Process for preparation of 2-{4-[(3S)-piperidin-3-YL] phenyl}-2h- indazole 7-carboxamide and its salts

Abstract

The present invention relates to a process for the preparation of (2-{4-[(3S)- piperidin-3-yl] phenyl}-2H- indazole 7-carboxamide and its salts (I). Niraparib salcaprozate The present invention relates to a process for the preparation of 2-{4- [(3s)-piperidin- 3-yl] phenyl}-2h- indazole 7-carboxamide or its pharmaceutically acceptable salts with enantiomer purity greater than 99.95%.

Description

[0001] “PROCESS FOR PREPARATION OF2-{4-[(3S)-PIPERIDIN-3-YL] PHENYL}-2H- INDAZOLE 7-CARBOXAMIDE AND ITS SALTS”

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of the earlier filing date of Indian Provisional Patent Application No. 202541014901 filed on February 21, 2025, and Indian Provisional Patent Application No. 202541056588 filed on Jun 12, 2025. and Indian provisional patent application No. 202541078482 filed on Aug 19, 2025.

[0004] FIELD OF THE INVENTION

[0005] The present invention relates to a process for the preparation of (2-{4-[(3S)-piperidin-3-yl] phenyl}-2H- indazole 7-carboxamide and its salts.

[0006] BACKGROUND OF THE INVENTION

[0007] Niraparib tosylate monohydrate, Niraparib tosylate monohydrate is an orally available poly(ADP -ribose) polymerase (PARP) inhibitor, for the treatment of maintenance treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAmut) recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. It is chemically designated as (2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole 7-carboxamide 4-methylbenzenesulfonate hydrate and is chemically represented by the following structural Formula (1).

[0008]

[0009] Niraparib tosylate monohydrate (1)US 8071623 B2 discloses Niraparib and its salts for the first time which discloses a process for the preparation of Niraparib salts.

[0010] US8436185B discloses Niraparib tosylate monohydrate.

[0011] US20210347760A1 discloses Niraparib (1) salts camphorate, mandelate and camsylate salts of niraparib.

[0012] The solubility of individual salt and crystalline forms of a drug substance in an aqueous environment is an important aspect of their relative bioavailability, since the manner in which the salt or crystalline form dissolves can correspond to the amount of the drug substance that is available to be absorbed into the body to provide the intended therapeutic effect. One measure of solubility is intrinsic dissolution rate (IDR), which is defined as the dissolution rate of a substance under constant surface area conditions. For low solubility substances, higher IDR values can correlate with higher bioavailability following administration. However, if the goal is to establish bioequivalence to an approved form of a drug, such as Ruxolitinib phosphate, substances with similar IDR values to the approved form are preferred. Alternatively, for the development of extended or sustained release products, forms exhibiting lower IDR values are often preferable since they can provide slower dissolution of the drug independent of the excipients used in the formulation.

[0013] Different salt and / or crystalline forms of the same compound may have different crystal packing, thermodynamic, spectroscopic, kinetic, surface, and mechanical properties. For example, different salts and / or crystalline forms may have different stability properties such that a particular form may be less sensitive to heat, relative humidity (RH) and / or light. Also, different salts and / or crystalline forms of a compound may be more susceptible to moisture uptake, resulting in a potential alteration of the chemical and / or physical stability. Different salts may exist in more than one crystalline form, which can cause complexity in ensuring the stability of a desired crystalline form in a drug product. Finally, different salts and / or crystalline forms of a compound may havedifferent dissolution rates, thereby providing different pharmacokinetic parameters, which allow for specific forms to be used in order to achieve specific pharmacokinetic targets.

[0014] Thus, there is always a need to prepare novel salts of Niraparib (1) that exhibit high solubility, stability, and commercial viability. Therefore, the present inventors disclose a novel salt of Niraparib (1).

[0015] OBJECTIVE OF THE INVENTION

[0016] In one objective, the present invention provides a process for the preparation of Niraparib salts (1).

[0017] In another objective, the present invention provides novel salt of Niraparib i.e. Niraparib salcaprozate, which is represented by the following structural formula,

[0018]

[0019] In another objective, the present invention provides a process for the preparation of solid form of Niraparib salt of formula (1)

[0020] The present invention relates to an improved process for the preparation of (S)-tertbutyl 2-(4-aminophenyl) piperidine- 1 -carboxylate (8) which is an intermediate useful in the preparation of Niraparib or its pharmaceutically acceptable salts.

[0021] The present invention further relates to pure (S)-tert-butyl 2-(4-aminophenyl) piperidine 1 -carboxylate (8) obtained by any of the described methods with purity greater than 99% by HPLC and more preferably greater than 99.5% and still more preferably 99.9% by HPLC.A further objective of the present invention provides solid forms of Niraparib salt of formula (1) with purity greater than 99.0% as determined by HPLC, preferably greater than 99.5% by HPLC, and more preferably greater than 99.8% by HPLC.

[0022] SUMMARY OF THE INVENTION

[0023] In one aspect, the present invention provides a process for the preparation of Niraparib and its salts, comprising the following steps.

[0024] a) reacting Methyl 3-formyl-2-nitrobenzoate (9) with Tert-butyl (3S)-3-(4- aminophenyl) piperidine- 1 -carboxylate (8) in presence suitable solvent to get (S, E)-tert-butyl 3 -(4-(3-(m ethoxy carbonyl)-2-nitrobenzylideneamino) phenyl) piperidine- 1 -carboxylate (7).

[0025] b) cyclization of compound of formula (7) with sodium azide in presence of suitable solvent to give (S)-methyl 2-(4-(l-(tert-butoxycarbonyl) piperi din-3 -yl) phenyl)- 2H-indazole-7-carboxylate (6).

