WO2017191562A1 - Process for the preparation of olaparib and polymorphs thereof - Google Patents

Process for the preparation of olaparib and polymorphs thereof Download PDF

Info

Publication number
WO2017191562A1
WO2017191562A1 PCT/IB2017/052549 IB2017052549W WO2017191562A1 WO 2017191562 A1 WO2017191562 A1 WO 2017191562A1 IB 2017052549 W IB2017052549 W IB 2017052549W WO 2017191562 A1 WO2017191562 A1 WO 2017191562A1
Authority
WO
WIPO (PCT)
Prior art keywords
olaparib
formula
crystalline form
compound
impurity
Prior art date
Application number
PCT/IB2017/052549
Other languages
French (fr)
Inventor
Mahender Rao Siripragada
Mahendar VELISOJU
Shreenivasa Prasad ANEGONDI
Yogesh Vasant JOSHI
Amit PANWAR
Malvika PATEL
Original Assignee
Alembic Pharmaceuticals Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Alembic Pharmaceuticals Limited filed Critical Alembic Pharmaceuticals Limited
Publication of WO2017191562A1 publication Critical patent/WO2017191562A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/30—Phthalazines
    • C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C07D249/18—Benzotriazoles

Definitions

  • TITLE PROCESS FOR THE PREPARATION OF OLAPARIB AND POLYMORPHS THEREOF
  • the present invention is directed to process for preparation of Olaparib of formula-l.
  • the present invention further relates to polymorphic forms of Olaparib, pharmaceutical compositions containing them, and method of treatment using the same.
  • Olaparib is a PARP-inhibitor, inhibiting poly ADP ribose polymerase (PARP), an enzyme involved in DNA repair. It acts against cancers in people with hereditary
  • BRCA1 and BRCA2 mutations which include some ovarian, breast and prostate cancer.
  • Olaparib is marketed as LY PARZATM by AstraZeneca for the treatment of patients with advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.
  • Olaparib is chemically known as 4-[3-(4-cyclopropanecarbonyl-piperazine-l- carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1 -one.
  • WO2004080976 discloses different phthalazinone derivatives including
  • Olaparib and as provided in Example 9, compound 168, it also discloses process for preparation of Olaparib as shown below:
  • WO2008047082 discloses process for the preparation of Olaparib as shown below:
  • CN105820126 and CN105985294 disclose process for the preparation of
  • Olaparib. CN105061328 disclose process for the purification of Olaparib.
  • WO2008047082 further discloses Olaparib in crystalline form A.
  • WO2009050469 discloses Olaparib in crystalline form L.
  • WO2016165650 discloses co-crystal of Olaparib and urea.
  • CN105254572, CN105439961 and CN105777651 disclose crystalline form of Olaparib.
  • the presently available coupling agents that are used for activation of carboxylic acid group in the Kinase inhibitor drug synthesis suffer several disadvantages, ranging, for example, from chemical inefficiency in terms of side products and low coupling aptitude and yield, and low compatibility with synthesizing techniques to production, maintenance and waste disposal costs.
  • the present inventors have identified the use of benzotriazole for the activation of carboxylic acid which is more effective than commonly used coupling agents, simple to produce and use in the activation of carboxylic acid functional group.
  • the present process also discloses novel polymorphic forms of Olaparib and the process for preparing the same.
  • the present invention relates to a process for preparation of
  • the present invention relates to novel intermediates useful in preparation of Olaparib, process for preparing such intermediates and process for the preparation of Olaparib which utilize these intermediates.
  • present invention relates to crystalline form of Olaparib.
  • the present invention provides crystalline form of Olaparib having enhanced stability and dissolution properties and process for preparation thereof.
  • the present invention relates to crystalline form of Olaparib characterized by X-ray diffraction pattern having characteristic peaks at about 6.4°, 6.8°, 8.3°, 12.6°, 15.0°, 15.8°, 16.3°, 16.6°, 19.7°, 20.7 and 22.0° ⁇ 0.2° 2 ⁇ .
  • the present invention relates to crystalline form of Olaparib having XPRD pattern as shown in as shown in figure 1 .
  • the present invention relates to process for the preparation of crystalline form of Olaparib comprising steps of:
  • present invention relates to process for the preparation of form A of Olaparib.
  • the present invention relates to process for the preparation of crystalline form A of Olaparib comprising steps of:
  • the present invention provides Olaparib which is substantially free of impurity A to G.
  • the present invention provides pharmaceutical compositions comprising crystalline form of Olaparib.
  • the present invention provides stable activated carboxylic acids having benztriazole as leaving group.
  • Figure 1 is an illustration of a PXRD pattern of crystalline form of Olaparib (I)
  • Figure 2 is an illustration of a Differential Scanning Calorimetry (DSC) curve of crystalline form of Olaparib (I)
  • Figure 3 is an illustration of a PXRD pattern of From A of Olaparib (I)
  • Figure 4 is an illustration of a PXRD pattern of 4-[3-(1 H-benzotriazol-1 -yl carbonyl)-4-fluorobenzyl]phthalazin-1 (2H)-one (VII)
  • Figure 5 is an illustration of a PXRD pattern of 1 -/-benzotriazol-1 -yl
  • the present invention relates to a process for preparation of Olaparib with improved yields making it reliable for large scale production as described below:
  • the acid (V) so obtained is converted to an acid derivative which is reacted with 1 H-benzotriazole (VI) to produce 4-[3-(1 H- benzotriazol-1 -ylcarbonyl)-4-fluorobenzyl]phthalazin-1 (2H)-one (VII).
  • the compound (VII) undergoes transamidation with piperazine (VIII) to produce 4-[4- fluoro-3-(piperazin-1 -ylcarbonyl) benzyl] phthalazin-1 (2H)-one (IX).
  • Olaparib is produced [high purity (HPLC: >99%) and good yield (>90%)] by reacting 4-[4-fluoro-3-(piperazin-1 -ylcarbonyl) benzyl] phthalazin-1 (2H)- one (IX) with 1 H-benzotriazol-1 -yl(cyclopropyl)methanone (X) using suitable solvent(s).
  • the present invention provides process for the preparation of 4-[3-(1 H-benzotriazol-1 -ylcarbonyl)-4-fluorobenzyl]phthalazin-1 (2H)- one (VII), as described below:
  • the reaction can be optionally carried out in presence of a base and a reagent selected from the group comprising: sulphonyl halide, alkane sulfonyl halides, aryl sulfonyl halide, cyanuric halide, AlkyI halo format, Alkanoyl halide, oxalyl halide, acid anhydride.
  • Sulphonyl halide can be thionyl chloride or the like.
  • Alkane sulphonyl halide can be methane sulfonyl chloride, ethane sulphonyl chloride, trifluoro methanesulfonyl chloride or the like.
  • Aryl suphonyl halide can be tosyl suphonyl chloride or the like.
  • Cyanuric halide can be Cyanuric chloride or the like.
  • AlkyI halo format can be ethyl chloro format or methyl chloro format or the like.
  • Alkanoyl halide can be pivaloyl chloride or the like.
  • Oxalyl halide can be oxalyl chloride or the like.
  • Acid anhydrides can be acetic anhydride or the like.
  • Solvents that used for the reaction is methylene chloride or acetonitrile or the like.
  • the reaction may be carried out at temperature ranging from about 25°C to about 60°C or higher.
  • the reaction may be carried out for time periods ranging from about 30 minutes to about 3 hours, or longer.
  • benzotriazole for the activation of carboxylic acid is beneficial for use in industrial manufacturing and found to be chemically efficient (i.e. to be reactive with a wide variety of substrates; reactive in stoichiometric quantities; can be simply monitored during the coupling reaction; prone to only no or few side reactions; simple to purify from its secondary products after coupling; exhibit a high conversion rate at mild conditions), cost efficient and safe for use (i.e safe for the environment; be non-toxic, non-corrosive and not self-reactive; and be stable with relatively low sensitivity to friction, spark, and electrostatic discharge, particularly during transportation and subsequent storage).
  • Olaparib prepared according to present invention process not only provides an economically and commercially viable process but also provides better purity and yields thereby overcoming drawbacks associated with prior art process.
  • present invention provides crystalline form of 4-[3-(1 H- benzotriazol-1 -ylcarbonyl)-4-fluorobenzyl]phthalazin-1 (2H)-one (VII).
  • the present invention provides to crystalline form of 4-[3-(1 H-benzotriazol-1 -ylcarbonyl)-4-fluorobenzyl]phthalazin-1 (2H)-one (VII) characterized by X-ray diffraction pattern having characteristic peaks at about 3.1 °, 6.6°, 8.3°, 1 1 .6°, 13.9°, 15.0°, 18.5°, 18.9°, 19.9°, 21 .2°, 21 .7°, 23.0°, 25.2° and 26.5° + 0.2° 2 ⁇ .
  • the present invention relates to crystalline form of 4-[3- (1 H-benzotriazol-1 -ylcarbonyl)-4-fluorobenzyl]phthalazin-1 (2H)-one (VII) having XPRD pattern as shown in figure 4.
