Crystalline forms of phthalazinones

Abstract

The present specification provides a crystalline form of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazine-1(2H)-one hydrochloride, a method for preparing the crystalline form, and a pharmaceutical composition comprising the crystalline form.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Serial No. 63 / 013,276, filed on April 21, 2020, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present invention relates to a crystalline form of a phthalazinone compound of formula 1, a method for preparing the phthalazinone compound, and a pharmaceutical composition comprising the phthalazinone compound. More specifically, the present invention relates to a crystalline form of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one hydrochloride, a method for preparing the same, and a pharmaceutical composition comprising the same.

[0004] [Formula 1]

[0005] Background Art

[0006] U.S. Pat. No. 9,682,973 ("US'973") discloses 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one of Formula 2 and its pharmaceutically acceptable salts as poly(ADP-ribose) polymerase (hereinafter referred to as "PARP") inhibitors having anticancer activity:

[0007] [Formula 2]

[0008]

[0009] US'973 also discloses a compound of formula 1 which is the hydrochloride salt of the compound of formula 2.

[0010] US'973 discloses a method for preparing a hydrochloride compound of Formula 1 from a compound of Formula 2. Specifically, after the compound of Formula 2 is dissolved in dichloromethane and then cooled to 0°C, a 1N HCl aqueous solution is added thereto, stirred at room temperature for 1 hour, and concentrated to prepare a compound of Formula 1.

[0011] However, when attempting to scale up the process based on the method disclosed in US'973, the compound of Formula 1 is obtained in a viscous oil phase, rather than a crystalline solid. Such an oil phase has lower purity and stability than a crystalline solid and is less suitable for commercial production. Further, since the method according to US'973 requires a concentration process, this method may not be preferred for commercially large-scale production of medical drug substances.

[0012] Furthermore, the preparation method of US'973 uses dichloromethane as a solvent, which may remain as a residual impurity even after removal. Therefore, due to the strict maximum requirements for the solvent, the preparation method of US'973 may be less than ideal in terms of safety. Summary of the invention

[0013]

Technical issues

[0014] One aspect of the present invention is to provide a crystalline form of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one hydrochloride having improved stability and purity and being more suitable for large-scale (i.e., commercial or large-scale) production.

[0015] Another aspect is to provide a pharmaceutical composition comprising a crystalline form of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one hydrochloride.

[0016] In another aspect, a process is provided for preparing a crystalline form of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one hydrochloride.

[0017] Other objects and advantages of the present invention will become apparent from the following detailed description and the appended claims. Certain contents not described in this specification can be fully recognized and inferred by those skilled in the art or similar fields of the present invention, and thus their description is omitted.

[0018]

Technical Solution

[0019] In one aspect of the present invention, there is provided a crystalline form of a compound of Formula 1 characterized by exhibiting an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ±0.2° values ​​of 13.7°, 15.9° and 24.1°:

[0020] [Formula 1]

[0021]

[0022] In another aspect, a pharmaceutical composition is provided, comprising as an active ingredient a crystalline form of a compound of Formula 1 and at least one pharmaceutically acceptable carrier or diluent.

[0023] In another aspect, there is provided a method for preparing a crystalline form of a compound of Formula 1, the method comprising:

[0024] dissolving 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one in one or more solvents selected from the group consisting of: C1-C3 alcohol, acetone, ethyl acetate and methyl tert-butyl ether; and

[0025] Add hydrochloric acid solution.

[0026] According to the present invention, in one embodiment, the method does not involve the use of a concentration process. Therefore, the method of the present invention is more preferred for commercial large-scale production.

[0027] In another aspect, there is provided a crystalline form of the compound of Formula 1 prepared by the above process. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 The X-ray powder diffraction (XRPD) pattern of crystalline Form A of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one hydrochloride prepared in Example 1 is shown.

[0029] Figure 2 is a graph showing the results of differential scanning calorimetry (DSC) of crystalline Form A of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one hydrochloride prepared in Example 1.

[0030] Figure 3 is a graph showing the results of thermogravimetric analysis (TGA) of crystalline Form A of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one hydrochloride prepared in Example 1.

[0031] Figure 4 is a comparative graph showing the XRPD patterns of crystalline Form A of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one hydrochloride prepared in Examples 1 to 6.

[0032] Figure 5 Shown is the XRPD pattern of crystalline Form C of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one hydrochloride.

[0033] Figure 6 is a graph showing the DSC results of crystalline Form C of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one hydrochloride.

[0034] Figure 7 is a graph showing the TGA results of crystalline Form C of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one hydrochloride.

[0035] Figure 8 Shown is an XRPD pattern of the amorphous form of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one hydrochloride. DETAILED DESCRIPTION

[0036] Hereinafter, the present invention will be described in more detail. Unless otherwise defined, all technical terms used in the present invention have the same meanings as those commonly understood by those skilled in the art to which the present invention relates.

[0037] The contents of all publications cited herein as reference documents are hereby incorporated by reference in their entirety into this specification.

[0038] The description and embodiment disclosed in a part of the present invention can be applied to other descriptions and embodiments in other parts of the present invention. That is to say, all combinations of various elements disclosed in the present invention belong to the scope of the present invention. Additionally, the scope of the present invention should not be limited to the specific description described below.

[0039] In addition, although preferred methods or samples are described in the specification, methods or samples similar or equivalent thereto are also within the scope of the present invention. In addition, the term "comprising" is intended to have an open-ended meaning and allows for the inclusion of unidentified additional elements.