[0026] c) hydrolysis of compound of formula (6) with base in presence of suitable solvent to get (S)-tert-butyl 3-(4-(7-carbamoyl-2H-indazol-2-yl) phenyl) piperidine-1- carboxylate (4) optionally purifying the compound of formula (5); and d) reacting compound of formula (5) with a base in presence of suitable solvent to get (S)-tert-butyl 3-(4-(7-carbamoyl-2H-indazol-2-yl) phenyl) piperidine-1- carb oxy late (4)

[0027] e) reacting to the compound of formula (4) with para-toluene sulfonic acid, followed by purification to obtain Niraparib tosylate salt of formula (3),

[0028] f) converting Niraparib tosylate salt of formula (3) to Niraparib free base of formula (2)

[0029] g) reacting to the compound of formula (2) with an acid to obtain Niraparib salt of formula (1).

[0030] In another aspect, the present invention provides novel salt of Niraparib i.e. Niraparib salcaprozate, which is represented by the following structural formula,

[0031]

[0032] In another aspect of the present invention provides a process for preparation of solid forms of Niraparib salt of formula (1), comprising the following steps,

[0033] a) dissolving Niraparib free base of formula (2) and an acid in a solvent or mixture of solvents,

[0034] b) isolating the solid form of Niraparib salt (1).

[0035] In another aspect, the present application provides a process for the preparation of Niraparib salt of formula (1), comprising the steps of:

[0036] A) dissolving Niraparib free base of formula (2) in a solvent or mixture of solvents, B) adding suitable acid in a solvent to the mixture obtained in step A), and C) isolating the solid Niraparib salt of formula (1).

[0037] In another aspect, the present invention provides a solid form of which is characterized by an which is characterized by X-ray diffractogram as shown in figure 1.

[0038] Accordingly, the present invention relates to an improved process for the preparation of (S)-tert-butyl 3-(4-aminophenyl) piperidine- 1 -carboxylate (8). Further in some embodiments, the present invention provides process for the preparation of intermediates with enantiomeric excess of greater than 50%.

[0039] In one aspect of the present invention relates to an improved process for the preparation of (S)-tert-butyl 3-(4-aminophenyl) piperidine- 1 -carboxylate (8), as depicted in scheme-4, which comprises:

[0040] a) reacting l-chloro-4-nitrobenzene (17) with methyl 2-cyanoacetate (16); in presence of suitable solvent and base to provide methyl 2-cyano-2-(4- nitrophenyl) acetate (15);b) reacting the compound of formula (15) with methyl acrylate in presence of suitable solvent to provide (R)-dimethyl 2-cyano-2-(4-nitrophenyl) pentanedioate (14);

[0041] c) decarboxylation of the compound of formula (14) in presence of base to provide methyl 4-cyano-4-(4-nitrophenyl) butanoate (13);

[0042] d) hydrogenating the compound of formula (13) with suitable hydrogenating agent in presence of suitable solvent to provide 5-(4-aminophenyl) piperidin-2-one (12);

[0043] e) reducing the compound of formula (12) with reducing agent to provide 4- (piperi din-3 -yl) aniline (11); resolving compound of formula C with resolving agent to provide (S)-4- (piperi din-3 -yl) aniline (Ila); and

[0044] f) converting compound of formula (Ila) to (S)-tert-butyl 3-(4-aminophenyl) piperidine- 1 -carboxylate (8).

[0045] In another aspect, (S)-tert-butyl 3-(4-aminophenyl) piperidine- 1 -carboxylate (8). obtained by any of the described methods is having purity greater than 99% by HPLC and more preferably greater than 99.5% and still more preferably 99.98% by HPLC.

[0046] In another aspect, the present invention is to provides solid forms of Niraparib salt of formula (1) obtained by any of the described methods is having purity greater than 99% by HPLC and more preferably greater than 99.5% and still more preferably 99.98% by HPLC.

[0047] BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1: X-ray powder diffraction (PXRD) of Niraparib salcaprozate (1) salt obtained according to reference example 1.

[0049] DETAILED DESCRIPTION OF THE INVENTION

[0050] The “suitable solvent” used in the present invention can be selected from but not limited to water, “hydrocarbon solvents” such as n-pentane, n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and mixtures thereof; “ethersolvents” such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 1,4-di oxane and mixtures thereof; “ester solvents” such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and mixtures thereof; “polar-aprotic solvents” such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and mixtures thereof; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and mixtures thereof; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone and mixtures thereof; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and mixtures thereof; “alcohol solvents” such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, 2-butanol, tert-butanol, ethane-1,2-diol, propane- 1,2-diol and mixtures thereof; “polar solvents” such as water; formic acid, acetic acid and the like or mixture of any of the afore mentioned solvents.

[0051] The term “base” used in the present invention refers to inorganic bases selected from “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkyl metals” such as n-butyl lithium and like; “metal hydrides” such as lithium hydride, sodium hydride, potassium hydride and the like; “alkali metal phosphates” such as disodium hydrogen phosphate, dipotassium hydrogen phosphate; ammonia such as aqueous ammonia, ammonia gas, methanolic ammonia and like and “organic bases” selected from but not limited to methyl amine, ethyl amine, diisopropyl amine, diisopropylethyl amine (DIPEA), diisobutylamine, triethylamine, tert.butyl amine, pyridine, N-methyl piperazine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), N-methyl pyridine (NMP), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0] non-5-ene (DBN), l,4-diazabicyclo[2.2.2]octane (DABCO), imidazole; “alkalimetal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide and the like; “alkalimetal amides” such as sodium amide, potassium amide, lithium amide, lithium diisopropyl amide (LDA), sodium bis(trimethylsilyl)amide (NaHMDS), potassiumbis(trimethylsilyl)amide, lithium bis(trimethysilyl)amide (LiHMDS) and the like; or mixtures thereof.