  • the present invention provides process for the preparation of 4-[4-fluoro-3-(piperazin-1 -ylcarbonyl) benzyl] phthalazin-1 (2H)-one (IX), as described below:
  • the present invention provides stable activated carboxylic acids wherein benztriazole is leaving group.
  • the direct conversion of a carboxylic acid to an amide is difficult because amines are basic and tend to convert carboxylic acids to their highly unreactive carboxylates.
  • the carboxylic acid adds to the benztriazole molecule to form a good leaving group which can then be displaced by an amine during nucleophilic substitution.
  • Carboxylic acid activated by benztriazole to form an amide linkage is an important reaction and can be used in the synthesis of therapeutically important molecules including but not limited to cobimetinib, Nilotinib, Dasatinib, Bosutinib, Bafetinib, saracatinib, Tozasertib, Danusertib, ubrogepant, Avatrombopag, Encenicline, Momelotinib, Prucalopride, Bentiromide, Conivaptan, Leflunomide, Nitazoxanide, piroxicam, Pranlukast, Sorafenib, Zafirlukast, sunitinib malate, Ensartinib, Dacomitinib, Foretinib, Capmatinibn, Nazatinib, Itacitinib, apatinib, imatinib mesylate, masit
  • present invention provides crystalline form of Olaparib.
  • the present invention provides crystalline form of Olaparib having enhanced stability and dissolution properties and process for preparation thereof.
  • the present invention provides to crystalline form of Olaparib characterized by X-ray diffraction pattern having characteristic peaks at about 6.4°, 6.8°, 8.3°, 12.6°, 15.0°, 15.8°, 16.3°, 16.6°, 19.7°, 20.7 and 22.0° ⁇ 0.2° 2 ⁇ .
  • the present invention relates to crystalline form of
  • Olaparib having XPRD pattern as shown in figure 1 Olaparib having XPRD pattern as shown in figure 1 .
  • the present invention relates to Differential Scanning Calorimetry (DSC) curve of crystalline form of Olaparib as shown in figure 2.
  • DSC Differential Scanning Calorimetry
  • the present invention provides process for the preparation of crystalline form of Olaparib comprising steps of:
  • the starting material, Olaparib used for the preparation of crystalline form is prepared according to process disclosed in WO2004080976.
  • present invention provides process for the preparation of form A of Olaparib. In another embodiment, the present invention provides process for the preparation of crystalline form A of Olaparib comprising steps of:
  • 1 H-benzotriazole (VIII) is reacted with cyclopropanecarboxylic acid (XI) in presence of a chlorinating agent, preferably thionyl chloride to produce ⁇ ⁇ - benzotriazol-1 -yl(cyclopropyl)methanone (X).
  • Solvent(s) used for the reaction is methylene chloride or the like.
  • the reaction may be carried out at temperature ranging from about 25°C to about 60°C or higher.
  • the reaction may be carried out for time periods ranging from about 2 hours to about 6 hours, or longer.
  • the reaction is carried out in absence of a base.
  • present invention provides crystalline form of 1 H- benzotriazol-1 -yl(cyclopropyl)methanone (X).
  • the present invention provides to crystalline form of 1 H-benzotriazol-1 -yl(cyclopropyl)methanone (X) characterized by X-ray diffraction pattern having characteristic peaks at about 8.7°, 1 1 .0°, 1 5.9°, 1 7.4°, 1 8.7° and 22.0° + 0.2° 2 ⁇ .
  • the present invention relates to crystalline form of 1 H- benzotriazol-1 -yl(cyclopropyl)methanone (X) having XPRD pattern as shown in figure 5.
  • the present invention provides pharmaceutical compositions comprising Olaparib.
  • the present invention provides a process of preparing a pharmaceutical composition of Olaparib which process comprises the step of mixing of Olaparib substantially as hereinbefore described together with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier for example, but not limited
  • Suitable premixing agents are pharmaceutically acceptable carrier or excipients include polymers/agents used in the process for manufacturing of the premix may be selected from group of cellulose derivatives but not limited to Croscarmellose Sodium, micro crystalline cellulose, hydroxyethylcellulose(HEC), hydroxypropylcellulose(HPC), hydroxypropyl methylcellulose (HPMC), hydroxymethylethylcellulose (HEMC), ethylcellulose (EC), methylcellulose (MC), cellulose esters, cellulose glycolate, hydroxypropyl methyl cellulose phthalate, polymethylacrylate (HPMCP), hypromellose, vinylpyrrolidone monomers but not limited to polyvinylpyrrolidone and polyol but not limited to mannitol.
  • the said polymers/agents are used to facilitate the presence of Olaparib.
  • Crystalline form of Olaparib as obtained by present invention is stable and not contaminated with any crystalline form.
  • the present invention provides Olaparib having particle size Dgo ⁇ 200pm; preferably, D go ⁇ 50pm, more preferably D go ⁇ 20pm.
  • the present invention provides Olaparib which is substantially free from impurity A to G.
  • Impurity-F vii) Impurity-G:
  • organic solvent or “solvent” as used herein includes but not limited to polar protic and aprotic solvents as well as non-polar solvents selected from water, hydrocarbons, ketones, alcohols, ethers, esters, halogenated solvents, dimethyl sulfoxide (DMSO) and dimethylformamide (DMF), pyridine, phenol, DMA, carbon disulphide, acetic acid, acetonitrile and mixtures thereof.
  • polar protic and aprotic solvents selected from water, hydrocarbons, ketones, alcohols, ethers, esters, halogenated solvents, dimethyl sulfoxide (DMSO) and dimethylformamide (DMF), pyridine, phenol, DMA, carbon disulphide, acetic acid, acetonitrile and mixtures thereof.
  • non-polar solvents selected from water, hydrocarbons, ketones, alcohols, ethers, esters, halogenated solvents, dimethyl sulfoxide (DMSO) and di
  • Hydrocarbons include but not limited to such as benzene, toluene, xylene, pentane, hexane, heptane, cyclo hexane and tetraline.
  • Ketones include but not limited to such as acetone, methyl ethyl ketone, cyclohexanone and methyl isobutyl ketone.
  • Alcohols include but not limited to such as methanol, ethanol, propanol, butanol, octanol, ethanediol, 1 , 2-propane diol and S (+)-1 , 2-propane diol.
  • Ethers include but not limited to such as diethyl ether, di isopropyl ether, di butyl ether, methyl tert-butyl ether, 1 ,4-dioxane, tetrahydrofuran and cyclo pentyl methyl ether.
  • Halogenated solvents include but not limited to such as chloroform, carbon tetrachloride, methylene chloride and 1 , 2-dichloro ethane.
  • Esters include but not limited to such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and n-propyl acetate.
  • base includes but not limited to inorganic base such as ammonia or hydroxide, carbonate, or bicarbonate of a metal cation or ammonia or organic bases such as organic primary, secondary, or tertiary amine.
  • inorganic base such as ammonia or hydroxide, carbonate, or bicarbonate of a metal cation or ammonia or organic bases such as organic primary, secondary, or tertiary amine.
  • the base may be chosen as appropriate depending on various reaction conditions known to those skilled in the art.
  • Oparib substantially free of impurity A to G relates to Olaparib having purity greater than 99.5 % by HPLC and the amount of impurity A to G present is not more than 0.15% by HPLC.
  • X-Ray powder d iff ractog rams were measured on a PANalytical X'Pert PRO X-Ray Diffractometer using CuKcd radiation. The samples were measured in reflection mode in the 26-range 2.5-40° using an X' celerator detector.
  • the melting points are measured using Differential Scanning Calorimetry (DSC).
  • DSC Differential Scanning Calorimetry
  • the equipment is a TA-lnstruments DSC-Q1000 calibrated at 10 min to give the melting point as onset value.
  • About 2 mg of sample is heated 10 min in a loosely closed pan under nitrogen flow.
  • Olaparib (10.0 g) was taken in water (200 mL) and the resulting mixture was stirred at 25-30 °C for 10-12 hours to grow crystalline solid material. The obtained solid material was filtered and washed with water (50.0 mL) then dried at 50-60 °C for 10-12 hours to provide pale yellow to white crystalline form of Olaparib.
  • the PXRD pattern of crystalline form of Olaparib thus obtained is illustrated in figure-1 . (Yield: 95%, HPLC purity: 99.98%)
  • Olaparib (10.0 g) was dissolved in acetonitrile by heating; the resulting clear solution was cooled and stirred at 25-30 °C to grow crystalline solid material. The obtained solid material was filtered and dried at 50-60 °C to provide white to off- white Olaparib form-A. (Yield: 95%, HPLC purity: 99.98%)
  • Example-12 Preparation of crystalline form A of Olaparib
  • Olaparib (10.0 g) was dissolved in acetic acid by heating; water was added to the resulting clear solution then cooled and stirred at 25-30°C to grow crystalline solid material. The obtained solid material was filtered and washed with water then dried at 50-60 °C to provide white to off-white Olaparib form-A. (Yield: 91 %, HPLC purity: 99.99%)