[0040] Unless otherwise indicated, all numbers representing the amount, properties (such as molecular weight, reaction conditions) of components as used in this specification and claims should be understood to be modified by the term "about" in all cases. Therefore, unless otherwise indicated, the numerical properties set forth in the following specification and claims are approximate values ​​that can be varied according to the desired properties sought to be obtained in embodiments of the present invention. As used herein, the term "about" refers to within 5% of a particular value or range, and more preferably within 1% to 2%. For example, "about 10%" refers to 9.5% to 10.5%, and preferably, 9.8% to 10.2%. For another example, "about 100°C" refers to 95°C to 105°C, and preferably, 98°C to 102°C.

[0041] Unless otherwise stated, it should be clear to those skilled in the art that the peak values ​​reported in X-ray powder diffraction studies in this application are related to experimental errors commonly observed in the art. Specifically, peak values ​​are interpreted as being within an angular variation of ±0.5° of the values ​​reported herein. Preferably, peak values ​​are interpreted as being within an angular variation of ±0.2° of the values ​​reported herein, and more preferably, within an angular variation of ±0.1°.

[0042] Crystalline form of the compound of formula 1

[0043] One aspect of the present invention provides a crystalline form of a compound of Formula 1 below, characterized in that it exhibits an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ±0.2° values ​​of 13.7°, 15.9° and 24.1°.

[0044] [Formula 1]

[0045]

[0046] Hereinafter, the crystalline form is referred to as crystalline form A.

[0047] In one aspect, crystalline Form A can exhibit an XRPD pattern comprising peaks at three or more, preferably four or more, 2θ±0.2° values ​​selected from the group consisting of 9.1°, 11.9°, 13.2°, 13.7°, 15.9°, 16.8°, 18.1°, 23.2°, 24.1°, 25.5°, and 26.6°.

[0048] Specifically, crystalline Form A may exhibit an XRPD pattern comprising peaks at 2θ±0.2° values ​​of 9.1°, 13.2°, 13.7°, 15.9°, 16.8°, 24.1°, and 26.6°.

[0049] More specifically, crystalline Form A may exhibit an XRPD pattern comprising peaks at 2θ±0.2° values ​​of 9.1°, 11.9°, 13.2°, 13.7°, 15.9°, 16.8°, 18.1°, 23.2°, 24.1°, 25.5°, and 26.6°.

[0050] When irradiated with a Cu-Ka light source, for example using a D8 Advance (Bruker ASX, Germany) analyzer, an XRPD pattern can be obtained. The Cu-Ka light source can have wavelength.

[0051] These peaks can be expressed as relative intensities (I / I o ) is about 10%, more specifically, about 15% or more.

[0052] In differential scanning calorimetry (DSC, 10° C. / min), crystalline form A may have an exothermic peak having a starting point of about 219° C. and a maximum point of about 225° C. In DSC (10° C. / min), crystalline form A may have an exothermic peak at about 222±4° C.

[0053] In thermogravimetric analysis (TGA), the crystalline form A may have a weight loss of 4% or less at up to 100°C, and decompose at or above 200°C.

[0054] In another aspect of the present invention, the crystalline Form A of the compound of Formula 1 may be in substantially pure form.

[0055] The term "substantially pure" as used herein means that any other form of the compound of Formula 1 (other crystalline forms, amorphous forms, etc.) is at least 95% pure, preferably 97% pure, or more preferably 99% pure, wherein 95% purity means no more than 5%, 97% purity means no more than 3%, and 99% purity means no more than 1%.

[0056] In one embodiment, the crystalline Form A of the compound of Formula 1 may have a crystalline form purity of 95% or more.

[0057] It was found that the crystalline form A of the compound of Formula 1 had significantly improved storage stability and purity (see Experimental Example 1). According to the long-term stability purity test of Experimental Example 1, after 24 months at 25±2°C, about 0.20wt% of the total impurities were found to be crystalline form A. Therefore, the crystalline form A of the compound of Formula 1 can prepare a drug with improved stability.

[0058] In addition, the crystalline form A of the compound of formula 1 can be prepared to have a higher safety curve. In the previous method for preparing the compound of formula 1, dichloromethane was used as a solvent. Dichloromethane is very toxic and is classified as a Class 2 solvent, i.e., according to the International Committee for Harmonization (ICH) Guideline Q3C [Impurity Guidelines for Residual Solvents], the residual amount in the drug is 600ppm or less solvent. However, due to the need for expensive processing, it is difficult to reduce the amount of residual solvent. Therefore, the crystalline form A of the compound of formula 1 has the advantages of being safer and more economical in terms of production as a medical drug substance.

[0059] Method for preparing crystalline form A of the compound of formula 1

[0060] Another aspect of the present invention provides a process for preparing crystalline Form A of the compound of Formula 1.

[0061] In one embodiment, the method comprises the following steps:

[0062] dissolving 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one in one or more solvents selected from the group consisting of: C1-C3 alcohol, acetone, ethyl acetate and methyl tert-butyl ether; and

[0063] Add hydrochloric acid solution.

[0064] In another embodiment, the method comprises the following steps:

[0065] dissolving 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one in one or more solvents selected from the group consisting of: C1-C3 alcohol, acetone, ethyl acetate and methyl tert-butyl ether to obtain a mixture;

[0066] cooling the mixture;

[0067] Add hydrochloric acid solution;

[0068] Raising the temperature to about room temperature, cooling and stirring to obtain a solid; and

[0069] The solid was filtered, washed and dried.