[0052] The term “suitable reducing agent” used in the present invention until unless specified is selected from, but are not limited to lithium aluminium hydride, sodium borohydride, sodium hydride, or sodium bis(2-methyoxyethoxy) aluminumhydride, sodium triacetoxyborohydrode, Aluminium hydride(AlH3), chlorohydroalane (A1H2C1), dichloroaluminum (A1HC12), Lithium borohydride (LiBH4), Lithium triethylborohydride (LiEt3BH), Borane(BH3), Borane tetrahydrofuran (BH3.THF), Zinc acetate(Zn(OAc)2), Triethoxysilane ((EtO)3SiH), Magnesium(Mg), Titanium tetrachloride(TiC14), Pinacolborane (HBpin) ,tris(4,4-dimethyl-2-oxazolinyl)phenylborateMgMe, Platinum (Pt) on alumina, palladium (Pd) on alumina, Palladium on carbon (Pd,C), palladium hydroxide on carbon ((Pd(OH2),C), Raney Ni, Rhodium on carbon (Rh,C), Rhodium on alumina (Rh,Al), Platinum on (Pt,C), Ruthenium (Ru,C), Platinum (IV) Oxide (PtO2), Sodium bis(2-methoxyethoxy)aluminium hydride (Red-Al), or combinations thereof.

[0053] As used herein the term “acid” used in the present invention refers to inorganic acid and organic acid; inorganic acid is selected from such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfuric acid; organic acids such as formic acid, acetic acid, tartaric acid, maleic acid, citric acid, malic acid, oxalic acid, succinic acid, fumaric acid, trifluoroacetic acid, phthalic acid, alkyl sulfonic acids is selected from such as methane sulfonic acid, ethane sulfonic acid, benzenesulfonic acid, Salcaprozic acid, or p-toluene sulfonic acid.

[0054] The term “resolving agent” used in the present invention until unless specified is selected from, but are not limited to Aspartic acid, O-Acetyl-Mandelic acid, cis-2-Benzamidocyclohexanecarboxylic acid, l,l'-Binapthyl-2,2'-diyl hydrogen phosphate, Camphoric acid, 10-Camphorsulfonic acid and (+)-a-phenyl ethylamine, mandelicacid, malic acid, trans- 1,2-Cy cl ohexanedicarboxylic acid, Dibenzoyl-Tartaric acid, Di acetyl -tartaric acid, Di -p-toluoyl -tartaric acid, N-(3,5- Dinitrobenzoyl)-a-phenylglycine, Di acetyl -tartaric anhydride, Di acetyl -tartaric acid, Glutamic acid, Malic acid, Mandelic acid, N-acetyl-L-leucine, N-acetyl-L-tyrosine; D- or Ltartartic acid, di-para-tolyl D-tartratic acid, di-benzoyl D-tartaric acid, N-(a-methylbenzyl)phthalamic acid, 2-(6- Methoxy-2-napthyl)propionic acid, Pyroglutamic acid, Quinic acid and Tartaric acid, or combinations thereof.

[0055] The term “hydrogenating agent” used in the present invention until unless specified is selected from but are not limited to H2 / Ni, H2 / Pt and H2 / Pd.

[0056] Accordingly, in the first embodiment, the present invention provides a process for the preparation of Niraparib salts (1), is having a purity greater than 99.5% by HPLC, as illustrated in Scheme 1.

[0057]

[0058] wherein, the salt is selected from the list above.

[0059] Scheme-1

[0060] In another embodiment, the steps involved in the preparation of Niraparib salts (1) as shown in scheme 1 are as follows:

[0061] The step a) of aforementioned process involves the reaction of Methyl 3-formyl-2-nitrobenzoate (9) with tert-butyl (3S)-3-(4-aminophenyl) piperidine- 1 -carboxylate (8) in the presence of a solvent under appropriate reaction conditions to provide (S,E)-tert-butyl 3 -(4-(3-(m ethoxy carbonyl)-2-nitrobenzylideneamino)phenyl) piperidine- 1-carboxylate (7). The solvent is selected from but not limited to methanol, ethanol, isopropyl alcohol, n-propanol and butanol, preferably using methanol. The said reaction is carried out at a suitable temperature of about 25°C-30°C to about reflux temperature of the solvent used, for a sufficient time.

[0062] The step b) of aforementioned process involves the reaction of 3-(4-(3-(m ethoxy carbonyl)-2-nitrobenzylideneamino) phenyl) piperidine- 1 -carboxylate (7) with sodium azide in the presence of a solvent under appropriate reaction conditions to give (S)-methyl 2-(4-(l-(tert-butoxy carbonyl) piperi din-3 -yl) phenyl)-2H-indazole-7-carboxylate(6). The solvent used in step b) is selected from but not limited to dimethylformamide, dimethylacetamide, or dimethylsulfoxide, preferably using dimethylsulfoxide. The said reaction is carried out at a suitable temperature of about 25°C-30°C to about reflux temperature of the solvent used, for a sufficient time.

[0063] The step c) of aforementioned process involves the hydrolysis of (S)-methyl 2-(4-(l-(tert-butoxycarbonyl) piperidin-3-yl)phenyl)-2H-indazole-7-carboxylate(6) in the presence of a base in a solvent under appropriate reaction condition, followed by purification in a solvent to get (S)-tert-butyl 3-(4-(7-carbamoyl-2H-indazol-2-yl)phenyl)piperidine-l-carboxylate(5); The base used in step c) is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide and the like. The solvent used in step c) is selected from but not limited dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane and tetrahydrofuran, preferablytetrahydrofuran. The solvent used for purification in step c) is selected from but not limited to methanol, ethanol, isopropyl alcohol, n-propanol and butanol, preferably methanol. The said reaction is carried out at a suitable temperature of about 40°C-45°C for a sufficient time.

[0064] The step d) of aforementioned process involves the reaction of reacting compound of formula (5) with ammonium carbonate in presence of suitable solvent to get (S)-tert-butyl 3-(4-(7-carbamoyl-2H-indazol-2-yl)phenyl)piperidine-l-carboxylate(4); suitable solvent selected from but not limited to dichloromethane, di chloroethane, chloroform, and carbon tetrachloride. The said reaction is carried out at a suitable temperature of about 25°C-30°C to about reflux temperature of the solvent used, for a sufficient time, optionally purifying the obtained compound in presence suitable solvent or mixture of solvents; suitable solvents selected from but not limited to dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and mixtures thereof.