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Biotechnology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The present invention is directed to process for preparation of Olaparib of formula (I). The present invention further relates to novel polymorphic forms of Olaparib, pharmaceutical compositions containing them, and method of treatment using the same.

Description

TITLE: PROCESS FOR THE PREPARATION OF OLAPARIB AND POLYMORPHS THEREOF
RELATED APPLICATIONS
This application claims the benefit of priority of our Indian patent application numbers 201621015481 filed on 4th May 2016, 201621019497 filed on 7th June 2016 and 201621028186 filled on 19th August 2016 which are incorporated herein by reference.
FIELD OF THE INVENTION
The present invention is directed to process for preparation of Olaparib of formula-l. The present invention further relates to polymorphic forms of Olaparib, pharmaceutical compositions containing them, and method of treatment using the same.
Figure imgf000002_0001
Formula-l
BACKGROUND OF THE INVENTION
Olaparib is a PARP-inhibitor, inhibiting poly ADP ribose polymerase (PARP), an enzyme involved in DNA repair. It acts against cancers in people with hereditary
BRCA1 and BRCA2 mutations, which include some ovarian, breast and prostate cancer. Olaparib is marketed as LY PARZA™ by AstraZeneca for the treatment of patients with advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.
Olaparib is chemically known as 4-[3-(4-cyclopropanecarbonyl-piperazine-l- carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1 -one.
WO2004080976 discloses different phthalazinone derivatives including
Olaparib and as provided in Example 9, compound 168, it also discloses process for preparation of Olaparib as shown below:
Figure imgf000003_0001
However the above process step of preparation of Olaparib is not satisfactory from purity point of view and requires column chromatography purification step providing less yields. Accordingly methods involving column chromatography purifications cannot be used for large-scale operations, thereby making the process commercially not viable.
WO2008047082 discloses process for the preparation of Olaparib as shown below:
CN105820126 and CN105985294 disclose process for the preparation of
Olaparib. CN105061328 disclose process for the purification of Olaparib.
WO2008047082 further discloses Olaparib in crystalline form A. WO2009050469 discloses Olaparib in crystalline form L. WO2016165650 discloses co-crystal of Olaparib and urea. CN105254572, CN105439961 and CN105777651 disclose crystalline form of Olaparib.
However the prior art processes described above for the preparation of Olaparib have major drawbacks such as difficulties with respect to removal of process related impurities; poor commercial viability due to use of hazardous reactants; use of column chromatography and/ or low yields and purity of intermediates and final product. Therefore, there remains a need to develop such a process, which overcomes one or more of the above drawbacks associates with prior art process for preparation of Olaparib.
The acid halides to amide reactions reported in general state of art are highly exothermic and additional base is required. Acid halide are mostly unstable hence convert back to acids, while EDC, DDC, and CDI methods of amide couplings require additional base and reagents which provides low yield and purity due to backward reactions and side reactions. Surprisingly the present inventors have identified the use of benzotriazole for the activation of carboxylic acid which undergo transamidation with amines without using any additional base, reagents, catalyst, additives or harsh conditions to complete reactions, and produce good to excellent yields and with high quality.
The presently available coupling agents that are used for activation of carboxylic acid group in the Kinase inhibitor drug synthesis suffer several disadvantages, ranging, for example, from chemical inefficiency in terms of side products and low coupling aptitude and yield, and low compatibility with synthesizing techniques to production, maintenance and waste disposal costs. Surprisingly, the present inventors have identified the use of benzotriazole for the activation of carboxylic acid which is more effective than commonly used coupling agents, simple to produce and use in the activation of carboxylic acid functional group.
Considering the importance of Olaparib in the pharmaceutical treatment, there is a need to develop alternative process for the preparation of Olaparib. Applicant diligently did research on the same and identified the use of benzotriazole for the activation of carboxylic acid group in the synthesis of Olaparib not only found to cost effective and also safe in commercial manufacturing.
The present process also discloses novel polymorphic forms of Olaparib and the process for preparing the same.
SUMMARY OF THE INVENTION
In one aspect, the present invention relates to a process for preparation of
Olaparib.
In another aspect, the present invention relates to novel intermediates useful in preparation of Olaparib, process for preparing such intermediates and process for the preparation of Olaparib which utilize these intermediates.
In one aspect, present invention relates to crystalline form of Olaparib.
In another aspect, the present invention provides crystalline form of Olaparib having enhanced stability and dissolution properties and process for preparation thereof. In one aspect, the present invention relates to crystalline form of Olaparib characterized by X-ray diffraction pattern having characteristic peaks at about 6.4°, 6.8°, 8.3°, 12.6°, 15.0°, 15.8°, 16.3°, 16.6°, 19.7°, 20.7 and 22.0°± 0.2° 2Θ.
In one aspect, the present invention relates to crystalline form of Olaparib having XPRD pattern as shown in as shown in figure 1 .
In one aspect, the present invention relates to process for the preparation of crystalline form of Olaparib comprising steps of:
a) dissolving Olaparib in a water;
b) isolating crystalline form of Olaparib.
In one aspect, present invention relates to process for the preparation of form A of Olaparib.
In another aspect, the present invention relates to process for the preparation of crystalline form A of Olaparib comprising steps of:
a) reacting 4-[4-fluoro-3-(piperazin-1 -ylcarbonyl) benzyl] phthalazin- 1 (2H)-one (IX) with 1 H-benzotriazol-1 -yl(cyclopropyl)methanone (X) in organic solvent;
Figure imgf000005_0001
b) isolating crystalline form A of Olaparib.
In another aspect, the present invention provides Olaparib which is substantially free of impurity A to G.
In one aspect, the present invention provides pharmaceutical compositions comprising crystalline form of Olaparib.
In one aspect, the present invention provides stable activated carboxylic acids having benztriazole as leaving group. BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is an illustration of a PXRD pattern of crystalline form of Olaparib (I) Figure 2 is an illustration of a Differential Scanning Calorimetry (DSC) curve of crystalline form of Olaparib (I)
Figure 3 is an illustration of a PXRD pattern of From A of Olaparib (I)
Figure 4 is an illustration of a PXRD pattern of 4-[3-(1 H-benzotriazol-1 -yl carbonyl)-4-fluorobenzyl]phthalazin-1 (2H)-one (VII)
Figure 5 is an illustration of a PXRD pattern of 1 -/-benzotriazol-1 -yl
(cyclopropyl)methanone (X)
DETAILED DESCRIPTION OF THE INVENTION
It is to be understood that the invention is not limited in its application to the details set forth in the following description or exemplified by the Examples. The invention is capable of other embodiments or of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting.
The present invention relates to a process for preparation of Olaparib with improved yields making it reliable for large scale production as described below:
Figure imgf000006_0001
2-Formyl 2-Fluoro-5-[(3-oxo-2-benzo 2-Fluoro-5-[(4-oxo-3,4-di 4-[3-(1 H-benzotriazol-1-yl benzoic acid furan- 1 (3H)-ylidene) hydrophthalazin-1 -yl) carbonyl)-4-fluorobenzyl] methyl] benzonitrile (IV) methyl]benzoic acid (V) phthalazin-1 (2H)-one (VII)
1 H-benzotriazol- 1 -yl (cyclopropyl) 4-[4-fluoro-3-(piperazin-1 -yl methanone (X) carbonyl) benzyl] phthalazin
Figure imgf000006_0002
