate (I).
  • Halogen is defined as non-metallic elements found in group VII of the periodic table and is selected from fluorine, bromine, chlorine and iodine.
  • Amino protecting group is defined as any amino protecting group as known in Greene et al., Protecting groups in organic chemistry, Third Edition, 1999. Examples include benzyloxy carbonyl (Cbz) and tert-Butyloxycarbonyl (Boc), acetyl and the like, preferably, the amino protecting group is tert-Butyloxy carbonyl (Boc).
  • Example 1 Preparation of 3-methyl-2-nitrobenzamide (VI) la) To a solution of methyl-3-methyl-2-nitrobenzoate (VII) (100 g) in DMF (200 mL) was added formamide (231 g) at 15 °C. A solution of sodium methoxide (41.5 g) in methanol (138 mL, 30%) is added dropwise to the above reaction mixture at the same temperature. The temperature of the reaction mixture is raised to 30 °C and stirred for 2 hours at the same temperature. The reaction mixture is then cooled to 10 °C and water (2 L) added, stirred at the same temperature for 2 hours for solid separation.
  • reaction mixture is transferred into the Centrifuge and filtered it by spinning.
  • the reaction mixture is further washed with water (4 X 500 L).
  • the resulting wet material was transferred to Rotocone vacuum dryer (RCVD) and dried under vacuum at 50 °C to get the title compound (VI) (41.54 Kg).
  • Example 4 Preparation of Niraparib (II) To a solution of tert-butyl (S)-3-(4-((3-carbamoyl-2-nitrobenzyl)amino)phenyl)piperidine-l- carboxylate (Illa) (55 g) in 1-butanol (550 mL) was added tin(II) chloride dihydrate (68.8 g). The reaction mixture was heated to 75 °C and stirred for 24 hours at the same temperature. The reaction mixture was then cooled to room temperature. After cooling the reaction mixture was filtered and washed with n-butanol (55 mL).
  • niraparib (II) 39 g
  • THF 624 mL
  • water 31.2 mL
  • p- toluenesulfonic acid hydrate 50.9 g
  • the reaction mixture was heated to 70 °C and stirred for 14 hours at the same temperature.
  • the reaction mixture was then cooled to 10 °C and filtered through Buchner funnel at room temperature.
  • the resulting solid was washed with THF (78 mL) and dried at 50 °C to get the title compound (I) as monohydrate (29 g).

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present application relates to a process for the preparation Niraparib of formula (II) or its pharmaceutically acceptable salts thereof. The present application also related to novel intermediates of Niraparib. Further, the present application also related to the application of such novel intermediates in the preparation of Niraparib of formula (II) and its tosylate salt of formula (I).

Description

PROCESS FOR PREPARATION OF NIRAPARIB TOSYEATE AND ITS INTERMEDIATES
CROSS REFERENCE
This specification claims the priority from Indian patent application number 202241076686 filed on 29 Dec 2022.
INTRODUCTION
The present application relates to a process for the preparation Niraparib of formula (II) and its tosylate salt of formula (I). The present application also related to the novel intermediates and their application in the preparation of Niraparib of formula (II) and its tosylate salt of formula (I).
Niraparib is developed by TESARO Inc., for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in a complete or partial response to platinum-based chemotherapy. Niraparib has already approved in US, Europe, Canada, China, Japan and marketed under the brand name ZEJULA. The active component is niraparib tosylate, which is chemically known as 2-[4-(3S)-3-piperidinylphenyl]-2H-Indazole-7- carboxamide.4-methylbenzenesulfonate. The chemical structure of Niraparib tosylate is given below:
Figure imgf000002_0001
US8071623B2 (hereinafter the US’623 patent) and US8436185B2 (hereinafter the US’ 185 patent) assigned to Merck Sharp & Dohme, discloses niraparib and its tosylate salt. Example 5 of US’ 623 and example 1 of US’ 185 discloses the process for preparation of niraparib tosylate (I). Numerous synthetic routes for preparation of niraparib tosylate (I) have been reported in the literature including process disclosed in US9580407B2, US11161834B2, US9738915B2, CN106467513A, US10927095B2, CN114195702A.
However, still there remains a need for an improved process for the commercial production of Niraparib of formula (II) or pharmaceutically acceptable salts thereof, particularly niraparib tosylate of formula (I).
SUMMARY
First aspect of the present application relates to the process for the preparation of compound of formula (V), comprising reacting compound of formula (VI) with a suitable halogenating agent
Figure imgf000003_0001
(VI) (V) wherein X is a halogen.
Second aspect of the present application relates to the process for the preparation of compound of formula (III), comprising reacting compound of formula (IV) with compound of formula (V) in presence of a suitable base
Figure imgf000003_0002
wherein, X is a halogen and Pi is an amino protecting groups; P is a hydrogen or amino protecting groups.
Third aspect of the present application relates to the process for the preparation of Niraparib of formula (II), comprising converting compound of formula (III) to niraparib of formula (II) or pharmaceutically acceptable salts thereof.
Figure imgf000003_0003
wherein, Pis a hydrogen or amino protecting groups.
Fourth aspect of the present application relates to the process for the preparation of compound of formula (lib) or (II), comprising converting compound of formula (III) to compound of formula (lib) or (II).
Figure imgf000003_0004
wherein, Pis a hydrogen or amino protecting groups.