[0065] The step e) of aforementioned process involves the reaction of compound of formula (4) with para-Toluene sulphonic acid monohydrate in presence of suitable solvent under appropriate conditions to provide crude Niraparib tosylate monohydrate (3), followed by purification in a solvent to obtain pure Niraparib tosylate monohydrate (3). The solvent used in step e) is selected from but not limited to dichloromethane, di chloroethane, chloroform, and carbon tetrachloride; “alcohol solvents” such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, 2-butanol, tertbutanol, ethane- 1,2-diol, propane- 1,2-diol and mixtures thereof; preferably using Methanol, di chloromethane. The solvent used for purification is selected form nitrile solvents such as acetonitrile, propionitrile, isobutyronitrile, water and mixtures thereof. The said reaction is carried out at a suitable temperature of about 25°C-30°C to about reflux temperature of the solvent used, for a sufficient time.The step f) of aforementioned process involves the reaction of compound of formula (3) with sodium hydroxide in water under appropriate conditions to provide Niraparib free base (2). The said reaction is carried out at a suitable temperature of about 55°C-65°C to about reflux temperature of the solvent used, for a sufficient time.

[0066] The step g) of aforementioned process involves the reaction of Niraparib free base (2) with an acid in a suitable solvent, followed by isolation under appropriate conditions to provide Niraparib salt of formula (1). The acid used in step vii) is selected from the list above, preferably using p-toluene sulfonic acid and Salcaprozic acid. The solvent is selected from “alcoholic solvents” such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; “chloro solvents” such as dichloromethane, ethylene dichloride, carbon tetrachloride, chloroform and the like and / or mixture thereof, preferably using methanol and dichloromethane.

[0067] In another preferred embodiment, the present invention provides a process for the preparation of Niraparib p-toluene sulfonate salt, which comprises the reaction of Niraparib free base (2) with p-toluene sulfonic acid in methanol to provide Niraparib p-toluene sulfonate salt.

[0068] In another preferred embodiment, the present invention provides a process for the preparation of solid form of Niraparib salcaprozate salt, which comprises the reaction of Niraparib free base (2) with Salcaprozic acid in a mixture of methanol and dichloromethane, followed by isolation to provide Niraparib salcaprozate salt.

[0069] In another preferred embodiment, the present invention provides a process for the preparation of solid form of Niraparib salcaprozate salt, which comprises dissolving Niraparib free base (2) in a mixture of methanol and dichloromethane, followed by adding with Salcaprozic acid which on further isolation to Niraparib salcaprozate salt.

[0070] In an embodiment, isolating involve removal of solvent is carrying out by suitable techniques which includes but not limited to decantation, evaporation under reducedpressure, flash evaporation, vacuum drying, concentrating the reaction mixture, atmospheric distillation, distillation under reduced pressure, distillation by using a rotational distillation device such as Buchi rotavapor, agitated thin film drying (ATFD), melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, cooling the clear solution to lower temperatures to precipitate the solid followed by filtration by gravity or suction, thin film drying, centrifugation or any other suitable techniques known in the art.

[0071] In an embodiment, dry Niraparib salcaprozate salt by a suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying can be carried out for any period required to obtain the desired quality, such as from about 15 minutes to 10 hours or longer.

[0072] Niraparib salt prepared according to the present invention can be further micronized or milled in conventional techniques to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but are not limited to ball milling, roll milling and hammer milling, and jet milling. Milling or Micronisation may be performed before drying, or after the completion of drying of the product.

[0073] In one aspect of the present invention, solid form of Niraparib Salcaprozate characterized by X-ray powder diffraction pattern according to FIG.-l.

[0074] In another embodiment, the present invention provides Niraparib salcaprozate could be hydrate or anhydrous, and hydrate selected from mono hydrate, di hydrate, tri hydrate and like.In another embodiment, the present invention provides Niraparib salcaprozate could be amorphous or crystalline.

[0075] In another embodiment, the present invention provides Niraparib particles have a specific surface area (SSA) of less than 5 m2 / g, preferably less than 4 m2 / g, m, more preferably less than 3 m2 / g.

[0076] In another embodiment, the present invention provides Niraparib salt particles have a specific surface area (SSA) of less than 5 m2 / g, preferably less than 4 m2 / g, m, more preferably less than 3 m2 / g.

[0077] Accordingly, in another embodiment, the present invention provides Niraparib starting material process for the preparation of compound (8), as illustrated in Scheme 2.

[0078]

[0079] Scheme 2

[0080] Accordingly, in another embodiment, the present invention provides Niraparib starting material process for the preparation of compound (9), as illustrated in Scheme 3.

[0081]

[0082] Scheme 3

[0083] Accordingly, in another embodiment the present invention provides a process for the preparation of (S)-tert-butyl 3-(4-aminophenyl) piperidine- 1 -carboxylate (8), as illustrated in Scheme 4. comprising the steps of:

[0084]

[0085] Scheme-4

[0086] The step A) of aforementioned process involves the reaction of the compound of formula (17) with compound of formula (16); in presence of suitable solvent selected from dimethylformamide, dimethylacetamide, dimethyl sulfoxide and the like, preferably dimethyl formamide and base is selected from sodium carbonate, potassium carbonate, lithium carbonate and the like preferably potassium carbonate; to provide methyl 2-cyano-2-(4-nitrophenyl) acetate (15). The said reaction is carried out at asuitable temperature of about 110°C-115°C to about reflux temperature of the solvent used, for a sufficient time

[0087] The step B) of aforementioned process involves the reaction of the compound of formula (15) with methyl acrylate in presence of suitable solvent selected from tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane and the like preferably tetrahydrofuran to provide (R)-dimethyl 2-cyano-2-(4-nitrophenyl) pentanedioate (14). The said reaction is carried out at a suitable temperature of about 25°C-30°C to about reflux temperature of the solvent used, for a sufficient time.