[0070] In another embodiment, the method comprises the following steps:

[0071] (a) dissolving 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one in one or more solvents selected from the group consisting of: C1-C3 alcohol, acetone, ethyl acetate and methyl tert-butyl ether to obtain a mixture;

[0072] (b) cooling the obtained mixture to about 0° C.;

[0073] (c) adding hydrochloric acid solution to the mixture, optionally together with a mixture of hydrochloric acid solution and one or more solvents selected from the group consisting of: C1-C3 alcohol, acetone, ethyl acetate and methyl tert-butyl ether;

[0074] (d) raising the temperature to about room temperature;

[0075] (e) stirring the mixture for about 10 to about 14 hours;

[0076] (f) cooling the mixture to about 10° C. to about 20° C.;

[0077] (g) stirring the cooled mixture for about 20 to about 60 minutes to obtain a solid; and

[0078] (h) filtering, washing and drying the solid.

[0079] In step (a), 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one, i.e., a compound of Formula 2, may be dissolved in one or more solvents selected from the group consisting of C1-C3 alcohols, acetone, ethyl acetate, and methyl tert-butyl ether, and then cooled to about 0° C. according to step (b), and thereafter step (c) may be performed. The solvent may be, for example, a single solvent such as methanol, ethanol, isopropanol, acetone, ethyl acetate, and methyl tert-butyl ether, or a mixed solvent thereof, for example, a mixed solvent of methanol and methyl tert-butyl ether.

[0080] The free base form of the compound of Formula 1, i.e., 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one, can be prepared according to the method disclosed in US'973, the disclosure of which is incorporated herein by reference in its entirety. However, the embodiments described herein are not limited thereto, and the free base form of the compound of Formula 1 can be prepared using any method known to a person of ordinary skill in the relevant art.

[0081] In the preparation method of the present invention, specifically, in step (c), the hydrochloric acid solution can be added as a solution in a solvent of water, alkyl acetate (e.g., ethyl acetate, etc.), alkyl ether (e.g., diethyl ether, etc.), or alkyl alcohol (e.g., isopropanol, ethanol, etc.). In a specific embodiment, the solvent can be water, ethyl acetate, diethyl ether, isopropanol, or ethanol. More specifically, the hydrochloric acid solution can be about 30-40%, such as a 37.0% aqueous solution, a 1.0M ethyl acetate solution, a 1.0M diethyl ether solution, a 5 to 6N isopropanol solution, or a 1.25M ethanol solution.

[0082] The amount of hydrochloric acid in the hydrochloric acid solution or the mixed solution of the hydrochloric acid solution and the solvent can be about 1.0 to about 2.0 equivalents relative to 1 equivalent of the compound of formula 1 in free base form. The volume of the hydrochloric acid solution or the mixed solution can be a ratio (v / w) of about 0.1:1 to about 20:1 relative to the weight of the compound of formula 1 in free base form. The solvent in step (c) can be one or more selected from the group consisting of: C1-C3 alcohol, acetone, ethyl acetate and methyl tert-butyl ether.

[0083] In step (f), the cooling temperature may be about 10° C. to about 20° C., and preferably about 12° C. to about 17° C., and more preferably about 15° C. In step (g), after cooling, stirring for about 20 minutes to about 60 minutes, and more preferably about 30 minutes to 40 minutes, a solid phase crystalline form A may be obtained. Thereafter, filtering, washing and drying may be performed in step (h).

[0084] The washing and drying steps are not particularly limited. The washing may be performed using the solvent used in step (a). The drying may be performed using any method that does not affect the stability of the crystalline form of the compound of Formula 1, for example, drying at a temperature of about 40° C. to about 50° C. for about 15 to 30 hours.

[0085] In the case of using a solvent other than the above solvents for crystallization, another crystalline form can be obtained. For example, when dichloromethane or a mixture of dichloromethane and methanol is used as a solvent, a crystalline form C of Formula 1 is obtained. Crystalline form C can exhibit an XRPD pattern including peaks at diffraction angles (2θ) ± 0.2° at 3.5°, 7.1°, 12.9°, 21.6°, 24.4° and 25.3°. Figure 5 The PXRD pattern of crystalline form C is shown in .

[0086] In another example, the amorphous form is obtained by a process comprising the steps of completely dissolving the compound of Formula 1 in excess methanolic HCl salt, concentrating the solvent, quickly adding acetone to the residue to obtain crystals, then concentrating the solvent, dispersing and stirring the residual solid in n-heptane, and filtering. Figure 8 The PXRD pattern of the amorphous form is shown in .

[0087] Medical uses and pharmaceutical compositions

[0088] Another aspect of the present invention provides a pharmaceutical composition comprising, as an active ingredient, the crystalline form A of the compound of Formula 1 and at least one pharmaceutically acceptable carrier or excipient.

[0089] The pharmaceutical composition may include about 80% or more, preferably about 90% or more, more preferably about 95% or more, and most preferably about 99% or more of the crystalline form A of the compound of Formula 1, relative to the total amount of the compound of Formula 1. The remainder may be any other form of the compound of Formula 1 (other possible crystalline forms, amorphous forms, etc.).

[0090] As disclosed in US'973, compounds of Formula 1 were found to exhibit PARP inhibitory activity and have anti-cancer activity, and therefore can be used to treat cancer, in particular cancers caused by defective DNA damage repair or genetic defects in BRCA1, BRCA2 or ERG fusion genes. As used herein, the term "genetic defect" may include but is not limited to gene mutations or gene absence (defect), or gene expression defects.

[0091] The pharmaceutical composition can be used to treat cancer.