Fifth aspect of the present application relates to a process for preparation of niraparib of formula (II) or pharmaceutically acceptable salts thereof comprising steps of: a) converting ester compound of formula (VII) to amide compound of formula (VI)
Figure imgf000004_0001
VII VI b) reacting compound of formula (VI) with a suitable halogenating agent to form compound of formula (V)
Figure imgf000004_0002
(VI) (V) c) reacting compound of formula (V) with compound of formula (IV) to form compound of formula
(HI)
Figure imgf000004_0003
d) converting compound of formula (III) to compound of formula (II) or pharmaceutically acceptable salts thereof
Figure imgf000004_0004
wherein, X is a halogen; Pi is an amino protecting group or P is a hydrogen or amino protecting groups.
Sixth aspect of the present application relates to a process for preparation of niraparib tosylate of formula (I) comprising steps of: a) converting ester compound of formula (VII) to amide compound of formula (VI)
Figure imgf000004_0005
(VII) (VI) b) reacting compound of formula (VI) with a suitable halogenating agent to form compound of formula (V)
Figure imgf000005_0001
(VI) (V) c) reacting compound of formula (V) with compound of formula (IV) to form compound of formula
(III)
Figure imgf000005_0002
d) converting compound of formula (III) to compound of formula (II)
Figure imgf000005_0003
e) reacting niraparib (II) with p-tolunesulfonic acid to form Niraparib tosylate of formula (I)
Figure imgf000005_0004
Niraparib (II) Niraparib tosylate (I) wherein, X is a halogen; Pi is an amino protecting groups and P is a hydrogen or amino protecting groups.
Seventh aspect of the present application relates to a process for preparation of niraparib tosylate of formula (I) comprising steps of: a) reacting compound of formula (VI) with a suitable halogenating agent to form compound of formula (V)
Figure imgf000005_0005
(VI) (V) b) reacting compound of formula (V) with compound of formula (IV) to form compound of formula (HI)
Figure imgf000006_0001
c) converting compound of formula (III) to compound of formula (lib) or (II)
Figure imgf000006_0002
d) converting compound of formula (lib) or (II) to compound of formula (I)
Figure imgf000006_0003
wherein, X is a halogen; Pi is an amino protecting groups and P is a hydrogen or amino protecting groups.
Eighth aspect of the present application relates to compound of formula (V) and/or (III)
Figure imgf000006_0004
(HI) (V) wherein X is a halogen; P is a hydrogen or amino protecting group.
Ninth aspect of the present application provides process for preparation of Niraparib or its pharmaceutically acceptable salts thereof said process comprising producing the Niraparib or a pharmaceutically acceptable salt thereof from compound of formula (V) and/or (Va) and/or (III) and/or (Illa). DETAILED DESCRIPTION
First aspect of the present application relates to the process for the preparation of compound of formula (V), comprising reacting compound of formula (VI) with a suitable halogenating agent
Figure imgf000007_0001
wherein, X is a halogen.
In an embodiment, the conversion of compound of formula (VI) to compound of formula (V) is carried out by reacting compound of formula (VI) with a suitable halogenating agent in a suitable solvent. The suitable halogenating agent may be any halogenating agent known in the art. Further, suitable halogenating agent include but not limited to bromine, bromine - 1,4-Dioxane Complex, bromotrichloromethane, carbon tetrabromide, tetrabutylammonium tribromide, pyridinium bromide perbromide, Carbon Tetrabromide, phosphorus tribromide, N-bromosuccinimide (NBS), N- bromophthalimide, N-chlorosuccinimide (NCS), N-chlorophthalimide, N-Chlorosaccharin, Cyanuric Chloride, Oxalyl Chloride, Trichloroisocyanuric Acid, phosphorus trichloride, Iodine, Hydriodic Acid, N-iodosuccinimide (NIS), N-Iodophthalimide, N-Iodosaccharin, Carbon Tetraiodide, 1,3- Diiodo-5,5-dimethylhydantoin, Pyrimidine-2-sulfonyl Fluoride, Cesium Fluoride, Tetrabutylammonium Fluoride, Morph-DAST, Pyrimidine-2-sulfonyl Fluoride, N- Fluorobenzenesulfonimide, F-TEDA-BF4, F5-Pyridine-HF, and the like. In a preferred embodiment halogenating agent is N-bromosuccinimide (NBS).
In an embodiment, the conversion of compound of formula (VI) to compound of formula (V) is carried out in presence of a suitable radical initiator. The suitable radical initiator may include bit not limited to dialkylperoxides, hydrogen peroxides and azo compounds. In a preferred embodiment radical initiator is azobisisobutyronitrile (AIBN). The suitable solvent may include but not limited to ethers such as 1,4-dioxane, tetrahydrofuran and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane and the like, nitrile solvent such as acetonitrile, propionitrile, preferably, the solvent may be a nitrile solvent. More preferably, acetonitrile. The reaction may be carried out at a temperature of about 30 °C to about boiling point of the solvent.
One Specific aspect of the present application relates to the process for the preparation of compound of formula (Va), comprising reacting compound of formula (VI) with a suitable brominating agent
Figure imgf000008_0001
(VI) (Va)
Second aspect of the present application relates to the process for the preparation of compound of formula (HI), comprising reacting compound of formula (IV) with compound of formula (V) in presence of a suitable base
Figure imgf000008_0002
wherein, X is a halogen and Pi is an amino protecting groups; P is a hydrogen or amino protecting group.