[0088] The step C) of aforementioned process involves decarboxylation of the compound of formula (14) in presence of base selected from sodium carbonate, potassium carbonate, lithium carbonate and the like preferably sodium carbonate to provide methyl 4-cyano4-(4-nitrophenyl) butanoate (13). The said reaction is carried out at a suitable temperature of about 25°C-30°C to about reflux temperature of the solvent used, for a sufficient time.

[0089] The step D) of aforementioned process involves hydrogenation of the compound of formula (13) in presence of hydrogenating agent selected from H2 / Ni, H2 / Pt and H2 / Pd and like preferably H2 / Ni and suitable solvent selected from methanol, ethanol, isopropyl alcohol, n-propanol, butanol preferably methanol to provide 5-(4-aminophenyl) piperidin-2-one (12). The said reaction is carried out at a suitable temperature of about 25°C-30°C to about reflux temperature of the solvent used, for a sufficient time.

[0090] The step E) of aforementioned process involves reduction of the compound of formula (12) in presence of reducing agent selected from lithium aluminium hydride, sodium borohydride, sodium hydride, or sodium bis(2-methyoxyethoxy) aluminumhydride, sodium triacetoxyborohydrode, Aluminium hydride(AlH3), chlorohydroalane (A1H2C1), dichloroaluminum (A1HC12), Lithium borohydride (LiBH4) preferably sodium borohydride to provide 4-(piperi din-3 -yl) aniline (11). with resolving agentselected from Aspartic acid, O-Acetyl-Mandelic acid, cis-2-Benzamidocyclohexanecarboxylic acid, l,l'-Binapthyl-2,2'-diyl hydrogen phosphate, Camphoric acid, Camphor sulfonic acid, trans- 1,2-Cy cl ohexanedicarboxylic acid, Dibenzoyl-Tartaric acid, Diacetyl-tartaric acid, preferably camphor sulfonic acid to provide (S)-4-(piperi din-3 -yl) aniline (Ila). The said reaction is carried out at a suitable temperature of about 25°C-30°C to about reflux temperature of the solvent used, for a sufficient time.

[0091] The step F) of aforementioned process involves reaction of compound of formula (Ila) with Di-tert-butyl dicarbonate (Boc anhydride) in presence of suitable solvent selected from di chloromethane, ethylene di chloride, carbon tetrachloride, chloroform and the like, preferably di chloromethane to provide (S)-tert-butyl 3 -(4-aminophenyl)piperidine-l -carboxylate (8). The said reaction is carried out at a suitable temperature of about 25°C-30°C to about reflux temperature of the solvent used, for a sufficient time.

[0092] In another embodiment, (S)-tert-butyl 3-(4-aminophenyl) piperidine- 1 -carboxylate (8). obtained by any of the described methods is having purity greater than 99% by HPLC and more preferably greater than 99.5% and still more preferably 99.98% by HPLC.

[0093] In another embodiment, (S)-tert-butyl 3-(4-aminophenyl) piperidine- 1 -carboxylate (8). used in the preparation of niraparib or its pharmaceutically acceptable salts.

[0094] In another embodiment, the present invention is to provides solid forms of Niraparib salt of formula (1) obtained by any of the described methods is having purity greater than 99% by HPLC and more preferably greater than 99.5% and still more preferably 99.98% by HPLC.The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

[0095] Examples:

[0096] Experimental procedure according to Scheme 1

[0097] Example 1:

[0098] Step A: Preparation of (S, E)-tert-butyl 3-(4-(3-(methoxycarbonyl)-2-nitrobenzylideneamino) phenyl) piperidine-l-carboxylate (7).

[0099] 100g of Methyl 3-formyl-2-nitrobenzoate (9) was dissolved in (700 mL) of methanol to the reaction mass (132g) of tert-butyl (3S)-3-(4-aminophenyl) piperidine-l-carboxylate (8) was added at room temperature heat the reaction mass to the reflux temperature and stirred for sufficient time till reaction completed, then filtered to yield the titled compound Yield: 200g.

[0100] Step B: Preparation of (S)-tert-butyl 3-(4-(7-carbamoyl-2H-indazol-2-yl) phenyl) piperidine-l-carboxylate (4).

[0101] 200g of 3 -(4-(3-(m ethoxy carbonyl)-2-nitrobenzylideneamino) phenyl) piperidine-l-carboxylate (7) dissolved in dimethyl sulfoxide and to the reaction mass (29g) of sodium azide was added at room temperature, then heat the reaction mass to 120-130°C, and stirred the reaction mass to sufficient time till the reaction complete at room temperature, separate the layers, to obtain the compound of formula (6), to the reaction mass (12 vol) of tetrahydrofuran was added at room temperature followed by 150 g of sodium hydroxide was added at room temperature and stirred the heat the reaction mass 40-45°C and stirred, separated the layers and distilled the solvent to get the crude compound of formula (5), to this crude compound of formula (5) dissolved in (14 vol) of methanol at room temperature and stirred for sufficient time, and solvent is distilled to get pure compound of formula (5), to the reaction mass dichloromethane was added followed by 50 mL of pyridine and 200 mL of Boc anhydride was added at room temperature and stirred then 130 g pf Ammonium carbonate was added to get compound of formula (4), the crude product was dissolved in methyl tert-butyl etherand ethyl acetate, and cool the reaction mass to 0-5° C and stirred, the obtained compound filtered and dried to get the titled compound. Yield: 85g

[0102] Step B: Preparation of (S)-tert-butyl 3-(4-(7-carbamoyl-2H-indazol-2-yl) phenyl) piperidine-l-carboxylate (4).