[0092] Cancer may be caused by defective DNA damage repair or genetic defects of BRCA1, BRCA2 or ERG fusion genes. For example, the cancer may be selected from the group consisting of breast cancer, ovarian cancer, pancreatic cancer, gastric cancer, lung cancer, colon cancer, brain tumors, prostate cancer and Ewing's sarcoma. Specifically, the cancer may be breast cancer or ovarian cancer.

[0093] When administered to human patients, the total daily dose of crystalline form A may vary depending on the administration route, administration time, the type of other compounds used in combination, or the patient's age, sex, weight, condition, medical history, etc. Therefore, the dose of the compound can be determined within the range of achieving the desired therapeutic effect without causing harmful or severe side effects.

[0094] The pharmaceutical composition may be in oral or parenteral dosage form.

[0095] For oral dosage forms, the carrier used may include sweeteners, binders, dissolving agents, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, flavoring agents, coating agents, etc. For example, the carrier may include lactose, calcium hydrogen phosphate, hydroxypropyl cellulose, carboxymethyl cellulose, colloidal silicon dioxide, fumed silicon dioxide, magnesium stearate, talc, agar, water, ethanol, polyethylene glycol, polyvinyl pyrrolidone, sodium chloride, calcium chloride, orange flavor, strawberry flavor, vanilla flavor, Opadray white, etc.

[0096] Examples of usable injectable carriers include distilled water, saline, glucose solution, pseudo-dextrose solution, alcohol, glycol ether (eg, polyethylene glycol 400), oil, fatty acid, fatty acid ester, glyceride, surfactant, suspending agent, emulsifier and the like.

[0097] Another aspect provides a method for preventing or treating cancer, comprising administering a therapeutically effective amount of crystalline Form A of the compound of Formula 1 to an individual or patient in need of preventing or treating cancer.

[0098] The above description of the pharmaceutical composition according to one aspect of the present invention can itself be applied to the details of the method for preventing or treating cancer.

[0099] The dosage used in the method for preventing or treating cancer may be a preventive or therapeutic effective amount.The above description of the dosage of the pharmaceutical composition itself can be applied to the method for preventing or treating cancer.

[0100] The descriptions on the medical uses and pharmaceutical compositions of the compound of Formula 1 disclosed in US'973 may be applicable to the crystalline form A of the compound of Formula 1 according to the present invention.

[0101] Hereinafter, the present invention will be described in more detail with reference to the following examples. However, these examples are only for illustrative purposes, and the present invention is not limited to these examples.

[0102] Analytical device and measuring method

[0103] 1. X-ray powder diffraction (XRPD)

[0104] X-ray powder diffraction (XRPD) analysis of the samples was performed in the range of 3°2θ to 50°2θ using a D8 Advance (Bruker ASX, Germany) analyzer. The measurement was performed as follows:

[0105] Anode material (Kα): Cu-Kα

[0106] Scanning range: 3° to 50°

[0107] Generator settings: 40mA, 40.0kV

[0108] Scanning speed: 0.5 seconds / step

[0109] Temperature: 20℃

[0110] Step size: 0.02° 2θ

[0111] Rotation: Not used

[0112] 2. Differential Scanning Calorimetry (DSC)

[0113] Differential Scanning Calorimetry (DSC) analysis was performed using AUTO MDSC Q20 / RSC40 (TA Instruments) in the temperature range of 25°C to 300°C at a heating rate of 5°C / min or 10°C / min. 5 to 10 mg of sample was weighed and added to an aluminum DSC fan, and the fan was sealed in a non-sealed manner with a perforated aluminum cover. The sample was then heated from 25°C to 300°C at a scanning rate of 5°C / min or 10°C / min, and the resulting heat flow reaction was monitored in the DSC.

[0114] 3. Thermogravimetric analysis (TGA)

[0115] Thermogravimetric analysis (TGA) was performed using a TGA Q50 (TA Instruments) in the temperature range of 25°C to 300°C at a heating rate of 10°C / min.

[0116] 4. Gas chromatography (GC)

[0117] Gas chromatography (GC) analysis was performed using an Agilent 7697A headspace sampler / 7890A GC ChemStation.

[0118] 5. Karl Fischer (KF) Analysis

[0119] Karl Fischer (KF) analysis was performed using (i) a Metrohm 795KFT Titrino system, 795 keyboard, 703Ti stand, and (ii) a Mettler Toledo V20S Compact KF titrator.

[0120] Preparation Example: Preparation of Compound of Formula 2

[0121] The compound of Formula 2, 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one, was prepared according to a process comprising steps 1 to 5 as described below.

[0122] Step 1. Preparation of tert-butyl 3-[(cyclopropylamino)methyl]azetidine-1-carboxylate

[0123]

[0124] 1.0kg of 3-formylazetidine-1-formic acid tert-butyl ester is added to the reactor, and 6.5kg of trifluoroethanol is added thereto. 0.3kg of cyclopropylamine is added at 0°C, stirred at ambient temperature for 1 hour, and then the reactor is cooled to 0°C. 0.2kg of sodium borohydride is slowly added, and stirred at ambient temperature for 1 hour, and then the reactor is cooled to 0°C. After 10.0kg of water is slowly added thereto, the reaction mixture is extracted with 6.7kg of dichloromethane, and the water layer thus obtained is further extracted with 6.7kg of dichloromethane. The organic layer is washed with 15% sodium chloride aqueous solution, treated with 0.5kg of anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure to produce 0.98kg of the title compound in the form of a yellow oil (yield: 80.1%). The title compound is used in subsequent processes without the need for a separate purification process.