In an embodiment, compound of formula (V) is treated with compound of formula (IV) in presence of a suitable base in a suitable solvent. The suitable base may be organic or inorganic base. Organic base includes but not limited to triethyl amine, diisopropyl ethyl amine (DIPEA), pyridine, dimethyl aminopyridine (DMAP); Preferably, diisopropyl ethyl amine (DIPEA). In organic base include but not limited to metal alkoxide base such as sodium methoxide, sodium tert-butoxide and the like; metal carbonate bases such as potassium carbonate, sodium carbonate and the like; metal hydroxide bases such as lithium hydroxide, sodium hydroxide and the like; preferably, sodium carbonate. The suitable solvent may include but not limited to ethers such as 1,4-dioxane, tetrahydrofuran and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane and the like, nitrile solvent such as acetonitrile, propionitrile, preferably, the solvent may be an ether solvent. More preferably, solvent is tetrahydrofuran (THF). The reaction may be carried out at a temperature of about 30 °C to about boiling point of the solvent. Amino protecting group may be selected from benzyloxycarbonyl (Cbz) and tert-Butyloxycarbonyl (Boc), acetyl and the like, preferably, the amino protecting group is tert-Butyloxycarbonyl (Boc).
One specific of the present application relates to the process for the preparation of compound of formula (Illa), comprising reacting compound of formula (IVa) with compound of formula (Va) in presence of a suitable base
Figure imgf000009_0001
Third aspect of the present application relates to the process for the preparation of Niraparib of formula (II), comprising converting compound of formula (III) to niraparib of formula (II) or pharmaceutically acceptable salts thereof.
Figure imgf000009_0002
wherein, P is hydrogen or amino protecting group.
In an embodiment, conversion of compound of formula (III) to compound of formula (II) is carried out in presence of a suitable acid reagent in a suitable solvent. The suitable acid reagent may include but not limited to hydrochloric acid, polyphosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, phosphoric acid, and phosphotungstic acid, scandium trifluoromethane sulfonate, tin chloride, tin tetrachloride, ferric trichloride, Zn/Ammonium formate, titanium tetrachloride /Fe, titanium tetrachloride /Mg, titanium tetrachloride /Al, titanium tetrachloride /Zn, titanium tetrachloride, tetraisopropyl titanyl, indium trifluoromethanesulfonate and copper trifluoromethanesulfonate, boron trifluoride, preferably, the acid reagent is tin chloride. The suitable solvent may include but not limited to ethers such as 1,4-dioxane, tetrahydrofuran and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; alcohol solvent such as methanol, ethanol, propanol, n-butanol, isopropyl alcohol and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane and the like, nitrile solvent such as acetonitrile, propionitrile, preferably, the solvent may be an alcohol solvent. More preferably, solvent is n-butanol. The reaction may be carried out at a temperature of about 30 °C to about boiling point of the solvent.
In a specific aspect of the present application relates to the process for the preparation of Niraparib of formula (II), comprising converting compound of formula (Illa) to niraparib of formula (II) or pharmaceutically acceptable salts thereof.
Figure imgf000010_0001
(Illa) Niraparib (II)
Fourth aspect of the present application relates to the process for the preparation of compound of formula (lib), comprising converting compound of formula (III) to compound of formula (lib).
Figure imgf000010_0002
wherein, P is hydrogen or amino protecting group.
In an embodiment, conversion of compound of formula (III) to compound of formula (lib) is carried out in presence of a suitable acid reagent in a suitable solvent and a suitable acid scavenger. The suitable acid reagent may include but not limited to hydrochloric acid, polyphosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, phosphoric acid, and phosphotungstic acid, scandium trifluoromethanesulfonate, tin chloride, tin tetrachloride, ferric trichloride, Zn/Ammonium formate, titanium tetrachloride /Fe, titanium tetrachloride /Mg, titanium tetrachloride /Al, titanium tetrachloride /Zn, titanium tetrachloride, tetraisopropyl titanyl, indium trifluoromethanesulfonate and copper trifluoromethanesulfonate, boron trifluoride, preferably, the acid reagent is tin chloride. The suitable acid scavenger may include but not limited to sodium acetate, potassium acetate, sodium phosphate, sodium dihydrogen phosphate, sodium hydrogen phosphate, sodium oxalate, triethylamine, diisopropyl ethyl amine (DIPEA), pyridine, dimethyl aminopyridine (DMAP) and the like. The suitable solvent may include but not limited to ethers such as 1,4-dioxane, tetrahydrofuran and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; alcohol solvent such as methanol, ethanol, propanol, n-butanol, isopropyl alcohol and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane and the like, nitrile solvent such as acetonitrile, propionitrile, preferably, the solvent may be an alcohol solvent. More preferably, solvent is methanol. The reaction may be carried out at a temperature of about 30 °C to about boiling point of the solvent.
Specific aspect of the present application relates to a process for the preparation of compound of formula (Ila), comprising converting compound of formula (Illa) to compound of formula (Ila).
Figure imgf000011_0001
Fifth aspect of the present application relates to a process for preparation of niraparib of formula (II) or pharmaceutically acceptable salts thereof comprising steps of: a) converting ester compound of formula (VII) to amide compound of formula (VI)
Figure imgf000011_0002
b) reacting compound of formula (VI) with a suitable halogenating agent to form compound of formula (V)
Figure imgf000011_0003
c) reacting compound of formula (V) with compound of formula (IV) to form compound of formula
(III)
Figure imgf000011_0004
d) converting compound of formula (III) to compound of formula (II) or pharmaceutically acceptable salts thereof
Figure imgf000011_0005
wherein, X is a halogen and Pi is an amino protecting groups; P is a hydrogen or amino protecting group.