[0103] 100g of 3 -(4-(3-(m ethoxy carbonyl)-2-nitrobenzylideneamino) phenyl) piperidine-l-carboxylate (7), 250 mL of dimethyl sulfoxide at 25-30, and 14.6g of sodium azide was added into RB flask at 25-30°C. heat the reaction mass to 120-130°C, and stirred the reaction mass to sufficient time till the reaction complete at room temperature, Cool the reaction mass to 40-50°C. added ethyl acetate (lOOOmL), sodium chloride solution into above RB flask at 40-50°C.cool the reaction mass to 25 -30°C. stirred the reaction mass and separate both layers. Take an aqueous layer into RB flask and added ethyl acetate, stirred the reaction mass at 10-15min at 25-30°C. separated layers, added sodium chloride solution at 25-30°C, Stirred the reaction mass for 10-15 min at 25-30° C. separated both layers, take organic layer into RB flask and added 10g of Ultra DX carbon into reaction mass at 25-30°C. heat and stirred the reaction mass for 50-60min at 50-55°C. filtered the reaction mass through 45g of Hyflo bed and wash the bed with 250 mL of ethyl acetate at 50-55°C. distill out completely under vacuum at below 60°C. degas the residue for 30 min at below 60°C. added 930 mL of Tetrahydrofuran into above reaction mass at 25-30°C. stirred the reaction mass. Sodium Hydroxide solution was added into the reaction mixture. Heat and stirred the reaction mass for 12-14 hrs at 40-45°C. layers were Separated. Take the aqueous layer into RBF and added 186 mL of Tetrahydrofuran, stirred and separated the layers, combine both organic layers and take into RBF and wash with 233 mL of IN Hydrochloric acid solution and 20 % Sodium Chloride solution at 25-30° C. Take organic layer into RBF and distill off solvent completely u / vacuum at below 50 °C. Cool the distilled crude to 25-30°C. added Methanol (465 mL), added 392 mL of Indion 810 OH-Resin into RB flask at 25-300C. stirred and filtered the reaction mass resin at 25-30° C. added 600 mL of Methanol at 25-300C. Slowly added 196 mL of Acetic acid to the reaction mass at 25-30°C. stirred and filtered the reaction mass, wash with 100 ml of methanol. Distill off the solvent completely under vacuum at below 55° C. Co-distill the distillation crude with 186 mL of methanol at below 550C. Cool to 25-300C. added 250 mL of methyl t-butyl ether at 25-30°C, Added 500 mL of 10% sodium carbonate solution, stirred and filtered the solid at 25-30°C. Wash the solid with 200 mL of DM water, dry the solid under vacuum for 10-12 hrs at 40-45°C. Take the dry solid into RB flask, added 700 mL of Dichloromethane into RBF at 25-300C. stirred the reaction mass for 10-15 min at 25-30°C. added 26.2 g of Pyridine and 94. 1g of Boc anhydride into reaction mixture at 25-30°C. added 63.7g of Ammonium Carbonate into above reaction mass at 25-30 0 C. stirred the reaction mass 3-4h at 25-30°C. added 490 mL of 2N Hydrochloric acid solution dropwise to the reaction mass at 25-30°C. stirred and separated the organic layers, added dichloromethane into an aqueous layer at 25-300C. separate layers, added 245 mL of 2N HCI solution, take organic layer into RB flask, added 350 mL of 20 % NaCl Solution at 25-30°C. Take the aqueous layer into RBF and charge 140 mL of dichloromethane, stirred and separated the organic layers, take combined organic layer into clean RBF. Distill out reaction mass completely under vacuum at below 40°C. Take dry material into RBF and DM water, sodium hydroxide, methanol at 25-300C. Heat and stirred the reaction mass to 50-55°C. Cool the reaction mass to 25-30°C. Filtered and wash with DM water at 0-50C. Unload the wet material and dry for 10-12h under vacuum at 50-550C to get the titled compound. Yield: 50%.

[0104] Example 2: preparation of niraparib tosylate (3)

[0105] 100g of (S)-tert-butyl 3-(4-(7-carbamoyl-2H-indazol-2-yl)phenyl)piperidine-l-carboxylate (4) dissolve in Methanol at room temperature to the reaction mass, added PF-511 carbon to reaction mass. Stirred the reaction mass for 20-30 min at 50-55°C. filtered the reaction mass through 15 g of Hyflo followed by 0.2-micron filter and wash with water. Distil the solvent completely under vacuum at 45-500C. added 1000 mL of Acetonitrile. Stirred the reaction mass for 10-15min at 40-45°C. added para toluene sulfonic acid monohydrate, was added at room temperature stirred for sufficient time till the reaction completed to get compound of formula (3), obtained crude compound was dissolved in acetonitrile and water to get the pure compound, filtered and dried to yield the titled compound Yield: 86%, Purity: 99.8% Example 3: Preparation of Niraparib free base (2)10g of Niraparib tosylate (3) dissolved in water (50ml), to the reaction mixture 10g of 10% sodium hydroxide was added at 25-30° C, reaction mass was heated to 55-65°C, maintained the reaction mass for 2 hours at the same temperature, there after filtered the reaction mass at 55-65°C, the obtained product washed with water and dried to get the title compound. Yield %: 96%

[0106] Example 4: Preparation of Niraparib Salcaprozate

[0107] Niraparib free Base (20g) was added to methanol (5 vol) and dichloromethane (2 vol) at room temperature, Salcaprozic acid (17.44 g) was added and stirred. Spray dried the obtained solution using spray dryer through following conditions:

[0108] Inlet Temperature : 80°C

[0109] Outlet Temperature : 45°C

[0110] Aspirator : 70%

[0111] Feeding rate : 16-20 mL / min

[0112] N2 Pressure : 2.0 kg / cm2

[0113] Yield: 59%; The PXRD pattern of the obtained compound is shown in figure 1. Example 5: Preparation of Niraparib Salcaprozate

[0114] Niraparib free Base(20g) was added to methanol (5 vol) and di chloromethane (2 vol) at room temperature, Salcaprozic acid (17.44 g) was added and stirred.

[0115] Yield: 59%; The PXRD pattern of the obtained compound is shown in figure 1.