[0125] 1 H NMR(CDCl3,400MHz)δ3.99(t,2H),3.60-3.57(m,2H),2.90(d,2H),2.66-2.62(m,1H) ,2.11-2.06(m,1H),1.59(br,1H),1.44(s,9H),0.46-0.42(m,2H),0.32-0.28(m,2H)

[0126] Step 2. Preparation of tert-butyl 3-([([(9H-fluoren-9-yl)methoxy]carbonyl)(cyclopropyl)amino]methyl)azetidine-1-carboxylate

[0127]

[0128] 4.0kg of dichloromethane is added to the reactor, 300.0g of tert-butyl 3-[(cyclopropylamino)methyl]azetidine-1-formate prepared in step 1 and 188.4g of diisopropylethylamine are added thereto in sequence, and the reactor is then cooled to 0°C. 377.2g of 9-fluorenylmethoxycarbonyl chloride is slowly added to the reactor so that the internal temperature of the reactor does not exceed 20°C, and the reaction mixture is stirred for 1 hour. 5.0kg of water is added thereto to wash the organic layer, and the organic layer is further washed with 5.0kg of 1N hydrochloric acid aqueous solution. The organic layer is further washed with 15% sodium chloride aqueous solution, and treated with 250.0g of anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to thereby quantitatively produce 576.7g of the title compound in the form of a yellow oil. The title compound is used in subsequent processes without a separate purification process.

[0129] 1 H NMR(CDCl3,400MHz)δ7.72(d,2H),7.56(d,2H),7.36(t,2H),7.30-7.26(m,2H),4.52(d,2H),4.17(t,1H),3 .89-3.85(m,2H),3.56(m,2H),3.30(m,2H),2.60(m,1H),2.28(m,1H),1.43(s,9H),0.61(m,2H),0.45(m,2H)

[0130] Step 3. Preparation of methyl (9H-fluoren-9-yl)methyl(azetidin-3-ylmethyl)(cyclopropyl)carbamate hydrochloride

[0131]

[0132] 1.0 L of ethanol was added to the reactor, 100.0 g of tert-butyl 3-([([(9H-fluorene-9-yl)methoxy]carbonyl)(cyclopropyl)amino]methyl)azetidine-1-carboxylate prepared in step 2 and 24.8 mL of concentrated hydrochloric acid were added thereto in sequence, and the resulting mixture was then heated. The reaction was carried out at reflux temperature for 30 minutes, and then the reaction mixture was concentrated under reduced pressure. 170 mL of ethyl acetate and 430 mL of n-hexane were added to the residue, stirred overnight at ambient temperature, filtered, and then dried at 40° C. to thereby produce 78.2 g of the title compound (yield: 91.2%).

[0133] 1H NMR(CDCl3,400MHz)δ9.63(br,1H),9.40(br,1H),7.75-7.70(m,2H),7.60-7.55(m,2H),7.38(t,2H),7.32-7.29(m,2H),4.5 2(d,2H),4.18(t,1H),3.99(m,2H),3.81(m,2H),3.44-3.28(m,2H),2.94(m,1H),2.27(m,1H),0.60-0.59(m,2H),0.43(m,2H)

[0134] Step 4. Preparation of (9H-fluoren-9-yl)methylcyclopropyl([1-(2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoyl)azetidin-3-yl]methyl)carbamate

[0135]

[0136] 300mL of dichloromethane was added to the reactor, and 29.8g of 2-fluoro-5-[(4-oxo-3,4-dihydrophthalazine-1-yl)methyl]benzoic acid and 17.9g of 1,1'-carbonyldiimidazole were added thereto in sequence. The reaction was carried out at ambient temperature for 1 hour, and the reactor was then cooled to 15°C. Then, 42.3g of (9H-fluorene-9-yl)methyl(azetidin-3-ylmethyl)(cyclopropyl)methylcarbamate hydrochloride prepared in step 3 was added thereto, and 19.4g of diisopropylamine was slowly added thereto. The reaction mixture was stirred at ambient temperature for 1 hour, 300mL of water was added thereto to wash the organic layer, and then the organic layer was further washed with 1N aqueous hydrochloric acid solution and 1N aqueous sodium carbonate solution. The organic layer was further washed with 5% aqueous sodium chloride solution, treated with 10.0g of anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. To the residue, 70 mL of ethyl acetate and 350 mL of n-hexane were added, stirred at ambient temperature overnight, filtered, and then dried at 50° C. to thereby produce 63.2 g of the title compound (yield: 91.3%).

[0137] 1H NMR(DMSO-d6,400MHz)δ12.60(s,1H),8.26-8.24(m,1H),7.97(d,1H),7.9 0-7.78(m,4H),7.65-7.62(m,2H),7.48-7.28(m,7H),4.51-4.48(m,2H),4. 32(s,2H),4.26-4.23(m,1H),3.97-3.86(m,2H),3.62-3.56(m,2H),3.30-3 .25(m,2H),2.24(m,1H),1.24-1.23(m,1H),0.48(m,2H),0.38-0.35(m,2H)

[0138] Step 5. Preparation of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one

[0139]

[0140] 150 mL of acetonitrile was added to the reactor, and 30.0 g of (9H-fluorene-9-yl) methylcyclopropyl ([1-(2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoyl)azetidin-3-yl]methyl)carbamate prepared in step 4 and 34.5 g of piperidine were added thereto in sequence, and stirred at ambient temperature for 1 hour. After the reaction mixture was concentrated under reduced pressure, 300 mL of 2N aqueous hydrochloric acid solution was added to the residue, stirred for 1 hour, and then filtered through diatomaceous earth. Then, the filtrate was adjusted to pH 9 or higher with 1N sodium hydroxide solution, and extracted by adding 300 mL of dichloromethane. The aqueous layer was further extracted by adding 300 mL of dichloromethane thereto, and then the organic layer was mixed therewith, washed with 5% aqueous sodium chloride solution, and then concentrated. To the residue were added 80 mL of methanol and 40 mL of dichloromethane, and then 150 mL of acetone was slowly added thereto. The resulting solid was stirred at ambient temperature overnight, filtered, and dried at 40°C to give 17.5 g of the title compound (yield: 90.1%).