In embodiments of step a) the ester compound of formula (VII) is converted to amide compound of formula (VI) by reacting compound of formula (VII) with formamide or any ammonia source in presence of a base in a suitable solvent. Suitable base may include but not limited to metal alkoxide base such as sodium methoxide, sodium tert-butoxide and the like; metal carbonate bases such as potassium carbonate, sodium carbonate and the like; metal hydroxide bases such as lithium hydroxide, sodium hydroxide and the like, preferably, the base may be sodium methoxide. The suitable solvent may include but not limited to polar aprotic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; alcoholic solvent such as methanol, isopropanol and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as methyl t-butyl ether, tetrahydrofuran and the like; chlorinated solvents such as dichloromethane, chloroform and the like and mixtures thereof. preferably, the solvent is dimethylformamide (DMF). The reaction may be carried out at a temperature of about 30 °C to about boiling point of the solvent.
In embodiments of step b), the conversion of compound of formula (VI) to compound of formula (V) is carried out by reacting compound of formula (VI) with a suitable halogenating agent in presence of a suitable radical initiator in a suitable solvent. The suitable halogenating agent may include but not limited to bromine, bromine - 1,4-Dioxane Complex, bromotrichloromethane, carbon tetrabromide, tetrabutylammonium tribromide, pyridinium bromide perbromide, Carbon Tetrabromide, phosphorus tribromide, N-bromosuccinimide (NBS), N-bromophthalimide, N-chlorosuccinimide (NCS), N- chlorophthalimide, N-Chlorosaccharin, Cyanuric Chloride, Oxalyl Chloride, Trichloroisocyanuric Acid, phosphorus trichloride, Iodine, Hydriodic Acid, N-iodosuccinimide (NIS), N-Iodophthalimide, N-Iodosaccharin, Carbon Tetraiodide, l,3-Diiodo-5,5-dimethylhydantoin, Pyrimidine-2-sulfonyl Fluoride, Cesium Fluoride, Tetrabutylammonium Fluoride, Morph-DAST, Pyrimidine-2 -sulfonyl Fluoride, N-Fluorobenzenesulfonimide, F-TEDA-BF4, F5-Pyridine-HF, and the like. In a preferred embodiment halogenating agent is N-bromosuccinimide (NBS). The suitable radical initiator may include bit not limited to dialkylperoxides, hydrogen peroxides and azo compounds. In a preferred embodiment radical initiator is azobisisobutyronitrile (AIBN). The suitable solvent may include but not limited to ethers such as 1,4-dioxane, tetrahydrofuran and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane and the like, nitrile solvent such as acetonitrile, propionitrile, preferably, the solvent may be a nitrile solvent. More preferably, acetonitrile. The reaction may be carried out at a temperature of about 30 °C to about boiling point of the solvent.
In embodiments of step c), compound of formula (V) is treated with compound of formula (IV) in presence of a suitable base in a suitable solvent. The suitable base may be organic or inorganic base. Organic base include but not limited to triethyl amine, diisopropyl ethyl amine (DIPEA), pyridine, dimethyl aminopyridine (DMAP), sodium methoxide, sodium tert-butoxide and the like; In organic base include but not limited to metal alkoxide base such as sodium methoxide, sodium tert-butoxide and the like; metal carbonate bases such as potassium carbonate, sodium carbonate and the like; metal hydroxide bases such as lithium hydroxide, sodium hydroxide and the like; preferably, the base is DIPEA. The suitable solvent may include but not limited to ethers such as 1,4-dioxane, tetrahydrofuran and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane and the like, nitrile solvent such as acetonitrile, propionitrile, preferably, the solvent may be an ether solvent. More preferably, solvent is tetrahydrofuran (THF). The reaction may be carried out at a temperature of about 30 °C to about boiling point of the solvent. In embodiments of step d), conversion of compound of formula (III) to compound of formula (II) is carried out in presence of a suitable acid reagent in a suitable solvent. The suitable acid reagent may include but not limited to hydrochloric acid, polyphosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, phosphoric acid, and phosphotungstic acid, scandium trifluoromethane sulfonate, tin chloride, tin tetrachloride, ferric trichloride, titanium tetrachloride, tetraisopropyl titanyl, indium trifluoromethanesulfonate and copper trifluoromethanesulfonate, boron trifluoride. preferably, the acid reagent is tin chloride. The suitable solvent may include but not limited to ethers such as 1,4-dioxane, tetrahydrofuran and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; alcohol solvent such as methanol, ethanol, propanol, n-butanol, isopropyl alcohol and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane and the like, nitrile solvent such as acetonitrile, propionitrile, preferably, the solvent may be an alcohol solvent. More preferably, solvent is n-butanol. The reaction may be carried out at a temperature of about 30 °C to about boiling point of the solvent.
Sixth aspect of the present application relates to a process for preparation of niraparib tosylate of formula (I) comprising steps of: a) converting ester compound of formula (VII) to amide compound of formula (VI)
Figure imgf000013_0001
b) reacting compound of formula (VI) with a suitable halogenating agent to form compound of formula (V)
Figure imgf000013_0002
c) reacting compound of formula (V) with compound of formula (IV) to form compound of formula (HI)
Figure imgf000014_0001
d) converting compound of formula (III) to compound of formula (II)
Figure imgf000014_0002
e) reacting niraparib (II) with p-tolunesulfonic acid to form Niraparib tosylate of formula (I)
Figure imgf000014_0003
Niraparib (II) Niraparib tosylate (I) wherein, X is a halogen and Pi is an amino protecting groups; P is a hydrogen or amino protecting group.