-1(2H)-one (IX) 2-formyl benzoic acid-(ll) [3-hydroxy-2-benzofuran-1 (3 -/)-one (II)] undergoes phosphorylation with diethyl phosphite in the presence of base in aqueous medium to provide a stabilized in situ phosphorus ylide intermediate which reacts with 2- flouro-5-formyl benzonitrile (III) to obtain 2-fluoro-5-[(3-oxo-2-benzofuran-1 (3H)- ylidene)methyl] benzonitrile (IV) which is further hydrolyzed using base and then reacted with hydrazine hydrate to produce 2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin- 1 -yl)methyl]benzoic acid (V). The acid (V) so obtained is converted to an acid derivative which is reacted with 1 H-benzotriazole (VI) to produce 4-[3-(1 H- benzotriazol-1 -ylcarbonyl)-4-fluorobenzyl]phthalazin-1 (2H)-one (VII). The compound (VII) undergoes transamidation with piperazine (VIII) to produce 4-[4- fluoro-3-(piperazin-1 -ylcarbonyl) benzyl] phthalazin-1 (2H)-one (IX).
Finally Olaparib is produced [high purity (HPLC: >99%) and good yield (>90%)] by reacting 4-[4-fluoro-3-(piperazin-1 -ylcarbonyl) benzyl] phthalazin-1 (2H)- one (IX) with 1 H-benzotriazol-1 -yl(cyclopropyl)methanone (X) using suitable solvent(s).
In one embodiment the present invention provides process for the preparation of 4-[3-(1 H-benzotriazol-1 -ylcarbonyl)-4-fluorobenzyl]phthalazin-1 (2H)- one (VII), as described below:
Figure imgf000007_0001
2-Fluoro-5-[(4-oxo-3,4-dihydrophthalazin- 4_[3_(1 H-benzotriazol-1 -ylcarbonyl)-4-fluor
1 -yl)methyl]benzoic acid (V) obenzyl]phthalazin-1 (2H)-one (VII)
2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1 -yl)methyl]benzoic acid (V) is reacted with 1 H-benzotriazole (VI) to produce 4-[3-(1 H-benzotriazol-1 -ylcarbonyl)- 4-fluorobenzyl]phthalazin-1 (2H)-one (VII). The reaction can be optionally carried out in presence of a base and a reagent selected from the group comprising: sulphonyl halide, alkane sulfonyl halides, aryl sulfonyl halide, cyanuric halide, AlkyI halo format, Alkanoyl halide, oxalyl halide, acid anhydride. Sulphonyl halide can be thionyl chloride or the like. Alkane sulphonyl halide can be methane sulfonyl chloride, ethane sulphonyl chloride, trifluoro methanesulfonyl chloride or the like. Aryl suphonyl halide can be tosyl suphonyl chloride or the like. Cyanuric halide can be Cyanuric chloride or the like. AlkyI halo format can be ethyl chloro format or methyl chloro format or the like. Alkanoyl halide can be pivaloyl chloride or the like. Oxalyl halide can be oxalyl chloride or the like. Acid anhydrides can be acetic anhydride or the like. Solvents that used for the reaction is methylene chloride or acetonitrile or the like. The reaction may be carried out at temperature ranging from about 25°C to about 60°C or higher. The reaction may be carried out for time periods ranging from about 30 minutes to about 3 hours, or longer.
The use of benzotriazole for the activation of carboxylic acid is beneficial for use in industrial manufacturing and found to be chemically efficient (i.e. to be reactive with a wide variety of substrates; reactive in stoichiometric quantities; can be simply monitored during the coupling reaction; prone to only no or few side reactions; simple to purify from its secondary products after coupling; exhibit a high conversion rate at mild conditions), cost efficient and safe for use (i.e safe for the environment; be non-toxic, non-corrosive and not self-reactive; and be stable with relatively low sensitivity to friction, spark, and electrostatic discharge, particularly during transportation and subsequent storage).
Olaparib prepared according to present invention process not only provides an economically and commercially viable process but also provides better purity and yields thereby overcoming drawbacks associated with prior art process.
In one embodiment, present invention provides crystalline form of 4-[3-(1 H- benzotriazol-1 -ylcarbonyl)-4-fluorobenzyl]phthalazin-1 (2H)-one (VII).
In another embodiment, the present invention provides to crystalline form of 4-[3-(1 H-benzotriazol-1 -ylcarbonyl)-4-fluorobenzyl]phthalazin-1 (2H)-one (VII) characterized by X-ray diffraction pattern having characteristic peaks at about 3.1 °, 6.6°, 8.3°, 1 1 .6°, 13.9°, 15.0°, 18.5°, 18.9°, 19.9°, 21 .2°, 21 .7°, 23.0°, 25.2° and 26.5° + 0.2° 2Θ.
In one embodiment, the present invention relates to crystalline form of 4-[3- (1 H-benzotriazol-1 -ylcarbonyl)-4-fluorobenzyl]phthalazin-1 (2H)-one (VII) having XPRD pattern as shown in figure 4.
In one embodiment the present invention provides process for the preparation of 4-[4-fluoro-3-(piperazin-1 -ylcarbonyl) benzyl] phthalazin-1 (2H)-one (IX), as described below:
Figure imgf000009_0001
4-[3-(1 - -benzotriazol-1 -ylcarbonyl)-4-fluor
4-[4-fluoro-3-(piperazin-1 -ylcarbonyl) obenzyl]phthalazin-1 (2H)-one (VII)
benzyl] phthalazin-1 (2H)-one (IX)
4-[3-(1 H-benzotriazol-1 -ylcarbonyl)-4-fluorobenzyl]phthalazin-1 (2H)-one (VII) is reacted with piperazine (VIII) to produce 4-[4-fluoro-3-(piperazin-1 -ylcarbonyl) benzyl] phthalazin-1 (2H)-one (IX). Solvents that used for the reaction is isopropyl alcohol or the like. The reaction may be carried out at temperature ranging from about 25°C to about 60°C or higher. The reaction may be carried out for time periods ranging from about 1 hours to about 4 hours, or longer.
In one embodiment the present invention provides process for the re aration of Ola arib I as described below:
Figure imgf000009_0002
4-[4-fluoro-3-(piperazin-1 -ylcarbonyl) benzyl] phthalazin-1 (2H)-one (IX) is reacted with 1 H-benzotriazol-1 -yl(cyclopropyl)methanone (X) to produce Olaparib (I). Solvent(s) used for the reaction is acetonitrile or the like. The reaction may be carried out at temperature ranging from about 25°C to about 60°C or higher. The reaction may be carried out for time periods ranging from about 30 minutes to about 2 hours, or longer. Preferably the reaction is carried out in absence of a base.
In one embodiment, the present invention provides stable activated carboxylic acids wherein benztriazole is leaving group. The direct conversion of a carboxylic acid to an amide is difficult because amines are basic and tend to convert carboxylic acids to their highly unreactive carboxylates. In this reaction the carboxylic acid adds to the benztriazole molecule to form a good leaving group which can then be displaced by an amine during nucleophilic substitution. Use of Carboxylic acid activated by benztriazole to form an amide linkage is an important reaction and can be used in the synthesis of therapeutically important molecules including but not limited to cobimetinib, Nilotinib, Dasatinib, Bosutinib, Bafetinib, saracatinib, Tozasertib, Danusertib, ubrogepant, Avatrombopag, Encenicline, Momelotinib, Prucalopride, Bentiromide, Conivaptan, Leflunomide, Nitazoxanide, piroxicam, Pranlukast, Sorafenib, Zafirlukast, sunitinib malate, Ensartinib, Dacomitinib, Foretinib, Capmatinibn, Nazatinib, Itacitinib, apatinib, imatinib mesylate, masitinib mesylate, tafetinib malate, flumatinib mesylate, radotinib dihydrochloride, merestinib, ulixertinib, entrectinib, fruquintinib, defactinib hydrochloride, acalabrutinib, ponatinib hydrochloride, telatinib mesylate, lucitanib, axitinib, capmatinib lumacaftor ivacaftor tezacaftor and the like.
In one embodiment, present invention provides crystalline form of Olaparib.
In another embodiment, the present invention provides crystalline form of Olaparib having enhanced stability and dissolution properties and process for preparation thereof.
In one embodiment, the present invention provides to crystalline form of Olaparib characterized by X-ray diffraction pattern having characteristic peaks at about 6.4°, 6.8°, 8.3°, 12.6°, 15.0°, 15.8°, 16.3°, 16.6°, 19.7°, 20.7 and 22.0° ± 0.2° 2Θ.
In one embodiment, the present invention relates to crystalline form of
Olaparib having XPRD pattern as shown in figure 1 .
In another embodiment, the present invention relates to Differential Scanning Calorimetry (DSC) curve of crystalline form of Olaparib as shown in figure 2.
In one embodiment, the present invention provides process for the preparation of crystalline form of Olaparib comprising steps of:
a) dissolving Olaparib in a water,
b) isolating crystalline form of Olaparib.
Preferably, the starting material, Olaparib used for the preparation of crystalline form (illustrated in Figure 1 ) is prepared according to process disclosed in WO2004080976.
In one embodiment, present invention provides process for the preparation of form A of Olaparib. In another embodiment, the present invention provides process for the preparation of crystalline form A of Olaparib comprising steps of:
a) reacting 4-[4-fluoro-3-(piperazin-1 -ylcarbonyl) benzyl] phthalazin- 1 (2H)-one (IX) with 1 H-benzotriazol-1 -yl(cyclopropyl)methanone (X) in organic solvent;
Figure imgf000011_0001
b) isolating crystalline form A of Olaparib.
In another embodiment the present invention provides process for the
preparation of 1 H-benzotriazol-1 -yl(cyclopropyl)methanone (X), as described
below:
Figure imgf000011_0002
cyclopropanecarboxylic acid 1 H-benzotriazole (VIII) H-benzotriazol-1 -yl(cyclopropyl)methanone (X)
(XI)
1 H-benzotriazole (VIII) is reacted with cyclopropanecarboxylic acid (XI) in presence of a chlorinating agent, preferably thionyl chloride to produce λ Η- benzotriazol-1 -yl(cyclopropyl)methanone (X). Solvent(s) used for the reaction is methylene chloride or the like. The reaction may be carried out at temperature ranging from about 25°C to about 60°C or higher. The reaction may be carried out for time periods ranging from about 2 hours to about 6 hours, or longer. Preferably the reaction is carried out in absence of a base.
In one embodiment, present invention provides crystalline form of 1 H- benzotriazol-1 -yl(cyclopropyl)methanone (X).
In another embodiment, the present invention provides to crystalline form of 1 H-benzotriazol-1 -yl(cyclopropyl)methanone (X) characterized by X-ray diffraction pattern having characteristic peaks at about 8.7°, 1 1 .0°, 1 5.9°, 1 7.4°, 1 8.7° and 22.0° + 0.2° 2Θ. In one embodiment, the present invention relates to crystalline form of 1 H- benzotriazol-1 -yl(cyclopropyl)methanone (X) having XPRD pattern as shown in figure 5.
In one embodiment, the present invention provides pharmaceutical compositions comprising Olaparib.
In another embodiment the present invention provides a process of preparing a pharmaceutical composition of Olaparib which process comprises the step of mixing of Olaparib substantially as hereinbefore described together with a pharmaceutically acceptable carrier. Conveniently the following combinations of carrier or excipient and co- precipitation medium can be employed in a process according to the present invention.
Suitable premixing agents are pharmaceutically acceptable carrier or excipients include polymers/agents used in the process for manufacturing of the premix may be selected from group of cellulose derivatives but not limited to Croscarmellose Sodium, micro crystalline cellulose, hydroxyethylcellulose(HEC), hydroxypropylcellulose(HPC), hydroxypropyl methylcellulose (HPMC), hydroxymethylethylcellulose (HEMC), ethylcellulose (EC), methylcellulose (MC), cellulose esters, cellulose glycolate, hydroxypropyl methyl cellulose phthalate, polymethylacrylate (HPMCP), hypromellose, vinylpyrrolidone monomers but not limited to polyvinylpyrrolidone and polyol but not limited to mannitol. The said polymers/agents are used to facilitate the presence of Olaparib.
Crystalline form of Olaparib as obtained by present invention is stable and not contaminated with any crystalline form.
In one embodiment, the present invention provides Olaparib having particle size Dgo <200pm; preferably, Dgo≤50pm, more preferably Dgo≤20pm.
In another embodiment, the present invention provides Olaparib which is substantially free from impurity A to G.
i) Impurity-A:
Figure imgf000012_0001
ii) Impurity-B iii) Impurity-C iv) Impurity-D v) Impurity-E
vi) Impurity-F:
Figure imgf000013_0001
vii) Impurity-G:
Figure imgf000014_0001
The term "organic solvent" or "solvent" as used herein includes but not limited to polar protic and aprotic solvents as well as non-polar solvents selected from water, hydrocarbons, ketones, alcohols, ethers, esters, halogenated solvents, dimethyl sulfoxide (DMSO) and dimethylformamide (DMF), pyridine, phenol, DMA, carbon disulphide, acetic acid, acetonitrile and mixtures thereof.
Hydrocarbons include but not limited to such as benzene, toluene, xylene, pentane, hexane, heptane, cyclo hexane and tetraline.
Ketones include but not limited to such as acetone, methyl ethyl ketone, cyclohexanone and methyl isobutyl ketone.
Alcohols include but not limited to such as methanol, ethanol, propanol, butanol, octanol, ethanediol, 1 , 2-propane diol and S (+)-1 , 2-propane diol.
Ethers include but not limited to such as diethyl ether, di isopropyl ether, di butyl ether, methyl tert-butyl ether, 1 ,4-dioxane, tetrahydrofuran and cyclo pentyl methyl ether.
Halogenated solvents include but not limited to such as chloroform, carbon tetrachloride, methylene chloride and 1 , 2-dichloro ethane.
Esters include but not limited to such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and n-propyl acetate.
The tern "base" as used herein includes but not limited to inorganic base such as ammonia or hydroxide, carbonate, or bicarbonate of a metal cation or ammonia or organic bases such as organic primary, secondary, or tertiary amine. The base may be chosen as appropriate depending on various reaction conditions known to those skilled in the art.
The term "Olaparib substantially free of impurity A to G" as used herein relates to Olaparib having purity greater than 99.5 % by HPLC and the amount of impurity A to G present is not more than 0.15% by HPLC. Examples
The following examples are provided here to enable one skilled in the art to practice the invention and merely illustrate the process of this invention. However, it do not intended in any way to limit the scope of the present invention.
1 H NMR spectra are recorded at 300 MHz on a Bruker Avance III instrument. Dimethyl sulfoxide (99.8% D) is used as solvent, and tetramethylsilane (TMS) is used as internal reference standard.
X-Ray powder d iff ractog rams were measured on a PANalytical X'Pert PRO X-Ray Diffractometer using CuKcd radiation. The samples were measured in reflection mode in the 26-range 2.5-40° using an X' celerator detector.
The melting points are measured using Differential Scanning Calorimetry (DSC). The equipment is a TA-lnstruments DSC-Q1000 calibrated at 10 min to give the melting point as onset value. About 2 mg of sample is heated 10 min in a loosely closed pan under nitrogen flow.
Example-1 : Preparation 2-fluoro-5-[(3-oxo-2-benzofuran-1 (3H)-ylidene)
methyl] benzonitrile (IV)
Figure imgf000015_0001
2-Formyl benzoic acid (II) 2-Fluoro-5-[(3-oxo-2-benzofuran-1 (3H)-ylide ne)methyl] benzonitrile (IV)
To a stirring solution of NaHCO3 (42 g) in water (400 mL) were added 2-formyl benzoic acid (II) (50 g) and dimethyl hydrogen phosphite (73.3 g) at room temperature. The resulting reaction mixture was stirred at room temperature. The reaction mixture was acidified by adding cone. HCI solution after consuming of 2- formyl benzoic acid (II) and the stirring was continued. The reaction mixture was then diluted by addition of water. NaHCO3 (168 g) was added followed by addition of 2-flouro-5-formyl benzonitrile (III) (50 g). The reaction mixture was stirred at room temperature. After completion of reaction, the obtained precipitate was filtered and washed with water, then suck dried by using vacuum to afford 2-fluoro-5-[(3-oxo-2- benzofuran-1 (3 -/)-ylidene)methyl] benzonitrile (IV). The resulting wet compound was used to next reaction without further purification and drying. (Yield: 72%)
Example-2: Preparation of 2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl) methyljbenzoic acid (V)
Figure imgf000016_0001
2-Fluoro-5-[(3-oxo-2-benzofuran-1 (3H)-ylide 2-Fluoro-5-[(4-oxo-3,4-dihydrophthalazin- ne)methyl] benzonitrile (IV) 1 -yl)methyl]benzoic acid (V)
The above semi dried compound 2-fluoro-5-[(3-oxo-2-benzofuran-1 {3H)- ylidene)methyl] benzonitrile (IV) as obtained by example-1 was suspended in water (500 imL) at room temperature followed by addition of aqueous solution of NaOH (50 g). The resulting reaction mixture was stirred at 60°C to 70 °C. After completion of the hydrolysis, it was cooled to room temperature and acidified by addition of cone. HCI until the pH was changed to 5-6. Then hydrazine hydrate (1 67 g) was added. The resulting reaction mass was stirred at 60°C to 70 °C. The reaction mass was cooled to room temperature, acidified by addition of cone. HCI until the pH was changed 4.0-4.5. The stirring was continued further at room temperature. The obtained precipitate was filtered and washed with water. The crude compound was purified by using isopropanol (or any other polar solvent) to afford pure 2- fluoro-5-[(4-oxo-3,4-di hydrophthalazin-1 -yl)methyl]benzoic acid (V) as a solid (70 g). (Yield: 68%)
Example-3: Preparation of 4-[3-(1 H-benzotriazol-1-ylcarbonyl)-4-fluorobenzyl] phthalazin-1 (2H)-one (VIII)