[0141] 1H NMR(DMSO-d6,400MHz)δ12.62(s,1H),8.27-8.25(m,1H),7.97(d,1H),7.90-7.86(m,1H),7.84-7.79(m,1H),7.46-7.43(m,2 H),7.22-7.18(m,1H),4.32(s,2H),4.04-3.56(m,4H),2.73-2.63(m,3H),2.30(br,1H),2.00-1.95(m,1H),0.33-0.12(m,4H)

[0142] Preparation of Crystalline Form A of the Compound of Formula 1

[0143] Example 1: 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazine-1 Preparation of Crystalline Form A of (2H)-Keto Hydrochloride

[0144] To 1.0 g of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one, 10.0 mL of methanol was added, mixed and cooled to 0°C. Subsequently, after adding 0.2 ml of a 37.0% aqueous hydrochloric acid solution thereto, the temperature was raised to room temperature, and the mixture was stirred for 12 hours. After cooling to 15°C, the mixture was further stirred for 30 minutes. The resulting solid was then filtered, washed with methanol, and dried to obtain 0.76 g of crystalline Form A of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one hydrochloride (yield: 69.7%, DSC maximum peak temperature at a heating rate of 10°C / min: 222.81°C).

[0145] The XRPD, DSC and TGA results of the obtained crystalline form A are respectively Figure 1 , 2 and 3 are shown.

[0146] The positions of the peaks of crystalline form A and their relative intensities are shown in the table below.

[0147] [Table 1]

[0148]

[0149] Example 2: 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazine-1 Preparation of Crystalline Form A of (2H)-Keto Hydrochloride

[0150] To 1.0 g of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one was added 20.0 mL of acetone, and then mixed together and cooled to 0°C. Subsequently, after 0.2 mL of a 37.0% aqueous hydrochloric acid solution was added thereto, the temperature was raised to room temperature, and the resulting mixture was stirred for 12 hours. After cooling to 15°C, the mixture was further stirred for 30 minutes. The solid thus obtained was filtered, washed with acetone, and then dried to thereby obtain 0.89 g of crystalline form A of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one hydrochloride. (Yield: 81.7%, DSC maximum peak temperature at a heating rate of 10°C / min: 223.26°C).

[0151] The XRPD results of the crystalline form A obtained were Figure 4 Shown in.

[0152] Example 3: 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazine-1 Preparation of Crystalline Form A of (2H)-Keto Hydrochloride

[0153] To 1.0 g of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one, 10.0 mL of ethanol was added, and then mixed together and cooled to 0° C. Subsequently, after 0.2 mL of a 37.0% hydrochloric acid aqueous solution and 5.0 mL of ethanol were mixed together and then added to the reaction solution, the temperature was raised to room temperature, and the resulting mixture was stirred for 12 hours. After cooling to 15° C., the mixture was further mixed for 30 minutes. The solid thus obtained was filtered, washed with ethanol, and then dried to thereby obtain 0.57 g of crystalline form A of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one hydrochloride. (Yield: 52.3%, DSC maximum peak temperature: 219.26° C.).

[0154] The XRPD results of the crystalline form A obtained were Figure 4 Shown in.

[0155] Example 4: 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazine-1 Preparation of Crystalline Form A of (2H)-Keto Hydrochloride

[0156] To 1.0 g of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one was added 15.0 mL of ethyl acetate, and then mixed together and cooled to 0°C. Subsequently, after 0.2 mL of a 37.0% hydrochloric acid aqueous solution and 5.0 mL of ethyl acetate were mixed together and then added to the reaction solution, the temperature was raised to room temperature, and the mixture was stirred for 12 hours. After cooling to 15°C, the mixture was further stirred for 30 minutes. After filtering the solid thus obtained, it was washed with ethyl acetate, and then dried to thereby obtain 0.93 g of crystalline form A of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one hydrochloride (yield: 85.3%, DSC maximum peak temperature at a heating rate of 10°C / min: 222.08°C).

[0157] The XRPD results of the crystalline form A obtained were Figure 4 Shown in.

[0158] Example 5: 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazine-1 Preparation of Crystalline Form A of (2H)-Keto Hydrochloride

[0159] To 1.0 g of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one, 15.0 mL of isopropanol was added, and then mixed together and cooled to 0° C. Subsequently, after 0.2 mL of a 37.0% hydrochloric acid aqueous solution and 5.0 mL of isopropanol were mixed together and then added to the reaction solution, the temperature was raised to room temperature, and the mixture was stirred for 12 hours. After cooling to 15° C., the mixture was further mixed for 30 minutes. The solid thus obtained was filtered, washed with isopropanol, and then dried to thereby obtain 0.96 g of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one hydrochloride crystalline form A (yield: 88.1%, DSC maximum peak temperature at a heating rate of 10°C / min: 223.81°C).

[0160] The XRPD results of the crystalline form A obtained were Figure 4 Shown in.