[0116] Experimental procedure according to Scheme 4

[0117] Example 6: Preparation of Methyl 2-cyano-2-(4-nitrophenyl) acetate (15) 500 g of l-chloro-4-nitrobenzene (17) dissolved in dimethyl formamide (900 mL) at 25- 30°C. To the reaction mass potassium carbonate (350 g) was added and stirred, followed by methyl cyano acrylate (16) (716 g) was added at the same temperature, heat the reaction mass at 110-115°C. after completion of recti on the reaction mass was cooled to 0-5°C, washed with water, pH adjusted with sulfuric acid, filter the solid and dried to get the title compound.

[0118] Yield:70%; Purity:99.05%.

[0119] Example 7: Preparation of methyl 4-cyano-4-(4-nitrophenyl) butanoate (13)(2000 mL) at 25-30°C. To the reaction mass 4-methyl morpholine (156.3 g) and methyl acrylate (133 g) was added at the same temperature, reaction mass stirred, and temperature raised to 60-65°C to get the compound (R)-dimethyl 2-cyano-2-(4-nitrophenyl) pentanedioate (14), reaction mass cooled to 25-30°C, to this reaction mas water was added the same temperature followed by triethylamine was added stirred and reaction temperature raised to 60-65°C,strirred till reaction complete and filter the solid and dried to get the title compound.

[0120] Example 8: Preparation of 5-(4-aminophenyl) piperidin-2-one (12).

[0121] 100 g of methyl 4-cyano-4-(4-nitrophenyl) butanoate (13) dissolved in methanol (700 mL) at 25-30°C. To the reaction mass Raney Nickel (100 g) was added and temperature raised to 60-65°C, stirred at the same temperature. After completion of reaction, reaction mass was washed with methanol, distill out and filtered the solid and dried to get the title compound. Yield: 75%; Purity: 99.6%.

[0122] Example 9: Preparation of (S)-4-(piperidin-3-yl) aniline (Ila).

[0123] 100 g of 5-(4-aminophenyl) piperidin-2-one (12) is dissolved in Tetrahydrofuran (500mL) at 20-35°C, and stirred, and the reaction mixture cooled to 0-5°C. To the reaction mass sodium borohydride (43.74g) was added stirred at the same temperature followed by Boron trifluoride etherate (164.1 g) was added slowly, maintaining the reaction temperature at 0-5 °C. After completion of the addition, the reaction mass was allowed to warm to 25-30 °C and stirred for 20-24 hours. Once the reaction was complete, the mixture was cooled again to 0-5 °C, and quench with HC1 (dissolve 180 mL of cone. HC1 in 420 mL of DM water) was added slowly at the same temperature. The reaction mass was stirred for 10-15 minutes. The temperature was then raised to 25-30 °C and stirred for 1-2 hours. Cool the reaction mass to 0-5°C. Adjust the pH by adding 800 mL of Sodium hydroxide solution into the reaction mass slowly at 0-5°C. Stirred for 20-30 minutes at 25-30°C. Ethyl acetate (500 mL) was added into the reaction and stirred for 10-15 minutes at 25-30 °C. The layers were allowed to separate, with ethyl acetate. The combined organic layers were dried over 30 g of Sodium sulphate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure at 50-55 °C. The residue was stripped with 200 mL of n-Heptane under vacuum at 50- 55 °C, followed by degas the crude material at 50-55 °C for 30-40 minutes. The reaction mass was cooled to 25-30 °C. Methanol (300 mL) was charged into the crude product and heated to 50-55 °C. was added slowly camphor sulfonic acid solution into the reaction mass at 50-55°C. Stirred for 50-60 minutes at 80-85°C. cool the reaction mass to 25-30°C. Further cool the reaction mass to 0-5°C. Stirred for 50-60 minutes at 0-5°C. Filter the solid under vacuum at 0-5°C. Wash with 50 mL of Methanol at 0-5°C. dry the material in Hot air oven at 50-55 °C for about 10-12 hrs. Take above dry material into RBF at 25-30°C. added 5.0 V of Methanol into RBF at 25-30°C. stirred for 50-60 mins at 60-65°C. cool the reaction mass to 25-30°C. Filter the solid under vacuum at 0-5°C. Wash with Methanol, solid to water into RB flask. Cool reaction mass to 0-5°C. Add Sodium hydroxide solution at 0-5°C to the reaction mass. Stirred for 50-60 minutes at 0-5°C. added Ethyl acetate into reaction mass. Stir for 20-30 minutes at 0-5°C. Settle and separate both layers at 0-5 °C. Take aqueous layer into RBF at 25-30 °C. Filter off Sodium sulphate, take filtrate and distilled off the solvent under vacuum at 50-55 °C. degas for 30-40 minutes at 50-55 °C. Cool the distilled crude to 25-30 °C. added DM water into RBF at 25-30°C. stirred and filtered the reaction mass at 25-30°C. Wash with DM water, dry the material in hot air oven at 50-55°C for about 12-15 hrs to get the title compound.

[0124] Yield: 33.73%; Purity: 99.95%.

[0125] Example 10: Preparation of (S)-tert-butyl 3-(4-aminophenyl) piperidine-1-carboxylate (8).

[0126] (S)-4-(piperi din-3 -yl) aniline (Ila) (100 g), addition of 700 mL of methylene dichloride. The reaction mass was stirred for 5-10 minutes at a temperature of 25-30 °C. The mixture was then cooled to a temperature range of 0-5 °C. and added triethylamine internal temperature between -5 °C and -10 °C. Subsequently, Boc anhydride was added slowly to the reaction mass, keeping the temperature maintained between -5 °C and -10 °C. reaction mass was stirred for a period of 60-70 minutes at -5 °C to -10 °C. 500 mL of DM water was added into the RBF at 25-30 °C. 300 mL of methylene dichloride was added stirred for 10-15 minutes at 25-30 °C. After stirred the layers were allowed to settle and were separated at 25-30 °C. The resulting methylene dichloride layer was dried over 30 g of sodium sulfate at 25-30 °C. Thesolvent was distilled off under vacuum at a temperature below 45 °C. The distilled crude was cooled to 25-30 °C. 500 mL of methyl tert-butyl ether was added at 25-30 °C, and the mixture was stirred for 20-30 minutes. The precipitated solid was filtered under vacuum at 25- 30 °C, washed with 50 mL of methyl tert-butyl ether at the same temperature, and dried in a hot air oven at 40-45 °C for 10-12 hours to get the title compound. Yield: 80.01% Purity: 99.6%.