Figure imgf000017_0001
2-Fluoro-5-[(4-oxo-3,4-dihydrophthalazin 4-[3-(1 H-benzotriazol-1 -ylcarbonyl)-4-fluor 1 -yl)methyl]benzoic acid (V) obenzyl]phthalazin-1 (2H)-one (VII)
Thionylchloride (22.0 mL) was added to a cold and stirring solution of 1 H- benzotriazole (VI) (85 g) and triethylamine (148 mL) in methylene chloride (700 mL). The resulting reaction mass stirred at 0-10 °C. Then 2-fluoro-5-[(4-oxo-3, 4- dihydro-phthalazin-1 -yl) methyl] benzoic acid (V) (70 g) was added at 0-10 °C and the resulting suspension was stirred at room temperature till completion of reaction. The organic volatiles of reaction mass were removed under reduced pressure after completion of the reaction. The crude compound was re-crystallized in water/isopropanol and dried under vacuum at 50-60 °C to afford 4-[3-(1 H- benzotriazol-1 -ylcarbonyl)-4-fluorobenzyl] phthalazin-1 (2 -/)-one (VII) as a white solid (84 g). The PXRD pattern of 4-[3-(1 H-benzotriazol-1 -ylcarbonyl)-4- fluorobenzyl] phthalazin-1 (2H)-one (VII) as thus obtained is illustrated in figure-4. (Yield: 81 %, HPLC purity: 99%) 1H NMR (300 MHz, DMSO-£/6): δ 12.63 (s, 1 H), 8.30-8.25 (m, 3H), 8.04-8.01 (d, 1 H, J = 7.8 Hz), 7.95-7.81 (m, 4H), 7.77-7.72 (m, 1 H), 7.69 -7.63 (m, 1 H), 7.46-7.40 (m, 1 H), 4.43 (s, 2H); 13C NMR (75 MHz, DMSO- d6): δ 164.00, 160.41 , 159.85, 157.08, 145.93, 145.21 , 135.78, 135.66, 135.10, 135.06, 133.99, 132.12, 132.03, 131 .56, 131 .29, 129.55, 128.34, 127.44, 126.52, 125.91 , 121 .38, 121 .20, 120.68, 1 16.91 , 1 16.63, 1 14.47, 36.89; MS (ESI): m/z [M+H] calcd. for C22H15FN5O2: 400.3; found: 400.3. Example-4: Preparation of 4-[3-(1 H-benzotriazol-1-ylcarbonyl)-4-fluorobenzyl] phthalazin-1 (2H)-one (VIII)
Figure imgf000018_0001
2-Fluoro-5-[(4-oxo-3,4-dihydrophthalazin- 4_[3_(1 H-benzotriazol-1 -ylcarbonyl)-4-fluor
1 -yl)methyl]benzoic acid (V) obenzyl]phthalazin-1 (2H)-one (VII)
Methanesulfonyl chloride (20.0 ml_) was added to a cold and stirring solution of 1 H- benzotriazole (VI) (85 g) and triethylamine (148 imL) in methylene chloride (700 imL). The resulting reaction mass stirred at 0-10 °C. Then 2-fluoro-5-[(4-oxo-3, 4- dihydro-phthalazin-1 -yl) methyl] benzoic acid (V) (70 g) was added at 0-10 °C and the resulting suspension was stirred at room temperature till completion of reaction. The organic volatiles of reaction mass were removed under reduced pressure after completion of the reaction. The crude compound was re-crystallized in water/isopropanol and dried under vacuum at 50-60 °C to afford 4-[3-(1 H- benzotriazol-1 -ylcarbonyl)-4-fluorobenzyl] phthalazin-1 (2 -/)-one (VII) as a white solid (84 g). (Yield: 78%, HPLC purity: 98%) Example-5: Preparation of 1 H-benzotriazol-1 -yl(cyclopropyl)methanone (X)
Figure imgf000018_0002
cyclopropanecarboxylic acid 1 H-benzotriazole (VI) H-benzotriazol-1 -yl(cyclopropyl)methanone (X)
(XI)
Thionylchloride (55 imL) was added to a cold and stirring solution of 1 H- benzotriazole (VI) (207 g) and the resulting reaction mass was stirred at 0-10 °C. Then cyclopropanecarboxylic acid (XI) (50 g) was added at 5-10 °C and the resulting suspension was stirred at room temperature. The organic volatiles of reaction mass were removed under reduced pressure after completion of the reaction. The crude compound was re-crystallized in methanol and dried under vacuum at 50-60 °C to afford 1 H-benzotriazol-1 -yl(cyclopropyl)methanone (X) as a white solid (92 g). The PXRD pattern of 1 H-benzotriazol-1 - yl(cyclopropyl)methanone (X) as thus obtained is illustrated in figure-5. (Yield: 70%, HPLC purity: 98%) 1H NMR (300 MHz, CDCI3): δ 8.30-8.27 (d, 1 H, J = 8.1 Hz), 8.16-8.13 (d, 1 H, J = 8.1 Hz), 7.68-7.63 (m, 1 H), 7.55-7.48 (m, 1 H), 3.45-3.38 (m, 1 H), 1 .50-1 .45 (m, 2H), 1 .34-1 .28 (m, 2H); 13C NMR (75 MHz, CDCI3): δ 173.35, 146.17, 131 .08, 130.23, 126.01 , 120.02, 1 14.48, 13.63, 1 1 .86; MS (ESI): m/z [M+H] calcd for C10H10N3O: 188.3; found: 188.3.
Example-6: Preparation of 1 H-benzotriazol-1-yl(cyclopropyl)methanone (X)
Figure imgf000019_0001
cyclopropanecar oxylic acid 1 /-/-benzotriazole (VI) 1 /- -benzotriazol-1 -yl(cyclopropyl)methanone (X)
(XI)
Methanesulfonyl chloride (45 mL) was added to a cold and stirring solution of 1 H- benzotriazole (VI) (196 g) and the resulting reaction mass was stirred at 0-10 °C. Then cyclopropanecarboxylic acid (XI) (40 g) was added at 5-10 °C and the resulting suspension was stirred at room temperature. The organic volatiles of reaction mass were removed under reduced pressure after completion of the reaction. The crude compound was re-crystallized in methanol and dried under vacuum at 50-60 °C to afford 1 H-benzotriazol-1 -yl(cyclopropyl)methanone (X) as a white solid (81 g). (Yield: 67%, HPLC purity: 97%)
Example-7: Preparation of 4-[4-fluoro-3-(piperazin-1-ylcarbonyl) benzyl]
phthalazin-1 2H -one IX
Figure imgf000019_0002
4-[3-(1 /-/-benzotriazol-1 -ylcarbonyl)-4-fluor
4-[4-fluoro-3-(piperazin-1 -ylcarbonyl) obenzyl]phthalazin-1 (2H)-one (VII)
benzyl] phthalazin-1 (2H)-one (IX)
To a solution of piperazine (VIII) (13 g) in acetonitrile (500 mL) was added 4-[3-(1 H- benzotriazol-1 -ylcarbonyl)-4-fluorobenzyl] phthalazin-1 (2 -/)-one (VII) (50 g) at room temperature and the resulting reaction mixture was stirred. After completion of the reaction, the obtained precipitate was filtered and washed with acetonitrile, then suck dried by using vacuum line to afford wet 4-[4-fluoro-3-(piperazin-1 -ylcarbonyl) benzyl] phthalazin-1 (2 -/)-one (IX). The semi dried compound was used to next reaction without further purification and drying. (Yield: 72%, HPLC purity: 98%)
Example-8: Preparation of 4-[4-fluoro-3-(piperazin-1-ylcarbonyl) benzyl] phthalazin-1 2H -one IX
Figure imgf000020_0001
4-[3-(1 /-/-benzotriazol-1 -ylcarbonyl)-4-fluor
4-[4-fluoro-3-(piperazin-1 -ylcarbonyl) obenzyl]phthalazin-1 (2H)-one (VII)
benzyl] phthalazin-1 (2H)-one (IX)
To a solution of piperazine (VIII) (200 g) in isopropanol (500 mL) was added lot wise 4-[3-(1 - -benzotriazol-1 -ylcarbonyl)-4-fluorobenzyl] phthalazin-1 (2/-/)-one (VII) (150 g) at room temperature and the resulting reaction mixture was stirred. After completion of the reaction, the solvent was distilled out and the residue was treated acetic acid (or any other organic or inorganic acid) and water to form salt, which was washed with organic solvent and then treated with base to produce solid material. The obtained solid material was filtered and washed with water (100 mL), then suck dried by using vacuum line to afford wet 4-[4-fluoro-3-(piperazin-1 - ylcarbonyl) benzyl] phthalazin-1 (2H)-one (IX). (Yield: 80%, HPLC purity: 99%)
Ex
Figure imgf000020_0002
4-[4-fluoro-3-(piperazin-1 -ylcarbonyl) benzyl] phthalazin-1 (2H)-one (IX) (40.0 g, 0.1 1 mol) and 1 H-benzotriazol-1 -yl(cyclopropyl)methanone (X) (26 g, 0.14 mol) were stirred in acetonitrile (320 mL) and the progress of reaction was monitored by HPLC. After completion of reaction, the resulted precipitate was filtered and washed with acetonitrile (40.0 mL) then dried to afford Olaparib (I) as a white to off- white solid. The PXRD pattern of Olaparib thus obtained matches with Form-A as illustrated in figure-3. (Yield: 90%, HPLC purity: 99.99%)
Example-10: Preparation of crystalline form of Olaparib
Olaparib (10.0 g) was taken in water (200 mL) and the resulting mixture was stirred at 25-30 °C for 10-12 hours to grow crystalline solid material. The obtained solid material was filtered and washed with water (50.0 mL) then dried at 50-60 °C for 10-12 hours to provide pale yellow to white crystalline form of Olaparib. The PXRD pattern of crystalline form of Olaparib thus obtained is illustrated in figure-1 . (Yield: 95%, HPLC purity: 99.98%)
Example-11 : Preparation of crystalline form A of Olaparib
Olaparib (10.0 g) was dissolved in acetonitrile by heating; the resulting clear solution was cooled and stirred at 25-30 °C to grow crystalline solid material. The obtained solid material was filtered and dried at 50-60 °C to provide white to off- white Olaparib form-A. (Yield: 95%, HPLC purity: 99.98%) Example-12: Preparation of crystalline form A of Olaparib
Olaparib (10.0 g) was dissolved in acetic acid by heating; water was added to the resulting clear solution then cooled and stirred at 25-30°C to grow crystalline solid material. The obtained solid material was filtered and washed with water then dried at 50-60 °C to provide white to off-white Olaparib form-A. (Yield: 91 %, HPLC purity: 99.99%)