[0161] Example 6: 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazine-1 Preparation of Crystalline Form A of (2H)-Keto Hydrochloride

[0162] To 1.0 g of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one, 10.0 mL of methanol was added, and then mixed together and cooled to 0° C. Subsequently, after 0.2 mL of a 37.0% aqueous hydrochloric acid solution was added to the reaction solution, and then 15.0 mL of methyl tert-butyl ether was added thereto, the temperature was raised to room temperature, and the mixture was stirred for 12 hours. After cooling to 15° C., the mixture was further stirred for 30 minutes. The solid thus obtained was filtered, then washed with acetone, and then dried to thereby obtain 0.95 g of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one hydrochloride crystalline form A (yield: 87.2%, DSC maximum peak temperature at a heating rate of 10°C / min: 225.02°C).

[0163] The XRPD results of the crystalline form A obtained were Figure 4 Shown in.

[0164] Preparation of Crystalline Form C of the Compound of Formula 1

[0165] Example 7: 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazine-1 Preparation of Crystalline Form C of (2H)-Ketohydrochloride

[0166] To 1.0 g of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one was added 10.0 mL of dichloromethane, and then mixed together and cooled to 0°C. Subsequently, after 0.2 mL of a 37.0% aqueous hydrochloric acid solution therein, the temperature was raised to room temperature, followed by stirring for 12 hours. After cooling to 15°C, the mixture was further stirred for 30 minutes. The solid thus obtained was filtered, washed with acetone, and then dried to obtain 1.07 g of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one hydrochloride crystalline form C (yield: 98.1%, DSC maximum peak temperature at a heating rate of 5°C / min: 214.60°C).

[0167] The XRPD pattern, DSC pattern and TGA pattern of the crystalline form C of Example 7 are respectively Figure 5 , 6 The positions of the characteristic peaks of crystalline form C and their relative intensities are presented in Table 2 below.

[0168] [Table 2]

[0169]

[0170] Example 8: 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazine-1 Preparation of Crystalline Form C of (2H)-Ketohydrochloride

[0171] To 1.0 g of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one, 12.0 mL of methanol and 6.0 mL of dichloromethane were added, and then mixed together and cooled to 0°C. Subsequently, after adding 2.5 mL of a 1.0 M hydrochloric acid solution containing ethyl acetate to the reaction solution, the temperature was raised to room temperature, followed by stirring for 5 hours. After cooling to 15°C, the mixture was further stirred for 30 minutes. The solid thus obtained was filtered, washed with methanol, and then dried to obtain 0.70 g of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one hydrochloride crystalline form C (yield: 64.2%, DSC maximum peak temperature at a heating rate of 10°C / min: 223.34°C).

[0172] Example 9: 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazine-1 Preparation of Crystalline Form C of (2H)-Ketohydrochloride

[0173] To 1.0 g of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one, 12.0 mL of methanol and 6.0 mL of dichloromethane were added, and then mixed together and cooled to 0°C. Subsequently, after adding 2.5 mL of a 1.0 M hydrochloric acid solution containing diethyl ether to the reaction solution, the temperature was raised to room temperature, followed by stirring for 5 hours. After cooling to 15°C, the mixture was further stirred for 30 minutes. The solid thus obtained was filtered, washed with methanol, and then dried to obtain 0.68 g of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one hydrochloride crystalline form C (yield: 62.4%, DSC maximum peak temperature at a heating rate of 10°C / min: 222.36°C).

[0174] Example 10: 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazine-1 Preparation of Crystalline Form C of (2H)-Ketohydrochloride

[0175] To 1.0 g of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one, 12.0 mL of methanol and 6.0 mL of dichloromethane were added, and then mixed together and cooled to 0°C. Subsequently, after adding 0.5 mL of a 5 to 6N hydrochloric acid solution containing isopropanol to the reaction solution, the temperature was raised to room temperature, followed by stirring for 5 hours. After cooling to 15°C, the mixture was further stirred for 30 minutes. The solid thus obtained was filtered, washed with acetone, and then dried to obtain 0.65 g of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one hydrochloride crystalline form C (yield: 59.6%, DSC maximum peak temperature at a heating rate of 10°C / min: 222.45°C).

[0176] Example 11: 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazine-1 Preparation of Crystalline Form C of (2H)-Ketohydrochloride

[0177] To 1.0 g of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one, 12.0 mL of methanol and 6.0 mL of dichloromethane were added, and then mixed together and cooled to 0°C. Subsequently, after adding 2.0 mL of a 1.25M hydrochloric acid solution containing ethanol to the reaction solution, the temperature was raised to room temperature, followed by stirring for 5 hours. After cooling to 15°C, the mixture was further stirred for 30 minutes. The solid thus obtained was filtered, washed with acetone, and then dried to obtain 0.43 g of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one hydrochloride crystalline form C (yield: 39.5%, DSC maximum peak temperature at a heating rate of 10°C / min: 221.16°C).

[0178] It was confirmed from Examples 7 to 11 that when dichloromethane alone or a mixed solvent of dichloromethane and methanol was used in any type of hydrochloric acid, crystalline Form C was obtained.

[0179] Preparation of the Amorphous Form of the Compound of Formula 1

[0180] Example 12: 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazine-1 Preparation of the Amorphous Form of (2H)-Ketohydrochloride

[0181] To 1.0 g of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one hydrochloride was added 90.0 mL of methanol, and then mixed together and concentrated. To the concentrated residue was quickly added 20.0 mL of acetone to produce crystals, followed by concentration. To the concentrated residue was quickly added 15.0 mL of n-heptane, stirred for 5 minutes, and filtered to obtain 0.75 g of 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one hydrochloride amorphous form (yield: 75.0%).