Seventh aspect of the present application relates to a process for preparation of niraparib tosylate of formula (I) comprising steps of: a) reacting compound of formula (VI) with a suitable halogenating agent to form compound of formula (V)
Figure imgf000014_0004
(VI) (V) b) reacting compound of formula (V) with compound of formula (IV) to form compound of formula
(HI)
Figure imgf000014_0005
c) converting compound of formula (III) to compound of formula (lib) or (II)
Figure imgf000015_0001
d) converting compound of formula (lib) or (II) to niraparib tosylate of formula (I)
Figure imgf000015_0002
wherein, X is a halogen and Pi is an amino protecting groups; P is a hydrogen or amino protecting group.
Specific aspect of the present application relates to a process for preparation of niraparib tosylate of formula (I) comprising steps of: a) converting ester compound of formula (VII) to amide compound of formula (VI)
Figure imgf000015_0003
b) reacting compound of formula (VI) with a suitable brominating agent to form compound of formula (Va)
Figure imgf000015_0004
c) reacting compound of formula (Va) with compound of formula (IVa) to form compound of formula (Illa)
Figure imgf000015_0005
d) converting compound of formula (Illa) to compound of formula (II)
Figure imgf000016_0001
(Illa) Niraparib (II) e) reacting niraparib (II) with p-tolunesulfonic acid to form Niraparib tosylate of formula (I)
Figure imgf000016_0002
Niraparib (II) Niraparib tosylate (I)
Another specific aspect of the present application relates to a process for preparation of niraparib tosylate of formula (I) comprising steps of: a) reacting compound of formula (VI) with a suitable halogenating agent to form compound of formula (Va)
Figure imgf000016_0003
(VI) (Va) b) reacting compound of formula (Va) with compound of formula (IVa) to form compound of formula (Illa)
Figure imgf000016_0004
(Va) (Illa) c) converting compound of formula (Illa) to compound of formula (Ila)
Figure imgf000016_0005
(Illa) d) converting compound of formula (Ila) to niraparib tosylate of formula (I)
Figure imgf000016_0006
Another aspect of the present application relates to a process for converting compound of formula (VII) to amide compound of formula (VI)
Figure imgf000017_0001
Eighth aspect of the present application relates to compound of formula (III) and/or (V)
Figure imgf000017_0002
wherein, X is a halogen; P is hydrogen amino protecting group.
Specific aspect of the present application relates to compound of formula (Illb) and/or (Va)
Figure imgf000017_0003
In another aspect, Niraparib prepared in the present application may be further converted to any physical form of Niraparib including salts, solvates, hydrates, anhydrous or amorphous, including monohydrate. In a specific aspect, Niraparib prepared in the present application is a monohydrate of tosylate salt, i.e. Nirapatib tosylate monohydrate.
In further aspect, the process steps disclosed in the present application may be carried out in situ, without isolation of intermediates for preparation of niraparib tosylate (I).
In another aspect of the present application relates to a process for purification of compound of formula (I) using of water as a solvent.
Ninth aspect of the present application provides process for preparation of Niraparib or its pharmaceutically acceptable salts thereof said process comprising producing the Niraparib or a pharmaceutically acceptable salt thereof from compound of formula (V) and/or (Va) and/or (III) and/or (Illa) and/or (lib) and/or (Ila).
DEFINITION
The following definitions are used in connection with the present disclosure unless the context indicates otherwise.
“Halogen” is defined as non-metallic elements found in group VII of the periodic table and is selected from fluorine, bromine, chlorine and iodine.
Amino protecting group is defined as any amino protecting group as known in Greene et al., Protecting groups in organic chemistry, Third Edition, 1999. Examples include benzyloxy carbonyl (Cbz) and tert-Butyloxycarbonyl (Boc), acetyl and the like, preferably, the amino protecting group is tert-Butyloxy carbonyl (Boc).
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner.
EXAMPLES
Example 1: Preparation of 3-methyl-2-nitrobenzamide (VI) la) To a solution of methyl-3-methyl-2-nitrobenzoate (VII) (100 g) in DMF (200 mL) was added formamide (231 g) at 15 °C. A solution of sodium methoxide (41.5 g) in methanol (138 mL, 30%) is added dropwise to the above reaction mixture at the same temperature. The temperature of the reaction mixture is raised to 30 °C and stirred for 2 hours at the same temperature. The reaction mixture is then cooled to 10 °C and water (2 L) added, stirred at the same temperature for 2 hours for solid separation. The resulting solid filtered and washed with water (300 mL), dried at 40°C to get the title compound (VI) (66 g). lb) To a solution of methyl-3-methyl-2-nitrobenzoate (VII) (50 Kg) in 1,4-Dioxane (25 L) was added formamide (115 Kg) at room temperature. The reaction mixture was cooled to 10 °C. A solution of sodium methoxide in methanol (103.85 Kg, 30% solution) is added dropwise to the above reaction mixture at the same temperature and stirred for 4 hours at the same temperature. The reaction mass was then added to pre chilled water (17500 L) and stir the reaction mixture for 7 hours at 10 °C. The reaction mixture is transferred into the Centrifuge and filtered it by spinning. The reaction mixture is further washed with water (4 X 500 L). The resulting wet material was transferred to Rotocone vacuum dryer (RCVD) and dried under vacuum at 50 °C to get the title compound (VI) (41.54 Kg).