Claims

A process for the prep
Figure imgf000022_0001
(I)
comprising:
a) reacting a compound of formula (V)
Figure imgf000022_0002
with 1 H-benzotriazole (VI)
H
Figure imgf000022_0003
to obtain compound of formula (VII) ;
Figure imgf000022_0004
b) reacting compound of formula (VII) with piperazine (VIII)
Figure imgf000022_0005
to obtain compound of formula (IX); and
Figure imgf000023_0001
Figure imgf000023_0002
2. The process according to claim-1 , wherein step-a) is performed in presence of a base which is selected from group comprising of ammonia, sodium hydroxide, potassium hydroxide, sodium methoixde, sodium t-butoxide, potassium t-butoxide, sodium carbonate, sodium bicarbonate, triethylamnie or tert-butyl amine.
3. The process according to claim-1 , wherein step-a) is performed in presence of a reagent which is selected from group comprising of thionyl chloride, methane sulfonyl chloride, ethane sulphonyl chloride, trifluoro methanesulfonyl chloride, tosyl chloride, cyanuric chloride, ethyl chloro format, methyl chloro format, pivaloyl chloride, oxalyl chloride or acetic anhydride.
Figure imgf000023_0003
Figure imgf000024_0001
with compound of formula (
Figure imgf000024_0002
to obtain Olaparib (I).
Crystalline form of Olaparib having characteristic peaks in X-ray diffraction pattern at about 6.4°, 8.3°, 12.6°, 15.0°, 15.8° and 19.7° + 0.2° 2Θ.
The crystalline form of Olaparib according to claim-5, having the following additional characteristic peaks in X-ray diffraction pattern at about 6.8°, 15.8°, 16.3°, 16.6°, 20.7 and 22.0° + 0.2° 2Θ.
A process for the preparation of crystalline form of Olaparib comprising steps of:
a) dissolving Olaparib in a water,
b) isolating crystalline form of Olaparib.
8. A process for the preparation of crystalline form A of Olaparib (I)
Figure imgf000025_0001
comprising steps of:
a) reacting 4-[4-fluoro-3-(piperazin-1 -ylcarbonyl) benzyl] phthalazin one (IX)
Figure imgf000025_0002
with 1 H-benzotriazol-1 -yl(cyclopropyl)methanone (X)
Figure imgf000025_0003
(X)
in organic solvent;
b) isolating crystalline form A of Olaparib.
A Compound of formula (VII)
Figure imgf000025_0004
10. Crystalline form of compound of formula (VII):
Figure imgf000026_0001
having characteristic peaks in X-ray diffraction pattern at about 3.1
1 1 .6°, 13.9°, 15.0°, 21 .2°, 21 .7°, 25.2° and 26.5° + 0.2° 2Θ.
1 1 . A process for the preparation of compound of formula (X),
Figure imgf000026_0002
comprising reaction of compound of formula (j):
Figure imgf000026_0003
with compound of formula (e):
Figure imgf000026_0004
wherein reaction is carried out in absence of a base.
12. Crystalline form of compound of formula (X):
Figure imgf000026_0005
having characteristic peaks in X-ray diffraction pattern at about 8.7°, 1 1 .0°, 15.9°, 17.4°, 18.7° and 22.0° + 0.2° 2Θ.
3. Olaparib of formula (I)
Figure imgf000027_0001
which is substantially free of: i) Impurity-A:
ii) Impurity-B:
Figure imgf000027_0002
iii) Impurity-C:
Figure imgf000027_0003
iv) Impurity-D:
Figure imgf000027_0004
v) Impurity-E
Figure imgf000028_0001
vi) Impurity-F:
vii) Impurity-G
Figure imgf000028_0002
PCT/IB2017/052549 2016-05-04 2017-05-03 Process for the preparation of olaparib and polymorphs thereof WO2017191562A1 (en)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
IN201621015481 2016-05-04
IN201621015481 2016-05-04
IN201621019497 2016-06-07
IN201621019497 2016-06-07
IN201621028186 2016-08-19
IN201621028186 2016-08-19