[0182] The XRPD results obtained for the amorphous form were Figure 8 Shown in.

[0183] The amorphous form obtained readily absorbs moisture during storage, ie it is hygroscopic, and thus becomes yellow in color. It was thus confirmed that the amorphous form is unsuitable for use as a medicinal drug substance.

[0184] Experimental Example 1: Stability test of crystalline form A

[0185] The crystalline form A of the compound of formula 1 prepared in Example 1 was stored under long-term storage conditions (25 ± 2°C, relative humidity: 60 ± 5%). Samples were taken after 3 months, 6 months, 9 months, 12 months, 18 months, and even 24 months after the start of storage to measure the total impurity content by high performance liquid chromatography (HPLC). The results are shown in Table 3.

[0186] [Table 3] Long-term stability purity test results of crystalline form A

[0187]

[0188] Therefore, the above results show that the crystalline form A of the compound of Formula 1 exhibits high stability under long-term storage conditions. Therefore, the crystalline form A is suitable for use as a medicinal drug substance.

[0189] Those skilled in the art will recognize that the present invention may be embodied in other specific forms without departing from the spirit or essential characteristics of the present invention. The described embodiments are to be considered in all respects as merely illustrative and not restrictive. Therefore, the scope of the present invention is indicated by the appended claims rather than by the foregoing description. All changes within the equivalent meaning and range of the claims shall be included within the scope of the present invention.

Claims

1. A crystalline form of a compound of Formula 1, characterized in that it exhibits an X-ray powder diffraction (XRPD) pattern comprising peaks at 2θ±0.2° values ​​of 9.1°, 13.2°, 13.7°, 15.9°, 16.8°, 24.1° and 26.6°: [Formula 1] 2. The crystalline form of claim 1, wherein the XRPD pattern comprises peaks at 2θ±0.2° values ​​of 9.1°, 11.9°, 13.2°, 13.7°, 15.9°, 16.8°, 18.1°, 23.2°, 24.1°, 25.5° and 26.6°.

3. The crystalline form of claim 1, wherein each 2θ value of the peak has an angular variation of ±0.1°.

4. The crystalline form of claim 1, having a DSC exotherm peak at a temperature of 222±4°C.

5. The crystalline form of claim 1, wherein the crystalline form has a weight loss of 4% or less in thermogravimetric analysis (TGA) at up to 100°C and decomposes at or above 200°C.

6. The crystalline form of claim 1, wherein the crystalline form is substantially pure.

7. The crystalline form of claim 1, wherein the crystalline form is at least 95% pure.

8. A pharmaceutical composition comprising as an active ingredient a crystalline form according to any one of claims 1 to 7 and at least one pharmaceutically acceptable carrier or diluent.

9. The pharmaceutical composition according to claim 8, wherein the crystalline form accounts for 80% or more of the total amount of the compound of Formula 1 in the pharmaceutical composition.

10. The pharmaceutical composition according to claim 8, wherein the pharmaceutical composition is used to treat cancer.

11. The pharmaceutical composition according to claim 10, wherein the cancer is caused by a genetic defect in the BRCA1 or BRCA2 gene.

12. The pharmaceutical composition according to claim 10, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, pancreatic cancer, gastric cancer, lung cancer, colon cancer, brain tumor, prostate cancer and Ewing's sarcoma.

13. A method for preparing a crystalline form according to any one of claims 1 to 7, comprising the steps of: dissolving 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one in one or more solvents selected from the group consisting of: C1-C3 alcohol, acetone, ethyl acetate and methyl tert-butyl ether; and Add hydrochloric acid solution.

14. A method for preparing a crystalline form according to any one of claims 1 to 7, comprising the steps of: dissolving 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one in one or more solvents selected from the group consisting of: C1-C3 alcohol, acetone, ethyl acetate and methyl tert-butyl ether to obtain a mixture; cooling the mixture; Add hydrochloric acid solution; Raising the temperature to room temperature, cooling and stirring to obtain a solid; and The solid was filtered, washed and dried.

15. A method for preparing a crystalline form according to any one of claims 1 to 7, the method comprising the steps of: dissolving 4-[3-(3-[(cyclopropylamino)methyl]azetidine-1-carbonyl)-4-fluorobenzyl]phthalazin-1(2H)-one in one or more solvents selected from the group consisting of: C1-C3 alcohol, acetone, ethyl acetate and methyl tert-butyl ether to obtain a mixture; The resulting mixture was cooled to 0°C; adding to the mixture an aqueous hydrochloric acid solution, or a mixture of a hydrochloric acid solution and one or more solvents selected from the group consisting of: a C1-C3 alcohol, acetone, ethyl acetate, and methyl tert-butyl ether; Bring the temperature to room temperature; The mixture is stirred for 10 to 14 hours; Cooling the mixture to 10°C to 20°C; Stirring the cooled mixture for 20 to 60 minutes to obtain a solid; and The solid was filtered, washed and dried.

16. A process for preparing a crystalline form according to any one of claims 13 to 15, wherein the hydrochloric acid solution is added as a solution in water, an alkyl acetate, an alkyl ether or an alkyl alcohol.

17. A process for preparing a crystalline form according to claim 16, wherein the hydrochloric acid solution is added as a solution in water, ethyl acetate, diethyl ether, isopropanol or ethanol.

18. A process for preparing a crystalline form according to any one of claims 13 to 17, wherein the process does not comprise a concentration step.

19. A crystalline form of a compound of formula 1 prepared by the method according to any one of claims 13 to 17: [Formula 1]

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