‘H-NMR (500MHz: DMSO-d6): 8.18 (s, 1H), 7.67 (s, 1H), 7.60 - 7.54 (m, 3H), 2.28 (s, 3H); 13C- NMR 125MHz: DMSO-d6): 166.16, 149.14, 133.53, 130.38, 129.99, 129.42, 126.28, 16.64; Mass spectra: 180.98 [M+l]+.
Example 2: Preparation of 3-(bromomethyl)-2-nitrobenzamide (Va)
2a) To a solution of 3 -methyl -2 -nitrobenzamide (VI) (60 g) in acetonitrile (600 mL) was added N- bromosuccinamide (NBS) (119 g) at room temperature. The reaction mixture is heated to 70 °C and added (Z)-2,2'-(diazene-l,2-diyl) bis(2-methylpropanenitrile (AIBN) (16.4 g) in lot wise (8 lots in 8 hours, one lot/hour) and stirred for 13 hours at the same temperature then distilled. The resulting reaction mass is treated with aqueous solution of Sodium metabisulfite (63 g in 300 mL) and stirred for 30 minutes at the same temperature then filtered. The resulting wet solid is mixed with methylene chloride (300 mL) at 25 °C and stirred for 3 hours. The reaction mixture is then filtered, washed with methylene chloride (120 mL) and dried at 40 °C to get the title compound (Va) (45 g).
2b) To a solution of 3 -methyl -2 -nitrobenzamide (VI) (100 g) in acetonitrile (300 mL) was added N- bromosuccinamide (NBS) (119 g) at room temperature. The reaction mixture is heated to 70 °C and added a solution of (Z)-2,2'-(diazene-l,2-diyl) bis(2 -methylpropanenitrile (AIBN) (31.92 g) in acetonitrile (200 mL) and stirred for 10 hours at the same temperature. The reaction mixture was then cooled to room temperature. An aqueous solution of Sodium metabisulfite (211 g in 500 mL) was added to the above reaction mixture and cooled to 5 °C and stirred for 30 minutes at the same temperature then filtered, washed with water (200 mL). The resulting solid was mixed with water (500 mL) and stirred for 30 minutes at room temperature. The resulting reaction mass is filtered and washed with water (200 mL) and dried at 50 °C to get the title compound (Va) (75 g).
’H-NMR (500MHz: DMSO-d6): 8.28 (s, 1H), 7.81- 7.80 (s, 1H), 7.77 (s, 1H), 7.71 - 7.66 (m, 2H), 4.71 (s, 2H); 13C-NMR 125MHz: DMSO-d6): 166.18, 148.10, 133.45, 131.43, 131.07, 130.01, 129.11, 27.31; Mass spectra: 260.86 [M+2]+.
Example 3: Preparation of tert-butyl (S)-3-(4-((3-carbamoyl-2- nitrobenzyl)amino)phenyl)piperidine-l-carboxylate (Illa)
3a) To a mixture of 3 -(bromomethyl) -2 -nitrobenzamide (Va) (39 g) and tert-butyl (S)-3-(4- aminophenyl)piperidine-l -carboxylate (IVa) (41.6 g) in THF (312 mL) was added N,N- Diisopropylethylamine (29.2 g) at 30 °C. The reaction mixture was heated to 60 °C and stirred at the same temperature for about 10 hours. The reaction mixture was distilled under vacuum at 50 °C. The resulting reaction mass is mixed with methylene chloride (78 mL) and further distilled at 50 °C. The reaction mass is again mixed with methylene chloride (156 mL) and stirred for 2 hours. The resulting solid is then filtered, washed with methylene chloride (156 mL) and dried at 45 °C to get the title compound (Illa) (49 g).
3b) To a mixture of 3 -(bromomethyl) -2 -nitrobenzamide (Va) (98.4 g) and tert-butyl (S)-3-(4- aminophenyl)piperidine-l -carboxylate (IVa) (100 g) in THF (700 mL) was added sodium carbonate (115 g) at room temperature. The reaction mixture was heated to 45 °C and stirred at the same temperature for 24 hours. The reaction mixture was then cooled to room temperature, filtered and washed with THF (2 X 250 mL). The resulting filtrate was distilled up to 2 volumes at below 50 °C. The resulting filtrate was then mixed with IP Ac (500 mL) and distilled up to 2 volumes (the process repeated for 3 times). The reaction mixture was again mixed with IP Ac (200 mL) and stirred for 1 hour at 45 °C. The reaction mass then cooled to 25 °C and stirred for about 5 hours at the same temperature. The resulting solid is then filtered, washed with IP Ac (200 mL) and dried at 50 °C to get the title compound (Illa) (140 g).
’H-NMR (500MHz: DMSO-d6): 8.21 (s, 1H), 7.70 (s, 1H), 7.66 - 7.64 (m, 1H), 7.62 -7.58 (m, 2H),
6.94 (d, J = 8.5Hz, 2H), 6.44 (d, J = 8.5Hz, 2H), 6.26 (t, J = 6.0Hz, 1H), 4.26 (d, J = 6.0Hz, 2H),
3.95 - 3.87 (m, 2H), 2.73 - 2.63 (m, 2H), 2.41 - 2.37 (m, 1H), 1.80 - 1.66 (m, 1H), 1.65 - 1.64 (m, 1H), 1.52 - 1.50 (m, 1H), 1.49 - 1.38 (m, 1H), 1.34 (s, 9H); 13C-NMR 125MHz: DMSO-d6): 166.29, 153.82, 147.99, 146.43, 132.84, 131.48, 130.70, 130.14, 127.47, 127.27, 112.17, 78.47, 50.87, 44.01, 42.24, 41.14, 31.43, 28.07, 25.03; Mass spectra: 453.16 [M-l]+.