Claims

We claim:

1. A process for the preparation of Niraparib and its salts, comprising the following steps.a) reacting Methyl 3-formyl-2-nitrobenzoate (9)9with Tert-butyl (3S)-3-(4-aminophenyl) piperidine- 1 -carboxylate (8)in presence suitable solvent to get (S, E)-tert-butyl 3-(4-(3- (m ethoxy carbonyl)-2-nitrobenzylideneamino) phenyl) piperidine- 1- carboxylate (7).b) cyclization of compound of formula (7) with sodium azide in presence of suitable solvent to give (S)-methyl 2-(4-(l-(tert-butoxy carbonyl) piperidin- 3-yl) phenyl)-2H-indazole-7-carboxylate (6).c) hydrolysis of compound of formula (6) with base in presence of suitable solvent to get (S)-tert-butyl 3-(4-(7-carbamoyl-2H-indazol-2-yl) phenyl)piperidine- 1 -carboxylate (4) optionally purifying the compound of formula (5); andd) reacting compound of formula (5) with a base in presence of suitable solvent to get (S)-tert-butyl 3-(4-(7-carbamoyl-2H-indazol-2-yl) phenyl) piperidine- 1 -carboxylate (4)e) reacting to the compound of formula (4) with para-toluene sulfonic acid, followed by purification to obtain Niraparib tosylate salt of formula (3),f) converting Niraparib tosylate salt of formula (3) with sodium hydroxide in water to Niraparib free base of formula (2)g) reacting to the compound of formula (2) with an acid to obtain Niraparib salt of formula (1). Wherein acid is Salcoprozic acid.

2. Niraparib salcaprozic acid salt, which is represented by the following structural formulaNiraparib salcaprozate3. A process for preparation of solid forms of Niraparib salt of formula (1), comprising the following steps,a) dissolving Niraparib free base of formula (2) and an acid in a solvent or mixture of solvents,b) isolating the solid form of Niraparib salt (1).

4. A process for the preparation of Niraparib salt of formula (1), comprising the steps of:a) dissolving Niraparib free base of formula (2) in a solvent or mixture of solvents,b) adding suitable acid in a solvent to the mixture obtained in step A), and c) isolating the solid Niraparib salt of formula (1).

5. A process for the preparation of (S)-tert-butyl 3-(4-aminophenyl)piperidine-l- carboxylate (8),which comprises,a) reacting l-chloro-4-nitrobenzene (17)with methyl 2-cy anoacetate (16);1in presence of suitable solvent and base to provide methyl 2-cyano-2-(4- nitrophenyl) acetate (15);oNCy >■y NO2(15)b) reacting the compound of formula (15) with methyl acrylate in presence of suitable solvent to provide (R)-dimethyl 2-cyano-2-(4-nitrophenyl) pentanedioate (14);c) decarboxylation of the compound of formula (14) in presence of base to provide methyl 4-cyano-4-(4-nitrophenyl) butanoate (13);d) hydrogenating the compound of formula (13) with suitable hydrogenating agent in presence of suitable solvent to provide 5-(4-aminophenyl) piperidin-2-one (12);e) reducing the compound of formula (12) with reducing agent to provide 4- (piperi din-3 -yl) aniline (11);resolving compound of formula (11) with resolving agent to provide (S)- 4- (piperi din-3 -yl) aniline (Ila);andf) converting compound of formula (Ila) to obtained (S)-tert-butyl 3-(4- aminophenyl)piperidine- 1 -carboxylate (8).

6. The process as claimed in any of the preceding claims, wherein the solvent is selected from “alcoholic solvents” such as methanol, ethanol, isopropyl alcohol, n-propanol and butanol; dimethylformamide, dimethylacetamide, or dimethylsulfoxide; dimethyl ether, diethyl ether, diisopropyl ether, methyl tertbutyl ether, 1,2-dimethoxy ethane and tetrahydrofuran; “chloro solvents” such as dichloromethane, di chloroethane, chloroform, and carbon tetrachloride; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile, water and mixtures thereof.

7. The process as claimed in any of the preceding claims, wherein the base is selected from “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal carbonates” sodium carbonate, potassium carbonate, lithium carbonate and the like.

8. The process as claimed in claim 1 and 5, wherein the “acid” is used in the present invention refers to inorganic acid and organic acid; inorganic acid is selected from such as hydrochloric acid, , phosphoric acid,; organic acids such as formic acid, , tartaric acid, maleic acid, citric acid, malic acid, oxalic acid, succinic acid, fumaric acid, alkyl sulfonic acids is selected from such as methane sulfonic acid, ethane sulfonic acid, Salcaprozic acid, or p-toluene sulfonic acid.

9. The process as claimed in claim 5, wherein the hydrogenating agent selected from H2 / Ni, H2 / Pt and H2 / Pd and like.

10. The process as claimed in claim 5, wherein the reducing agent selected from lithium aluminium hydride, sodium borohydride, sodium hydride, or sodium bi s(2-methy oxy ethoxy) aluminumhydride, sodium triacetoxyborohydrode, Aluminium hydride(AlH3), , Lithium borohydride (LiBH4).

11. The process as claimed in claim 1, solid forms of Niraparib salt of formula (1) obtained is having purity greater than 99% by HPLC and more preferably greater than 99.5% and still more preferably 99.98% by HPLC.

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