Publications (1)

Publication Number Publication Date
WO2017191562A1 true WO2017191562A1 (en) 2017-11-09

Family

ID=60203630

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2017/052549 WO2017191562A1 (en) 2016-05-04 2017-05-03 Process for the preparation of olaparib and polymorphs thereof

Country Status (1)

Country Link
WO (1) WO2017191562A1 (en)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108794405A (en) * 2018-08-02 2018-11-13 南京工业大学 A method of continuously preparing olaparib intermediate using microchannel module reaction unit
US10662178B2 (en) 2018-01-31 2020-05-26 Apotex Inc. Crystalline form of Olaparib
US10940149B1 (en) 2018-06-15 2021-03-09 Handa Oncology, Llc Kinase inhibitor salts and compositions thereof
CN112500379A (en) * 2020-12-23 2021-03-16 南京方生和医药科技有限公司 Olapari intermediate and preparation method of Olapari
WO2021220120A1 (en) 2020-04-28 2021-11-04 Rhizen Pharmaceuticals Ag Novel compounds useful as poly(adp-ribose) polymerase (parp) inhibitors
CN113720927A (en) * 2021-06-28 2021-11-30 神隆医药（常熟）有限公司 Method for detecting purity of Olapari by adopting reversed-phase high performance liquid chromatography
WO2022090938A1 (en) 2020-10-31 2022-05-05 Rhizen Pharmaceuticals Ag Phthalazinone derivatives useful as parp inhibitors
WO2022215034A1 (en) 2021-04-08 2022-10-13 Rhizen Pharmaceuticals Ag Inhibitors of poly(adp-ribose) polymerase
EP3986870A4 (en) * 2019-06-18 2023-07-12 ScinoPharm Taiwan, Ltd. A novel crystalline form of olaparib and a process for preparing the same
JP2023538455A (en) * 2020-09-16 2023-09-07 ナフォーミックス テクノロジーズ リミテッド Olaparib oxalic acid cocrystal and its pharmaceutical use

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004080976A1 (en) * 2003-03-12 2004-09-23 Kudos Pharmaceuticals Limited Phthalazinone derivatives
WO2008047082A2 (en) * 2006-10-17 2008-04-24 Kudos Pharmaceuticals Limited Polymorphic form of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2h-phthalazin-1-one

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004080976A1 (en) * 2003-03-12 2004-09-23 Kudos Pharmaceuticals Limited Phthalazinone derivatives
WO2008047082A2 (en) * 2006-10-17 2008-04-24 Kudos Pharmaceuticals Limited Polymorphic form of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2h-phthalazin-1-one

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10662178B2 (en) 2018-01-31 2020-05-26 Apotex Inc. Crystalline form of Olaparib
US10940149B1 (en) 2018-06-15 2021-03-09 Handa Oncology, Llc Kinase inhibitor salts and compositions thereof
US11007195B2 (en) 2018-06-15 2021-05-18 Handa Oncology, Llc Kinase inhibitor salts, and compositions thereof
US11052088B2 (en) 2018-06-15 2021-07-06 Handa Oncology, Llc Kinase inhibitor salts, and compositions thereof
US11160805B2 (en) 2018-06-15 2021-11-02 Handa Onocology, Llc Kinase inhibitor salts and compositions thereof
CN108794405A (en) * 2018-08-02 2018-11-13 南京工业大学 A method of continuously preparing olaparib intermediate using microchannel module reaction unit
EP3986870A4 (en) * 2019-06-18 2023-07-12 ScinoPharm Taiwan, Ltd. A novel crystalline form of olaparib and a process for preparing the same
WO2021220120A1 (en) 2020-04-28 2021-11-04 Rhizen Pharmaceuticals Ag Novel compounds useful as poly(adp-ribose) polymerase (parp) inhibitors
JP2023538455A (en) * 2020-09-16 2023-09-07 ナフォーミックス テクノロジーズ リミテッド Olaparib oxalic acid cocrystal and its pharmaceutical use
JP7453475B2 (en) 2020-09-16 2024-03-19 ナフォーミックス テクノロジーズ リミテッド Olaparib oxalic acid cocrystal and its pharmaceutical use
US12012386B2 (en) 2020-09-16 2024-06-18 Nuformix Technologies Limited Olaparib oxalic acid cocrystals and their pharmaceutical use
WO2022090938A1 (en) 2020-10-31 2022-05-05 Rhizen Pharmaceuticals Ag Phthalazinone derivatives useful as parp inhibitors
CN112500379A (en) * 2020-12-23 2021-03-16 南京方生和医药科技有限公司 Olapari intermediate and preparation method of Olapari
CN112500379B (en) * 2020-12-23 2024-01-23 南京方生和医药科技有限公司 Olaparib intermediate and preparation method of Olaparib
WO2022215034A1 (en) 2021-04-08 2022-10-13 Rhizen Pharmaceuticals Ag Inhibitors of poly(adp-ribose) polymerase
CN113720927A (en) * 2021-06-28 2021-11-30 神隆医药（常熟）有限公司 Method for detecting purity of Olapari by adopting reversed-phase high performance liquid chromatography

Similar Documents

Publication Publication Date Title
WO2017191562A1 (en) Process for the preparation of olaparib and polymorphs thereof
CA2477350C (en) Novel crystalline forms of the anti-cancer compound zd1839
US10071092B2 (en) Polymorphic forms of vortioxetine and its pharmaceutically acceptable salts
AU2009313970A1 (en) Methods of preparing quinoline derivatives
WO2010065838A1 (en) Methods of preparing quinoline derivatives
JP6873053B2 (en) Method for Producing Protein Deacetylation Inhibitor
WO2017186140A1 (en) Method for preparing tyrosine kinase inhibitor and derivative thereof
JP2015096553A (en) Crystalline forms of prasugrel salts
EP1515716A2 (en) Indole derivatives having anti-angiogenetic activity
EP3527556B1 (en) Method for preparing deuterated imidazole diketone compound
WO2005102997A1 (en) 3,4-disubstituted maleimides for use as vascular damaging agents
WO2020119772A1 (en) Mefuparib hydrochloride polymorphic substance and preparation method therefor
US20090312351A1 (en) Processes for the Preparation of Alfuzosin
WO2019206155A1 (en) Ezh2 inhibitor and pharmaceutically acceptable salts and polymorphic substances thereof, and application of ezh2 inhibitor
WO2020053660A1 (en) Solid forms of a bet inhibitor
WO2019037591A1 (en) Melphalan hydrochloride crystal form, preparation method therefor and application thereof
EP3687987A1 (en) Crystalline forms of lenalidomide
WO2023140809A1 (en) Novel polymorph of vismodegib and method of preparation
CA3214107A1 (en) New process for the synthesis of 5-{5-chloro-2-[(3s)-3- [(morpholin-4-yl)methyl]-3,4-dihydroisoquinoline-2(1h)- carbonyl]phenyl}-1,2-dimethyl-1h-pyrrole-3-carboxylic acid derivatives and its application for the production of pharmaceutical compounds
WO2023060022A1 (en) Synthesis of macrocyclic compounds
WO2020140957A1 (en) Method for preparing sulfonamides drugs
KR101432351B1 (en) Synthesis Method of Goshuyuamide Ⅱ and Wuchuyuamide Ⅱ
JP2022025121A (en) Method of producing prolinamide compound
JP2000247970A (en) Production of 5-amino-8-methyl-7-pyprolidinylquinoline-3- carboxylic acid derivative and intermediate therefor
WO2010107329A2 (en) Aripiprazole salts

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17792581

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 17792581

Country of ref document: EP

Kind code of ref document: A1