Example 4: Preparation of Niraparib (II) To a solution of tert-butyl (S)-3-(4-((3-carbamoyl-2-nitrobenzyl)amino)phenyl)piperidine-l- carboxylate (Illa) (55 g) in 1-butanol (550 mL) was added tin(II) chloride dihydrate (68.8 g). The reaction mixture was heated to 75 °C and stirred for 24 hours at the same temperature. The reaction mixture was then cooled to room temperature. After cooling the reaction mixture was filtered and washed with n-butanol (55 mL). The resulting solid was mixed with methylene chloride (1.1 L) and 2M sodium hydroxide solution (3.3 L), stirred for 30 minutes. Layers were separated and aqueous layer was further extracted with methylene chloride (550 mL). Combined organic layers were distilled under vacuum at 45 °C to get the title compound (II), which is proceeded to the next step without further purification.
Example 5: Preparation of Niraparib tosylate (I)
To a solution of niraparib (II) (39 g) in THF (624 mL) was added water (31.2 mL) and p- toluenesulfonic acid hydrate (50.9 g) at room temperature. The reaction mixture was heated to 70 °C and stirred for 14 hours at the same temperature. The reaction mixture was then cooled to 10 °C and filtered through Buchner funnel at room temperature. The resulting solid was washed with THF (78 mL) and dried at 50 °C to get the title compound (I) as monohydrate (29 g). ’H-NMR (500MHz: DMSO-ds): 9.32 (s, 1H), 8.83 (d, J = 10.5Hz, 1H), 8.56 (d, J = 2Hz, 1H), 8.48 (d, J = 10.5Hz, 1H), 8.13 (d, J = 9.0Hz, 2H), 8.07 (dd, J = 0.5Hz, J = 1.0Hz, 1H), 8.02 (dd, J = 0.5Hz, J = 1.0Hz, 1H), 7.91 (d, J = 2.5Hz, 1H), 7.54 - 7.50 (m, 4H), 7.29 - 7.26 (m, 1H), 7.12 (d, J = 8.0Hz, 2H), 3.43 - 3.33 (m, 2H), 3.15 - 3.11 (m, 1H), 3.06 - 3.02 (m, 1H), 2.98 - 2.91 (m, 1H), 2.28 (s, 3H), 1.94 - 1.92 (m, 2H), 1.78 - 1.75 (m, 2H). 13C-NMR 125MHz: DMSO-d6): 165.50, 146.08, 145.52, 142.04, 138.30, 137.72, 129.78, 128.51, 128.09, 125.47, 125.36, 123.47, 123.41, 121.95, 121.48, 120.93, 47.73, 43.03, 38.99, 29.32, 22.26, 20.75; Mass spectra: 321.11 [M+l]+ .
Example 6: Preparation of tert-butyl (S)-3-(4-(7-carbamoyl-2H-indazol-2-yl)phenyl)piperidine- 1-carboxylate (Ila)
A mixture of tert-butyl (S)-3-(4-((3-carbamoyl-2-nitrobenzyl)amino)phenyl)piperidine-l-carboxylate (Illa) (1 Kg), Sodium acetate (0.9 Kg), acetic acid (0.66 Kg), stannous chloride anhydrous (0.42 Kg) in methanol (20 L) was heated to 60 °C and stirred for 4 hours. The reaction mixture was then cooled to room temperature. After cooling, Stannous chloride anhydrous lot-2 (0.42 Kg) was added to the reaction mixture and again heated to 60 °C and stirred for 24 hours. The reaction mixture was then cooled to 60 °C and distilled up to 5-7 volumes. Toluene (20 L) was added to the above reaction mixture and cooled 10 °C. A solution of sodium hydroxide (2 Kg) in water (20 L) was added to the above reaction mixture and stirred for 30 minutes at 10 °C. Aqueous layer was separated from the reaction mixture. To the remaining reaction mixture was added ethyl acetate (10 L) and heated to 30 °C. Ammonia solution (lot-1, 5 L) and water (Lot-1, 5 L) were added to the above reaction mixture and stirred for 60 minutes. Aqueous layer was separated from the reaction mixture. To the remaining reaction mixture was added ammonia solution (Lot 2, 5 L) and water (Lot 2, 5 L) at 30 °C, stirred for 60 minutes. Aqueous layer was separated from the reaction mixture. To the remaining reaction mixture was added ammonia solution (Lot 3, 5 L) and water (Lot 3, 5 L) at 30 °C, stirred for 60 minutes. Aqueous layer was separated from the reaction mixture. To the remaining reaction mixture was added a solution of EDTA (Lot 1, 0.3 Kg) in water (10 L) at 30 °C, stirred for 60 minutes. Aqueous layer was separated from the reaction mixture. To the remaining reaction mixture was added a solution of EDTA (Lot 2, 0.3 Kg) in water (10 L) at 30 °C, stirred for 60 minutes. Aqueous layer was separated from the reaction mixture. The remaining organic layer was distilled up to 1 volume and mixed with Methyl tert-butyl ether (6 L). The reaction mixture was then heated to 50 °C, stirred for 120 minutes. The reaction mixture was then cooled to 30 °C and stirred for 5 hours at the same temperature. The resulting solid was fdtered, washed with Methyl tert-butyl ether (2 L) and dried under vacuum at 40 °C, for 12 hours to get the title compound (Ila) (0.75 Kg).
Example 7: Preparation of Niraparib tosylate (I)
To a solution of tert-butyl (S)-3-(4-(7-carbamoyl-2H-indazol-2-yl)phenyl)piperidine-l-carboxylate (lib) (1 Kg) in THF (6.5 L) was added p-toluene sulfonic acid monohydrate (1 Kg) at room temperature. The reaction mixture was heated to 60 °C and stirred for 6 hours at the same temperature. The reaction mixture was then cooled to room temperature and added water (1 L), stirred for 1 hour. Tetrahydrofuran (9.5 L) was added to the above reaction mixture and stirred for 4 hours. The reaction mixture was then fdtered and mixed with tetrahydrofuran (5 L), stirred for 30 minutes. The resulting solid was fdtered and dried to get the title compound (I) as monohydrate (1.09 Kg).
Example 8: Purification of Niraparib tosylate (I)
A solution of Compound of formula (I) (1 Kg) in water (45 L) was heated to 95 °C and stirred for 30 minutes. Filter the reaction mixture to separate the undissolved particles. The reaction mixture was then cooled to room temperature to 85 °C and added seed compound. The reaction mixture was then cooled to 75 °C and stirred for 1 hour. The reaction mixture was further cooled to 25 °C and stirred for 2 hours. The resulting solid was fdtered and washed with water (5 L), dried to get the title compound (I) as monohydrate (1.09 Kg).

Claims

We Claim:
1. A process for preparation of niraparib tosylate of formula (I) comprising steps of: a) reacting compound of formula (VI) with a suitable halogenating agent to form compound of formula (V)
Figure imgf000022_0001
(VI) (V) b) reacting compound of formula (V) with compound of formula (IV) to form compound of formula
(HI)
Figure imgf000022_0002
c) converting compound of formula (III) to compound of formula (lib) or (II)
Figure imgf000022_0003
d) converting compound of formula (lib) to compound of formula (I)
Figure imgf000022_0004
wherein, X is a halogen and Pi is an amino protecting groups; P is a hydrogen or amino protecting groups.
2. The process as claimed claim 1, wherein halogenating agent is selected form N-bromosuccinamide, l,3-Dibromo-5,5-dimethylhydantoin, bromine or mixture thereof; solvent is a nitrile solvent.
3. The process as claimed in step b) of claim 1, wherein suitable base is selected from group comprising triethyl amine, diisopropyl ethyl amine (DIPEA), pyridine, sodium methoxide, sodium tert-butoxide, potassium carbonate, sodium carbonate, lithium hydroxide and sodium hydroxide.
4. The process as claimed in step c) claim 1, is carried out in presence of a tin chloride.
5. The process as claimed step c) claim 1, is carried out in presence of an acid scavenger selected from sodium acetate, potassium acetate, sodium phosphate, sodium dihydrogen phosphate, sodium hydrogen phosphate, sodium oxalate, triethyl amine.
6. A process for the preparation of compound of formula (V), comprising reacting compound of formula (VI) with a suitable halogenating agent in a solvent
Figure imgf000023_0001
wherein X is a halogen.
7. A process for the preparation of compound of formula (III), comprising reacting compound of formula (IV) with compound of formula (V) in presence of a suitable base
Figure imgf000023_0002
wherein, X is a halogen; Pi is an amino protecting groups; Pis a hydrogen or amino protecting groups.
8. A process for the preparation of compound of formula (lib), comprising converting compound of formula (III) to compound of formula (lib) or (II).
Figure imgf000023_0003
wherein, P is a hydrogen or amino protecting group.
9. Compound of formula selected from
Figure imgf000024_0001
wherein X is a halogen and P is hydrogen or amino protecting group.
10. A process for preparation of Niraparib or its pharmaceutically acceptable salts thereof said process comprising producing the Niraparib or a pharmaceutically acceptable salt thereof from one or more compounds of claim 9.
PCT/IN2023/051221 2022-12-29 2023-12-26 Process for preparation of niraparib tosylate and its intermediates WO2024142096A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008084261A1 (en) * 2007-01-10 2008-07-17 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Amide substituted indazoles as poly(adp-ribose)polymerase (parp) inhibitors
WO2018200517A1 (en) * 2017-04-24 2018-11-01 Tesaro, Inc. Methods of manufacturing of niraparib

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008084261A1 (en) * 2007-01-10 2008-07-17 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Amide substituted indazoles as poly(adp-ribose)polymerase (parp) inhibitors
WO2018200517A1 (en) * 2017-04-24 2018-11-01 Tesaro, Inc. Methods of manufacturing of niraparib

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* Cited by examiner, † Cited by third party
Title
HUGHES ET AL.: "Patent Review of Manufacturing Routes to Recently Approved PARP Inhibitors: Olaparib, Rucaparib, and Niraparib", ORG. PROCESS RES. DEV., vol. 21, no. 9, 9 August 2017 (2017-08-09), pages 1227 - 1244, XP055455394, DOI: 10.1021/acs.oprd.7b00235 *
WALLACE ET AL.: "Development of a Fit-for-Purpose Large-Scale Synthesis of an Oral PARP Inhibitor", ORG. PROCESS RES. DEV., vol. 15, 17 May 2011 (2011-05-17), pages 831 - 840, XP055263721, DOI: dx. doi.org/10.1021/o p2000783 *

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